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Depression in long-term care patients : evaluation of a screening protocol and outcomes of drug therapy Soon, Judith Alice 2000

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DEPRESSION IN LONG-TERM C A R E PATIENTS: EVALUATION OF A SCREENING PROTOCOL AND OUTCOMES OF DRUG THERAPY by JUDITH ALICE SOON B.Sc, T h e University of British Columbia, 1974 M.Sc. (Clinical Pharmacy), University o f British C o l u m b i a , 1995 D i p l o m a ( E p i d e m i o l o g y a n d Biostatistics), M c G i l l University, 1996  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR T H E D E G R E E OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Faculty of Pharmaceutical Sciences) (Division of Clinical Pharmacy) W e a c c e p t this thesis as c o n f o r m i n g to the r e q u i r e d s t a n d a r d  THE UNIVERSITY OF BRITISH C O L U M B I A February 2000 © Judith Alice Soon, 2000  In presenting this thesis in partial fulfilment  of the  requirements for an advanced  degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or by  his  or  her  representatives.  It  is  understood  that  copying or  publication of this thesis for financial gain shall not be allowed without my written permission.  F#Cut-Ty  Department of  -  /^A^W^^O^*^  The University of British Columbia Vancouver, Canada  Date  DE-6 (2/88)  2-Q<D&  .  11  ABSTRACT  D e p r e s s i o n is o f t e n u n d e r d i a g n o s e d  a n d u n d e r t r e a t e d i n e l d e r l y l o n g - t e r m c a r e patients.  R e c o m m e n d a t i o n s h a v e b e e n m a d e to i n c r e a s e the i d e n t i f i c a t i o n a n d treatment o f d e p r e s s i o n i n late l i f e , d e s p i t e the f a c t that e f f i c a c y a n d o u t c o m e s o f a n t i d e p r e s s a n t treatment h a v e n o t b e e n e s t a b l i s h e d i n this p o p u l a t i o n . T h e first c o m p o n e n t o f this r e s e a r c h was a n 8 - w e e k r a n d o m i z e d c l i n i c a l trial to assess the effect o f a s c r e e n i n g p r o t o c o l o n p h y s i c i a n s ' i d e n t i f i c a t i o n a n d treatment o f depression. T h e c l i n i c a l s c r e e n i n g study o f 1602 patients i n 22 long-term care facilities i d e n t i f i e d 103 u n t r e a t e d patients > 65 y e a r s w i t h a d e q u a t e c o g n i t i v e f u n c t i o n a n d a G e r i a t r i c D e p r e s s i o n S c a l e s c o r e >13. T h e  77  p h y s i c i a n s o f the 103 patients w e r e r a n d o m i z e d b y c l u s t e r i n t o a n e a r l y ( e x p e r i m e n t a l , n o t i f i e d o f s c r e e n i n g results) o r a d e l a y e d ( c o n t r o l , n o t i f i e d 4 w e e k s later) g r o u p . T h e p r i m a r y o u t c o m e w a s the e f f e c t o f the s c r e e n i n g p r o t o c o l o n p h y s i c i a n s ' d e c i s i o n s to p r e s c r i b e a n t i d e p r e s s a n t t h e r a p y o r r e f e r to m e n t a l h e a l t h s e r v i c e s . P h y s i c i a n r e s p o n s e i n the e a r l y g r o u p ( 2 5 % ) w a s greater than that i n the d e l a y e d g r o u p ( 2 % ) (p < 0.005) b y 4 w e e k s f r o m b a s e l i n e . T h e c o m b i n e d p h y s i c i a n r e s p o n s e rate w a s 3 6 % ( 9 5 % C I , 2 6 % to 4 6 % ) at 8 w e e k s f r o m n o t i f i c a t i o n , a n d o v e r a l l p h y s i c i a n a c t i o n o c c u r r e d i n 6 9 % ( 9 5 % C I , 6 0 % to 7 8 % ) . L o g i s t i c r e g r e s s i o n s u g g e s t e d that p h y s i c i a n s ' d e c i s i o n s to treat o r r e f e r w e r e n o t r e l a t e d to s e v e r i t y o f s y m p t o m s o f d e p r e s s i o n o r o t h e r p a t i e n t c h a r a c t e r i s t i c s , but w e r e p r i m a r i l y a s s o c i a t e d w i t h p h y s i c i a n - r e l a t e d c h a r a c t e r i s t i c s . T h e s e c o n d c o m p o n e n t o f the r e s e a r c h was a 2 6 - w e e k p r o s p e c t i v e , o b s e r v a t i o n a l o u t c o m e s s t u d y o f d e p r e s s e d patients n e w l y treated w i t h antidepressants, a n d a s i m i l a r g r o u p o f untreated patients. T h e r a p e u t i c o u t c o m e s o f interest w e r e m e a n w i t h i n - g r o u p c h a n g e s i n s y m p t o m s o f d e p r e s s i o n , c o g n i t i v e f u n c t i o n , s e l f - p e r c e i v e d h e a l t h status, a n d f u n c t i o n a l a b i l i t y at 6, 12, a n d 26 w e e k s f o r treated patients, a n d at 26 w e e k s f o r u n t r e a t e d patients.  While symptoms of  d e p r e s s i o n i m p r o v e d i n t r e a t e d patients o v e r the p e r i o d o f 26 w e e k s , o t h e r m e a s u r e s o f q u a l i t y o f life a n d p h y s i c a l f u n c t i o n d i d n o t i m p r o v e . S i m i l a r o b s e r v a t i o n s w e r e m a d e i n the u n t r e a t e d  iii g r o u p . T h e r e s u l t s s u p p o r t the i d e a that r a n d o m i z e d c o n t r o l l e d e f f e c t i v e n e s s s t u d i e s i n l o n g - t e r m c a r e patients are b o t h e t h i c a l a n d n e c e s s a r y .  iv T A B L E OF  CONTENTS Page  ABSTRACT TABLE OF CONTENTS LIST OF T A B L E S LIST OF FIGURES LIST OF A P P E N D I C E S LIST OF A B B R E V I A T I O N S ACKNOWLEDGEMENTS 1.0  INTRODUCTION . 1.1  1 2  1.2  TREATMENT OF ADULT DEPRESSION 6 1.2.1 T r e a t m e n t g u i d e l i n e s f o r a d u l t d e p r e s s i o n 6 1.2.2 E f f i c a c y o f a n t i d e p r e s s a n t s f o r d e p r e s s i o n 9 1.2.2.1 E f f i c a c y o f a n t i d e p r e s s a n t s f o r the t r e a t m e n t o f m a j o r d e p r e s s i o n 9 1.2.2.2.Efficacy o f a n t i d e p r e s s a n t s f o r the t r e a t m e n t o f m i n o r d e p r e s s i o n ^  1.3  DEPRESSION IN L A T E LIFE  15  1.4  I N T E R V E N T I O N S T O I N C R E A S E T H E I D E N T I F I C A T I O NA N D T R E A T M E N T OF DEPRESSION IN L A T E LIFE 1.4.1 S c r e e n i n g f o r d e p r e s s i o n i n late l i f e 1.4.2 P h y s i c i a n - t a r g e t e d i n t e r v e n t i o n trials  24  1.5  1.6  2.0  OVERVIEW OF ADULT DEPRESSION  ii iv ix xi xiii xiv xvi  24 28  T R E A T M E N T OF DEPRESSION IN L A T E LIFE 1.5.1 T r e a t m e n t g u i d e l i n e s f o r d e p r e s s i o n i n late l i f e 1.5.2 E f f i c a c y o f a n t i d e p r e s s a n t s f o r d e p r e s s i o n i n late l i f e 1.5.2.1 E f f i c a c y o f a n t i d e p r e s s a n t s f o r the t r e a t m e n t o f m a j o r depression 1.5.2.2 E f f i c a c y o f a n t i d e p r e s s a n t s f o r the t r e a t m e n t o f m i n o r depression 1.5.3 E f f e c t i v e n e s s o f a n t i d e p r e s s a n t s f o r d e p r e s s i o n i n late l i f e  31 31 37 37  OBJECTIVES 1.6.1 Part A : C l i n i c a l s c r e e n i n g s t u d y 1.6.2 P a r t B : T h e r a p e u t i c o u t c o m e s study  46 46 46  40 42  METHODS  47  2.1  47  OVERVIEW OF THE CLINICAL SCREENING AND THERAPEUTIC OUTCOMES STUDIES 2.1.1 E t h i c s a p p r o v a l 2.1.2 L o n g - t e r m care facility a p p r o v a l  47 49  V  2.2  CLINICAL SCREENING STUDY 50 2.2.1 P H A S E A : C a s e - f i n d i n g c o m p o n e n t 50 2.2.1.1 S t u d y s a m p l e 52 2.2.1.2 E x c l u s i o n a n d i n c l u s i o n criteria 53 2.2.1.3 R a t i n g i n s t r u m e n t s 57 2.2.1.3.1. G e r i a t r i c D e p r e s s i o n S c a l e ( G D S ) 57 2.2.1.3.2 M i n i - M e n t a l State E x a m i n a t i o n ( M M S E ) 59 2.2.1.3.3 C o n s i s t e n c y o f G D S a n d M M S E a d m i n i s t r a t i o n 61 2.2.1.4 B a s e l i n e data c o l l e c t i o n 62 2.2.1.4.1 D e m o g r a p h i c i n f o r m a t i o n 62 2.2.1.4.2 M e d i c a l d i a g n o s e s 62 2.2.1.4.3 C o n c o m i t a n t d r u g t h e r a p y 62 2.2.1.5 C l i n i c a l trial c o n s i d e r a t i o n s i n l o n g - t e r m care patients 63 2.2.1.6 R e s e a r c h p e r s o n n e l 64 2.2.1.7 Statistical a n a l y s i s o f the c a s e - f i n d i n g c o m p o n e n t 66 2.2.2 P H A S E B : R a n d o m i z e d c l i n i c a l trial c o m p o n e n t 66 2.2.2.1 D e s i g n o f the r a n d o m i z e d c l i n i c a l trial 66 2.2.2.2 I m p l e m e n t a t i o n 71 2.2.2.3 E v a l u a t i o n o f p h y s i c i a n r e s p o n s e to the letters o f n o t i f i c a t i o n 71 2.2.2.4 C l u s t e r r a n d o m i z a t i o n a n d g r o u p a s s i g n m e n t s o f patients 72 2.2.2.5 S a m p l e size estimate 73 2.2.2.5.1 A priori estimates o f b a s e rate a n d p h y s i c i a n r e s p o n s e 73 rate 2.2.2.5.2 S a m p l e size estimate f o r s i m p l e r a n d o m i z a t i o n 75 2.2.2.5.3 S a m p l e size adjustment f o r cluster r a n d o m i z a t i o n 75 2.2.2.5.4 P i l o t study i n t w o l o n g - t e r m care facilities t o v e r i f y the 7 9 p h y s i c i a n r e s p o n s e rate f o r n e w antidepressants o r d e r s or referral to m e n t a l h e a l t h services, a n d p h y s i c i a n cluster size 2.2.2.6 R a t i n g instruments 79 2.2.2.6.1 H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H A M - D ) 80 2.2.2.7 Statistical a n a l y s i s o f the r a n d o m i z e d c l i n i c a l trial c o m p o n e n t 81  2.3  THERAPEUTIC OUTCOMES STUDY 2.3.1 D e s i g n o f the therapeutic o u t c o m e s s t u d y 2.3.2 E x c l u s i o n a n d i n c l u s i o n criteria 2.3.3 S a m p l e size estimate 2.3.4 S t u d y e x e c u t i o n 2.3.4.1 B a s e l i n e e v a l u a t i o n 2.3.4.2 A c u t e a n d m a i n t e n a n c e treatment p h a s e e v a l u a t i o n 2.3.4.3 C o n c o m i t a n t d r u g t h e r a p y 2.3.4.4 D o c u m e n t a t i o n o f antidepressant d o s i n g 2.3.4.5 D i s c o n t i n u a t i o n o f antidepressant t h e r a p y 2.3.4.6 R a t i n g instruments 2.3.4.6.1 C l i n i c a l G l o b a l I m p r e s s i o n s ( C G I ) 2.3.4.6.2 S i c k n e s s I m p a c t P r o f i l e - N u r s i n g H o m e s ( S I P - N H ) 2.3.4.6.3 B a r t h e l Index ( B l ) 2.3.4.6.4 P h y s i c a l P e r f o r m a n c e T e s t ( P P T ) 2.3.4.6.5 U K U S i d e E f f e c t R a t i n g S c a l e ( U K U )  83 83 84 85 85 85 85 86 86 86 87 87 88 90 91 93  2.3.5 2.4  2.3.4.6.6 Inter-rater reliability Statistical a n a l y s i s o f the therapeutic o u t c o m e s study  CHARACTERISTICS O F T H ELONG-TERM C A R E CROSSSECTIONAL SAMPLE OF PATIENTS 2.4.1 Patterns o f l e n g t h o f stay a n d type o f d i s c h a r g e 2.4.2 M o r t a l i t y at s i x a n d t w e l v e m o n t h s  RESULTS 3.1 CLINICALSCREENING STUDY 3.1.1 P H A S E A : C a s e - f i n d i n g c o m p o n e n t 3.1.1.1 D e m o g r a p h i c c h a r a c t e r i s t i c s o f the s a m p l e o f l o n g - t e r m c a r e patients 3.1.1.2 P a t i e n t s s c r e e n e d o u t o f c a s e - f i n d i n g p r i o r t o a d m i n i s t r a t i o n ofthe G D S 3.1.1.3 C a s e - f i n d i n g a s s e s s m e n t w i t h the G D S a n d M M S E 3.1.2 P H A S E B : R a n d o m i z e d c l i n i c a l trial c o m p o n e n t 3.1.2.1 D e m o g r a p h i c c h a r a c t e r i s t i c s o f r a n d o m i z e d p h y s i c i a n s 3.1.2.2 B a s e l i n e c h a r a c t e r i s t i c s o f p a t i e n t s i n the r a n d o m i z e d c l i n i c a l trial 3.1.2.2.1 D e m o g r a p h i c c h a r a c t e r i s t i c s , d i a g n o s e s a n d medication use 3.1.2.2.2 C l i n i c a l a s s e s s m e n t s 3.1.2.3 E f f e c t s o f the letters o f n o t i f i c a t i o n o n p h y s i c i a n r e s p o n s e 3.1.2.3.1 P r i m a r y e n d p o i n t - f r e q u e n c y o f p h y s i c i a n r e s p o n s e by W e e k 4 from baseline 3.1.2.3.2 A d j u s t m e n t f o r cluster r a n d o m i z a t i o n - intracluster correlation 3.1.2.3.3 T i m e course o f p h y s i c i a n response 3.1.2.3.4 P h y s i c i a n a c t i o n s u b s e q u e n t t o t h e letters o f notification 3.1.2.3.5 T y p e o f p h y s i c i a n r e s p o n s e 3.1.2.4 Patient, p h y s i c i a n a n d f a c i l i t y c h a r a c t e r i s t i c s a s s o c i a t e d w i t h a physician response 3.1.2.4.1 U n i v a r i a t e l o g i s t i c r e g r e s s i o n 3.2  vi 95 97 98 98 98 100 100 100 100 100 104 108 108 108 108 114 114 114 118 120 120 124 124 124  THERAPEUTIC OUTCOMES STUDY 130 3.2.1 C o m p l e t i o n rates a n d r e a s o n s that patients w e r e u n a b l e t o b e a s s e s s e d 131 at 2 6 w e e k s 3.2.2 B a s e l i n e c h a r a c t e r i s t i c s o f treated a n d u n t r e a t e d p a t i e n t s 133 3.2.3 U s e o f a n t i d e p r e s s a n t m e d i c a t i o n s o v e r t i m e 136 3.2.4 O u t c o m e m e a s u r e s : S y m p t o m s o f d e p r e s s i o n ( H A M - D , G D S , C G I ) 1 3 6 3.2.4.1 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n H A M - D s c o r e s 1 3 6 over time 3.2.4.2 C a t e g o r i c a l f i n d i n g s o f a d e c l i n e o f > 5 0 % i n H A M - D s c o r e b y 141 26 weeks 3.2.4.3 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n G D S , C G I 141 (severity), a n d C G I ( i m p r o v e m e n t ) o v e r t i m e  3.2.5  O u t c o m e measures: Cognitive function ( M M S E ) 3.2.5.1 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n c o g n i t i v e function over time 3.2.6 O u t c o m e m e a s u r e s : S e l f - p e r c e i v e d h e a l t h status ( S I P - N H ) 3.2.6.1 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n s e l f - p e r c e i v e d h e a l t h status o v e r t i m e 3.2.6.2 Inter-rater r e l i a b i l i t y a s s e s s m e n t f o r the S I P - N H 3.2.6.3 A d m i n i s t r a t i o n o f t h e S I P - N H 3.2.7 O u t c o m e m e a s u r e s : A c t i v i t i e s o f d a i l y l i v i n g ( B I ) 3.2.7.1 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n a c t i v i t i e s o f daily living over time 3.2.8 O u t c o m e m e a s u r e s : F u n c t i o n a l status ( P P T ) 3.2.8.1 D e s c r i p t i v e f i n d i n g s o f w i t h i n - g r o u p c h a n g e i n f u n c t i o n a l status o v e r t i m e 3.2.8.2 Inter-rater r e l i a b i l i t y a s s e s s m e n t f o r the P P T 3.2.8.3 A d m i n i s t r a t i o n o f t h e P P T 3.2.9 C o n v e r g e n t a n d d i s c r i m i n a n t v a l i d i t y o f m e a s u r e s o f s e l f - p e r c e i v e d h e a l t h status ( S I P - N H ) , activities o f d a i l y l i v i n g ( B I ) , a n d p h y s i c a l p e r f o r m a n c e ( P P T ) at b a s e l i n e 3.2.10 O u t c o m e m e a s u r e s : A d v e r s e events ( U K U S i d e E f f e c t R a t i n g S c a l e ) 3.2.11 U s e o f c o n c o m i t a n t m e d i c a t i o n o v e r t i m e  3.3  4.0  CHARACTERISTICS OF T H E L O N G - T E R M C A R E CROSSSECTIONAL SAMPLE OF PATIENTS 3.3.1 Patterns o f l e n g t h o f stay a n d types o f d i s c h a r g e 3.3.2 M o r t a l i t y at s i x a n d t w e l v e m o n t h s  vii 143 143 151 151 151 151 154 154 154 154 154 157 157 159 164 164 164 166  DISCUSSION 4.1 CLINICAL SCREENING STUDY 4.1.1 P H A S E A : C a s e - f i n d i n g c o m p o n e n t 4.1.2 P H A S E B : R a n d o m i z e d c l i n i c a l trial c o m p o n e n t 4.1.2.1 E v i d e n c e f o r the i m p a c t o f the c l i n i c a l s c r e e n i n g p r o t o c o l on physician response 4.1.2.2 T y p e a n d p a t t e r n o f p h y s i c i a n r e s p o n s e 4.1.2.3 F a c t o r s a s s o c i a t e d w i t h p h y s i c i a n r e s p o n s e 4.2 THERAPEUTIC OUTCOMES STUDY 4.2.1 E f f e c t i v e n e s s o f antidepressants i n treating d e p r e s s i o n 4.2.2 E f f e c t i v e n e s s o f antidepressants i n i m p r o v i n g q u a l i t y o f life a n d physical function 4.2.3 A n t i d e p r e s s a n t s a n d c o g n i t i v e f u n c t i o n 4.2.4 A n t i d e p r e s s a n t d o s i n g c o n s i d e r a t i o n s 4.2.5 M o r t a l i t y c o n s i d e r a t i o n s  169 169 169 173 173  5.0  SUMMARY AND CONCLUSIONS  204  6.0  FUTURE DIRECTIONS 6.1 Future directions for research 6.2 Future directions for health p o l i c y  206 206 208  180 183 192 192 195 196 200 202  7.0  REFERENCES  vm 209  8.0  APPENDICES  231  ix LIST OF TABLES Table  Page  1  D e m o g r a p h i c c h a r a c t e r i s t i c s o f the 22 l o n g - t e r m c a r e f a c i l i t i e s i n s o u t h w e s t B r i t i s h C o l u m b i a that p a r t i c i p a t e d i n the c l i n i c a l s c r e e n i n g a n d t h e r a p e u t i c o u t c o m e s studies  54  2  E s t i m a t e s o f s a m p l e s i z e r e q u i r e d to detect a d i f f e r e n c e b e t w e e n e a r l y ( e x p e r i m e n t a l ) a n d d e l a y e d ( c o n t r o l ) g r o u p u s i n g simple r a n d o m i z a t i o n  76  3  R e l a t i o n s h i p b e t w e e n i n t r a c l u s t e r c o r r e l a t i o n , i n f l a t i o n factor, e f f e c t i v e s a m p l e s i z e , a n d the s a m p l e s i z e u s i n g b o t h simple a n d cluster r a n d o m i z a t i o n  78  4  D e m o g r a p h i c c h a r a c t e r i s t i c s o f l o n g - t e r m c a r e patients i n the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s t u d y  101  5  P a t i e n t s s c r e e n e d out o f the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s t u d y p r i o r to a d m i n i s t r a t i o n o f the G D S  103  6  D e m o g r a p h i c c h a r a c t e r i s t i c s o f the p h y s i c i a n s i n the r a n d o m i z e d c l i n i c a l trial  109  7  D i s t r i b u t i o n o f n u m b e r o f patients p e r p h y s i c i a n c l u s t e r i n the r a n d o m i z e d c l i n i c a l trial  110  8  D e m o g r a p h i c c h a r a c t e r i s t i c s o f the patients e n r o l l e d i n the r a n d o m i z e d c l i n i c a l trial  111  9  R e g u l a r a n d P R N m e d i c a t i o n use o f the patients e n r o l l e d i n the r a n d o m i z e d c l i n i c a l trial  113  10  B a s e l i n e c l i n i c a l a s s e s s m e n t s o f patients e n r o l l e d i n the r a n d o m i z e d c l i n i c a l trial  115  11  P a t i e n t a n d p h y s i c i a n c h a r a c t e r i s t i c s f o r those n o t y e t p r e s c r i b e d a n a n t i d e p r e s s a n t 1 2 2 o r r e f e r r e d to m e n t a l h e a l t h s e r v i c e s b y 4 w e e k s f r o m r a n d o m i z a t i o n  12  P h y s i c i a n a c t i o n s u b s e q u e n t to the letters o f n o t i f i c a t i o n i n the r a n d o m i z e d c l i n i c a l trial  123  13  Pattern o f antidepressant prescribing i n n e w l y treated long-term care patients in the r a n d o m i z e d c l i n i c a l trial  125  14  D e m o g r a p h i c a n d c l i n i c a l patient b a s e l i n e c h a r a c t e r i s t i c s a s s o c i a t e d w i t h a n t i d e p r e s s a n t treatment o r r e f e r r a l b y the p h y s i c i a n f o l l o w i n g the letters o f notification  127  15  P h y s i c i a n a n d f a c i l i t y c h a r a c t e r i s t i c s a s s o c i a t e d w i t h a n t i d e p r e s s a n t treatment o r r e f e r r a l b y the p h y s i c i a n f o l l o w i n g the letters o f n o t i f i c a t i o n N u m b e r o f treated a n d u n t r e a t e d patients w h o c o m p l e t e d the 2 6 - w e e k t h e r a p e u t i c  128  16  132  X  o u t c o m e s s t u d y a n d reasons that patients w e r e u n a b l e to c o m p l e t e t h e s t u d y 17  Baseline d e m o g r a p h i c characteristics o f treated a n d untreated patients w h o c o m p l e t e d the 26-week therapeutic o u t c o m e s study  134  18  B a s e l i n e c l i n i c a l a s s e s s m e n t s o f treated a n d u n t r e a t e d p a t i e n t s w h o c o m p l e t e d t h e 26-week therapeutic outcomes study  135  19  D i s t r i b u t i o n o f d i a g n o s e s o n t h e m e d i c a l chart at b a s e l i n e o f t r e a t e d a n d u n t r e a t e d patients w h o c o m p l e t e d t h e 2 6 - w e e k t h e r a p e u t i c o u t c o m e s s t u d y  137  20  R e g u l a r a n d P R N m e d i c a t i o n u s e at b a s e l i n e o f treated a n d u n t r e a t e d p a t i e n t s w h o c o m p l e t e d the 26-week therapeutic outcomes study  138  21  I m p r o v e m e n t i n s y m p t o m s o f d e p r e s s i o n b e t w e e n b a s e l i n e a n d t h e e n d o f the 26w e e k s t u d y i n t r e a t e d a n d u n t r e a t e d patients i n t h e t h e r a p e u t i c o u t c o m e s s t u d y  142  22  C o r r e l a t i o n m a t r i x f o r t h e S I P - N H , B I , P P T a n d o t h e r h e a l t h m e a s u r e s at b a s e l i n e for patients in the 26-week therapeutic outcomes study  158  23  N u m b e r o f s o m a t i c s y m p t o m s e x p e r i e n c e d b y 2 3 patients w i t h n e w l y p r e s c r i b e d a n t i d e p r e s s a n t t h e r a p y as m e a s u r e d b y t h e U K U s i d e e f f e c t r a t i n g s c a l e at b a s e l i n e  160  24  N u m b e r o f treatment-emergent side effects experienced b y 23 patients with n e w l y p r e s c r i b e d a n t i d e p r e s s a n t t h e r a p y as m e a s u r e d b y t h e U K U s i d e e f f e c t r a t i n g s c a l e at w e e k 6, w e e k 12, a n d w e e k 2 6  162  25  R e g u l a r a n d P R N m e d i c a t i o n u s e at b a s e l i n e a n d at 2 6 w e e k s o f t r e a t e d a n d u n t r e a t e d patients i n t h e t h e r a p e u t i c s o u t c o m e s s t u d y  165  26  M o r t a l i t y rates at s i x a n d t w e l v e m o n t h s a m o n g a c o h o r t o f l o n g - t e r m c a r e p a t i e n t s  167  xi LIST OF FIGURES Figure  1  A l g o r i t h m for treating patients with major depressive disorder  8  2  F l o w c h a r t o f l o n g - t e r m c a r e p a t i e n t p a r t i c i p a t i o n i n the t w o - p h a s e c l i n i c a l s c r e e n i n g s t u d y a n d the f o l l o w - u p t h e r a p e u t i c o u t c o m e s s t u d y  48  3  F l o w c h a r t o f the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s c r e e n i n g s t u d y  51  4  F l o w c h a r t o f the p r i m a r y o u t c o m e f o r the r a n d o m i z e d c l i n i c a l trial p h a s e o f the c l i n i c a l s c r e e n i n g s t u d y  68  5  F l o w c h a r t o f the s e c o n d a r y o u t c o m e s f o r the r a n d o m i z e d c l i n i c a l trial p h a s e o f the c l i n i c a l s c r e e n i n g s t u d y  70  6  D i s t r i b u t i o n o f d i a g n o s e s i n 1 6 0 2 l o n g - t e r m c a r e p a t i e n t s i n the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s t u d y  102  7  D i s t r i b u t i o n o f G D S s c o r e s a m o n g 7 0 1 l o n g - t e r m c a r e p a t i e n t s a s s e s s e d i n the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s t u d y  105  8  D i s t r i b u t i o n o f M M S E s c o r e s a m o n g 175 l o n g - t e r m c a r e p a t i e n t s w i t h G D S s c o r e 1 0 6 > 13 a s s e s s e d i n the c a s e - f i n d i n g c o m p o n e n t o f the c l i n i c a l s t u d y  9  S u m m a r y o f c a s e - f i n d i n g f o r the r a n d o m i z e d c l i n i c a l trial  107  10  D i s t r i b u t i o n o f d i a g n o s e s a m o n g p a t i e n t s i n the r a n d o m i z e d c l i n i c a l trial  112  11  P r o t o c o l f o r the r a n d o m i z e d c l i n i c a l trial: p r i m a r y e n d p o i n t - p h y s i c i a n r e s p o n s e to 1 1 6 the letter o f n o t i f i c a t i o n b y W e e k 4 f r o m b a s e l i n e  12  E f f e c t o f letters o f n o t i f i c a t i o n o n the f r e q u e n c y o f a p r e s c r i p t i o n f o r a n a n t i d e p r e s s a n t o r r e f e r r a l to m e n t a l h e a l t h s e r v i c e s  117  13  P r o t o c o l f o r the r a n d o m i z e d c l i n i c a l trial: f r e q u e n c y o f p h y s i c i a n r e s p o n s e t o the letters o f n o t i f i c a t i o n b y 4 a n d 8 w e e k s after the initial letter  119  14  T i m e c o u r s e o f p h y s i c i a n r e s p o n s e to letters o f n o t i f i c a t i o n  121  15  C h a n g e i n m e a n antidepressant dose over time i n treated patients  139  16  C h a n g e i n H A M - D score over time  140  17  C h a n g e i n G D S score over time  144  18  C h a n g e i n C G I (severity) over time  145  19  C h a n g e i n C G I (improvement) score over time  xii 146  20  C h a n g e i n M M S E score over time  147  21  Individual change i n M M S E score a m o n g the 2 9 treated patients during the 2 6 - w e e k t h e r a p e u t i c o u t c o m e s s t u d y  148  22  I n d i v i d u a l c h a n g e i n M M S E s c o r e a m o n g t h e 51 u n t r e a t e d p a t i e n t s d u r i n g the 2 6 - w e e k t h e r a p e u t i c o u t c o m e s s t u d y  150  23  Change i n S I P - N H Total Disability Score over time  152  24  C h a n g e i n S I P - N H and subscale scores over time  153  25  C h a n g e i n B I activities o f d a i l y l i v i n g s c o r e o v e r t i m e  155  26  C h a n g e i n P P T score over time  156  27  N u m b e r o f treatment-emergent side effects during the 26-week therapeutic outcomes study  163  xiii LIST OF APPENDICES Appendix  Page  1  Certificate of Approval: Clinical Screening Committee for Research Involving H u m a n Subjects  231  2  Certificate of Approval: Behavioural Sciences Screening Committee for Research Involving H u m a n Subjects  232  3  S a m p l e letter o f a p p r o v a l f r o m a d m i n i s t r a t o r at a p a r t i c i p a t i n g l o n g - t e r m c a r e facility  233  4  L e t t e r o f i n t r o d u c t i o n d e s c r i b i n g the c l i n i c a l s c r e e n i n g s t u d y a n d the t h e r a p e u t i c o u t c o m e s s t u d y to p h y s i c i a n s a t t e n d i n g p a t i e n t s at a p a r t i c i p a t i n g long-term care facility  234  5  Informed consent form: Clinical Screening Study  6  Informed consent form: Therapeutic O u t c o m e s Study  238  7  Geriatric Depression Scale  241  8  M i n i - M e n t a l State E x a m  243  9  I n i t i a l letter o f n o t i f i c a t i o n sent to the p r i m a r y c a r e p h y s i c i a n  245  10  F o l l o w - u p letter o f n o t i f i c a t i o n sent to the p r i m a r y c a r e p h y s i c i a n f o u r w e e k s later  246  11  S t r u c t u r e d I n t e r v i e w G u i d e f o r the H a m i l t o n D e p r e s s i o n R a t i n g S c a l e  247  12  Patient schedule for clinical assessments  252  13  Clinical Global Impression  253  14  Sickness Impact Profile - Nursing H o m e  254  15  Barthel Index  260  16  Physical Performance Test  261  17  U K U Side Effect Rating Scale  262  18  E n d p o i n t a n a l y s e s o f p h y s i c i a n r e s p o n s e to the letters o f n o t i f i c a t i o n i n the r a n d o m i z e d c l i n i c a l trial, a d j u s t e d f o r cluster r a n d o m i z a t i o n  264  236 •  XIV  LIST OF ABBREVIATIONS  ADR  Adverse drug reaction  AHCPR  A g e n c y f o r H e a l t h C a r e P o l i c y a n d R e s e a r c h ( U n i t e d States)  Bl  Barthel Index  CGI  Clinical G l o b a l Impressions  CI  Confidence interval  CCOHTA  Canadian Coordinating Office for Health Technology Assessment  DDD  Defined D a i l y D o s e - W o r l d Health Organization technical unit o f drug consumption/adult/day  DSM-IV  D i a g n o s t i c a n d Statistical M a n u a l o f M e n t a l D i s o r d e r s , F o u r t h E d i t i o n  GDS  Geriatric Depression Scale  HAM-D  Hamilton Rating Scale for Depression  LTC  L o n g - t e r m care  MADRS  Montgomery-Asberg Depression Rating Scale  MAOI  M o n o a m i n e oxidase inhibitor  MMSE  M i n i - M e n t a l State E x a m  N/A  Not available  NIMH  N a t i o n a l Institute o f M e n t a l H e a l t h ( U n i t e d States)  PPT  Physical Performance Test  PRN  P r o r e n a t a (as n e e d e d )  RIMA  Reversible inhibitor o f m o n o a m i n e oxidase  SD  Standard deviation  SIP-NH  Sickness Impact Profile for Nursing H o m e s  SNRI  Serotonin noradrenaline reuptake inhibitors  SSRI  Selective serotonin reuptake inhibitor  XV  TCA  T r i c y c l i c antidepressant  WHO  W o r l d Health Organization  UKU  Udvalg for Kliniske Unders0gelser Side Effect Rating Scale  xvi ACKNOWLEDGEMENTS I w i s h t o s i n c e r e l y t h a n k m y mentor, D r . M a r c L e v i n e , f o r h i s o n g o i n g  encouragement  a n d t h o u g h t - p r o v o k i n g d i s c u s s i o n s t h r o u g h o u t this p r o j e c t . I a l s o w i s h t o t h a n k m y r e s e a r c h committee members, Dr. Bruce Carleton, Mr. Derek Daws, Dr. Jack Diamond, Dr. D a v i d Fielding, D r . G r a y d o n M e n e i l l y , a n d Dr. W a y n e R i g g s for their expert guidance a n d valuable suggestions. T h e e n t h u s i a s t i c s u p p o r t a n d e n c o u r a g e m e n t o f the a d m i n i s t r a t i o n , n u r s e s a n d p h y s i c i a n s at t h e t w e n t y - t w o  participating L o n g T e r m Care Facilities is gratefully acknowledged:  B u r q u i t l a m L i o n s Care Centre, D a n i a H o m e , Evergreen Baptist H o m e , G o l d e n Ears Retirement Centre, Grand-Vu  Lodge, G r a n d Street Lodge, H a n e y Intermediate C a r e Centre, H i g h l a n d  Lodge, H i l t o n V i l l a Care Centre, H o l y r o o d Manor, J a c k m a n M a n o r , K i n s m e n Place Lodge, L a n g l e y Lodge, M c i n t o s h Lodge, M a p l e w o o d House, M S A M a n o r , Northcrest Care Centre, Ocean V i e w Care H o m e , Pleasant V i e w Care Home, S h e r w o o d Crescent Manor, Tabor Home, and Westminster House. I w o u l d also like to sincerely thank Dr. M a r t i n M i l e w s k i a n d Dr. W i l l i a m M a g o w a n f o r their v a l u a b l e s u g g e s t i o n s r e g a r d i n g t h e f o r m a t o f t h e i n f o r m a t i o n provided to primary care physicians. encouragement  T h e dedication, enthusiasm, humour, support a n d  o f m y r e s e a r c h assistants, M s . L o r n a A d a i r , M s . C a t h e r i n e D a v i e s , M s . P a u l a  J a k e m a n a n d M s . J a c q u e l i n L i e b e is m o s t s i n c e r e l y a p p r e c i a t e d . T h e h e l p f u l assistance o f M r . Jonathan B e r k o w i t z a n d M r . A r u n V e r m a with logistic r e g r e s s i o n m o d e l l i n g a n d M r . J a s o n M a t t h e w s w i t h the d e v e l o p m e n t o f the r e l a t i o n a l d a t a b a s e management system is gratefully acknowledged.  S i n c e r e t h a n k s are a l s o g i v e n t o M s . B a r b a r a  C a d a r i o f o r f a c i l i t a t i n g a s e a r c h o f the A d v e r s e D r u g R e a c t i o n R e p o r t i n g P r o g r a m database. T h e financial support o f a M R C - C D M A - C E M Studentship i n Pharmacoepidemiology a n d a U n i v e r s i t y o f B r i t i s h C o l u m b i a G r a d u a t e F e l l o w s h i p is g r a t e f u l l y a c k n o w l e d g e d . S p e c i a l t h a n k s to m y h u s b a n d , Stan, a n d c h i l d r e n , G o r d o n , K r i s t i n , a n d M e r e d i t h f o r their unfailing support a n d constant encouragement throughout m y graduate studies.  1 INTRODUCTION  D e p r e s s i o n is a s e r i o u s , c o m m o n a n d t r e a t a b l e m e d i c a l c o n d i t i o n w i t h f a r - r e a c h i n g e f f e c t s o n a n i n d i v i d u a l ' s g e n e r a l h e a l t h a n d f u n c t i o n a l status ( B u r k e , 1996).  I n 1988, the  N a t i o n a l Institute o f M e n t a l H e a l t h r e p o r t e d that "unrecognized, untreated, and undertreated depressive disorders extract an inordinate human and economic cost, despite the availability of an extensive array of effective clinical interventions" ( R e g i e r et al., 1988). S i n c e that time, m a j o r  e d u c a t i o n a n d r e s e a r c h i n i t i a t i v e s h a v e b e e n u n d e r t a k e n to e n h a n c e the awareness, r e c o g n i t i o n , a n d treatment o f d e p r e s s i v e d i s o r d e r s i n the g e n e r a l p o p u l a t i o n ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993; D e p r e s s i o n G u i d e l i n e P a n e l , 1993 a; D e p r e s s i o n G u i d e l i n e P a n e l , 1993b; K a t o n et al., 1995; W e l l s et al., 1989). N e v e r t h e l e s s , the d i a g n o s i s a n d t r e a t m e n t o f d e p r e s s i o n c o n t i n u e s to be a n " e l u s i v e a n d v e x i n g p r o b l e m " ( C a l l a h a n et al., 1996b).  A consensus  c o n f e r e n c e o r g a n i z e d b y the N a t i o n a l D e p r e s s i v e a n d M a n i c D e p r e s s i v e A s s o c i a t i o n i n 1996  was  c o n v e n e d to a d d r e s s the q u e s t i o n : "In light of the prevalence and perniciousness of depression, the economic cost of the illness, its treatability, and previous public and professional educational efforts, why are so many people with depression receiving inadequate treatment or getting no treatment at all? " ( H i r s c h f e l d et al., 1997)  T h e m e m b e r s o f the e x p e r t p a n e l c o n c l u d e d that the r e a s o n s f o r the g a p b e t w e e n k n o w l e d g e o f the d i a g n o s i s a n d treatment o f d e p r e s s i o n a n d a c t u a l t r e a t m e n t r e c e i v e d w e r e a c o m b i n a t i o n o f patient, p r o v i d e r a n d h e a l t h c a r e s y s t e m f a c t o r s ( H i r s c h f e l d et al., 1997). S t r a t e g i e s p r o p o s e d to i m p r o v e the q u a l i t y o f c a r e f o r i n d i v i d u a l s w i t h d e p r e s s i o n i n c l u d e d recommendations awareness,  to d e v e l o p e d u c a t i o n a l p r o g r a m s that i n c r e a s e d h e a l t h c a r e p r a c t i t i o n e r  enhanced  skills i n screening and diagnosis, and increased use o f effective  p h a r m a c o l o g i c a l a n d p s y c h o s o c i a l i n t e r v e n t i o n s ( H i r s c h f e l d et al., 1997). T h e c o n s e n s u s p a n e l a l s o s t r e s s e d the i m p o r t a n c e o f c o n d u c t i n g r e s e a r c h o n the d e v e l o p m e n t treatments f o r d e p r e s s i o n i n s p e c i a l p o p u l a t i o n s i n c l u d i n g the e l d e r l y .  and testing o f new  2 1.1  OVERVIEW OF  ADULT DEPRESSION  Depression is diagnosed according to the nosological system i n the Diagnostic a n d Statistical  Manual o f Mental  Disorders, 4  th  Edition (DSM-IV) (American  Psychiatric  A s s o c i a t i o n , 1994). T o e s t a b l i s h a d i a g n o s i s o f a Major Depressive Episode, d e p r e s s e d m o o d o r loss o f interest o r p l e a s u r e m u s t b e p r e s e n t m o s t o f the d a y , n e a r l y e v e r y d a y , f o r a p e r i o d o f at least 2 c o n s e c u t i v e w e e k s . F o u r o r m o r e o f the f o l l o w i n g s y m p t o m s o f d e p r e s s i o n m u s t a l s o b e present  during  the same  period:  significant weight  p s y c h o m o t o r agitation/retardation, f a t i g u e / l o s s o f energy,  loss/gain,  insomnia/hypersomnia,  feelings o f worthlessness/guilt,  i m p a i r e d c o n c e n t r a t i o n / i n d e c i s i v e n e s s , a n d r e c u r r e n t t h o u g h t s o f d e a t h o r s u i c i d e . Dysthymic Disorder is d e f i n e d as a c h r o n i c a l l y d e p r e s s e d m o o d that o c c u r s f o r m o s t o f the d a y , n e a r l y e v e r y  d a y f o r at least 2 years, that is a c c o m p a n i e d b y at least 2 a d d i t i o n a l s y m p t o m s o f d e p r e s s i o n (see above).  Minor Depressive Disorder ( d e p r e s s i v e s y m p t o m s ) a n d Subsyndromal Depression  ( s u b c l i n i c a l d e p r e s s i o n , m i l d d e p r e s s i o n ) h a v e f e w e r s y m p t o m s present. R e c e n t l y , i n v e s t i g a t o r s h a v e m o v e d a w a y f r o m t h e strict c a t e g o r i z a t i o n o f c l i n i c a l d e p r e s s i o n as a c o l l e c t i o n o f d i s c r e t e d i s o r d e r s (e.g. t h e D S M - I V system), a n d t o w a r d t h e n o t i o n o f t h e d i s o r d e r as a c o n d i t i o n w i t h v a r i a t i o n s a l o n g a " c l i n i c a l l y h o m o g e n e o u s s y m p t o m a t i c c o n t i n u u m " o f s e v e r i t y (Judd, 1997). T h e first onset o f m a j o r d e p r e s s i o n is o f t e n i n y o u n g adults, a l t h o u g h t h e c o n d i t i o n m a y b e g i n at a n y a g e ( G i l e s et al., 1989). S y m p t o m s o f m a j o r d e p r e s s i v e d i s o r d e r t y p i c a l l y d e v e l o p over a period o f days to weeks, and m a y be preceded over a period o f several months b y prodromal symptoms, including generalized anxiety and subsyndromal depressive symptoms. (American  P s y c h i a t r i c A s s o c i a t i o n , 1993).  Depression  may  also occur suddenly  when  p r e c i p i t a t e d b y a s e v e r e p s y c h o s o c i a l stressor ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993). T h e duration o f a depressive episode is variable, although most untreated episodes o f major d e p r e s s i o n w i l l last 6 t o 2 4 m o n t h s ( R u s h et al., 1991). W h i l e s o m e i n d i v i d u a l s h a v e o n l y a s i n g l e e p i s o d e o f m a j o r d e p r e s s i o n , 5 0 % to 8 5 % w i l l e v e n t u a l l y d e v e l o p a r e c u r r e n t episode,  3 w i t h a b o u t 5 0 % e x p e r i e n c i n g r e c u r r e n c e w i t h i n 2 y e a r s o f the i n i t i a l e p i s o d e ( N I M H / N I H C o n s e n s u s D e v e l o p m e n t C o n f e r e n c e Statement, 1985). T h e c o u r s e o f r e c u r r e n t m a j o r d e p r e s s i o n is v a r i a b l e , w i t h s o m e i n d i v i d u a l s h a v i n g e p i s o d e s s e p a r a t e d b y m a n y y e a r s o f n o r m a l f u n c t i o n i n g , w h i l e o t h e r s h a v e clusters o f e p i s o d e s o r h a v e i n c r e a s i n g l y f r e q u e n t e p i s o d e s as t h e y age ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993). W h e n a n i n d i v i d u a l has h a d three o r m o r e e p i s o d e s , the r i s k o f r e c u r r e n c e is greater t h a n 9 0 % ( K e l l e r et al., 1982). F o l l o w i n g an episode of major depression, s y m p t o m s will completely remit i n about 6 5 % o f cases. I n 5 % to 1 0 % o f cases, the f u l l e p i s o d e m a y p e r s i s t f o r a p e r i o d o f m o r e t h a n 2 years. I n the r e m a i n i n g 2 0 % to 2 5 % , h o w e v e r , r e c o v e r y b e t w e e n e p i s o d e s m a y b e o n l y p a r t i a l , w i t h depressive symptoms superimposed on a low-grade chronic depression (Depression Guideline P a n e l , 1993a). T h i s f o r m o f s u b s y n d r o m a l d e p r e s s i o n is n o w r e c o g n i z e d to r e p r e s e n t a c l i n i c a l l y significant, interepisode, depressive subtype o f major depression associated with harmful d y s f u n c t i o n , i n c r e a s e d p r e v a l e n c e o f past e p i s o d e s o f m a j o r d e p r e s s i o n , a n d a n e l e v a t e d l i f e t i m e p r e v a l e n c e o f s u i c i d e attempts ( J u d d et al., 1997; S t r e i m et al., 1997). P r e v a l e n c e e s t i m a t e s o f m a j o r d e p r e s s i v e d i s o r d e r v a r y d e p e n d i n g o n the s t u d y setting, assessment m e t h o d and data collection instrument, w i t h estimates based o n p h y s i c i a n diagnosis l o w e r t h a n t h o s e u s i n g i n t e r v i e w s o r q u e s t i o n n a i r e s ( M o o r e et al., 1978).  The prevalence o f  m a j o r d e p r e s s i v e d i s o r d e r i n a d u l t s has b e e n e s t i m a t e d to b e 2 . 3 % to 3 . 2 % f o r m e n a n d 4 . 5 % to 9 . 3 % f o r w o m e n i n l a r g e c o m m u n i t y s a m p l e s s u c h as the E p i d e m i o l o g i c C a t c h m e n t A r e a P r o g r a m ( E C A ) ( W e i s s m a n , 1987). T h e p r e v a l e n c e o f m i n o r d e p r e s s i o n i n the s a m e p o p u l a t i o n r a n g e s f r o m 2 . 5 % to 9 . 4 % ( W e i s s m a n et al., 1978). In o u t p a t i e n t s s e e n i n p r i m a r y c a r e c l i n i c s , the p r e v a l e n c e o f m a j o r d e p r e s s i v e d i s o r d e r has b e e n r e p o r t e d to r a n g e f r o m 5 % to 9 % ( B l a c k e r a n d C l a i r e , 1988) a n d 6 % to 1 1 % f o r m i n o r d e p r e s s i o n ( B r o a d h e a d et a l , 1990).  In adult  m e d i c a l i n p a t i e n t s w i t h a n o n p s y c h i a t r i c , g e n e r a l m e d i c a l c o n d i t i o n , the p r e v a l e n c e o f m a j o r d e p r e s s i o n is a b o u t 1 2 % to 1 6 % ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 a ; F e l d m a n et a l , 1987), a n d  i  4 1 8 % to 2 9 % f o r m i n o r d e p r e s s i o n ( K o e n i g et al., 1996). I n the p r e s e n c e o f c o m o r b i d diseases, including Parkinson's disease, dementia, diabetes mellitus, postpartum, and f o l l o w i n g m y o c a r d i a l i n f a r c t i o n o r stroke, the p r e v a l e n c e o f m a j o r d e p r e s s i o n m a y b e as h i g h as 2 0 % to 5 0 % ( B u r k e , 1996; D e p r e s s i o n G u i d e l i n e P a n e l , 1993a). R i s k f a c t o r s f o r m a j o r d e p r e s s i v e d i s o r d e r i n c l u d e f e m a l e gender, l a c k o f s o c i a l supports, s t r e s s f u l life events, p r i o r s u i c i d e attempts, g e n e r a l m e d i c a l disorder, a history o f depressive illness i n first-degree relatives, and prior episodes o f m a j o r d e p r e s s i o n o r d e p r e s s i v e s y m p t o m s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993a). Forty-three classes o f medications have been implicated i n drug-induced depression, a l t h o u g h a c a u s a l l i n k is o f t e n d i f f i c u l t to e s t a b l i s h ( A b r a m o w i c z ,  1998). L a r g e , w e l l - c o n d u c t e d  studies h a v e s h o w n that c o r t i c o s t e r o i d s , d i g o x i n , a n d f l u n a r i z i n e (a c a l c i u m c h a n n e l b l o c k e r ) are a s s o c i a t e d w i t h d e p r e s s i o n ( P a t t e n et al., 1997).  P r e l i m i n a r y findings suggest  that  a n t i h y p e r l i p i d e m i c agents, a n g i o t e n s i n c o n v e r t i n g e n z y m e i n h i b i t o r s , s e d a t i v e h y p n o t i c s , p s y c h o s t i m u l a n t s a n d c e r t a i n h o r m o n a l agents m a y a l s o b e a s s o c i a t e d w i t h d e p r e s s i o n ( G a n z i n i et al., 1993; P a t t e n et a l , 1997). S i n c e m o s t p a t i e n t s r e c e i v i n g a m e d i c a t i o n i m p l i c a t e d i n d r u g induced depression will not actually develop depressive symptoms, factors i n c l u d i n g genetic p r e d i s p o s i t i o n , p l a s m a d r u g c o n c e n t r a t i o n , p o l y p h a r m a c y , a n d s o c i a l a n d e n v i r o n m e n t a l stressors m a y a l s o p l a y a r o l e ( B u r k e , 1996; D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 a ; G a n z i n i et al., 1993; W h i t l o c k et al., 1978). G o o d c l i n i c a l p r a c t i c e d i c t a t e s that i f a p a t i e n t d e v e l o p s d e p r e s s i o n a f t e r d r u g treatment is initiated, t h e n the m e d i c a t i o n s h o u l d b e d i s c o n t i n u e d o r c h a n g e d ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993a). P r i m a r y c a r e p h y s i c i a n s see a b o u t three-quarters o f the p a t i e n t s i n the g e n e r a l p o p u l a t i o n w h o e x p e r i e n c e s y m p t o m s o f d e p r e s s i o n ( S h a p i r o et a l , 1984).  Community-dwelling  adults  w i t h c u r r e n t m a j o r o r m i n o r d e p r e s s i o n h a v e b e e n r e p o r t e d to b e f o u r t i m e s m o r e l i k e l y to see a n o n p s y c h i a t r i c p h y s i c i a n t h a n t h o s e w h o are not d e p r e s s e d ( W e i s s m a n et al., 1981). A s n o t e d b y the A g e n c y f o r H e a l t h C a r e P o l i c y a n d R e s e a r c h  ( A H C P R ) , h o w e v e r , d e p r e s s i o n is  underdiagnosed  5 and undertreated b y primary care and other nonpsychiatric practitioners  ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993a).  T h e A g e n c y e s t i m a t e s that o n l y o n e - t h i r d to o n e - h a l f o f  adults w i t h m a j o r d e p r e s s i v e d i s o r d e r are p r o p e r l y r e c o g n i z e d b y p r i m a r y c a r e p h y s i c i a n s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993 a). F a i l u r e to r e c o g n i z e d e p r e s s i o n d e n i e s p a t i e n t s p o t e n t i a l l y e f f e c t i v e treatment; a n d w h e n d e p r e s s i o n is n o t r e c o g n i z e d , the p a t i e n t c a n b e s u b j e c t e d to u n n e c e s s a r y , c o s t l y a n d p o t e n t i a l l y h a r m f u l d i a g n o s t i c p r o c e d u r e s i n a n e f f o r t to f i n d a p h y s i c a l e x p l a n a t i o n f o r h i s o r h e r s y m p t o m s ( M o o r e et al., 1978). P r i m a r y c a r e p h y s i c i a n s c o n t i n u e to b e e n c o u r a g e d to treat m o s t f o r m s o f m a j o r d e p r e s s i o n . H o w e v e r , r e f e r r a l to a m e n t a l h e a l t h s p e c i a l i s t m a y b e d e s i r a b l e f o r p a t i e n t s w h o h a v e s e v e r e s y m p t o m s , are a s u i c i d e risk, h a v e c o m o r b i d m e d i c a l , p s y c h i a t r i c , o r s u b s t a n c e u s e d i s o r d e r s , o r w h o f a i l to r e s p o n d to a p p r o p r i a t e treatment ( S c h u l b e r g et al., 1998). T h e m o r b i d i t y o f m a j o r d e p r e s s i o n is s u b s t a n t i a l , s i n c e b y D S M - I V d e f i n i t i o n , a d e p r e s s i v e " e p i s o d e m u s t be a c c o m p a n i e d  by clinically significant distress or impairment i n  s o c i a l , o c c u p a t i o n , o r o t h e r i m p o r t a n t areas o f f u n c t i o n i n g " ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1994). S y m p t o m s o f d e p r e s s i o n m a y a l s o c o n t r i b u t e to d i f f i c u l t y i n m a i n t a i n i n g r e l a t i o n s h i p s a n d i n a b i l i t y to m a n a g e a c t i v i t i e s o f d a i l y l i v i n g ( B u r k e , 1996). M a j o r a n d m i n o r d e p r e s s i o n a l s o a f f e c t the i n d i v i d u a l ' s g e n e r a l h e a l t h , w i t h d e c r e a s e d p r o d u c t i v i t y , i n c r e a s e d s i c k days, a n d a l m o s t d o u b l e the h e a l t h c a r e c o s t s w h e n c o m p a r e d w i t h age- a n d d i s e a s e m a t c h e d p a t i e n t s w i t h o u t d e p r e s s i o n ( K l e r m a n et al., 1992; S i m o n et al., 1995). D e p r e s s i o n i s a s s o c i a t e d w i t h i n c r e a s e d rates o f s u i c i d e a n d n o n - s u i c i d e m o r t a l i t y . T h e l i f e t i m e m o r t a l i t y r i s k b y s u i c i d e f o r d e p r e s s e d a d u l t s is 1 5 % c o m p a r e d w i t h l e s s t h a n 1 % f o r the g e n e r a l p o p u l a t i o n w i t h o u t p s y c h i a t r i c i l l n e s s ( C o r y e l l et al., 1982). W h i l e p r e e x i s t i n g m a j o r d e p r e s s i v e i l l n e s s m a y b e a s s o c i a t e d w i t h u p to 6 0 % o f s u i c i d e c a s e s ( G u z e et a l , 1970;  Roy,  1982), s u b s t a n c e abuse, p s y c h o s i s , a n d p e r s o n a l i t y d i s o r d e r s a l s o c o n t r i b u t e to s u i c i d e - r e l a t e d  deaths ( K a t z , 1996).  6 M a j o r d e p r e s s i o n i s a l s o a s s o c i a t e d w i t h a n i n c r e a s e d n u m b e r o f fatal  a c c i d e n t s ( W e l l s , 1985). 1.2  TREATMENT  1.2.1  Treatment guidelines for adult depression  OF ADULT  DEPRESSION  S u c c e s s f u l t r e a t m e n t o f patients w i t h m a j o r d e p r e s s i o n is b a s e d o n a t h o r o u g h a s s e s s m e n t o f t h e patient's s y m p t o m s , p a s t m e d i c a l a n d p s y c h i a t r i c h i s t o r y , l i f e stressors, f a m i l y , p s y c h o s o c i a l , a n d c u l t u r a l e n v i r o n m e n t , a n d their p r e f e r e n c e f o r s p e c i f i c t r e a t m e n t o r t h e r a p e u t i c a p p r o a c h ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993).  T h e goals o f treatment are to decrease  symptoms o f depression, reduce risk o f relapse a n d recurrence, increase quality o f life, improve m e d i c a l h e a l t h status, a n d d e c r e a s e h e a l t h c a r e c o s t s a n d m o r t a l i t y ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993b).  T r e a t m e n t f o r d e p r e s s i o n m a y i n v o l v e biological t h e r a p y (e.g. p h a r m a c o t h e r a p y ,  e l e c t r o c o n v u l s i v e therapy, l i g h t t h e r a p y ) , psychosocial t h e r a p y (e.g. p s y c h o t h e r a p e u t i c m a n a g e m e n t , i n t e r p e r s o n a l therapy, b e h a v i o u r t h e r a p y , c o g n i t i v e b e h a v i o u r t h e r a p y ) , o r a combination o f t h e t w o f o r m s o f t h e r a p y ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993). E a c h t y p e  o f t h e r a p y w i l l h a v e b e n e f i t s a n d r i s k s f o r t h e i n d i v i d u a l patient, a n d these m u s t b e c a r e f u l l y reviewed b y the p h y s i c i a n a n d patient w h e n selecting a treatment option (Depression G u i d e l i n e P a n e l , 1993b). A l t h o u g h s u c c e s s f u l t r e a t m e n t o f d e p r e s s i o n u s u a l l y results f r o m a c o m b i n a t i o n o f p s y c h o s o c i a l a n d b i o l o g i c a l i n t e r v e n t i o n s , a f o c u s o f the p r e s e n t r e s e a r c h is o n t h e o u t c o m e s associated with antidepressant pharmacotherapy.  Thus, the role o f other treatment modalities  will not be reviewed. Antidepressant treatment o f depressive episodes consists o f three phases  (American  P s y c h i a t r i c A s s o c i a t i o n , 1993; K u p f e r , 1991). T h e g o a l o f t r e a t m e n t o f t h e acute p h a s e i s t o r e l i e v e s y m p t o m s a n d i n d u c e r e m i s s i o n . F o l l o w i n g t h e a c u t e phase, t h e continuation p h a s e o f 4 t o 9 m o n t h s i s r e c o m m e n d e d t o p r e v e n t t h e r e l a p s e o r r e c u r r e n c e o f the d e p r e s s i v e e p i s o d e . F o r patients w i t h a p a s t h i s t o r y o f r e c u r r e n t d e p r e s s i v e e p i s o d e s , a l o n g - t e r m maintenance p h a s e w i t h  7 the a n t i d e p r e s s a n t d o s e u s e d i n the acute a n d c o n t i n u a t i o n p h a s e s is r e c o m m e n d e d to p r e v e n t f u r t h e r d e p r e s s i v e e p i s o d e s o r to r e d u c e their s e v e r i t y a n d d u r a t i o n . P a t i e n t s w h o h a v e o n l y a p a r t i a l r e s p o n s e to acute treatment w i l l t e n d to h a v e m o r e s y m p t o m s d u r i n g c o n t i n u a t i o n treatment, a n d t h o s e w i t h p o o r s y m p t o m c o n t r o l i n the c o n t i n u a t i o n p h a s e w i l l t e n d to h a v e a h i g h e r i n c i d e n c e o f e a r l y r e l a p s e a n d r e c u r r e n c e ( P r i e n et a l , 1986). Recently, specific guidelines and algorithms have been developed appropriate antidepressant therapy  i n adults ( A m e r i c a n  to  encourage  Psychiatric Association,  1993;  D e p r e s s i o n G u i d e l i n e P a n e l , 1993b). F i g u r e 1 d e s c r i b e s a n a p p r o a c h to the treatment f o r d e p r e s s i o n that is a d a p t e d f r o m the A H C P R g u i d e l i n e s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993b). F o r p a t i e n t s w h o h a v e o n l y a p a r t i a l r e s p o n s e to t h e r a p y at 6 to 12 w e e k s , c o n t i n u a t i o n o f antidepressant therapy is recommended, with or without a dosage adjustment  (Depression  G u i d e l i n e P a n e l , 1 9 9 3 b ) . A b o u t 2 0 % to 3 0 % o f p a t i e n t s w i t h m a j o r d e p r e s s i o n w i l l f a i l to a c h i e v e a s a t i s f a c t o r y r e s p o n s e f r o m initial treatment w i t h a n t i d e p r e s s a n t m e d i c a t i o n  (American  P s y c h i a t r i c A s s o c i a t i o n , 1993). T h e i n a d e q u a t e treatment r e s p o n s e m a y a c t u a l l y b e a result o f f a u l t y d i a g n o s i s , i n a d e q u a t e d u r a t i o n o r d o s a g e o f therapy, o r f a i l u r e to a d d r e s s  comorbid  m e d i c a l c o n d i t i o n s o r p s y c h o s o c i a l f a c t o r s ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993).  Poor  c o m p l i a n c e r e l a t e d to the p e s s i m i s m , a n d l o w m o t i v a t i o n a n d e n e r g y o f d e p r e s s e d p a t i e n t s m a y a l s o c o n t r i b u t e to a n i n a d e q u a t e r e s p o n s e ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 b ; Z i s o o k , 1996). R e s u l t s b y L i n et a l . ( L i n et al., 1995) s u g g e s t that a b o u t 2 8 % o f p r i m a r y care p a t i e n t s stop a n t i d e p r e s s a n t t h e r a p y d u r i n g the first m o n t h , a n d that 4 4 % s t o p b y the t h i r d m o n t h .  While  c o n f l i c t i n g i n f o r m a t i o n exists as to p r e c i s e l y w h e n a c l i n i c i a n s h o u l d c o n s i d e r s w i t c h i n g a n a n t i d e p r e s s a n t drug, u s e o f a n agent f r o m a n alternate d r u g c l a s s has b e e n s u g g e s t e d i f the p a t i e n t d o e s not r e s p o n d b y 12 w e e k s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 b ) . F u r t h e r r e s e a r c h i n t o the p r e f e r r e d t i m e p o i n t at w h i c h the initial acute a n t i d e p r e s s a n t treatment s h o u l d b e a u g m e n t e d o r c h a n g e d is w a r r a n t e d ( S c h u l b e r g et al., 1998).  Figure 1  A l g o r i t h m for treating patients with major depressive disorder  DIAGNOSIS 1 Select and initiate treatment I  Monitor acute treatment (every 1 -2 weeks)  Assess response (week 6) I  r  Clearly better  Not better at all  Somewhat better i  Continue treatment (adjust dosage) Continue treatment for 6 more weeks  Augment or change treatment  Monitor treatment (every 1-2 weeks)  Assess response (week 12)  Clearly better «-  Not better  Complete remission?  > No -•  Relapse?-  Yes 1r Medication continued for 4-9 months. Consider maintenance treatment  Refer or consult a psychiatrist or other mental health professional  Change treatment  9 1.2.2  Efficacy of antidepressants for depression  1.2.2.1 Efficacy of antidepressants for the treatment of major depression  G u i d e l i n e s f o r treatment are p r e d i c a t e d o n the n o t i o n that a n t i d e p r e s s a n t s are e f f i c a c i o u s . " A s t u d y o f d r u g efficacy is a s t u d y o f w h e t h e r , under ideal conditions, a d r u g has the a b i l i t y to b r i n g a b o u t the e f f e c t i n t e n d e d w h e n p r e s c r i b i n g i t . " ( S t r o m , 1989). "Efficacy i s t h e m e a s u r e o f a medication's  e x p e c t e d action* w h e n g i v e n t o a defined population for a defined problem, regardless o f other considerations, such as t o l e r a b i l i t y , s i d e effects, o r dropouts." ( S c h n e i d e r , 1996). The e f f i c a c y o f antidepressant drugs has been extensively evaluated i n randomized, c o n t r o l l e d trials i n a d u l t s b e t w e e n 18 a n d 6 5 y e a r s o f age w i t h m a j o r d e p r e s s i o n . T h e H a m i l t o n Rating Scale f o r Depression ( H A M - D ) a n d the Clinical Global Improvement (CGI) are considered the "gold standard" b y which  researchers evaluate antidepressant efficacy  ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 b ; S c h u l b e r g et a l , 1998).  T h e primary outcome o f  a n t i d e p r e s s a n t r e s p o n s e is u s u a l l y c a l c u l a t e d a s the p r o p o r t i o n o f p a t i e n t s w h o s e s c o r e o n the H A M - D improved  b y at least 5 0 % , o r w h o s e C G I s c o r e i n d i c a t e d m a r k e d o r e x t e n s i v e  i m p r o v e m e n t d u r i n g acute-phase  pharmacotherapy.  Recovery  from a n episode o f major  d e p r e s s i o n is t y p i c a l l y c a l c u l a t e d as t h e p r o p o r t i o n o f p a t i e n t s w h o s e s c o r e o n the H A M - D d e c l i n e d to < 7. F o r i n t e r v a l - t y p e s c a l e s i n c l u d i n g the H A M - D , t r e a t m e n t o u t c o m e m a y a l s o b e r e p o r t e d as the c h a n g e i n m e a n s c o r e w i t h i n g r o u p s b e f o r e a n d a f t e r therapy. r e c o m m e n d s the c o n s i s t e n t r e p o r t i n g o f b o t h d i c h o t o m o u s  The A H C P R  a n d c o n t i n u o u s treatment o u t c o m e s  (Depression G u i d e l i n e Panel, 1993b). S i x m a j o r c l a s s e s o f a n t i d e p r e s s a n t agents are c u r r e n t l y a v a i l a b l e i n C a n a d a a n d i n c l u d e tertiary a n d s e c o n d a r y a m i n e t r i c y c l i c a n t i d e p r e s s a n t s (TCAs), m o n o a m i n e o x i d a s e i n h i b i t o r s (MAOIs), s e l e c t i v e s e r o t o n i n r e u p t a k e i n h i b i t o r s (SSRIs), r e v e r s i b l e M A O I s (RIMAs), s e r o t o n i n  n o r a d r e n a l i n e r e u p t a k e i n h i b i t o r s (SNRIs) a n d s e r o t o n i n r e c e p t o r b l o c k e r s (e.g. trazodone, nefazodone). T h e s e c l a s s e s o f a n t i d e p r e s s a n t s d i f f e r i n t e r m s o f t h e i r c l i n i c a l a c t i v i t y , s a f e t y a n d  10 t o l e r a b i l i t y , ease o f a d m i n i s t r a t i o n , a n d the l i k e l i h o o d o f p h a r m a c o d y n a m i c a n d p h a r m a c o k i n e t i c i n t e r a c t i o n s w i t h c o n c o m i t a n t l y p r e s c r i b e d d r u g s ( P r e s k o r n a n d B u r k e , 1992). R e s p o n s e to d i f f e r e n t agents w i l l v a r y b e t w e e n i n d i v i d u a l s ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993; D e p r e s s i o n G u i d e l i n e P a n e l , 1993b). A m e t a - a n a l y s i s o f a l m o s t 2 0 0 acute-phase r a n d o m i z e d c o n t r o l l e d trials, p r e d o m i n a n t l y i n p s y c h i a t r i c p a t i e n t s , s u g g e s t s that d i f f e r e n t a n t i d e p r e s s a n t s h a v e c o m p a r a b l e e f f i c a c y ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993b).  I n the p r i m a r y c a r e s e t t i n g , a m e t a - a n a l y s i s o f 28  r a n d o m i z e d c o n t r o l l e d trials r e p o r t e d o v e r a l l e f f i c a c y (± S D ) o f 6 4 % ± 1 1 % f o r t r i c y c l i c s , 6 5 % + 1 3 % f o r h e t e r o c y c l i c s , a n d 5 4 % + 7 % f o r S S R I s ( S c h u l b e r g et al., 1998). B a s e d o n these m e t a a n a l y s e s a n d r e c e n t r a n d o m i z e d c o n t r o l l e d trials ( R a v i n d r a n et al., 1997; S c h u l b e r g et al., 1996; S i m o n et a l , 1996), the A H C P R g u i d e l i n e p a n e l c o n c l u d e d that " a n t i d e p r e s s a n t m e d i c a t i o n s p r e s c r i b e d f o r acute- a n d c o n t i n u a t i o n - p h a s e t r e a t m e n t o f d e p r e s s e d p r i m a r y c a r e p a t i e n t s are a s s o c i a t e d w i t h a r e s p o n s e rate o f 5 0 % to 6 0 % , w h i c h a p p r o x i m a t e s that f o u n d f o r p s y c h i a t r i c p a t i e n t s " ( S c h u l b e r g et al., 1998). S i n c e that time, a m e t a - a n a l y s i s o f v e n l a f a x i n e , S S R I s a n d T C A s b y E i n a r s o n et al. ( E i n a r s o n et al., 1998) s u g g e s t s that i n the r a n d o m i z e d , c o n t r o l l e d trials i n c l u d e d i n the a n a l y s i s , v e n l a f a x i n e h a d s i m i l a r o r g r e a t e r e f f i c a c y rates a n d l o w e r d r o p - o u t rates t h a n the S S R I s a n d T C A s . P h a r m a c o t h e r a p y h a s b e e n d e m o n s t r a t e d to r e d u c e rates o f recurrence i n psychiatric patients o n long-term maintenance, w i t h about 9 1 % o f patients on active treatment s u r v i v i n g an additional 2 years without a recurrence, even after 3 years o f c l i n i c a l r e m i s s i o n ( K u p f e r et al., 1992). I n contrast, o n l y a b o u t 3 3 % o f p a t i e n t s o n p l a c e b o s u r v i v e d the a d d i t i o n a l 2-year p e r i o d w i t h o u t a r e c u r r e n c e ( K u p f e r et al., 1992). T h i s has b e e n s u p p o r t e d b y a r e c e n t s t u d y that i n d i c a t e d that p a t i e n t s w h o d i s c o n t i n u e d t h e i r a n t i d e p r e s s a n t early had an increased risk o f experiencing relapse or recurrence c o m p a r e d w i t h those  who  c o n t i n u e t h e r a p y w i t h their i n i t i a l a n t i d e p r e s s a n t f o r m o r e t h a n 6 m o n t h s ( r i s k ratio = 1.77; P < 0.01) ( M e l f i e t a l , 1998).  11 T h e r e are a n u m b e r o f c l i n i c a l f a c t o r s that n e e d to be c o n s i d e r e d w h e n s e l e c t i n g the " o p t i m a l " a n t i d e p r e s s a n t ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). P a t i e n t - r e l a t e d c l i n i c a l factors to be c o n s i d e r e d  i n c l u d e the patient's d i a g n o s t i c  c o n c u r r e n t m e d i c a l illness, p o t e n t i a l f o r d r u g - d r u g i n t e r a c t i o n s f r o m c o n c o m i t a n t and  h i s t o r y o f r e s p o n s e to antidepressants  ( M a n d o s , 1996;  features,  medications,  Tourigny-Rivard,  1997).  A n t i d e p r e s s a n t - r e l a t e d factors a l s o n e e d to be c o n s i d e r e d w h e n c o m p a r i n g agents, i n c l u d i n g the short a n d l o n g - t e r m s i d e e f f e c t p r o f i l e , age-related p h a r m a c o k i n e t i c  changes, safety i n overdose  a n d c o s t ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). S i n c e e f f i c a c y i s c o n s i d e r e d to be s i m i l a r , s i d e e f f e c t p r o f i l e s a n d p o t e n t i a l t o x i c i t y o f antidepressant a g e n t s are c r i t i c a l factors to be c o n s i d e r e d i n treatment s e l e c t i o n . W h i l e T C A s a n d M A O I s w e r e the m a i n s t a y o f antidepressant t h e r a p y u n t i l the late 1980s, a n d c o n t i n u e to be f r e q u e n t l y p r e s c r i b e d , p o o r l y t o l e r a t e d s i d e e f f e c t s a n d d r u g i n t e r a c t i o n s c o m p l i c a t e t h e i r use ( T o u r i g n y - R i v a r d , 1997). Tertiary TCAs i n c l u d i n g a m i t r i p t y l i n e , i m i p r a m i n e , a n d d o x e p i n c a u s e s u b s t a n t i a l a n t i c h o l i n e r g i c (e.g. u r i n a r y retention, m e m o r y i m p a i r m e n t ) ,  may  antihistaminic  (e.g. w e i g h t g a i n , sedation) a n d a l p h a - a d r e n e r g i c (e.g. o r t h o s t a t i c h y p o t e n s i o n ) s i d e effects, a n d a h i g h fatality rate i n o v e r d o s e s i t u a t i o n s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y  Care  P h y s i c i a n s , 1993). Secondary amine TCAs, i n c l u d i n g n o r t i p t y l i n e a n d d e s i p r a m i n e , h a v e a m o r e f a v o u r a b l e s i d e e f f e c t p r o f i l e t h a n the tertiary T C A s , w i t h a l o w e r i n c i d e n c e o f sedation, orthostatic hypotension, cardiac arrhythmias and anticholinergic effects ( A m e r i c a n Psychiatric A s s o c i a t i o n , 1993; D e p r e s s i o n G u i d e l i n e P a n e l , 1993b). W i t h MAOIs, t r o u b l e s o m e  insomnia,  p o s t u r a l h y p o t e n s i o n , p o t e n t i a l l y fatal d r u g i n t e r a c t i o n s a n d p r o b l e m a t i c d i e t a r y r e s t r i c t i o n s t e n d to l i m i t t h e i r use, s i n c e there are n o w safer a l t e r n a t i v e s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993b). T h e n e w e r antidepressants h a v e d i f f e r e n t s i d e e f f e c t p r o f i l e s , thus a l l o w i n g c l i n i c i a n s to treat patients w h o  c o u l d not tolerate T C A s o r M A O I s ( T o u r i g n y - R i v a r d ,  currently available in Canada, fluoxetine, fluvoxamine,  1997). T h e SSRIs  s e r t r a l i n e a n d p a r o x e t i n e , are less  12 sedating, h a v e f e w e r a n t i c h o l i n e r g i c a n d c a r d i a c s i d e e f f e c t s , a n d l o w e r o v e r d o s e t o x i c i t y t h a n the o l d e r agents ( A m e r i c a n  P s y c h i a t r i c A s s o c i a t i o n , 1993). T h e s i d e e f f e c t s o f S S R I s are  generally similar, and include nausea, anorexia, diarrhea, anxiety, agitation, insomnia,  and  nervousness  The  (Canadian Coordinating Office for Health Technology  A s s e s s m e n t , 1997).  S S R I s differ, h o w e v e r , i n t h e i r in vivo a n d in vitro i n h i b i t i o n o f s p e c i f i c d r u g - m e t a b o l i z i n g c y t o c h r o m e P 4 5 0 i s o e n z y m e s , r e s u l t i n g i n d i f f e r e n t c l i n i c a l l y s i g n i f i c a n t i n t e r a c t i o n s w i t h other d r u g s m e t a b o l i z e d b y the s a m e i s o e n z y m e s ( N e m e r o f f et al., 1996; R i e s e n m a n , 1995;  Von  M o l t k e e t al., 1993). S e r o t o n e r g i c s y n d r o m e is a n i a t r o g e n i c c o m p l i c a t i o n that o c c u r s m o s t c o m m o n l y w h e n t w o o r m o r e d r u g s that h a v e d i f f e r e n t s e r o t o n e r g i c m e c h a n i s m s o f a c t i o n are g i v e n c o n c u r r e n t l y , o r s e q u e n t i a l l y after a n i n s u f f i c i e n t w a s h o u t p e r i o d ( B r o w n et al., 1996; L y n d , 1997; M i l l s , 1995). H i g h d o s e s o f a s i n g l e s e r o t o n e r g i c d r u g h a v e a l s o b e e n a s s o c i a t e d w i t h the s y n d r o m e ( M i l l s , 1995; Sporer, 1995). A n t i d e p r e s s a n t s , i n c l u d i n g S S R I s , M A O I s , a n d T C A s , are the m o s t c o m m o n l y i m p l i c a t e d c l a s s o f d r u g s a l t h o u g h m a n y o t h e r agents m a y  c o n t r i b u t e to the  d e v e l o p m e n t o f s e r o t o n e r g i c s y n d r o m e ( M i l l s , 1995). S y m p t o m s f r e q u e n t l y o c c u r w i t h i n h o u r s o f the a d d i t i o n o r i n c r e a s e i n d o s a g e o f a s e r o t o n e r g i c d r u g ( M i l l s , 1995). T h e s y n d r o m e is c h a r a c t e r i z e d b y c h a n g e s i n b e h a v i o u r a n d c o g n i t i v e f u n c t i o n (i.e. c o n f u s i o n a n d a g i t a t i o n ) , a u t o n o m i c n e r v o u s s y s t e m d y s f u n c t i o n (i.e. h y p e r t h e r r m i a a n d d i a p h o r e s i s ) , a n d  neuromuscular  a b n o r m a l i t i e s (i.e. m y o c l o n u s a n d h y p e r r e f l e x i a ) ( M i l l s , 1995). P r o m p t m a n a g e m e n t o f the s y n d r o m e is a s s o c i a t e d w i t h a g o o d p r o g n o s i s , a n d i n v o l v e s d i s c o n t i n u a t i o n o f the s e r o t o n e r g i c agent, f o l l o w e d b y s y m p t o m a t i c a n d s u p p o r t i v e c a r e ( L y n d , 1997; M i l l s , 1995). A n "abrupt w i t h d r a w a l s y n d r o m e " has b e e n r e p o r t e d w i t h S S R I s (Iskandar, 1996; L y n d , 1996; S k a e h i l l , 1997), w i t h s y m p t o m s o f a n x i e t y , h e a d a c h e s , i n s o m n i a , b i z a r r e d r e a m s , s h o c k l i k e s e n s a t i o n s a n d " f l u - l i k e i l l n e s s " . T h e w i t h d r a w a l s y n d r o m e i s m o s t l i k e l y to o c c u r f o r patients w h o are a b r u p t l y w i t h d r a w n f r o m S S R I s w i t h a short h a l f - l i f e , i n c l u d i n g p a r o x e t i n e a n d  13 sertraline, a n d m a y b e m i n i m i z e d b y r e s t a r t i n g the d r u g a n d t h e n t a p e r i n g s l o w l y ( S k a e h i l l , 1997). Moclobemide is a r e v e r s i b l e a n d s e l e c t i v e i n h i b i t o r o f m o n o a m i n e o x i d a s e i s o e n z y m e A  that is p e r c e i v e d to h a v e a m o r e f a v o r a b l e s i d e e f f e c t p r o f i l e (e.g. h e a d a c h e s ,  insomnia,  d i z z i n e s s , s e d a t i o n ) , a p p e a r s safe i n o v e r d o s e situations, a n d d o e s n o t n e c e s s i t a t e s p e c i a l d i e t a r y r e s t r i c t i o n s ( G i l l i s , 1999;  Tourigny-Rivard,  1997).  Venlafaxine b l o c k s  the r e u p t a k e  of  n o r a d r e n a l i n e , s e r o t o n i n a n d d o p a m i n e , has s i d e e f f e c t s that i n c l u d e nausea, a n x i e t y , i n s o m n i a , p a l p i t a t i o n s , tremor, i s less t o x i c i n o v e r d o s e , a n d is n o t a p o t e n t i n h i b i t o r o f c y t o c h r o m e e n z y m e s ( T o u r i g n y - R i v a r d , 1997).  P450  Trazodone is a n a n t i d e p r e s s a n t w i t h a n x i o l y t i c a n d h y p n o t i c  a c t i v i t y that has f e w a n t i c h o l i n e r g i c , c a r d i o v a s c u l a r o r s e r o t o n e r g i c a g o n i s t s i d e e f f e c t s . S i n c e the d r u g f r e q u e n t l y c a u s e s d r o w s i n e s s a n d c o g n i t i v e s l o w i n g , t r a z o d o n e i s o f t e n g i v e n at b e d t i m e f o r a g i t a t e d d e p r e s s i o n ( M a n d o s , 1996). T h e o n l y other a n t i d e p r e s s a n t a v a i l a b l e i n C a n a d a at the t i m e o f the study, nefazodone, is a l s o p e r c e i v e d to h a v e a m o r e f a v o u r a b l e s i d e e f f e c t p r o f i l e (e.g. drowsiness, dry mouth, confusion, blurred v i s i o n and postural hypotension) and low toxicity i n o v e r d o s e ( T o u r i g n y - R i v a r d , 1997). 1.2.2.2 Efficacy of antidepressants for the treatment of minor depression  R a n d o m i z e d , c o n t r o l l e d trials o f a d u l t s w i t h m i n o r d e p r e s s i o n s e e m to i n d i c a t e that pharmacotherapy  may  be h e l p f u l , u s i n g a n t i d e p r e s s a n t d o s a g e s that h a v e e f f i c a c y i n m a j o r  d e p r e s s i o n ( T o u r i g n y - R i v a r d , 1997). P a y k e l et al. ( P a y k e l et al., 1988) e v a l u a t e d the e f f i c a c y o f a m i t r i p t y l i n e (125 to 1 7 5 m g / d a y ) o r p l a c e b o f o r p a t i e n t s 18 to 64 y e a r s o f age w i t h m i n o r d e p r e s s i o n w h o w e r e t r e a t e d f o r 4 to 6 w e e k s . P a t i e n t s w e r e d i v i d e d i n t o three g r o u p s b y  HAM-  D s c o r e s : < 13 ( 2 0 p a t i e n t s ) , 13 to 15 (47 p a t i e n t s ) , a n d 16 to 2 4 ( 7 4 p a t i e n t s ) . P a t i e n t s w i t h H A M - D s c o r e s o f 13 to 15 a n d w i t h s c o r e s o f 16 to 24 o n a m i t r i p t y l i n e s h o w e d i m p r o v e m e n t c o m p a r e d w i t h p l a c e b o (P < 0.05), a l t h o u g h t h o s e w i t h a H A M - D < 13 s h o w e d n o b e n e f i t f r o m the a c t i v e drug. S t e w a r t et al. ( S t e w a r t et al., 1992) a s s e s s e d the e f f i c a c y o f i m i p r a m i n e (up to  14 3 0 0 m g / d a y ) , p h e n e l z i n e ( u p to 9 0 m g / d a y ) o r p l a c e b o i n a d u l t p a t i e n t s w i t h a t y p i c a l d e p r e s s i o n w h o w e r e t r e a t e d f o r 6 w e e k s . P a t i e n t s w e r e d i v i d e d i n t o three g r o u p s b y H A M - D s c o r e s : < 13 ( 1 4 0 patients), 13 to 15 ( 1 2 6 patients), a n d 16 o r h i g h e r (135 patients). P a t i e n t s w i t h C G I g l o b a l i m p r o v e m e n t s c o r e s o f 1 ( v e r y m u c h i m p r o v e d ) o r 2 ( m u c h i m p r o v e d ) w e r e c o n s i d e r e d to h a v e h a d a r e s p o n s e . T h e three g r o u p s o f patients ( s e p a r a t e d b y H A M - D s c o r e s ) h a d s i m i l a r results: p h e n e l z i n e > i m i p r a m i n e » p l a c e b o . I n the g r o u p w i t h H A M - D s c o r e s o f < 13,  improvement  w a s r e p o r t e d i n 8 3 % o f p h e n e l z i n e - t r e a t e d patients, 6 0 % o f i m i p r a m i n e - t r e a t e d p a t i e n t s , a n d 3 3 % o f p l a c e b o p a t i e n t s (P < 0.001). H e l l e r s t e i n et al. ( H e l l e r s t e i n et al., 1993) e v a l u a t e d the e f f i c a c y o f fluoxetine ( 2 0 m g / d a y ) o r p l a c e b o i n a d u l t p a t i e n t s w i t h d y s t h y m i a w h o w e r e t r e a t e d for 8 w e e k s . R e s p o n s e w a s d e f i n e d a s a d e c l i n e i n H A M - D s c o r e > 5 0 % a n d a C G I g l o b a l i m p r o v e m e n t s c o r e o f 1 o r 2. F l u o x e t i n e s u b j e c t s s h o w e d s i g n i f i c a n t l y g r e a t e r i m p r o v e m e n t at w e e k 8 than placebo subjects did. In a f u r t h e r r e v i e w o f t r e a t m e n t s t u d i e s o f m i n o r d e p r e s s i o n b e t w e e n 1 9 8 0 a n d 1991, C o n t e a n d K a r a s u ( C o n t e et al., 1 9 9 2 ) e x a m i n e d  studies o f antidepressant therapy a n d  p s y c h o t h e r a p y . T h e a u t h o r s i d e n t i f i e d c o n s i d e r a b l e m e t h o d o l o g i c a l p r o b l e m s w i t h the trials (e.g. i n a d e q u a t e s a m p l e size, l a c k o f c o n t r o l s , i n a d e q u a t e a n t i d e p r e s s a n t d o s a g e s , l a c k o f e x p l i c i t c r i t e r i a f o r r e s p o n s e , d i a g n o s t i c i n c o n s i s t e n c i e s ) . N e v e r t h e l e s s , the a u t h o r s n o t e d that " a l l s t u d i e s o f a n t i d e p r e s s a n t d r u g t r e a t m e n t s h o w e d d r u g s to b e e f f i c a c i o u s a n d s u p e r i o r to p l a c e b o , w i t h f e w d i f f e r e n c e s f o u n d b e t w e e n drugs". In contrast, a s t u d y o f 2 3 9 p s y c h i a t r i c o u t p a t i e n t s w i t h m a j o r d e p r e s s i o n s u g g e s t e d that i n t h o s e w i t h l e s s s e v e r e m a j o r d e p r e s s i o n ( b a s e l i n e H A M - D s c o r e < 20), t h e r e w a s n o d i f f e r e n c e b e t w e e n p l a c e b o a n d t r e a t m e n t (either p s y c h o t h e r a p y o r i m i p r a m i n e > 1 5 0 m g / d a y ) ( E l k i n et al., 1989). F o r this less s e v e r e l y d e p r e s s e d g r o u p , the a u t h o r s r a i s e the q u e s t i o n o f the n e e d f o r a n t i d e p r e s s a n t m e d i c a t i o n , a n d s u g g e s t that s u p p o r t i v e t h e r a p y b y e x p e r i e n c e d c l i n i c i a n s m a y b e a d e q u a t e treatment. I n their r e v i e w o f the literature, B e c k a n d K o e n i g ( B e c k et al., 1996) n o t e  that "treatment s t u d i e s o f m i n o r d e p r e s s i o n r e p o r t m a r g i n a l r e s p o n s e s to m e d i c a t i o n " .  15 The  e x c e p t i o n that t h e y n o t e d w a s the r a n d o m i z e d , c o n t r o l l e d , d o u b l e - b l i n d s t u d y o f p o s t - s t r o k e patients w i t h e i t h e r m i n o r o r m a j o r d e p r e s s i o n , i n w h i c h p a t i e n t s t r e a t e d w i t h n o r t r i p t y l i n e s h o w e d g r e a t e r i m p r o v e m e n t (P < 0.006) t h a n t h o s e r e c e i v i n g p l a c e b o ( L i p s e y et al., 1984). B e c k a n d K o e n i g ( B e c k et al., 1996) c o n c l u d e that "the e f f e c t i v e n e s s o f a n t i d e p r e s s a n t s i s u n k n o w n " i n m i n o r d e p r e s s i o n a n d stress the i m p o r t a n c e o f f u t u r e r a n d o m i z e d , c o n t r o l l e d trials to d e t e r m i n e " i n w h i c h patients, i f any, m e d i c a t i o n is i n d i c a t e d " . T h i s c a l l f o r f u r t h e r s t u d i e s is e c h o e d b y o t h e r s ( S h e r b o u r n e et al., 1994), w h o s u g g e s t that " g i v e n the c l i n i c a l s i g n i f i c a n c e o f s u b t h r e s h o l d d e p r e s s i o n , it is c r i t i c a l l y i m p o r t a n t to e x t e n d s u c h s t u d i e s to f o c u s o n d e v e l o p i n g a n d t e s t i n g the e f f e c t s o f treatment o n o u t c o m e , i n terms o f r e d u c i n g d e p r e s s i v e s y m p t o m s a n d a s s o c i a t e d m o r b i d i t y , f o r these patients." 1.3  D E P R E S S I O N IN L A T E  LIFE  T h e r e has b e e n a g r o w i n g a w a r e n e s s  o v e r the p a s t d e c a d e that d e p r e s s i o n i n b o t h  ambulatory and long-term care elderly patients is a major p u b l i c health problem. T h e N a t i o n a l Institutes o f H e a l t h C o n s e n s u s C o n f e r e n c e o n the D i a g n o s i s a n d T r e a t m e n t o f D e p r e s s i o n i n L a t e L i f e i n 1991 c o n c l u d e d that c o m p l e x p h y s i c a l , s o c i a l , a n d e c o n o m i c p r o b l e m s i n the e l d e r l y c o n s p i r e to m a k e the i l l n e s s u n d i a g n o s e d and, m o r e i m p o r t a n t l y , u n d e r t r e a t e d ( N I H  Consensus  D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992). T o i m p r o v e i d e n t i f i c a t i o n a n d d i a g n o s i s o f the d i s o r d e r , the p a n e l stated that "professionals cannot wait for depressed older people to come to them; they must instead be active and aggressive in their efforts to reach those in need of help."  T o e n s u r e t h a t d e p r e s s e d o l d e r p e o p l e h a d a c c e s s to the m e n t a l h e a l t h s e r v i c e s that  t h e y needed, the p a n e l r e c o m m e n d e d the n e e d f o r "training programs for care providers, including nursing staff and "hands on " staff, in both community and institutional settings must be directed at identification of the behavioural manifestations of depression and improvement of the care provided". T h e c o n s e n s u s p a n e l i d e n t i f i e d that a h i g h p r i o r i t y a r e a f o r f u t u r e r e s e a r c h  16 s h o u l d i n v o l v e the c o n d u c t o f "clinical trials and observation studies of treatment in the very old, the elderly ... in institutional settings, and the elderly with medical illness".  Furthermore,  the p a n e l r e c o m m e n d e d that r e s e a r c h e r s s h o u l d "carry out long-term clinical trials with broadbased assessment of outcome ... to determine the extent to which effective recognition and treatment benefit patients and society" ( N I H C o n s e n s u s  Development Panel on Depression in  L a t e L i f e , 1992). W h i l e a r e c e n t c o n s e n s u s u p d a t e a c k n o w l e d g e s that r e s e a r c h o n a l l a s p e c t s o f d e p r e s s i o n i n late l i f e has b e e n a c c e l e r a t i n g , there is s t i l l a p r e s s i n g n e e d f o r "the design of systems of care, particularly those outside the mental health sector, such as...nursing homes" ... "approaches to recognizing all forms of depression (major and subsyndromal) earlier in the clinical course", a n d  "assessment of the long-term efficacy of continuation and maintenance  SSRIs" ( L e b o w i t z et a l . , 1997).  R e l a t i v e l y f e w s t u d i e s h a v e b e e n p u b l i s h e d that f o c u s s p e c i f i c a l l y o n d e p r e s s i o n i n l o n g t e r m c a r e patients. H o w e v e r , d a t a f r o m p r i m a r y c a r e a n d s p e c i a l t y m e d i c a l s e r v i c e s , the s e t t i n g f o r the m a n a g e m e n t o f m o s t late l i f e d e p r e s s i o n , c a n a l s o c o n t r i b u t e to a n u n d e r s t a n d i n g o f d e p r e s s i o n i n e l d e r l y i n s t i t u t i o n a l i z e d patients. I n t h i s r e v i e w o f the literature, these s t u d i e s h a v e b e e n u t i l i z e d to d e v e l o p a n a w a r e n e s s o f i m p o r t a n t i s s u e s i n the i d e n t i f i c a t i o n , m a n a g e m e n t , a n d o u t c o m e s o f p a t i e n t s w i t h late l i f e d e p r e s s i o n . F o r the p u r p o s e o f the p r e s e n t r e s e a r c h , the t e r m elderly is a r b i t r a r i l y d e f i n e d as i n d i v i d u a l s o v e r the c h r o n o l o g i c a l age o f 65 y e a r s . T h e  term  "young-old" is u s e d to r e f e r to o l d e r a d u l t s b e t w e e n 65 a n d 74 y e a r s o f age, w h i l e "old-old"  refers to t h o s e 75 y e a r s o f age a n d o l d e r ( S a l z m a n et a l . , 1993). L a t e l i f e d e p r e s s i o n is d i a g n o s e d a c c o r d i n g to the s a m e D S M - I V c r i t e r i a u s e d to d i a g n o s i s d e p r e s s i o n i n y o u n g e r a d u l t s ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1994). I n the e l d e r l y , h o w e v e r , s t u d i e s s u g g e s t that f r o m 5 0 % to 9 0 % o f p a t i e n t s w i t h d e p r e s s i o n are u n d i a g n o s e d b y p r i m a r y c a r e p h y s i c i a n s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). T h e d i a g n o s i s o f late l i f e d e p r e s s i o n is c o m p l i c a t e d b y the p r e s e n c e o f s u b s t a n t i a l m e d i c a l  17 c o m o r b i d i t y , p a r t i c u l a r l y f o r t h o s e i n l o n g - t e r m c a r e f a c i l i t i e s ( K a t z , 1996). I n the m e d i c a l l y i l l elderly individual, s y m p t o m s o f medical illness can c o n f o u n d  the c l i n i c a l i m p o r t a n c e  of  s y m p t o m s o f d e p r e s s i o n . I n the c o g n i t i v e l y i m p a i r e d , the patient's a b i l i t y to r e c a l l a n d r e p o r t s y m p t o m s o f d e p r e s s i o n a n d to p r o v i d e h i s t o r i c a l i n f o r m a t i o n m a y b e g r e a t l y i m p a i r e d .  Thus,  d i a g n o s t i c d i f f i c u l t y c a n o c c u r i n 1) d e t e r m i n i n g w h i c h s i g n s a n d s y m p t o m s are p a r t o f the m e d i c a l i l l n e s s a n d w h i c h s i g n i f y the p r e s e n c e o f a d e p r e s s i v e d i s o r d e r , a n d 2) d e c i d i n g w h e n s y m p t o m s o f d e p r e s s i o n s h o u l d be c o n s i d e r e d e x c e s s i v e o r i n a p p r o p r i a t e i n a p e r s o n w h o  "has  g o o d r e a s o n to b e d e p r e s s e d " ( C a m e r o n , 1990). Ambulatory  e l d e r l y i n the c o m m u n i t y a v e r a g e a b o u t f o u r c h r o n i c m e d i c a l c o n d i t i o n s  ( M a y et al., 1982), w h i l e those i n l o n g - t e r m c a r e f a c i l i t i e s a v e r a g e m o r e t h a n 9 ( H a n l o n et a l , 1996; Z i m m e r et al., 1985). T h i s i s i n c o n t r a s t w i t h the d e p r e s s e d a d u l t s b e t w e e n the a g e s o f 18 a n d 64 t y p i c a l l y e n r o l l e d i n r a n d o m i z e d , c o n t r o l l e d trials o f a n t i d e p r e s s a n t s , w h o are u s u a l l y e x c l u d e d i f t h e y h a v e a " c l i n i c a l l y s i g n i f i c a n t m e d i c a l i l l n e s s " ( W e r n i c k e et al., 1987). C o m o r b i d m e d i c a l i l l n e s s m a y c a u s e o r c o n t r i b u t e to d e p r e s s i o n b y v a r i o u s b i o l o g i c a l , p s y c h o l o g i c a l a n d p s y c h o s o c i a l m e c h a n i s m s ( K a t z , 1996; L y n e s s et al., 1996).  Medical  d i s o r d e r s , i n c l u d i n g c a r d i o v a s c u l a r disease, r e n a l disease, n e u r o l o g i c disease, t h y r o i d disease, a d r e n a l disease, m a l i g n a n c i e s , a n d v i t a m i n B12 d e f i c i e n c y h a v e b e e n i m p l i c a t e d i n the o n s e t o f late life d e p r e s s i o n ( B a n , 1984; K o e n i g et al., 1988). I n a d d i t i o n , r e s e a r c h i n t o r e l a t i o n b e t w e e n d e p r e s s i o n , h e a l t h status, a n d f u n c t i o n a l i m p a i r m e n t h a v e d e m o n s t r a t e d that d e p r e s s i o n c a n l e a d to i n c r e a s e d d i s a b i l i t y f o r p a t i e n t s w i t h stroke, m y o c a r d i a l i n f a r c t i o n , c h r o n i c o b s t r u c t i v e p u l m o n a r y disease, h i p f r a c t u r e , Parkinson's D i s e a s e a n d arthritis ( K a t z , 1996). I n the l o n g - t e r m care setting, K a t z a n d c o w o r k e r s h a v e r a i s e d q u e s t i o n s a b o u t w h e t h e r there are d e p r e s s i v e s u b s y n d r o m e s a s s o c i a t e d w i t h " f a i l u r e to t h r i v e " that c o u l d b e a d i r e c t e f f e c t o f s u b n u t r i t i o n o r stresses a s s o c i a t e d w i t h c h r o n i c i l l n e s s a n d s e l f - c a r e d e f i c i t s ( K a t z et al., 1990; S t r e i m et al., 1997). I n a r e v i e w o f the r e l a t i o n b e t w e e n age a n d d e p r e s s i o n , B l a z e r ( B l a z e r , 1994) c o m m e n t e d  18 o n data that r e v e a l e d a 3 0 % i n c r e a s e i n d e p r e s s i v e s y m p t o m s i n t h o s e o v e r 85 y e a r s o f age. A f t e r c o n t r o l l i n g f o r f a c t o r s r e l a t e d t o c o m o r b i d p h y s i c a l illness, h o w e v e r , t h i s a g e r e l a t i o n w a s no longer significant. C o m p l e x multiple drug regimens are often prescribed for elderly individuals with m a n y c h r o n i c m e d i c a l c o n d i t i o n s , i n c r e a s i n g t h e r i s k o f d r u g - i n d u c e d d e p r e s s i o n ( G a n z i n i et al., 1993; P a t t e n et al., 1997). O l d e r adults i n t h e c o m m u n i t y , f o r e x a m p l e , u s e a b o u t 3 t o 6 m e d i c a t i o n s d a i l y ( B l o o m et al., 1993; M a y et al., 1982), a n d those i n l o n g - t e r m c a r e f a c i l i t i e s a v e r a g e b e t w e e n 9 a n d 10 ( T o b i a s et al., 1997; Z i m m e r et al., 1985). T h e u s e o f m u l t i p l e  concomitant  d r u g s a l s o i n c r e a s e s t h e l i k e l i h o o d o f d r u g i n t e r a c t i o n s , w h i c h m a y c o n t r i b u t e to d e p r e s s i o n , d e p r e s s i o n - l i k e s y m p t o m s o r c o g n i t i v e d y s f u n c t i o n ( W i l l i a m s - R u s s o , 1996). S e v e r a l p a t i e n t - r e l a t e d f a c t o r s c o m p l i c a t e t h e r e c o g n i t i o n a n d d i a g n o s i s o f geriatric d e p r e s s i o n b y p r i m a r y care p h y s i c i a n s .  F o r o l d e r patients, there m a y b e a greater s t i g m a  associated with a diagnosis o f mental illness than with y o u n g e r adults (Williams-Russo,  1996).  T h i s r e l u c t a n c e o f the e l d e r l y to a d m i t t o p s y c h o l o g i c a l s y m p t o m s f r e q u e n t l y r e s u l t s i n a m a s k e d presentation o f depression, with somatic complaints o f persistent p h y s i c a l s y m p t o m s including l a c k o f appetite, i n s o m n i a , p a i n , a n d a n x i e t y ( B a n , 1984; P a r m e l e e et al., 1 9 9 1 a ; S m a l l , 1991). Concurrent medical illness m a y confound the diagnosis o f depression b y focussing the attention o f the p h y s i c i a n a n d patients o n m e d i c a l rather t h a n p s y c h o l o g i c a l s y m p t o m s ( L e b o w i t z , 1996; N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992). T h e b e l i e f o f the patient, f a m i l y m e m b e r s a n d p h y s i c i a n that d e p r e s s i v e s y m p t o m s a r e a n o r m a l c o n s e q u e n c e o f a g i n g m a y a l s o r e s u l t i n t h e u n d e r d i a g n o s i s o f patients w i t h less s e v e r e d e p r e s s i v e i l l n e s s ( K a n o w s k i , 1994; N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992). W o m e n a r e m o r e l i k e l y t h a n m e n t o r e p o r t s y m p t o m s o f d e p r e s s i o n o r p o o r e r m e n t a l h e a l t h f u n c t i o n , after a d j u s t m e n t f o r p h y s i c a l a n d d e m o g r a p h i c f a c t o r s ( W e l l s et al., 1989); a n d e t h n i c i t y , c u l t u r a l  19 factors, a n d l i m i t e d v e r b a l s k i l l s m a y a l s o c o n f o u n d r e c o g n i t i o n a n d a p p r o p r i a t e treatment o f d e p r e s s i o n ( W i l l i a m s - R u s s o , 1996). N u m e r o u s physician-related factors have been associated with the underdiagnosis o f d e p r e s s i o n i n o l d e r adults. T h e d i f f e r e n t i a t i o n o f d e p r e s s i o n f r o m d e m e n t i a i s o f t e n d i f f i c u l t , s i n c e the d i s o r d e r s f r e q u e n t l y c o e x i s t , a n d m a n y o f t h e s y m p t o m s i n c l u d i n g m e m o r y i m p a i r m e n t , l a c k o f interest, distractibility, a n d d e p r e s s e d a n d irritable m o o d o v e r l a p ( B u r k e , 1996; Y e s a v a g e , 1993). W i n s t e a d ( W i n s t e a d et al., 1990), f o r e x a m p l e , h a s e s t i m a t e d that m o r e t h a n 2 5 % o f elderly patients with dementia m a y initially b e misdiagnosed  as h a v i n g d e p r e s s i o n . C o r r e c t l y  distinguishing irreversible dementia from the dementia o f depression is m o s t difficult w h e n the impairments  a r e m i l d ( J o n e s et al., 1994). I n f o r m a t i o n o n d e p r e s s i o n - r e l a t e d s y m p t o m s f r o m  family members a n d caregivers m a y be particularly helpful w h e n m a k i n g a diagnosis i n c o g n i t i v e l y i m p a i r e d o l d e r adults, w h o m a y b e u n a b l e t o g i v e a n a c c u r a t e h i s t o r y , u n d e r s t a n d questions posed b y the physician, or recall s y m p t o m s o f depression (Williams-Russo,  1996;  Z i s o o k , 1996). T h e d i f f e r e n t i a t i o n o f b e r e a v e m e n t f r o m m a j o r d e p r e s s i o n m a y a l s o b e d i f f i c u l t i n the e l d e r l y , p a r t i c u l a r l y after t h e d e a t h o f a s p o u s e ( B u r k e , 1996). O t h e r p h y s i c i a n - r e l a t e d r e a s o n s a r e a l s o c i t e d as c o n t r i b u t i n g t o the u n d e r d i a g n o s i s o f d e p r e s s i o n i n o l d e r adults. T h e s e i n c l u d e l a c k o f r e c o g n i t i o n o f the i n c r e a s e d m e d i c a l m o r b i d i t y a n d m o r t a l i t y a s s o c i a t e d w i t h d e p r e s s i o n ( W i l l i a m s - R u s s o , 1996), p o o r p r o f e s s i o n a l s c h o o l e d u c a t i o n a b o u t d e p r e s s i o n , l i m i t e d t r a i n i n g i n i n t e r p e r s o n a l skills, i n a d e q u a t e t i m e t o e v a l u a t e d e p r e s s i o n ( H i r s c h f e l d et al., 1997), a n d a n a s s u m p t i o n that e l d e r l y patients w i l l n o t r e s p o n d to treatment ( F o r d et al., 1980). In t h e e l d e r l y , d e p r e s s i o n i s c o n s i d e r e d t o b e c o m p r i s e d o f a h e t e r o g e n e o u s g r o u p o f d i s o r d e r s that h a v e d i s t i n c t i v e c l i n i c a l a n d b i o l o g i c a l patterns ( A b r a m s et al., 1994). T h e onset o f d e p r e s s i o n i n the e l d e r l y is o f t e n d i f f e r e n t i a t e d i n t o " e a r l y - o n s e t " o r "late-onset" ( L e b o w i t z et al., 1997). E a r l y - o n s e t d e p r e s s i o n i s d i a g n o s e d w h e n the first e p i s o d e o f d e p r e s s i o n o c c u r s b e f o r e 60 y e a r s o f age, w h i l e late-onset r e f e r s t o the i n i t i a l onset o f d e p r e s s i o n that o c c u r s after that t i m e  20 ( K a l a y a m et al., 1990). E a r l y - o n s e t d e p r e s s i o n a p p e a r s t o b e m o r e c l o s e l y a s s o c i a t e d w i t h a family  history o f depression  (Alexopoulos  et al., 1 9 8 8 b ) a n d  lifetime personality  p s y c h o p a t h o l o g y ( A b r a m s et al., 1994) t h a n late-onset d e p r e s s i o n . L a t e - o n s e t d e p r e s s i o n h a s been reported to have a greater association than early-onset depression w i t h age-related p h y s i o l o g i c a n d a n a t o m i c c h a n g e s i n the b r a i n ( A l e x o p o u l o s et al., 1997; K r i s h n a n et al., 1996), m e d i c a l i l l n e s s ( E a s t w o o d et a l , 1986), d e l u s i o n s ( M e y e r s et al., 1986), a n d c h r o n i c c o u r s e o f the i l l n e s s ( C o n w e l l , 1996). T h e o n s e t o f d e p r e s s i o n i n e l d e r l y p a t i e n t s h a s b e e n a s s o c i a t e d w i t h subsequent development o f irreversible dementia, i n c l u d i n g Alzheimer's disease or vascular d e m e n t i a ( A l e x o p o u l o s et al., 1993). A b o u t 4 0 % o f e l d e r l y p a t i e n t s a d m i t t e d t o h o s p i t a l f o r m a j o r d e p r e s s i o n are e x p e r i e n c i n g t h e i r first e p i s o d e o f d e p r e s s i o n ( M y e r s et al., 1984). D e p r e s s i o n is o n e o f the m o s t f r e q u e n t p s y c h i a t r i c d i s o r d e r s e x p e r i e n c e d i n late l i f e , w i t h h i g h e r p r e v a l e n c e rates i n s a m p l e s o f p h y s i c a l l y i l l o r i n s t i t u t i o n a l i z e d p a t i e n t s ( B l a z e r , 1990; T a n n o c k et al., 1995).  I n a m b u l a t o r y e l d e r l y i n the c o m m u n i t y , t h e p r e v a l e n c e o f m a j o r  d e p r e s s i o n h a s b e e n e s t i m a t e d t o b e 1 % to 5 % ( B l a z e r et al., 1987; M y e r s et al., 1984), w i t h e s t i m a t e s o f m i n o r d e p r e s s i o n r a n g i n g f r o m 7 % t o 2 7 % ( B l a z e r et al., 1987). F o l l o w - u p s t u d i e s o f s a m p l e s o f e l d e r l y i n the c o m m u n i t y i n d i c a t e that u p t o 2 5 % o f t h o s e w i t h m i n o r d e p r e s s i o n d e v e l o p m a j o r d e p r e s s i o n w i t h 2 y e a r s ( W e l l s et al., 1989). I n e l d e r l y p a t i e n t s h o s p i t a l i z e d w i t h a c u t e m e d i c a l illness, the p r e v a l e n c e o f m a j o r d e p r e s s i v e d i s o r d e r i s e s t i m a t e d to r a n g e f r o m 6 % to 1 2 % , a n d f o r m i n o r d e p r e s s i o n 1 5 % t o 3 5 % ( K o e n i g et al., 1991; M a g n i et a l , 1985; R a p p et al., 1988). T h e s e p r e v a l e n c e rates f o r m a j o r a n d m i n o r d e p r e s s i o n a r e s i m i l a r t o t h o s e i n y o u n g c o m m u n i t y d w e l l i n g , outpatients, a n d m e d i c a l inpatients. T h e p r e v a l e n c e o f d e p r e s s i o n a m o n g nursing h o m e residents, however, is estimated to be considerably higher. M a j o r depression has b e e n r e p o r t e d t o b e p r e s e n t i n 1 2 % t o 2 5 % o f n o n - d e m e n t e d p a t i e n t s ( H y e r et a l , 1982; P a r m e l e e et al., 1989a; R o v n e r et a l , 1991), a n d m i n o r d e p r e s s i o n p r e s e n t i n a n a d d i t i o n a l 1 8 % t o 3 0 % ( H y e r et al., 1982; P a r m e l e e et al., 1989a; R o v n e r et al., 1991). O v e r t h e p e r i o d o f o n e year, a n  21 additional 1 3 % o f nursing h o m e patients develop major depression a n d another 1 8 % develop new depressive symptoms ( N I H Consensus Development  Panel o n Depression i n Late Life,  1992). D e p r e s s i o n h a s a l s o b e e n r e p o r t e d to o c c u r i n a b o u t 3 0 % o f n u r s i n g h o m e p a t i e n t s w i t h d e m e n t i a ( P a r m e l e e et al., 1989a; R o v n e r et al., 1989). T h e m a j o r s o c i a l a n d d e m o g r a p h i c r i s k f a c t o r s f o r d e p r e s s i o n i n the e l d e r l y are s i m i l a r to t h o s e o f y o u n g e r a g e g r o u p s : f e m a l e gender, a h i s t o r y o f d e p r e s s i v e i l l n e s s i n f i r s t - d e g r e e relatives, p r i o r e p i s o d e s o f d e p r e s s i o n ( H o r w a t h et al., 1992), r e c e n t b e r e a v e m e n t ( H a r l o w et al., 1991), p h y s i c a l d i s a b i l i t y ( W e s t et al., 1998), l a c k o f a s u p p o r t n e t w o r k ( G r e e n et al., 1992; W e s t et al., 1998), a n d m e d i c a l i l l n e s s ( L y n e s s et al., 1996).  I n the elderly, religious beliefs a n d  b e h a v i o r are p r e v a l e n t , a n d a s t r o n g i n t r i n s i c r e l i g i o u s f a i t h h a s b e e n i n v e r s e l y a s s o c i a t e d w i t h d e p r e s s i o n ( K o e n i g , 1999; K o e n i g et al., 1992a). A l t h o u g h n o c o n s e n s u s h a s y e t b e e n r e a c h e d on the relation between the development o f depression a n d length o f stay i n a long-term care f a c i l i t y ( P a r m e l e e et al., 1989a; R o v n e r et al., 1991; S n o w d o n et al., 1986), there i s s p e c u l a t i o n that there m a y b e t w o p e r i o d s o f i n c r e a s e d r i s k f o r d e p r e s s i o n ( A b r a m s et al., 1992). T h e first h i g h risk p e r i o d m a y b e shortly after admission, reflecting a reaction to lifestyle change, w h i l e the s e c o n d m a y o c c u r s o m e t i m e a f t e r t h e first y e a r o f r e s i d e n c e , i n w h i c h i n c r e a s i n g m e d i c a l i l l n e s s a n d d i s a b i l i t y m a y b e a s s o c i a t e d w i t h d e p r e s s i v e s y m p t o m s ( A b r a m s et al., 1992). T h e c o n s e q u e n c e s o f late life d e p r e s s i o n c a n b e s e r i o u s , s i n c e s y m p t o m s o f m a j o r a n d m i n o r depression lead to excess disability, cognitive impairment, increased s y m p t o m s f r o m c o m o r b i d m e d i c a l illness, a n d p h y s i o l o g i c a l d e t e r i o r a t i o n ( K a t z , 1 9 9 6 ; W i l l i a m s - R u s s o , 1996). B o t h c r o s s - s e c t i o n a l a n d l o n g i t u d i n a l s t u d i e s h a v e s u g g e s t e d that d e p r e s s i v e s y m p t o m s ( w i t h o r without unipolar depressive disorder) are associated with impairment  o f well-being and  functional ability comparable with o r worse than those o f other serious m e d i c a l conditions, i n c l u d i n g h y p e r t e n s i o n , diabetes, c o r o n a r y a r t e r y d i s e a s e , arthritis, a n d g a s t r o i n t e s t i n a l ( B r o a d h e a d et al., 1 9 9 0 ; H a y s et al., 1 9 9 5 ; W e l l s et al., 1989). O n l y p a t i e n t s w i t h a d v a n c e d  22 c o r o n a r y a r t e r y d i s e a s e a n d c o n c u r r e n t a n g i n a h a v e b e e n f o u n d to h a v e p h y s i c a l i m p a i r m e n t that e x c e e d s that o f d e p r e s s i v e i l l n e s s ( B r o a d h e a d et a l . , 1990; H a y s et a l . , 1995; W e l l s et a l . , 1989). D e p r e s s i o n i n the e l d e r l y c a n a l s o r e p r e s e n t a s u b s t a n t i a l s o u r c e o f stress a n d b u r d e n t o t h o s e w h o care for them, with detrimental effects o n the quality o f life a n d social functioning o f f a m i l y , f r i e n d s a n d c a r e g i v e r s ( H i n r i c h s e n et a l . , 1992; N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992). W h e n d e p r e s s i o n is u n d i a g n o s e d a n d u n t r e a t e d , the b u r d e n to the h e a l t h c a r e s y s t e m a n d to the i n d i v i d u a l c a n b e substantial, w i t h r e p e a t p h y s i c i a n visits, f r e q u e n t a n d u n p r o d u c t i v e l a b o r a t o r y tests, a n d h i g h l e v e l s o f c a r e r e q u i r e d f o r e v e n s i m p l e a c t i v i t i e s o f d a i l y l i v i n g ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993; K a t z , 1996). L a t e l i f e d e p r e s s i o n is a s s o c i a t e d w i t h i n c r e a s e d m o r t a l i t y i n the e l d e r l y w h e n c o m p a r e d t o n o n - d e p r e s s e d e l d e r l y i n d i v i d u a l s , e v e n w h e n deaths f r o m s u i c i d e a r e e x c l u d e d .  In the  c o m m u n i t y - b a s e d E p i d e m i o l o g i c C a t c h m e n t A r e a p r o g r a m , t h e m o r t a l i t y rate f o r p a t i e n t s 5 5 y e a r s a n d o l d e r w i t h m a j o r d e p r e s s i v e d i s o r d e r w a s f o u r t i m e s h i g h e r t h a n that o f n o n - d e p r e s s e d a g e - m a t c h e d c o n t r o l s o v e r a p e r i o d o f 15 m o n t h s ( B r u c e et al., 1989). develop symptomatic  Depressed patients  a n d fatal i s c h e m i c heart d i s e a s e at a h i g h e r rate t h a n  non-depressed  patients, a n d are m o r e l i k e l y to h a v e a r e - i n f a r c t i o n , e v e n a f t e r c o n t r o l l i n g f o r the s e v e r i t y o f the patient's c a r d i a c d i s e a s e ( F r a s u r e - S m i t h et al., 1995; F r a s u r e - S m i t h et al., 1993; G l a s s m a n et al., 1998). I n n u r s i n g h o m e s , p a t i e n t s w i t h m a j o r d e p r e s s i v e d i s o r d e r ( b u t n o t t h o s e w i t h d e p r e s s i v e s y m p t o m s ) have been reported to have h a d a 5 9 % greater l i k e l i h o o d o f death w i t h i n 1 year o f a d m i s s i o n t o the f a c i l i t y t h a n d i d p a t i e n t s w i t h o u t the d i s o r d e r ( R o v n e r et a l , 1991). H o w e v e r , P a r m e l e e et a l . ( P a r m e l e e et a l . , 1992) stated that w h i l e d e p r e s s i o n w a s a s s o c i a t e d w i t h m o r t a l i t y in institutionalized elderly, the effects o f depression were "inextricable f r o m those o f physical h e a l t h a n d f u n c t i o n i n g " w h e n the d a t a w e r e c o n t r o l l e d f o r e f f e c t s o f m e d i c a l c o m o r b i d i t y . D e p r e s s i o n i s the m o s t c o m m o n f a c t o r l e a d i n g t o b o t h a t t e m p t e d a n d s u c c e s s f u l late l i f e s u i c i d e ( B l a z e r et al., 1986).  W h i l e suicide i n younger adults c a n b e attributed to several  23 p s y c h i a t r i c d i s o r d e r s , s u i c i d e i n e l d e r l y i n d i v i d u a l s is m o r e s p e c i f i c a l l y r e l a t e d to d e p r e s s i o n ( C o n w e l l , 1996). P e r s o n s 65 y e a r s a n d o l d e r c o m m i t s u i c i d e at a h i g h e r rate t h a n o t h e r age g r o u p s i n the U n i t e d States, w i t h the rate f o r e l d e r l y w h i t e m a l e s h i g h e r t h a n f o r f e m a l e s o r f o r o t h e r age o r r a c i a l g r o u p ( B l a z e r et al., 1986; N n a d i - O k o l o et al., 1995). A s m a n y as 5 0 % to 7 0 % o f s u i c i d e s i n the e l d e r l y are e s t i m a t e d to be c o m m i t t e d d i a g n o s a b l e d e p r e s s i o n ( K a t z et al., 1988).  by individuals who  have  T h e i m p o r t a n c e o f r e c o g n i z i n g d e p r e s s i o n i n the  p r i m a r y c a r e s e t t i n g i s d e m o n s t r a t e d b y r e s e a r c h f i n d i n g s that the m a j o r i t y o f e l d e r l y p a t i e n t s w h o c o m m i t s u i c i d e h a v e s e e n t h e i r p h y s i c i a n s s h o r t l y b e f o r e t h e i r d e a t h ( K a t z , 1996). A s t u d y i n v e s t i g a t i n g s u i c i d e c o m p l e t e r s o v e r the age o f 75 years, f o r e x a m p l e , n o t e d that w h i l e a b o u t 7 5 % w e r e r e p o r t e d to h a v e s e e n a p h y s i c i a n w i t h i n 1 m o n t h o f d e a t h a n d 3 5 % w i t h i n 1 w e e k , their d e p r e s s i v e d i s o r d e r g e n e r a l l y r e m a i n e d u n d i a g n o s e d a n d u n t r e a t e d ( C a i n e et al., 1996). I n the past, the p r o g n o s i s o f d e p r e s s i o n i n the e l d e r l y has n o t b e e n c o n s i d e r e d as h o p e f u l as i n y o u n g e r patients. I n 1972, a t h r e e - y e a r f o l l o w - u p s t u d y o f d e p r e s s e d g e r i a t r i c i n p a t i e n t s o n maintenance  a n t i d e p r e s s a n t t h e r a p y i n d i c a t e d that 2 6 % h a d s u s t a i n e d r e c o v e r y , 3 7 % h a d a  r e c u r r e n c e w i t h s u b s e q u e n t r e c o v e r y , 2 5 % h a d r e c u r r e n t attacks w i t h c h r o n i c m i l d s y m p t o m s , a n d 1 2 % w e r e c o n t i n u o u s l y i l l (Post, 1972). S u b s e q u e n t l y , M u r p h y ( M u r p h y , 1983) r e p o r t e d that o n l y o n e t h i r d o f a g r o u p o f 124 e l d e r l y d e p r e s s e d p a t i e n t s h a d a g o o d o u t c o m e at o n e year. T h i s l e d M i l l a r d ( M i l l a r d , 1983) to c o n c l u d e that the p r o g n o s i s o f d e p r e s s i o n i n the e l d e r l y w a s r e l a t i v e l y p o o r : " N o m a t t e r w h a t is d o n e , o n e - t h i r d get better, o n e - t h i r d stay the s a m e a n d onet h i r d get worse."  I n a r e v i e w o f t e n o r i g i n a l s t u d i e s c o n d u c t e d b e t w e e n 1955 a n d 1988 o n the  p r o g n o s i s o f d e p r e s s i o n i n the e l d e r l y , the a u t h o r e s t i m a t e d that at l e a s t 6 0 % o f the p a t i e n t s r e m a i n e d w e l l o r h a d r e l a p s e s w i t h r e c o v e r y ( m e a n f o l l o w - u p o f 31.9 m o n t h s ) , a b o u t  25%  r e m a i n e d c o n t i n u o u s l y i l l , a n d 1 5 % w e r e c a t e g o r i z e d as " o t h e r " o u t c o m e s (i.e. d i e d , r e l a p s e , lost to f o l l o w - u p , u n k n o w n a n d other) ( C o l e , 1990).  P o o r p r o g n o s i s w a s f r e q u e n t l y r e l a t e d to  p h y s i c a l illness, c o g n i t i v e i m p a i r m e n t a n d s e v e r e d e p r e s s i v e s y m p t o m s . C o l e c o n c l u d e d , " w h e n  24 o n l y the o u t c o m e s o f the studies c o n d u c t e d o v e r the past 4 0 y e a r s are c o m p a r e d there is n o e v i d e n c e that the n e w treatments i n t r o d u c e d d u r i n g this p e r i o d (e.g., a n t i d e p r e s s a n t drugs a n d e x p a n d e d p s y c h o g e r i a t r i c s e r v i c e s ) a p p r e c i a b l y c h a n g e d the p r o g n o s i s . " ( C o l e , 1990). R e s e a r c h e r s h a v e s u g g e s t e d that o u t c o m e s w i t h a n t i d e p r e s s a n t treatment m a y be s i m i l a r i n y o u n g e r a n d o l d e r adults, a l t h o u g h the t i m e to r e c o v e r y f r o m the i n d e x e p i s o d e m a y  be  s i g n i f i c a n t l y greater f o r e l d e r l y patients ( B r o d a t y et a l . , 1993). M o r e o v e r , f u l l r e c o v e r y f r o m a n e p i s o d e o f m a j o r d e p r e s s i o n f o l l o w i n g treatment m a y b e less l i k e l y i n e l d e r l y patients, w h o o f t e n h a v e d i f f i c u l t y r e t u r n i n g to t h e i r f o r m e r l i f e - s t y l e b e c a u s e o f the p r e s e n c e o f l i n g e r i n g r e s i d u a l s y m p t o m s o f d e p r e s s i o n ( B l a z e r , 1989; T u m a , 1996). T h e r e c o g n i t i o n a n d d i a g n o s i s o f d e p r e s s i o n i n late l i f e , p a r t i c u l a r l y a m o n g r e s i d e n t s o f l o n g - t e r m facilities, m a y b e m o r e d i f f i c u l t t h a n f o r y o u n g e r p a t i e n t s b e c a u s e o f the p r e s e n t a t i o n o f " m a s k e d " d e p r e s s i o n , the c o n c e r n f o r c o m o r b i d m e d i c a l c o n d i t i o n s , the p r e s e n c e o f c o g n i t i v e i m p a i r m e n t , the p e r c e i v e d s o c i a l s t i g m a o f m e n t a l h e a l t h illness, a n d the b e l i e f o f the patient, f a m i l y m e m b e r s , c a r e g i v e r s a n d the p h y s i c i a n that d e p r e s s i v e s y m p t o m s are a n o r m a l c o n s e q u e n c e o f a g i n g . T h e p r e v a l e n c e o f u n d i a g n o s e d m a j o r a n d m i n o r d e p r e s s i o n i n the l o n g t e r m c a r e setting is a c k n o w l e d g e d to b e h i g h , y e t f e w f a c i l i t y s t a f f h a v e the k n o w l e d g e , t r a i n i n g o r the t i m e to s y s t e m a t i c a l l y i d e n t i f y patients at h i g h r i s k f o r the d i s o r d e r . I n v i e w o f the s e r i o u s c o n s e q u e n c e s o f u n d i a g n o s e d , u n t r e a t e d o r i n a d e q u a t e l y treated d e p r e s s i o n o n q u a l i t y o f l i f e , f u n c t i o n a l a b i l i t y , a n d m o r t a l i t y , i n n o v a t i v e a n d e f f i c i e n t m e t h o d s o f c a s e - f i n d i n g are i n d i c a t e d to facilitate the i d e n t i f i c a t i o n a n d treatment o f d e p r e s s e d e l d e r l y i n l o n g - t e r m c a r e facilities. 1.4  INTERVENTIONS T O INCREASE T H E IDENTIFICATION AND T R E A T M E N T OF D E P R E S S I O N IN L A T E L I F E  1.4.1  Screening for depression in late life  " T o r e d u c e the b u r d e n o f d e p r e s s i o n i n the e l d e r l y , i t i s n e c e s s a r y to i n i t i a l l y detect the illness. T h i s r e q u i r e s e f f e c t i v e screening...and r e c o g n i t i o n o f the s y m p t o m s " ( H u g h e s et al., 1997)  25 S c r e e n i n g a n d c a s e - f i n d i n g are c o n s i d e r e d a p p r o p r i a t e w h e n a c o n d i t i o n i s c o m m o n a n d c a r r i e s a h i g h b u r d e n o f s u f f e r i n g ( P a t t e r s o n et al., 1999a). B o t h these c r i t e r i a are p r e s e n t i n d e p r e s s i o n i n late l i f e , p a r t i c u l a r l y a m o n g p a t i e n t s o f l o n g - t e r m c a r e facilities. F o r s c r e e n i n g a n d c a s e - f i n d i n g to b e c o n s i d e r e d e f f e c t i v e , h o w e v e r , there m u s t b e e v i d e n c e that e a r l y i d e n t i f i c a t i o n c h a n g e s the n a t u r a l h i s t o r y o f a d i s o r d e r i n a b e n e f i c i a l w a y ( P a t t e r s o n et al., 1999a).  Research  i n v o l v i n g y o u n g e r a d u l t s w i t h r e c u r r e n t d e p r e s s i o n s u g g e s t s that i d e n t i f i c a t i o n a n d treatment o f m a j o r d e p r e s s i v e d i s o r d e r i s m o r e e f f e c t i v e e a r l y i n the e p i s o d e , b e f o r e it b e c o m e s c h r o n i c ( K u p f e r et al., 1989).  S i m i l a r l y , i n i t i a t i o n o f e a r l y " h i g h i n t e n s i t y " a n t i d e p r e s s a n t treatment has  b e e n a s s o c i a t e d w i t h a s h o r t e r t i m e to r e c o v e r y i n e l d e r l y o u t p a t i e n t s ( A l e x o p o u l o s et al., 1996). N u m e r o u s r e s e a r c h e r s a n d c l i n i c i a n s h a v e c a l l e d f o r c a s e - f i n d i n g i n i t i a t i v e s to assist i n the i d e n t i f i c a t i o n a n d treatment o f d e p r e s s e d e l d e r l y , p a r t i c u l a r l y t h o s e i n l o n g - t e r m c a r e f a c i l i t i e s ( A b r a m s et al., 1992; A m e s , 1993; H u g h e s et al., 1997; N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992; T a n n o c k et al., 1995). A l t h o u g h r a n d o m i z e d , c o n t r o l l e d trials o f the i m p a c t o f c a s e - f i n d i n g i n i t i a t i v e s h a v e n o t y e t b e e n c o n d u c t e d , c a s e - f i n d i n g i n s t r u m e n t s s u i t a b l e f o r u s e i n s u c h a trial h a v e b e e n d e v e l o p e d . F o r e x a m p l e , c a s e - f i n d i n g instruments that h a v e b e e n d e v e l o p e d to i d e n t i f y d e p r e s s i v e s y m p t o m s i n p r i m a r y care c o m m u n i t y d w e l l i n g e l d e r l y i n c l u d e the G e n e r a l H e a l t h Q u e s t i o n n a i r e ( V o n K o r f f et al., 1987), the B e c k D e p r e s s i o n I n v e n t o r y ( G a l l a g h e r et al., 1983), the C e n t e r f o r E p i d e m i o l o g i c S t u d i e s - D e p r e s s i o n S c a l e ( R a d l o f f et al., 1986), the Z u n g S e l f - R a t i n g D e p r e s s i o n S c a l e ( Z u n g , 1965), the B r i e f C a r r o l D e p r e s s i o n R a t i n g S c a l e ( G e r e t y et a l , 1994b),  a n d the G e r i a t r i c D e p r e s s i o n S c a l e  (GDS)  ( Y e s a v a g e et al., 1983). H o w e v e r , m a n y o f these r a t i n g scales are n o t a p p r o p r i a t e f o r use w i t h frail, e l d e r l y l o n g - t e r m care patients ( C o u l e h a n et al., 1989; G e r e t y et al., 1994b).  O f the f o u r case-  f i n d i n g i n s t r u m e n t s that h a v e b e e n u s e d i n l o n g - t e r m c a r e f a c i l i t i e s , the G D S , the C e n t e r f o r E p i d e m i o l o g i c S t u d i e s - D e p r e s s i o n Scale, the B r i e f C a r r o l D e p r e s s i o n R a t i n g S c a l e , a n d the B e c k D e p r e s s i o n Inventory, the G D S is r e c o m m e n d e d . A d v a n t a g e s o f the G D S i n c l u d e the f o l l o w i n g :  26 the i n s t r u m e n t is brief, the yes/no f o r m a t is easy to a d m i n i s t e r a n d s i m p l e t o understand, s o m a t i c s y m p t o m s o f d e p r e s s i o n i n c l u d i n g sleep disturbances, c o n s t i p a t i o n , a n d d i s c o m f o r t o f p a i n that are c o m m o n i n n o n - d e p r e s s e d e l d e r l y are m i n i m i z e d , a n d the i n s t r u m e n t is d e s i g n e d to b e a d m i n i s t e r e d b y a l a y p e r s o n ( G e r e t y et al., 1994b; Y e s a v a g e et al., 1983). D e p r e s s i o n i n long-term care patients often coexists w i t h dementia, w h i c h frequently c o n f o u n d s the d i a g n o s i s o f o n e o r b o t h o f these d i s o r d e r s ( M e y e r s et al., 1998; P a r m e l e e et al., 1989a; P a r m e l e e et al., 1991b). T h e m o s t c o m m o n i n s t r u m e n t u s e d to assess c o g n i t i v e f u n c t i o n i n the l o n g - t e r m c a r e s e t t i n g is the M i n i - M e n t a l State E x a m ( M M S E ) ( F o l s t e i n et al., 1975). T h e G D S h a s b e e n v a l i d a t e d i n the n u r s i n g h o m e s e t t i n g w i t h a M M S E c u t - o f f o f > 15 ( M c G i v n e y et a l , 1994). B y u s i n g a two-step p r o c e d u r e o f first s e l e c t i n g p a t i e n t s w i t h M M S E s c o r e s > 15, a n d t h e n a d m i n i s t e r i n g the G D S , the r e s e a r c h e r s w e r e a b l e t o i m p r o v e the s e n s i t i v i t y a n d s p e c i f i c i t y of the case-finding instrument f o r identifying patients w i t h m a j o r a n d m i n o r depression ( M c G i v n e y et al., 1994). T h u s , the c o m b i n e d u s e o f the M M S E a n d the G D S p r o v i d e s a s i m p l e , reliable a n d valid procedure f o r rapidly identifying long-term care patients with a high probability of major a n d m i n o r depression. W e conducted a prospective pilot study to evaluate the feasibility o f developing a n efficient case-finding protocol to identify long-term care patients w i t h possible m a j o r depression w h o w o u l d b e e l i g i b l e to p a r t i c i p a t e i n a r a n d o m i z e d , c o n t r o l l e d trial ( S o o n , 1994a). T h r e e l o n g t e r m c a r e facilities w i t h a total o f 3 1 5 p a t i e n t s p a r t i c i p a t e d i n the r e s e a r c h . A two-step p r o c e d u r e w a s used, w i t h a l l c a p a b l e p a t i e n t s i n i t i a l l y a d m i n i s t e r e d the G D S b y t r a i n e d c a r e aides. O n l y t h o s e w h o e x c e e d e d the G D S c r i t e r i o n o f > 11 w e r e s u b s e q u e n t l y a d m i n i s t e r e d the M M S E b y a r e s e a r c h assistant. T h e s e steps w e r e i n t e n t i o n a l l y r e v e r s e d f r o m t h o s e o f M c G i v n e y to m i n i m i z e the t i m e r e q u i r e d o f the m o r e h i g h l y t r a i n e d r e s e a r c h assistants, w h o a d m i n i s t e r e d the M M S E . P a t i e n t s w i t h a M M S E > 19 w e r e t h e n a d m i n i s t e r e d the H A M - D , a n d t h o s e w h o m e t o r e x c e e d e d  27 the H A M - D o f > 18 w e r e i n v i t e d to p a r t i c i p a t e i n a r a n d o m i z e d trial o f f l u o x e t i n e . T h e G D S , w h i c h r e q u i r e d o n l y a b o u t 8 m i n u t e s to b e a d m i n i s t e r e d b y a c a r e aide, w a s thus u s e d a s the c a s e - f i n d i n g i n s t r u m e n t . T h e H A M - D , w h i c h r e q u i r e d a b o u t 2 2 m i n u t e s to a d m i n i s t e r b y a m o r e h i g h l y s k i l l e d c l i n i c i a n , w a s t h e n g i v e n s e l e c t i v e l y to t h o s e p a t i e n t s w h o m e t a l l the criteria f o r the trial, to d e t e r m i n e the s e v e r i t y o f d e p r e s s i o n . A M M S E s c o r e > 19, a m o r e c o n s e r v a t i v e cuto f f f o r c o g n i t i v e f u n c t i o n t h a n that d e t e r m i n e d b y M c G i v n e y , w a s s e l e c t e d to p r o v i d e g r e a t e r a s s u r a n c e that the p a t i e n t s w o u l d b e a b l e t o u n d e r s t a n d the i n f o r m e d c o n s e n t p r o c e s s . T h e s e n s i t i v i t y a n d s p e c i f i c i t y o f the G D S w a s e s t i m a t e d f o r v a r i o u s G D S s c o r e s u s i n g the H A M - D as the " g o l d s t a n d a r d " a n d a H A M - D s c o r e o f > 18 as the c u t - o f f f o r s e v e r i t y o f d e p r e s s i o n . T h e o p t i m a l G D S c r i t e r i o n f o r this s a m p l e o f l o n g - t e r m c a r e p a t i e n t s w a s d e t e r m i n e d to be > 13. G D S a n d H A M - D s c o r e s w e r e h i g h l y c o r r e l a t e d , c o n s i s t e n t w i t h the r e s u l t s o f o t h e r s t u d i e s ( F e h e r et al., 1992; Y e s a v a g e et al., 1983). E s t i m a t e s o f the p o s i t i v e p r e d i c t i v e v a l u e o f the G D S to i d e n t i f y p a t i e n t s w i t h p o s s i b l e s y m p t o m s o f m a j o r d e p r e s s i o n ( H A M - D > 18) r a n g e d f r o m a b o u t 6 0 % f o r a G D S s c o r e o f 13, to m o r e t h a n 9 0 % f o r a G D S s c o r e o f > 19. S i n c e the p r e v a l e n c e o f m a j o r d e p r e s s i o n i n the l o n g - t e r m c a r e s e t t i n g is a b o u t 1 5 % , the p o s i t i v e p r e d i c t i v e v a l u e s r e p r e s e n t e d a b o u t a 4- to 6 - f o l d i n c r e a s e o v e r the sample's b a s e rate. O f the 3 1 5 patients, 21 ( 7 % ) m e t the c r i t e r i a f o r the r a n d o m i z e d trial, a n d 17 p a t i e n t s w e r e e n r o l l e d ( 5 % ) . A l l 13 patients able t o b e administered the computerized D i a g n o s t i c Interview Schedule m e t the inclusion criteria o f D S M - I I I - R M a j o r Depression. T h e p i l o t s t u d y p r o v i d e d a v a l u a b l e o p p o r t u n i t y to e x p l o r e the a c c e p t a b i l i t y o f the casef i n d i n g p r o t o c o l , to e s t i m a t e the p o s i t i v e p r e d i c t i v e v a l u e o f the G D S , a n d to g a u g e the p o s s i b l e r e c r u i t m e n t rate f o r f u t u r e c l i n i c a l trials o f a n t i d e p r e s s a n t t r e a t m e n t i n the l o n g - t e r m c a r e setting. R e s u l t s o f the p i l o t s t u d y s u g g e s t e d that the two-step p r o c e d u r e h a s the p o t e n t i a l to b e r o u t i n e l y  28 a p p l i e d i n the l o n g - t e r m c a r e setting, a n d to b e i n c l u d e d i n the d e s i g n o f f u t u r e s t u d i e s a s s e s s i n g the i d e n t i f i c a t i o n a n d t r e a t m e n t o f d e p r e s s i o n i n the l o n g - t e r m c a r e setting. 1.4.2  Physician-targeted intervention trials  W h e n patients are identified as p o s s i b l y depressed b y a case-finding instrument, the i n f o r m a t i o n is o n l y u s e f u l i f p h y s i c i a n s e m p l o y it t o f o r m u l a t e t h e p s y c h i a t r i c d i a g n o s i s m o r e f r e q u e n t l y a n d a c c u r a t e l y ( C o u l e h a n et a l , 1 9 8 9 ) a n d p a t i e n t o u t c o m e s i m p r o v e ( K a t o n et al., 1994).  I n p r i m a r y care, w h e r e t h e p r e v a l e n c e o f d e p r e s s i o n i s r e l a t i v e l y l o w , s e v e r a l  r a n d o m i z e d , c o n t r o l l e d trials h a v e b e e n c o n d u c t e d i n a n attempt t o i m p r o v e the r e c o g n i t i o n a n d t r e a t m e n t o f d e p r e s s i o n i n a d u l t patients. S o m e s t u d i e s h a v e p r o v i d e d p h y s i c i a n s w i t h the results o f case-finding instruments to observe the effect o n the diagnosis, treatment a n d outcomes o f d e p r e s s i o n ( D o w r i c k et al., 1 9 9 5 ; L i n n et al., 1980; M o o r e et a l , 1 9 7 8 ; S h a p i r o et al., 1987), w h i l e others h a v e p r o v i d e d p h y s i c i a n s w i t h a d i a g n o s i s a n d a b r i e f treatment p r o t o c o l ( S m i t h et al., 1986). W h i l e s o m e e v i d e n c e exists that f e e d b a c k to p h y s i c i a n s i n c r e a s e s the f r e q u e n c y w i t h w h i c h they diagnose depression, m i n i m a l differences have been noted i n patient outcomes o f functional disability o r h e a l t h c a r e u t i l i z a t i o n ( D o w r i c k et al., 1995; L i n n et a l , 1984; M o o r e et al., 1978; S m i t h et al., 1986). O v e r a l l , r a n d o m i z e d trials h a v e f a i l e d to p r o v i d e adequate e v i d e n c e to s u p p o r t the u s e o f r o u t i n e c a s e - f i n d i n g instruments f o r the e a r l y d e t e c t i o n o f d e p r e s s i o n i n a d u l t p r i m a r y care patients (U.S. P r e v e n t i v e S e r v i c e s T a s k F o r c e , 1989). S o m e m u l t i f a c e t e d , i n t e n s i v e p r o g r a m s that c o m b i n e  o r g a n i z e d treatment p r o t o c o l s , s t r u c t u r e d f o l l o w - u p p r o g r a m s , a n d s y s t e m a t i c  c o m p l i a n c e m o n i t o r i n g h a v e s u c c e s s f u l l y i m p l e m e n t e d A H C P R t r e a t m e n t g u i d e l i n e s ( K a t o n et al., 1995; S c h u l b e r g et al., 1996). O t h e r less i n t e n s i v e p r o g r a m s t o i m p r o v e d e p r e s s i o n t r e a t m e n t i n a d u l t p r i m a r y c a r e p a t i e n t s h a v e n o t b e e n as s u c c e s s f u l ( G o l d b e r g et al., 1998; L i n et al., 1997). A s i n g l e r a n d o m i z e d , c o n t r o l l e d trial h a s b e e n c o n d u c t e d i n e l d e r l y patients w i t h c o m o r b i d m e d i c a l a n d p s y c h i a t r i c illness to assess the effect o f a m u l t i f a c e t e d , p h y s i c i a n - t a r g e t e d i n t e r v e n t i o n o n the r e c o g n i t i o n a n d treatment o f d e p r e s s i o n ( C a l l a h a n et al., 1994b). T h e s t u d y w a s c o n d u c t e d i n  29 a n a m b u l a t o r y care c l i n i c a s s o c i a t e d w i t h a n i n n e r - c i t y t e a c h i n g h o s p i t a l , w h e r e t e a m s o f p r i m a r y care p h y s i c i a n s w e r e r a n d o m i z e d to a c o n t r o l o r a n " i n t e r v e n t i o n " g r o u p ( C a l l a h a n et al., 1994b). Intervention p h y s i c i a n s w e r e p r o v i d e d w i t h their patient's H A M - D s c o r e a n d its interpretation, patient e d u c a t i o n materials, a n d p a t i e n t - s p e c i f i c treatment r e c o m m e n d a t i o n s d u r i n g 3 a d d i t i o n a l c l i n i c visits s c h e d u l e d s p e c i f i c a l l y to address the patient's d e p r e s s i v e s y m p t o m s . Patients o f c o n t r o l p h y s i c i a n s r e c e i v e d u s u a l care, a n d their p h y s i c i a n s d i d not r e c e i v e f e e d b a c k o n d e p r e s s i o n scores o r treatment suggestions d u r i n g the n i n e - m o n t h p e r i o d o f the study. N e a r l y h a l f o f the patients r e p o r t i n g s i g n i f i c a n t s y m p t o m s o f d e p r e s s i o n d e c l i n e d to p a r t i c i p a t e i n the study ( C a l l a h a n et al., 1996b). T h e study e n r o l l e d 100 i n t e r v e n t i o n a n d 7 5 c o n t r o l patients, w i t h a m e a n age o f 65 years, m e a n n u m b e r o f diagnoses o f 4.9, a n d a m e a n H A M - D s c o r e o f 22 ( C a l l a h a n et al., 1994b). B o t h g r o u p s o f patients c o m p l e t e d extended a s s e s s m e n t i n t e r v i e w s at baseline, 1,3,6, a n d 9 m o n t h s . A t the 6 - m o n t h assessment, a larger p r o p o r t i o n o f i n t e r v e n t i o n patients h a d a d i a g n o s i s o f d e p r e s s i o n ( 3 2 % vs 1 2 % , P = 0.002) a n d h a d b e e n n e w l y p r e s c r i b e d a n antidepressant agent ( 2 6 % v s 8 % , P = 0.01). H o w e v e r , i n t e r v e n t i o n patients w e r e not m o r e l i k e l y to h a v e h a d a target d r u g a s s o c i a t e d w i t h d e p r e s s i o n d i s c o n t i n u e d ( 2 3 % v s 2 2 % ) , o r to h a v e b e e n r e f e r r e d to m e n t a l h e a l t h s e r v i c e s ( 1 2 % vs 1 4 % ) . O f the 2 2 patients r e f e r r e d to m e n t a l h e a l t h services, o n l y 12 ( 5 5 % ) w e r e a c t u a l l y seen i n the m e n t a l h e a l t h clinic. I n addition, p h y s i c i a n s n o t e d that 1 3 % o f the patients either r e f u s e d o r h a d a c o n t r a i n d i c a t i o n to antidepressant treatment. T h e H A M - D scores d e c l i n e d i n b o t h groups, f r o m a m e a n o f 22 at b a s e l i n e to about 17 at 6 m o n t h s a n d 15 at 9 m o n t h s . T h u s , the m e a n H A M - D score d e c r e a s e d b y about 5 p o i n t s at 6 m o n t h s , a n d 7 p o i n t s at 9 m o n t h s , w h i c h w o u l d "represent o n l y a m o d e s t i m p r o v e m e n t i n c l i n i c a l s y m p t o m s " ( C a l l a h a n et al., 1994b). W h i l e b o t h the i n t e r v e n t i o n a n d c o n t r o l g r o u p s s h o w e d i m p r o v e m e n t i n m e a n H A M - D scores at 6 m o n t h s b y w i t h i n - g r o u p p a i r e d t tests (P < 0.001), there w a s n o d i f f e r e n c e b e t w e e n the g r o u p s at 6 m o n t h s . It s h o u l d b e n o t e d that due to the d e s i g n o f the study, the i n t e r v e n t i o n a n d c o n t r o l g r o u p s i n c l u d e d b o t h treated a n d untreated patients. O n l y 1 3 % o f i n t e r v e n t i o n patients a n d 1 2 % o f c o n t r o l c o u l d b e  30 c o n s i d e r e d responders, d e f i n e d as a H A M - D score o f < 10 at 6 m o n t h s . T h e r e was n o s i g n i f i c a n t i m p r o v e m e n t i n self-rated h e a l t h status S i c k n e s s I m p a c t P r o f i l e scores f o r either g r o u p at 6 m o n t h s . C a l l a h a n ( C a l l a h a n et al., 1 9 9 4 b ) s u g g e s t e d that o n e o f t h e p o s s i b l e e x p l a n a t i o n s f o r the l o w treatment r e s p o n s e rate i n the i n t e r v e n t i o n g r o u p a n d the l o w s p o n t a n e o u s r e c o v e r y rate i n the c o n t r o l g r o u p m a y h a v e b e e n the h i g h l e v e l o f c o m o r b i d m e d i c a l a n d p s y c h i a t r i c illness. O t h e r p o s s i b l e r e a s o n s i n c l u d e d the l a c k o f a n t i d e p r e s s a n t treatment o f s o m e  experimental  patients a n d the treatment o f s o m e c o n t r o l patients, a n d the r e l a t i v e l y l o w m e a n d o s e o f a n t i d e p r e s s a n t s p r e s c r i b e d (e.g. d e s i p r a m i n e  14 m g / d a y ( m e a n D D D 0 . 1 4 ) , n o r t r i p t y l i n e 41 1 =  mg/day (mean DDD=0.55). M o r e i n f o r m a t i o n is c l e a r l y n e e d e d o n the p o t e n t i a l b e n e f i t o f r o u t i n e s c r e e n i n g a n d casef i n d i n g f o r d e p r e s s i v e s y m p t o m s i n l o n g - t e r m care patients, w h o are o l d e r a n d h a v e e v e n greater f u n c t i o n a l a n d c o g n i t i v e d y s f u n c t i o n t h a n the C a l l a h a n s a m p l e o f " y o u n g - o l d "  ambulatory  p r i m a r y c a r e patients. Past r e s e a r c h i n p r i m a r y care has f o c u s e d o n i n t e r v e n t i o n s to i m p r o v e the rate o f r e c o g n i t i o n o f d e p r e s s i v e s y m p t o m s ( M o o r e et al., 1978; S c h u l b e r g et al., 1985;  Shapiro  et al., 1987; V o n K o r f f et a l , 1987). T h e s u c c e s s o f these i n t e r v e n t i o n s , h o w e v e r , relies o n the presumption  that treatment i n t e n t i o n s a n d a c t i o n s w i l l c o n s i s t e n t l y f o l l o w f r o m  physician  r e c o g n i t i o n o f d e p r e s s i v e s y m p t o m s ( C a l l a h a n et al., 1996a). T h e r e i s i n c r e a s i n g e v i d e n c e that r e c o g n i t i o n o f d e p r e s s i v e s y m p t o m s b y the p h y s i c i a n d o e s n o t n e c e s s a r i l y l e a d to a d i a g n o s i s o f d e p r e s s i o n i n the m e d i c a l chart, a n d that treatment o f d e p r e s s i o n d o e s n o t n e c e s s a r i l y f o l l o w f r o m a d i a g n o s i s ( G e r m a n et al., 1987). F u r t h e r m o r e , the l o w rate o f r e s p o n s e r e p o r t e d i n these elderly patients with c o m o r b i d  medical illness once antidepressant therapy was  initiated  ( C a l l a h a n et al., 1994a), c a l l s i n t o q u e s t i o n w h e t h e r this treatment strategy is a d e q u a t e f o r the treatment o f late l i f e d e p r e s s i o n , i n either p r i m a r y c a r e o r l o n g - t e r m c a r e patients.  31 T h u s , d a t a are c u r r e n t l y l a c k i n g to s u g g e s t that the e a r l y i d e n t i f i c a t i o n a n d treatment o f major and minor depression w o u l d improve patient outcomes or decrease health care resource u s e i n e l d e r l y p a t i e n t s m a n a g e d b y p r i m a r y c a r e p h y s i c i a n s ( C a l l a h a n et a l , 1 9 9 6 b ; K a t o n et a l . , 1994). C a l l a h a n et a l . s u g g e s t that the p h r a s e " d e p r e s s i o n o f t e n g o e s u n r e c o g n i z e d a n d u n t r e a t e d i n p r i m a r y c a r e " s h o u l d b e r e v i s e d to " p r i m a r y c a r e p h y s i c i a n s a n d t h e i r o l d e r p a t i e n t s r e m a i n f r u s t r a t e d b y the l a c k o f s c i e n t i f i c d a t a a v a i l a b l e to g u i d e the c a r e o f late-life d e p r e s s i o n " ( C a l l a h a n et al., 1996b).  I n the l o n g - t e r m c a r e setting, there is a p a u c i t y of r e s e a r c h i n this area.  T h u s , r e s e a r c h i n l o n g - t e r m c a r e facilities is u r g e n t l y n e e d e d , f i r s t to d e t e r m i n e  whether  i d e n t i f i c a t i o n o f p a t i e n t s w i l l l e a d to t r e a t m e n t o r r e f e r r a l to m e n t a l h e a l t h s e r v i c e s b y the p h y s i c i a n s , a n d then, to d e t e r m i n e t h e r a p e u t i c o u t c o m e s o v e r t i m e f o r p a t i e n t s n e w l y p r e s c r i b e d a n t i d e p r e s s a n t s a n d f o r patients w i t h o u t t r e a t m e n t f o r t h e i r d e p r e s s i v e d i s o r d e r . 1.5  T R E A T M E N T OF D E P R E S S I O N IN L A T E L I F E  1.5.1 T r e a t m e n t g u i d e l i n e s f o r d e p r e s s i o n i n l a t e l i f e O n c e a n e l d e r l y i n d i v i d u a l h a s b e e n d i a g n o s e d w i t h d e p r e s s i o n , t r e a t m e n t o f the d i s o r d e r i s r e c o m m e n d e d ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 b ; K a t z et a l . , 1988; K o e n i g , 1999).  The  C o n s e n s u s P a n e l o f D e p r e s s i o n i n L a t e L i f e has e m p h a s i z e d that " A w a i t - a n d - s e e a p p r o a c h i s n o t t e n a b l e i n m o d e r a t e a n d s e v e r e d e p r e s s i o n a n d m a y b e u n d e s i r a b l e e v e n i n m i l d cases"..."Put s i m p l y , d e p r e s s i o n c a n r u i n a person's l i f e , b u t t r e a t m e n t i s e f f e c t i v e " ( N I H  Consensus  D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992). T r e a t m e n t g u i d e l i n e s f o r e l d e r l y p a t i e n t s w i t h late l i f e d e p r e s s i o n are g e n e r a l l y s i m i l a r to t h o s e i n y o u n g e r a d u l t s . T h e r e is i n c r e a s i n g r e c o g n i t i o n , h o w e v e r , that s h o r t c o m i n g s s t i l l exist i n the c a r e o f f r a i l , e l d e r l y d e p r e s s e d p a t i e n t s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993).  Recently developed  g u i d e l i n e s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993; N I H  Consensus  Defined Daily Dose (DDD) is a technical unit of measurement established on the basis ofthe assumed mean daily dose for the drug's main indication in adults. The proportion of DDD prescribed equals the mean daily dose/DDD (World Health Organization, 1999). 1  32 D e v e l o p m e n t Panel o n Depression i n Late Life, 1992) specifically address m a n y o f the issues that c o m p l i c a t e t h e treatment o f late l i f e d e p r e s s i o n , p a r t i c u l a r l y i n r e s i d e n t s o f l o n g - t e r m care facilities. T h e g u i d e l i n e s a n d r e c e n t c o m p r e h e n s i v e  r e v i e w s o f t h e m a n a g e m e n t o f late l i f e  d e p r e s s i o n ( K a t z et a l . , 1988; M a n d o s , 1996; S m a l l , 1991; T o u r i g n y - R i v a r d , 1 9 9 7 ) a s s i s t t h e c l i n i c i a n w i t h strategies t o i d e n t i f y a n d treat f r a i l , e l d e r l y p a t i e n t s u s i n g a c o n s e r v a t i v e , s y s t e m a t i c , a n d r a t i o n a l a p p r o a c h to a n t i d e p r e s s a n t therapy. I n a d d i t i o n , there i s n o w r e c o g n i t i o n o f t h e n e c e s s i t y t o d e v e l o p treatment strategies o f d e m o n s t r a t e d e f f i c a c y n o t o n l y f o r p a t i e n t s w i t h m a j o r d e p r e s s i v e e p i s o d e s , b u t a l s o f o r p a t i e n t s w i t h less s e v e r e d e p r e s s i v e i l l n e s s ( N I H Consensus  D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992; T a n n o c k et al., 1995;  T o u r i g n y - R i v a r d , 1997). H o w e v e r , f o r m a l e v a l u a t i o n o f t h e e f f i c a c y o f s p e c i f i c treatments f o r d e p r e s s i v e s y m p t o m s i n t h e e l d e r l y is l a r g e l y l a c k i n g ( T a n n o c k et a l . , 1 9 9 5 ) T h e g u i d e l i n e s f o r late l i f e d e p r e s s i o n r e c o m m e n d a s y s t e m a t i c e v a l u a t i o n o f the p a t i e n t p r i o r to i n i t i a t i n g a n t i d e p r e s s a n t therapy. S i n c e e f f e c t i v e t r e a t m e n t d e p e n d s o n a n a c c u r a t e d i a g n o s i s ( D e p r e s s i o n G u i d e l i n e P a n e l , 1993b), t h e p r e s e n c e o r a b s e n c e o f D S M - I V c r i t e r i a (see I n t r o d u c t i o n 1.1) i n c l u d i n g d e p r e s s e d m o o d , l o s s o f i n t e r e s t i n a l m o s t a l l activities, s l e e p d i s t u r b a n c e , f a t i g u e a n d i m p a i r e d c o n c e n t r a t i o n s h o u l d b e c a r e f u l l y a s s e s s e d ( M a n d o s , 1996; S m a l l , 1991). A c o m p r e h e n s i v e m e d i c a l e v a l u a t i o n is a l s o r e c o m m e n d e d t o e n s u r e u n d e r l y i n g p h y s i c a l i l l n e s s e s that m a y b e c o n t r i b u t i n g to d e p r e s s i v e s y m p t o m s a r e i d e n t i f i e d a n d t r e a t e d i f n e c e s s a r y ( K a t z et a l . , 1988; S m a l l , 1991). F o r e x a m p l e , a m o n g p a t i e n t s d e p r e s s e d o n a d m i s s i o n to an acute care hospital, depressive s y m p t o m s resolved i n 2 8 % once they h a d recovered f r o m their p h y s i c a l i l l n e s s ( M o f f i c et a l . , 1975). T h e c o n t r i b u t i o n o f p o l y p h a r m a c y t o s y m p t o m s o f d e p r e s s i o n s h o u l d a l s o b e c o n s i d e r e d i n m e d i c a l l y i l l e l d e r l y patients, w i t h a d j u s t m e n t s d e s i g n e d t o s i m p l i f y d r u g t h e r a p y i n t r o d u c e d o n e at a t i m e ( S m a l l , 1991). P r i o r t o i n i t i a t i n g a n t i d e p r e s s a n t therapy, m e d i c a t i o n s w i t h k n o w n d e p r e s s o g e n i c e f f e c t s ( A b r a m o w i c z ,  1 9 9 8 ; P a t t e n et a l . , 1 9 9 7 )  s h o u l d b e r e p l a c e d w i t h m e d i c a t i o n s w i t h f e w e r c e n t r a l n e r v o u s s y s t e m effects, a n d t h e n u m b e r  33 o f m e d i c a t i o n s a d m i n i s t e r e d to t h e p a t i e n t s h o u l d b e m i n i m i z e d ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993).  T h e presence o f concurrent depression i n  patients w i t h d e m e n t i a s h o u l d a l s o c o n s i d e r e d , p a r t i c u l a r l y i n t h o s e w i t h a f a m i l y h i s t o r y o f d e p r e s s i o n o r a n a c u t e w o r s e n i n g o f their c o n d i t i o n ( S m a l l , 1991). W h e n c l i n i c a l s y m p t o m s s u g g e s t d e p r e s s i o n i n a n i n d i v i d u a l w i t h d e m e n t i a , a trial o f a n t i d e p r e s s a n t s s h o u l d b e c o n s i d e r e d ( J o n e s et al., 1994; P a t t e r s o n et al., 1999b). I f s y m p t o m s o f d e p r e s s i o n c o n t i n u e t o p e r s i s t i n s i t u a t i o n s o f c l i n i c a l a m b i g u i t y , K a t z et al. ( K a t z et al., 1 9 8 8 ) a d v o c a t e "when in doubt, treat." S i n c e there i s l a r g e i n t e r - i n d i v i d u a l v a r i a t i o n i n a n t i d e p r e s s a n t d o s e r e s p o n s e f o r t h e e l d e r l y ( J e n i k e , 1989), c l i n i c i a n s a r e a d v i s e d t o initiate t h e r a p y at a l o w d o s e a n d t h e n i n c r e a s e g r a d u a l l y w h i l e m o n i t o r i n g c l o s e l y f o r p o t e n t i a l d r u g - r e l a t e d p r o b l e m s ( S m a l l , 1991).  Some  researchers r e c o m m e n d starting antidepressant therapy even m o r e gradually, b y initiating a n t i d e p r e s s a n t s at " v e r y , v e r y l o w d o s e s " (e.g. sertraline 12.5 m g d a i l y f o r 1 w e e k , t h e n 2 5 m g d a i l y f o r 2 w e e k s , t h e n reassess) ( K o e n i g , 1999). T h e g u i d e l i n e s e m p h a s i z e , h o w e v e r , that l o w d o s e s s h o u l d n o t b e s u s t a i n e d i f there i s i m p r o v e m e n t o n l y i n s y m p t o m s o f s l e e p a n d a n x i e t y ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). U n i i t z e r et al. ( U n i i t z e r et al., 1 9 9 9 ) n o t e that d i a g n o s i n g d e p r e s s i o n a n d i n i t i a t i n g a c u t e - p h a s e t r e a t m e n t a l o n e i s i n a d e q u a t e , s i n c e as m a n y as 5 0 % o f patients w i l l n o t r e s p o n d t o i n i t i a l t h e r a p y o r w i l l h a v e t o c h a n g e their a n t i d e p r e s s a n t at least once.  T h e authors r e c o m m e n d active follow-up until  remission has occurred, a n d suggest the possible use o f a depression rating scale to monitor c h a n g e s o v e r t i m e ( U n i i t z e r et al., 1999). S i n c e f a i l u r e t o r e s p o n d m a y i n d i c a t e a n i n a d e q u a t e d o s e ( S m a l l , 1991), c l i n i c i a n s a r e a d v i s e d to i n c r e a s e t h e d o s e u n t i l m o o d i m p r o v e s o r s i d e e f f e c t s a r e i n t o l e r a b l e ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). A s i n y o u n g e r adults, p o o r a n t i d e p r e s s a n t c o m p l i a n c e m a y a l s o c o n t r i b u t e t o a n i n a d e q u a t e r e s p o n s e , a n d it h a s b e e n e s t i m a t e d that 7 0 % o f e l d e r l y p a t i e n t s f a i l t o t a k e 2 5 % t o 5 0 % o f their m e d i c a t i o n ( N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992).  34 T h e r a t i o n a l a p p r o a c h to the s e l e c t i o n o f a s p e c i f i c a n t i d e p r e s s a n t agent is b a s e d o n e v i d e n c e f r o m a l i m i t e d n u m b e r o f r a n d o m i z e d c l i n i c a l trials o f a n t i d e p r e s s a n t e f f i c a c y i n the elderly and clinical experience (Canadian C o u n c i l on Depression for Primary Care Physicians, 1993; N I H C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992;  Tourigny-Rivard,  1997). M a n y o f the p a t i e n t a n d d r u g - r e l a t e d f a c t o r s that n e e d to b e c o n s i d e r e d w h e n s e l e c t i n g the " o p t i m a l " a n t i d e p r e s s a n t f o r a n e l d e r l y i n d i v i d u a l are the s a m e as t h o s e f o r y o u n g e r adults (see I n t r o d u c t i o n 1.2) ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). T h u s , p a t i e n t - r e l a t e d c l i n i c a l f a c t o r s to b e c o n s i d e r e d i n c l u d e the patient's d i a g n o s t i c features, c o n c u r r e n t m e d i c a l illness, p o t e n t i a l f o r d r u g - d r u g i n t e r a c t i o n s f r o m c o n c o m i t a n t and  history o f response  to antidepressants  (Mandos,  1996;  medications,  Tourigny-Rivard,  1997).  A n t i d e p r e s s a n t - r e l a t e d f a c t o r s to b e c o n s i d e r e d i n c l u d e the s h o r t a n d l o n g - t e r m side e f f e c t p r o f i l e , a g e - r e l a t e d p h a r m a c o k i n e t i c c h a n g e s , a n d the s a f e t y o f the agent i n o v e r d o s e  (Canadian  C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). T h e c r i t i c a l f a c t o r s to be c o n s i d e r e d i n treatment s e l e c t i o n i n the e l d e r l y are s i d e e f f e c t profiles and potential overdose toxicity. A l t h o u g h prescriptions for T C A s and M A O I s continue to b e f r e q u e n t l y w r i t t e n a n d c o n t i n u e d , p o o r l y t o l e r a t e d s i d e e f f e c t s a n d d r u g i n t e r a c t i o n s complicate  t h e i r use i n e l d e r l y patients ( T o u r i g n y - R i v a r d ,  amitriptyline, imipramine)  should  be  avoided  i n the  1997). Tertiary TCAs (e.g.  elderly because o f substantial  a n t i c h o l i n e r g i c , a n t i h i s t a m i n i c a n d a l p h a - a d r e n e r g i c s i d e e f f e c t s , a n d a h i g h m o r t a l i t y rate i n o v e r d o s e s i t u a t i o n s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993). W h i l e secondary amine TCAs (e.g. n o r t i p t y l i n e , d e s i p r a m i n e ) h a v e a m o r e f a v o u r a b l e s i d e e f f e c t p r o f i l e t h a n the tertiary T C A s ( G e o r g o t a s et al., 1 9 8 9 b ; K a t z et al., 1990), m u l t i p l e s i d e e f f e c t s may  l e a d to c o m p l i c a t i o n s a n d p r e m a t u r e d i s c o n t i n u a t i o n w i t h l o n g - t e r m m a i n t e n a n c e u s e  (Tourigny-Rivard,  1997).  S i m i l a r l y , MAOIs (e.g. p h e n e l z i n e ) h a v e t r o u b l e s o m e  insomnia,  p o s t u r a l h y p o t e n s i o n , p o t e n t i a l l y fatal d r u g i n t e r a c t i o n s a n d p r o b l e m a t i c d i e t a r y r e s t r i c t i o n s that  35 l i m i t t h e i r u s e i n the e l d e r l y ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993; T o u r i g n y - R i v a r d , 1997). N e w e r antidepressants, i n c l u d i n g the SSRIs, RIMAs, SNRIs a n d trazodone, are p e r c e i v e d to h a v e m o r e f a v o r a b l e s i d e e f f e c t p r o f i l e s a n d l o w e r o v e r d o s e t o x i c i t y , thus a l l o w i n g c l i n i c i a n s to treat m a n y e l d e r l y patients w h o c o u l d n o t tolerate T C A s o r M A O I s ( T o u r i g n y - R i v a r d , 1997). T h e m o s t c o m m o n s i d e e f f e c t s o f S S R I s i n the e l d e r l y are n a u s e a , a n o r e x i a , d i a r r h e a , a n x i e t y , agitation, s e x u a l d y s f u n c t i o n , i n s o m n i a , a n d n e r v o u s n e s s ( C a n a d i a n C o u n c i l o n D e p r e s s i o n f o r P r i m a r y C a r e P h y s i c i a n s , 1993).  In a d d i t i o n , the S S R I s are less s e d a t i n g , h a v e f e w e r  a n t i c h o l i n e r g i c a n d c a r d i a c s i d e e f f e c t s , a n d l o w e r o v e r d o s e t o x i c i t y t h a n the T C A s  (American  P s y c h i a t r i c A s s o c i a t i o n , 1993). Moclobemide, venlafaxine, a n d nefazodone are w e l l t o l e r a t e d i n the e l d e r l y , are p e r c e i v e d to h a v e m o r e f a v o r a b l e s i d e e f f e c t p r o f i l e s a n d a p p e a r safe i n o v e r d o s e situations ( G i l l i s , 1999; T o u r i g n y - R i v a r d , 1997). S i n c e trazodone f r e q u e n t l y c a u s e s  drowsiness  a n d c o g n i t i v e s l o w i n g , the d r u g is o f t e n g i v e n at b e d t i m e to e l d e r l y p a t i e n t s w i t h a g i t a t e d d e p r e s s i o n ( M a n d o s , 1996). T h e g u i d e l i n e s f o r the treatment o f d e p r e s s i o n i n the e l d e r l y are p r e d i c a t e d o n the n o t i o n that a n t i d e p r e s s a n t s are e f f i c a c i o u s . T h e e f f i c a c y o f a n t i d e p r e s s a n t d r u g s has b e e n e x t e n s i v e l y e v a l u a t e d i n r a n d o m i z e d , c o n t r o l l e d trials i n adults b e t w e e n 18 a n d 65 y e a r s o f age w i t h m a j o r d e p r e s s i o n . In c o m p a r i s o n , there are r e l a t i v e l y f e w r a n d o m i z e d , c o n t r o l l e d trials o f the treatment o f m a j o r d e p r e s s i o n i n e l d e r l y patients, v e r y f e w trials w i t h p a t i e n t s o v e r 80 y e a r s o f age, a n d o n l y one trial c o n d u c t e d i n a l o n g - t e r m c a r e s e t t i n g ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1993; K a t z et a l , 1990; N I H  C o n s e n s u s D e v e l o p m e n t P a n e l o n D e p r e s s i o n i n L a t e L i f e , 1992).  M o r e o v e r , s i n c e there is a p a u c i t y o f r a n d o m i z e d , c o n t r o l l e d trials that h a v e e v a l u a t e d the treatment o f patients w i t h m i n o r d e p r e s s i o n , "there is l i t t l e k n o w n a b o u t w h a t to d o f o r t h e m " ( B r o a d h e a d et al., 1990). S i m i l a r l y , C a l l a h a n et al. ( C a l l a h a n et al., 1 9 9 6 b ) i n d i c a t e that "there is n o t a great d e a l o f l i t e r a t u r e q u a n t i f y i n g the p e r c e n t a g e o f o l d e r a d u l t s i n p r i m a r y c a r e w i t h  depressive symptoms who  36 r e q u i r e a n d c o u l d b e e x p e c t e d to r e s p o n d to c u r r e n t l y a v a i l a b l e  treatments." I n 1993, the C l i n i c a l P r a c t i c e G u i d e l i n e s f o r D e p r e s s i o n i n P r i m a r y C a r e d e v e l o p e d b y the A g e n c y f o r H e a l t h C a r e P o l i c y a n d R e s e a r c h ( D e p r e s s i o n G u i d e l i n e P a n e l , 1 9 9 3 b ) a c k n o w l e d g e d that " N e a r l y a l l r a n d o m i z e d c o n t r o l l e d treatment trials i n e l d e r l y d e p r e s s e d i n d i v i d u a l s to date h a v e b e e n c o n d u c t e d i n the o t h e r w i s e m e d i c a l l y h e a l t h y . T h e s e p a t i e n t s are n o t r e p r e s e n t a t i v e o f a l l d e p r e s s e d e l d e r l y . I n fact, o t h e r n o n p s y c h i a t r i c m e d i c a l c o n d i t i o n s are r i s k f a c t o r s f o r d e p r e s s i o n . T h u s , i n r e c o m m e n d i n g treatments, the p a n e l is assuming that t h o s e treatments e f f e c t i v e i n the d e p r e s s e d , but otherwise healthy, elderly will be effective i n those with other concurrent medical conditions." T h u s , d e s p i t e c u r r e n t r e c o g n i t i o n o f the i m p o r t a n c e o f r i g o r o u s o u t c o m e a s s e s s m e n t i n e v i d e n c e - b a s e d m e d i c i n e ( G u y a t t et al., 1 9 9 3 b ; G u y a t t et al., 1994), t r e a t m e n t g u i d e l i n e s f o r late life d e p r e s s i o n are l a r g e l y e x t r a p o l a t e d f r o m data i n y o u n g e r a d u l t s (see I n t r o d u c t i o n 1.2) a n d limited studies i n otherwise healthy older adults ( N I H C o n s e n s u s D e v e l o p m e n t Panel on D e p r e s s i o n i n L a t e L i f e , 1992; R i g l e r et al., 1998). a n t i d e p r e s s a n t t h e r a p y has b o t h e f f i c a c y A N D  N e v e r t h e l e s s , the " a s s u m p t i o n "  that  e f f e c t i v e n e s s i n the f r a i l e l d e r l y w i t h s y m p t o m s o f  d e p r e s s i o n a n d c h r o n i c m e d i c a l i l l n e s s has c o n t r i b u t e d to the p r e s c r i b i n g o f a n t i d e p r e s s a n t s to a b o u t 2 0 % o f n u r s i n g h o m e p a t i e n t s i n the U n i t e d States i n 1993 ( S i m o n s o n et a l , 1996) a n d a b o u t 2 6 % i n 1997 ( T o b i a s et al., 1997). I n B r i t i s h C o l u m b i a , a b o u t 2 0 % o f l o n g - t e r m c a r e patients w e r e p r e s c r i b e d a n t i d e p r e s s a n t s i n 1988 a n d a b o u t 2 2 % i n 1992 ( S o o n , 1994b), a n d the f r e q u e n c y o f u s e has l i k e l y i n c r e a s e d s i n c e that time. It is p a r a d o x i c a l that, at the p r e s e n t time, a b o u t 2 5 % o f l o n g - t e r m c a r e p a t i e n t s are p r e s c r i b e d a n t i d e p r e s s a n t s a n d o f those, a b o u t 8 0 % are l i k e l y b e i n g t r e a t e d f o r d e p r e s s i o n ( S i m o n s o n et al., 1996). T h e p r e v a l e n c e o f m a j o r d e p r e s s i o n i s e s t i m a t e d to 1 2 % t o 2 5 % i n l o n g - t e r m c a r e patients. Y e t c l i n i c a l w r i t e r s s u g g e s t that the d e p r e s s i o n i s u n d e r d i a g n o s e d  and  37 undertreated, a n d i n d i c a t e that e v e n m o r e patients s h o u l d b e i n i t i a t e d o n d r u g therapy, d e s p i t e v e r y l i t t l e e v i d e n c e that t h e r a p y is e f f e c t i v e , p a r t i c u l a r l y i n m i n o r d e p r e s s i o n . 1.5.2  Efficacy of antidepressants for late life depression  1.5.2.1 Efficacy of antidepressants for the treatment of major depression  W h a t is c u r r e n t l y k n o w n a b o u t the treatment o f late l i f e d e p r e s s i o n , b a s e d o n f i n d i n g s f r o m r a n d o m i z e d , c o n t r o l l e d trials? G e r s o n et a l . ( G e r s o n et a l . , 1988) r e v i e w e d 2 5 d o u b l e - b l i n d r a n d o m i z e d , c o n t r o l l e d trials c o n d u c t e d b e t w e e n 1 9 6 4 a n d 1 9 8 6 that s t u d i e d p a t i e n t s o v e r t h e age o f 5 5 y e a r s w i t h a d i a g n o s i s o f u n i p o l a r d e p r e s s i v e d i s o r d e r . A f t e r e x c l u d i n g  imipramine  a n d a m i t r i p t y l i n e b e c a u s e o f t h e i r s e r i o u s s i d e - e f f e c t s i n the e l d e r l y , t h e y r e p o r t e d that d u r i n g the 23 y e a r p e r i o d 1 9 8 patients h a d p a r t i c i p a t e d i n d o u b l e - b l i n d s t u d i e s a n d o f those, o n l y 6 0 patients h a d p a r t i c i p a t e d i n p l a c e b o - c o n t r o l l e d trials. D e s p i t e the f a c t that there w e r e o n l y 6 0 patients i n the c o n t r o l l e d , r a n d o m i z e d studies a n d n o m e t a - a n a l y s i s w a s p e r f o r m e d , t h e authors  concluded  that a n t i d e p r e s s a n t s w e r e " c l e a r l y s u p e r i o r " to p l a c e b o w i t h a b o u t a 5 0 % i m p r o v e m e n t i n H A M D s c o r e s c o m p a r e d w i t h 2 0 % t o 2 5 % f o r patients t a k i n g p l a c e b o . N o a n t i d e p r e s s a n t e m e r g e d as m o r e e f f e c t i v e t h a n others a n d e l d e r l y patients w e r e j u s t a s l i k e l y t o e x p e r i e n c e r e m i s s i o n a s y o u n g e r patients w e r e . T h e m e d i a n d r o p o u t rate w a s 1 8 % . G e r s o n et a l . ( G e r s o n et a l . , 1 9 8 8 ) c o n c l u d e d that p a r t i a l i m p r o v e m e n t m a y b e less c o m m o n a n d the f r e q u e n c y a n d s e v e r i t y o f s i d e e f f e c t s m o r e c o m m o n a m o n g the e l d e r l y . S i m i l a r c o n c l u s i o n s w e r e r e a c h e d b y R o c k w e l l et a l . ( R o c k w e l l et a l . , 1988), w h o s u g g e s t e d that t h e r a p y w a s e f f e c t i v e i n the m a n a g e m e n t o f geriatric d e p r e s s i o n w h e n t h e y c r i t i c a l l y r e v i e w e d 2 3 r a n d o m i z e d , c o n t r o l l e d trials o f a n t i d e p r e s s a n t s w i t h patients o v e r the a g e o f 6 0 years. T h e authors o f these t w o r e v i e w s n o t e d that the n u m b e r o f patients i n c l u d e d i n t h e r a n d o m i z e d , c o n t r o l l e d trials w a s s m a l l , d i a g n o s t i c c r i t e r i a a n d r a t i n g m e a s u r e s v a r i e d , o u t c o m e s w e r e d i f f i c u l t t o interpret, a n d the t e r m " e l d e r l y " r e f e r r e d t o patients as y o u n g a s i n t h e i r forties b u t s e l d o m o v e r 7 5 ( G e r s o n et a l . , 1988; R o c k w e l l et a l . , 1988). T h e  authors e m p h a s i z e d t h e u r g e n t n e e d f o r w e l l - d e s i g n e d  38 r a n d o m i z e d , c o n t r o l l e d trials o f  a n t i d e p r e s s a n t s u s e d i n the treatment o f g e r i a t r i c d e p r e s s i o n . A n s t e y a n d B r o d a t y ( A n s t e y et al., 1 9 9 5 ) s u b s e q u e n t l y  reviewed  22 double-blind  a n t i d e p r e s s a n t r a n d o m i z e d trials c o n d u c t e d b e t w e e n 1 9 8 7 a n d 1 9 9 2 that i n c l u d e d 1 7 7 4 patients o v e r the a g e o f 5 5 y e a r s w i t h a p r i m a r y d i a g n o s i s o f m a j o r o r c l i n i c a l [sic] d e p r e s s i o n . S u b j e c t s i n c l u d e d outpatients, inpatients, a m b u l a t o r y patients, a n d 3 0 T r a i l e l d e r l y ' n u r s i n g h o m e patients (see d e t a i l e d d e s c r i p t i o n b e l o w ( K a t z et al., 1990)). F o u r o f the s t u d i e s w e r e p l a c e b o - c o n t r o l l e d (313 patients), 3 o f w h i c h i n v o l v e d n o r t r i p t y l i n e . T h e l e n g t h o f the trials r a n g e d f r o m 4 t o 8 w e e k s , w i t h l o n g e r s t u d i e s r e p o r t i n g h i g h e r r e s p o n s e rates. O v e r a l l , a b o u t 2 7 % o f patients c o m m e n c i n g trials w i t h d r e w p r i o r to c o m p l e t i o n , w i t h trials o f 8 w e e k s d u r a t i o n h a v i n g d r o p o u t rates a s h i g h as 5 0 % . O f those w h o c o m p l e t e d , the m e a n r e d u c t i o n i n H A M - D s c o r e s w a s about 5 5 % f o r those o n a n t i d e p r e s s a n t s ( A n s t e y et al., 1995) a n d 1 1 % f o r t h o s e o n p l a c e b o  (Georgotas  et al., 1986; K a t z et al., 1990). N o d i f f e r e n c e s i n e f f i c a c y w e r e n o t e d b e t w e e n drugs, c o n s i s t e n t w i t h t h e p r e v i o u s i m p r e s s i o n s o f G e r s o n et a l . ( G e r s o n et al., 1988). W h i l e s i d e e f f e c t s w e r e c o m m o n , a n d a f f e c t e d 1 8 % t o 8 2 % o f patients, o n l y 5 s t u d i e s u s e d a s t r u c t u r e d s i d e - e f f e c t a s s e s s m e n t q u e s t i o n n a i r e s u c h as the U K U ( L i n g j a e r d e et al., 1987). T h e a u t h o r s n o t e d that the studies o f t e n l a c k e d statistical p o w e r , that the H A M - D w a s n o t c o n s i s t e n t l y u s e d a s a n o u t c o m e m e a s u r e , that o u t c o m e r a t i n g s o f f u n c t i o n w e r e g e n e r a l l y n o t i n c l u d e d , a n d that there w a s l a c k o f i n f o r m a t i o n o n s i d e e f f e c t s a n d reasons f o r p a t i e n t dropouts. T h e authors s t r e s s e d that: " A s l o n g a s the m a j o r antidepressants d o n o t d i f f e r i n e f f i c a c y , d e t a i l e d k n o w l e d g e o f the s i d e - e f f e c t p r o f i l e o f a n a n t i d e p r e s s a n t i n c o m b i n a t i o n w i t h the s y m p t o m s f o r w h i c h it is m o s t b e n e f i c i a l a n d c o m m o n reasons f o r w i t h d r a w a l w o u l d b e o f m o s t a s s i s t a n c e t o t h e c l i n i c i a n . U n t i l s t a n d a r d i z e d m e t h o d s o f a s s e s s i n g these three f a c t o r s are u s e d c o n s i s t e n t l y i n d o u b l e - b l i n d trials o f a n t i d e p r e s s a n t s i n the e l d e r l y , a r a t i o n a l b a s i s t o g u i d e t h e c l i n i c i a n i n m a t c h i n g treatment t o p a t i e n t a n d d e p r e s s i v e c o n d i t i o n r e m a i n s l i m i t e d . " ( A n s t e y et al., 1995). T h e o n l y r a n d o m i z e d , d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d trial f o r i n s t i t u t i o n a l i z e d e l d e r l y w a s that c o n d u c t e d b y K a t z et al. ( K a t z et al., 1990), w h o c o m p a r e d n o r t r i p t y l i n e t o p l a c e b o i n  39 3 0 f r a i l , m e d i c a l l y - i l l e l d e r l y patients. S u b j e c t s i n the trial h a d a m e a n a g e o f 84.1 years, 9 3 % w e r e f e m a l e , a n d 6 0 % l i v e d i n the n u r s i n g h o m e w h i l e 4 0 % l i v e d i n c o n g r e g a t e care. O f the 3 0 patients, 7 ( 2 3 % ) w i t h d r e w f r o m the s t u d y d u e to a d v e r s e events, r e s u l t i n g i n 12 p a t i e n t s t r e a t e d w i t h n o r t r i p t y l i n e a n d 11 w h o r e c e i v e d p l a c e b o . T h e s t u d y w a s c o n d u c t e d w i t h d o s e a d j u s t m e n t s c a l c u l a t e d to a c h i e v e n o r t r i p t y l i n e p l a s m a l e v e l s t h o u g h t to b e e f f e c t i v e i n y o u n g e r a n d h e a l t h i e r patients. C o m p a r a b l e  ( d u m m y ) dose adjustments were performed for patients treated with  placebo, b y an u n b l i n d e d psychopharmacologist who alone had access to data o n plasma levels. T h e r e s u l t s o f the 7 - w e e k s t u d y i n d i c a t e d that n o r t r i p t y l i n e w a s e f f e c t i v e i n t r e a t i n g d e p r e s s i o n c o m p a r e d to p l a c e b o (P < 0.05). B e t w e e n b a s e l i n e a n d 7 w e e k s , t r e a t e d p a t i e n t s e x p e r i e n c e d a d e c l i n e i n H A M - D s c o r e ( m e a n ± S D s ) f r o m 21.7 + 2.5 to 13.1 ± 6.7 c o m p a r e d w i t h the d e c l i n e in p l a c e b o p a t i e n t s f r o m 23.7 ± 4 . 1 to 21.2 ± 5.7. T h e r e w a s a l s o a d r u g - p l a c e b o d i f f e r e n c e i n C G I ( i m p r o v e m e n t ) as 5 8 % o f the n o r t r i p t y l i n e g r o u p , b u t o n l y 9 % o f the p l a c e b o g r o u p w e r e m u c h i m p r o v e d o r v e r y m u c h i m p r o v e d (P < 0.001). H o w e v e r , the r e d u c t i o n i n s y m p t o m s o f d e p r e s s i o n w a s n o t s i g n i f i c a n t as m e a s u r e d b y the G D S (treated: 21.2 ± 5.2 at b a s e l i n e to 13.3 ± 7.2 at 7 - w e e k s v s p l a c e b o : 21.4 ± 3.8 at b a s e l i n e to 19.2 ± 8.0 at 7-weeks). A t the c o n c l u s i o n o f the 7 - w e e k trial, t r e a t e d p a t i e n t s w e r e r e c e i v i n g a m e a n ± S D n o r t r i p t y l i n e d o s e o f 65.3 ± 24.5 mg, w h i c h is e q u i v a l e n t 0.87 ± 0.32 D D D  (see M e t h o d s 2.2.2.1). I m p r o v e m e n t s i n s y m p t o m s o f  d e p r e s s i o n w e r e n o t a s s o c i a t e d w i t h a m a j o r r e d u c t i o n i n s e l f - c a r e d i s a b i l i t y i n this setting. M e t a - a n a l y s e s o f the e f f i c a c y a n d s a f e t y o f a n t i d e p r e s s a n t s f o r m a j o r d e p r e s s i o n i n late l i f e h a v e b e e n p e r f o r m e d ( K l a w a n s k y , 1994; M c C u s k e r et a l . , 1998; M i t t m a n et a l , 1997). Klawansky  ( K l a w a n s k y , 1994) c o n d u c t e d c o m p a r i s o n s o f T C A s v e r s u s p l a c e b o a n d T C A s  v e r s u s S S R I s f o r the N I H C o n s e n s u s C o n f e r e n c e o n L a t e L i f e D e p r e s s i o n , u s i n g a s m a l l n u m b e r o f s t u d i e s p r i m a r i l y c o n d u c t e d i n p s y c h i a t r i c i n p a t i e n t s ( m e a n a g e s o f 69.0 y e a r s ) w i t h s e v e r e d e p r e s s i o n . T h e r e v i e w i n d i c a t e d that T C A s w e r e m o r e e f f i c a c i o u s t h a n p l a c e b o , a l t h o u g h  40 d r o p o u t rates (total a n d d u e t o a d v e r s e e v e n t s ) w e r e s i m i l a r . W h i l e S S R I s a n d T C A s w e r e o b s e r v e d t o b e e q u i v a l e n t i n e f f i c a c y , S S R I s h a d l o w e r d r o p o u t rates d u e t o a d v e r s e events. M i t t m a n et al. ( M i t t m a n et al., 1 9 9 7 ) r e v i e w e d 2 1 3 p u b l i c a t i o n s o f r a n d o m i z e d c o n t r o l l e d trials conducted between  1 9 6 6 a n d 1 9 9 6 that e v a l u a t e d a t y p i c a l a n t i d e p r e s s a n t s (e.g. m i a n s e r i n ,  nomifensine), R I M A s , SSRIs a n d T C A s i n moderate/severe depressed patients over 6 0 years o f a g e i n trials w i t h a d u r a t i o n o f at least f o u r w e e k s . T h e m e t a - a n a l y s i s o f s t u d i e s that m e t t h e i n c l u s i o n c r i t e r i a i n d i c a t e d n o s i g n i f i c a n t d i f f e r e n c e s a m o n g the f o u r a n t i d e p r e s s a n t c l a s s e s w i t h r e s p e c t to e f f i c a c y a n d t o l e r a b i l i t y . R e s p o n s e rates, as m e a s u r e d b y a d e c r e a s e o f > 5 0 % H A M - D score were: T C A s ( 6 3 % ) ; SSRIs ( 5 8 % ) ; R I M A (not available); atypical 3 3 % ; a n d placebo ( 2 7 % ) . T h e m e a n a n t i d e p r e s s a n t dose, a s a p r o p o r t i o n o f the D D D , that w a s s t u d i e d i n t h e r a n d o m i z e d , c o n t r o l l e d trials r a n g e d f r o m 0.2 t o 4.0 t i m e s t h e s t a n d a r d a d u l t d a i l y dose. M c C u s k e r et al. ( M c C u s k e r et al., 1 9 9 8 ) c o n d u c t e d a m e t a - a n a l y s i s o f 4 0 p r o s p e c t i v e , c o n t r o l l e d trials b e t w e e n 1 9 8 1 a n d 1 9 9 5 that f o c u s s e d o n the e f f i c a c y o f p h a r m a c o l o g i c a l a n d p s y c h o l o g i c a l treatments o f d e p r e s s i o n i n a m b u l a t o r y p a t i e n t s o v e r t h e a g e o f 5 5 y e a r s i n outpatient, c o m m u n i t y , a n d n u r s i n g h o m e settings. D r u g - p l a c e b o c o m p a r i s o n s h a d a m o d e s t m e a n posttreatment difference o f about - 6 points o n the H A M - D scale. W h e n heterocyclic a n d S S R I antidepressants were compared, they appeared to b e equally efficacious. T h e authors cautioned that, i n m a n y a m b u l a t o r y settings, t h e m o d e s t e f f e c t o n t h e s e v e r i t y o f d e p r e s s i o n w o u l d b e reduced b y poor patient compliance, presence o f chronic medical conditions, concomitant treatment w i t h other medications, a n d limited p h y s i c i a n expertise. 1.5.2.2 Efficacy of antidepressants for the treatment of minor depression  L i t t l e is k n o w n o f the e f f i c a c y o f a n t i d e p r e s s a n t s f o r t h e t r e a t m e n t o f m i n o r d e p r e s s i o n a n d s u b s y n d r o m a l d e p r e s s i v e d i s o r d e r s i n a m b u l a t o r y a n d i n s t i t u t i o n a l i z e d e l d e r l y ( K o e n i g et al., 1996; T o u r i g n y - R i v a r d , 1997). N e v e r t h e l e s s , p r i m a r y c a r e p h y s i c i a n s d i a g n o s e d e p r e s s i o n i n e l d e r l y p a t i e n t s w h o d o n o t m e e t strict D S M criteria f o r m a j o r d e p r e s s i o n o r d y s t h y m i a , a n d i n  41 m a n y cases p r e s c r i b e a n t i d e p r e s s a n t s ( B r o a d h e a d et al., 1990; G e r b e r et al., 1989). R e s e a r c h h a s n o t y e t b e e n c o n d u c t e d that w o u l d e n a b l e c l i n i c i a n s t o d i f f e r e n t i a t e b e t w e e n i n d i v i d u a l s w i t h m i n o r d e p r e s s i o n w h o w o u l d r e s p o n d t o treatment f r o m those w h o w o u l d n o t ( S n a i t h , 1987). A t the p r e s e n t time, e v i d e n c e o n t h e o p t i m a l m a n a g e m e n t o f m i n o r d e p r e s s i o n i n t h e e l d e r l y w i t h a s s o c i a t e d m e d i c a l c o m o r b i d i t y is l a c k i n g ( T a n n o c k et al., 1995). S t u d i e s c o n d u c t e d i n y o u n g e r a d u l t s ( H e l l e r s t e i n et al., 1993; P a y k e l et al., 1988; S t e w a r t et al., 1 9 9 2 ) s u p p o r t t h e c o m m e n t m a d e b y T a n n o c k a n d K a t o n a i n t h e i r r e v i e w o f m i n o r d e p r e s s i o n i n t h e a g e "that there is n o e v i d e n c e that m i l d o r m i n o r d e p r e s s i o n r e q u i r e s s m a l l e r d o s a g e s o f a n t i d e p r e s s a n t t h a n m a j o r d e p r e s s i o n " ( T a n n o c k et al., 1995). T h e i n f e r e n c e that antidepressants a r e e f f i c a c i o u s i n t r e a t i n g d e p r e s s i v e d i s o r d e r s a m o n g l o n g - t e r m c a r e patients r e q u i r e s g e n e r a l i z a t i o n o f the results o f r a n d o m i z e d , c o n t r o l l e d trials i n s p e c i a l t y a n d p r i m a r y c a r e settings t o t h e i n s t i t u t i o n a l setting. H o w e v e r , there a r e a n u m b e r o f r e a s o n s that t h e e x t e r n a l v a l i d i t y o r " g e n e r a l i z a b i l i t y " o f the r e s u l t s o f these trials t o patients i n long-term care i s questionable.  First, s i n c e t h e m a j o r i t y o f s u b j e c t s i n trials o f late life  d e p r e s s i o n h a v e b e e n acute i n p a t i e n t s i n p s y c h i a t r i c settings, t h e y r e p r e s e n t the " e x t r e m e e n d " o f the c l i n i c a l s p e c t r u m a n d a r e n o t r e p r e s e n t a t i v e o f the b r o a d r a n g e o f d e p r e s s i v e c o n d i t i o n s that o c c u r a m o n g t h e e l d e r l y ( C a i n e et al., 1993). S e c o n d , t h e e x c l u s i o n o f p a t i e n t s w i t h  comorbid  medical conditions limits generalizability, since m o s t elderly long-term care patients have o n e o r m o r e c h r o n i c m e d i c a l d i s o r d e r s that m i g h t c o n t r i b u t e t o a d e p r e s s i v e c o n d i t i o n , r e d u c e  response  to treatment, o r l e a d t o i n c r e a s e d s u s c e p t i b i l i t y t o a n t i d e p r e s s a n t s i d e e f f e c t s ( C a i n e et al., 1993; K a t o n et al., 1994). T h i r d , t h e h e a l t h care p r o f e s s i o n a l s w h o c o n d u c t i n t h e trial m a y b e u n r e p r e s e n t a t i v e o f t h e p r i m a r y care p h y s i c i a n s w h o a r e r e s p o n s i b l e f o r t h e i d e n t i f i c a t i o n , treatment  and monitoring  methodological  o f long-term  care patients ( B l a c k , 1996).  In addition, two  l i m i t a t i o n s o f m a n y o f t h e r a n d o m i z e d , c o n t r o l l e d trials r e f e r r e d t o a b o v e  u n d e r m i n e t h e g e n e r a l i z a b i l i t y o f the data: t h e p o t e n t i a l l y i n a d e q u a t e d o s a g e s o f antidepressants  42 ( M i t t m a n et al., 1997; Q u i t k i n , 1992) a n d the i n a d e q u a t e d u r a t i o n o f 4 to 6 w e e k s ' a c u t e p h a s e t r e a t m e n t ( G e o r g o t a s et al., 1989a; Q u i t k i n et al., 1986). A l t h o u g h t h r e e s t u d i e s h a v e d o c u m e n t e d the p r e v a l e n c e o f m i n o r d e p r e s s i o n i n the l o n g - t e r m c a r e s e t t i n g ( H y e r et al., 1982; L e s h e r , 1986; P a r m e l e e et al., 1989a), n o r a n d o m i z e d , c o n t r o l l e d trials o f t h e r a p e u t i c o u t c o m e s o f this d i s o r d e r h a v e y e t b e e n c o n d u c t e d . C o n s e q u e n t l y , o t h e r t h a n the s t u d y o f 23 p a t i e n t s b y K a t z et al. ( K a t z et al., 1990), there is n o d i r e c t e v i d e n c e at the p r e s e n t t i m e that a n t i d e p r e s s a n t t h e r a p y i s e f f i c a c i o u s i n the t r e a t m e n t o f m a j o r d e p r e s s i o n o r d e p r e s s i v e s y m p t o m s a m o n g s t n u r s i n g h o m e patients. 1.5.3  Effectiveness of antidepressants in late life depression  " A s t u d y o f d r u g effectiveness is a s t u d y o f whether, i n the real w o r l d , a d r u g i n fact a c h i e v e s the e f f e c t i n t e n d e d w h e n p r e s c r i b i n g it ( S t r o m , 1989). "Effectiveness i s e f f i c a c y plus p e r f o r m a n c e  u n d e r o r d i n a r y c o n d i t i o n s b y the a v e r a g e p r a c t i t i o n e r f o r t y p i c a l patients." ( S c h n e i d e r , 1996) S c h n e i d e r a n d O l i n ( S c h n e i d e r et al., 1995) h a v e n o t e d that, d e s p i t e the e v i d e n c e f o r e f f i c a c y a m o n g o l d e r a m b u l a t o r y patients, "there is v e r y l i t t l e e f f e c t i v e n e s s r e s e a r c h f o r geriatric d e p r e s s i o n treatment. T h e p r o b l e m i n g e r i a t r i c d e p r e s s i o n t r e a t m e n t is that a l o t is k n o w n a b o u t e f f i c a c y a n d l i t t l e a b o u t e f f e c t i v e n e s s , w i t h m o s t r e c o m m e n d a t i o n s m a d e to p r a c t i c i n g p h y s i c i a n s b a s e d o n e f f i c a c y trials." S i m i l a r l y , B e c k a n d K o e n i g h a v e n o t e d that "the e f f e c t i v e n e s s o f a n t i d e p r e s s a n t s ( i n m i n o r d e p r e s s i o n ) is u n k n o w n . R a n d o m i z e d c o n t r o l l e d s t u d i e s are n e c e s s a r y to d e t e r m i n e i n w h i c h patients, i f any, m e d i c a t i o n is i n d i c a t e d " ( B e c k et al., 1996). Prospective, observational, effectiveness studies can address how  a drug actually  p e r f o r m s i n c u s t o m a r y c l i n i c a l p r a c t i c e . T h i s is i n c o n t r a s t to the s h o r t - t e r m , h i g h l y c o n t r o l l e d r a n d o m i z e d c l i n i c a l trials u s e d to e s t a b l i s h d r u g e f f i c a c y u n d e r i d e a l c i r c u m s t a n c e s ( H a r t z e m a et a l . , 1987). O u t c o m e s r e s e a r c h d o c u m e n t s treatment e f f e c t i v e n e s s t h r o u g h the u s e o f e x p a n d e d d e s c r i p t i o n s o f p a t i e n t o u t c o m e s a n d n o n r a n d o m i z e d r e s e a r c h m e t h o d s ( P i c c i r i l l o , 1994). T h e c o n d u c t o f scientifically s o u n d o u t c o m e s r e s e a r c h has f o u r m e t h o d o l o g i c a l requirements: 1)  43 d i a g n o s t i c criteria f o r the disease are r e q u i r e d to insure the p r o p e r i d e n t i f i c a t i o n o f e l i g i b l e patients; 2) a n i n d e x o f c l i n i c a l s e v e r i t y is r e q u i r e d to d o c u m e n t d i f f e r e n c e s i n pretreatment c o n d i t i o n ; 3) c o m o r b i d c o n d i t i o n s that m a y affect diagnosis, treatment a n d p r o g n o s i s m u s t be d o c u m e n t e d ; a n d 4) appropriate m u l t i d i m e n s i o n a l patient o u t c o m e s m u s t be assessed ( P i c c i r i l l o , 1994). O u t c o m e s r e s e a r c h a d d r e s s e s issues o f i m p o r t a n c e to the patient. In a d d i t i o n to m e a s u r i n g c l i n i c a l a n d p h y s i o l o g i c a l e n d p o i n t s , e f f e c t i v e n e s s o u t c o m e s r e s e a r c h t y p i c a l l y e v a l u a t e the e f f e c t s o f a n i n t e r v e n t i o n o n h e a l t h - r e l a t e d q u a l i t y o f l i f e , f u n c t i o n a l status, a n d patient s a t i s f a c t i o n ( A m e r i c a n G a s t r o e n t e r o l o g i c a l A s s o c i a t i o n , 1995). O b s e r v a t i o n a l o u t c o m e s studies u s u a l l y i n c l u d e p a t i e n t - d e r i v e d data o b t a i n e d i n p r a c t i c e settings, a n d m a y  also examine  a p p r o p r i a t e n e s s o f care, c o n f o r m a n c e to r e c o m m e n d e d standards o f p e r f o r m a n c e , a n d a n a n a l y s i s o f costs o r r e s o u r c e use ( A m e r i c a n G a s t r o e n t e r o l o g i c a l A s s o c i a t i o n , 1995). B l a c k ( B l a c k , 1996) suggests that the o b s e r v a t i o n a l m e t h o d s o f o u t c o m e s r e s e a r c h a n d the e x p e r i m e n t a l m e t h o d s o f r a n d o m i z e d , c o n t r o l l e d trials s h o u l d be seen as c o m p l e m e n t a r y . H e states that o b s e r v a t i o n a l m e t h o d s c a n "generate c l i n i c a l uncertainty; generate hypotheses; i d e n t i f y the structures, processes, a n d o u t c o m e s that s h o u l d be m e a s u r e d i n a trial; a n d h e l p to e s t a b l i s h the appropriate s a m p l e s i z e f o r a r a n d o m i z e d trial." T h e c o n d u c t o f e f f e c t i v e n e s s r e s e a r c h a l s o o f f e r s the o p p o r t u n i t y to e s t a b l i s h h i g h external validity, w h i c h is d i f f i c u l t to a c h i e v e i n r a n d o m i z e d trials. N o w e l l - d e s i g n e d e f f e c t i v e n e s s studies o f antidepressant agents h a v e b e e n c o n d u c t e d i n the long-term care setting. H o w e v e r , a n open-label, non-comparative,  o b s e r v a t i o n a l , multicentre, eight-  w e e k antidepressant e f f e c t i v e n e s s study has b e e n c o n d u c t e d i n 1405 outpatients o v e r the age o f 60 years i n S p a i n ( A r r a n z et al., 1997). P s y c h i a t r i s t s p r e s c r i b e d sertraline to outpatients ( m e a n age 68 years, 6 8 % f e m a l e ) w h o h a d a D S M - I I I R d i a g n o s i s o f m a j o r d e p r e s s i o n o r d y s t h y m i c  disorder.  Patients w e r e initially p r e s c r i b e d sertraline 50 m g o n c e daily, w h i c h was i n c r e a s e d b y 50 m g / d a y at 2 - w e e k i n t e r v a l s a c c o r d i n g to patient response a n d tolerability, up to a m a x i m u m o f 200 mg/day. D e p r e s s i v e s y m p t o m s w e r e assessed b y the M o n t g o m e r y Asberg D e p r e s s i o n R a t i n g  Scale  44 ( M A D R S ) ( M o n t g o m e r y et al., 1979) at baseline, a n d w e e k s 2, 4, 6 a n d 8. P o t e n t i a l adverse drugrelated s y m p t o m s w e r e elicited b y patient i n t e r v i e w a n d i n v e s t i g a t o r o b s e r v a t i o n at e a c h visit. T h e m e a n dose o f sertraline at the final visit w a s 85.2 mg/day, a n d 4 8 % o f the patients w e r e g i v e n the initial dose o f 5 0 m g t h r o u g h o u t the study. A t the e n d o f 8 w e e k s , the m e a n p e r c e n t a g e d e c l i n e o f M A D R S f r o m b a s e l i n e w a s 6 1 % , a n d a > 5 0 % decrease i n M A D R S total s c o r e w a s o b s e r v e d i n 7 0 % o f patients. D r u g - r e l a t e d adverse events o c c u r r e d i n 2 3 % o f the patients, a n d 5 % w i t h d r e w b e c a u s e o f adverse events. H o w e v e r , the g e n e r a l i z a b i l i t y o f these results to patients i n the l o n g t e r m care setting is l i m i t e d , s i n c e patients i n the sertraline s t u d y w e r e r e l a t i v e l y y o u n g , r e l a t i v e l y ambulatory, h a d a l o w e r p r e v a l e n c e o f c o m o r b i d c o n d i t i o n s ( 7 8 % ) a n d c o n c u r r e n t m e d i c a t i o n s ( 6 8 % ) , a n d the h e a l t h care p r o f e s s i o n a l s s u p e r v i s i n g a n d m o n i t o r i n g the patients w e r e psychiatrists ( A r r a n z et al., 1997). U n f o r t u n a t e l y , m u l t i d i m e n s i o n a l p a t i e n t o u t c o m e s s u c h a s h e a l t h status, a c t i v i t i e s o f d a i l y l i v i n g a n d p h y s i c a l f u n c t i o n w e r e n o t assessed. Initial e v i d e n c e o f the e f f e c t i v e n e s s o f a n t i d e p r e s s a n t t h e r a p y i n l o n g - t e r m c a r e p a t i e n t s has b e e n s u g g e s t e d b y a m u l t i c e n t r e drug-use e v a l u a t i o n c o n d u c t e d i n 4 0 n u r s i n g facilitites i n f o u r r e g i o n s o f the U n i t e d States ( S i m o n s o n et al., 1996). O f the 3,338 patients s c r e e n e d f o r i n c l u s i o n i n the study ( m e a n a g e 81 years, 9 3 % w e r e > 6 5 y e a r s o f age, 7 8 % female), 6 5 4 ( 2 0 % ) w e r e r e c e i v i n g antidepressant therapy, a n d o f those, 5 1 1 w e r e r e c e i v i n g antidepressant m o n o t h e r a p y for a d i a g n o s i s o f d e p r e s s i o n , a n d f o r m e d the study sample. C o n s u l t a n t p h a r m a c i s t s r e t r o s p e c t i v e l y c o l l e c t e d drug-use data from t h e patients' m e d i c a l r e c o r d s at e a c h facility.  Antidepressant  m o n i t o r i n g m e t h o d s w e r e c a t e g o r i z e d as c l i n i c a l assessment ( d o c u m e n t a t i o n i n the r e s i d e n t care plan, m i n i m u m data set, o r p r o g r e s s notes about d e p r e s s i o n s y m p t o m s ) , p s y c h i a t r i c c o n s u l t a t i o n , use o f the G D S , a n d s e r u m concentrations. B a s e d o n i n f o r m a t i o n i n the m e d i c a l r e c o r d , c l i n i c a l o u t c o m e w a s d e f i n e d as i m p r o v e d symptoms), worsened  (improvement  i n symptoms), unchanged (no change i n  (worsening o f symptoms), o r undocumented i f the information was  i n c o m p l e t e . O f the 5 1 1 patients i n the sample, c l i n i c a l o u t c o m e w a s d o c u m e n t e d f o r o n l y 2 6 4  45 patients. O f those, 5 0 % w e r e c l a s s i f i e d as i m p r o v e d , 4 2 % w e r e u n c h a n g e d a n d 8 % w o r s e n e d . T h e rates o f i m p r o v e m e n t f o r i n d i v i d u a l d r u g classes w e r e 5 3 % f o r S S R I s , 5 0 % f o r trazodone, a n d 4 4 % for T C A s . A n t i d e p r e s s a n t s h a d b e e n p r e s c r i b e d f o r m o r e than f i v e m o n t h s to about h a l f o f the 511 patients i n the sample. T h e c o n c l u s i o n s that c a n be d r a w n f r o m this s t u d y are l i m i t e d , h o w e v e r , s i n c e o u t c o m e s w e r e a v a i l a b l e f o r o n l y h a l f o f the patients, a n d the o u t c o m e s that w e r e r e c o r d e d w e r e g e n e r a l l y u n v a l i d a t e d c l i n i c a l g l o b a l i m p r e s s i o n s r e c o r d e d b y f a c i l i t y staff m e m b e r s i n the m e d i c a l chart. T h e G D S  was u s e d to m o n i t o r antidepressant t h e r a p y i n o n l y about 3 % o f the  patients. S i n c e this study u s e d a c r o s s - s e c t i o n a l s a m p l e a n d r e l i e d o n r e t r o s p e c t i v e chart review, the m a g n i t u d e o f o u t c o m e s c o u l d n o t be d e t e r m i n e d , s i n c e d i a g n o s t i c c r i t e r i a f o r d e p r e s s i o n , pretreatment clinical severity, and multidimensional patient o u t c o m e s were not available. I m p o r t a n t g a p s r e m a i n i n o u r u n d e r s t a n d i n g o f the u s e f u l n e s s o f a n t i d e p r e s s a n t therapy. D e s p i t e the p r e s c r i b i n g o f a n t i d e p r e s s a n t agents to a b o u t 2 5 % o f the l o n g - t e r m care p o p u l a t i o n , authors s t i l l m a k e the case that d e p r e s s i o n is o f t e n u n r e c o g n i z e d a n d t h u s u n t r e a t e d i n the l o n g t e r m c a r e setting. O n c e p a t i e n t s are i d e n t i f i e d b y c a s e - f i n d i n g i n i t i a t i v e s , the q u e s t i o n m u s t b e r a i s e d as to w h e t h e r r o u t i n e a n t i d e p r e s s a n t t h e r a p y o f the p a t i e n t s w h o h a v e b e e n i d e n t i f i e d is t r u l y j u s t i f i e d b a s e d o n the m o d e s t i m p r o v e m e n t s i n o u t c o m e o b s e r v e d i n p r i m a r y c a r e patients. A d d i t i o n a l r e s e a r c h i s c l e a r l y n e e d e d to e v a l u a t e the e f f e c t i v e n e s s o f a n t i d e p r e s s a n t t h e r a p y i n l o n g - t e r m c a r e p a t i e n t s w i t h late life d e p r e s s i o n . T h e current p r e s u m p t i o n o f antidepressant e f f i c a c y i n the e l d e r l y a n d the frail h e a l t h status o f l o n g - t e r m care patients m i g h t cause s o m e c l i n i c i a n s to q u e s t i o n the ethics o f a r a n d o m i z e d , p l a c e b o - c o n t r o l l e d trial o f antidepressants i n this p o p u l a t i o n . T h e c o n d u c t o f a w e l l - d e s i g n e d , o b s e r v a t i o n a l s t u d y w i t h d i r e c t p a t i e n t assessment, c o n s i s t e n t d i a g n o s t i c criteria, t h o r o u g h b a s e l i n e e v a l u a t i o n o f c l i n i c a l severity, d o c u m e n t a t i o n  of  c o m o r b i d c o n d i t i o n s , a n d e v a l u a t i o n o f m u l t i d i m e n s i o n a l patient o u t c o m e s o v e r t i m e w o u l d p r o v i d e i m p o r t a n t n e w i n f o r m a t i o n o n w h i c h to base future r a n d o m i z e d , c o n t r o l l e d trials i n the long-term care setting.  46 1.6  OBJECTIVES  T h e o v e r a l l p u r p o s e o f this r e s e a r c h w a s to e v a l u a t e the i m p a c t o f a d e p r e s s i o n s c r e e n i n g p r o t o c o l o n p h y s i c i a n s ' d e c i s i o n - m a k i n g , a n d t h e n to assess the t h e r a p e u t i c o u t c o m e s o f patients n e w l y treated w i t h a n t i d e p r e s s a n t s a n d i n a s i m i l a r g r o u p o f u n t r e a t e d patients. 1.6.1  Part A : Clinical screening study  T h e primary o b j e c t i v e w a s to assess the effect o f a c l i n i c a l s c r e e n i n g p r o t o c o l o n p h y s i c i a n s ' i d e n t i f i c a t i o n a n d treatment o f depression. The secondary hypothesis-generating objectives were the following:  1) to o b t a i n a n estimate o f the p r e v a l e n c e o f s y m p t o m s o f u n t r e a t e d d e p r e s s i o n ( G D S > 13) i n l o n g - t e r m c a r e p a t i e n t s f r o m a c o h o r t o f a b o u t 1600 r e s i d e n t s o f l o n g - t e r m care facilities, 2) to o b t a i n a n estimate o f the f r e q u e n c y w i t h w h i c h p h y s i c i a n s w o u l d p r e s c r i b e a n t i d e p r e s s a n t t h e r a p y o r r e f e r to m e n t a l h e a l t h s e r v i c e s w h e n patients are i d e n t i f i e d as p o t e n t i a l l y d e p r e s s e d using a screening protocol, and 3) to i d e n t i f y patient, p h y s i c i a n , a n d f a c i l i t y c h a r a c t e r i s t i c s a s s o c i a t e d w i t h the p h y s i c i a n s ' d e c i s i o n s to p r e s c r i b e a n t i d e p r e s s a n t t h e r a p y o r refer to m e n t a l h e a l t h s e r v i c e s . 1.6.2  Part B: Therapeutic outcomes study  T h e primary o b j e c t i v e w a s t o assess therapeutic o u t c o m e s i n patients w i t h s y m p t o m s o f d e p r e s s i o n n e w l y treated w i t h antidepressants a n d a s i m i l a r g r o u p o f untreated patients. The secondary hypothesis-generating objectives were the following:  1) to o b t a i n a n e s t i m a t e o f the p r o p o r t i o n o f p o t e n t i a l l y d e p r e s s e d p a t i e n t s w h o w o u l d e x p e r i e n c e a d e c l i n e o f > 5 0 % H A M - D s c o r e b y 2 6 w e e k s , w i t h o r w i t h o u t a n t i d e p r e s s a n t therapy, 2) to o b t a i n a n estimate o f the p r o p o r t i o n o f p o t e n t i a l l y d e p r e s s e d p a t i e n t s w h o w o u l d e x p e r i e n c e a H A M - D s c o r e o f < 7 b y 2 6 w e e k s , w i t h o r w i t h o u t a n t i d e p r e s s a n t therapy, a n d 3) to d e t e r m i n e the m o r t a l i t y rate at 6 a n d 12 m o n t h s i n the p r e s e n t c r o s s - s e c t i o n a l s a m p l e o f a b o u t 1600 l o n g - t e r m care patients, w i t h o r w i t h o u t s y m p t o m s o f d e p r e s s i o n at b a s e l i n e .  47 METHODS 2.1  OVERVIEW OF THE CLINICAL OUTCOMES STUDIES  SCREENING  AND  THERAPEUTIC  T h i s c l i n i c a l r e s e a r c h w a s d e s i g n e d to evaluate a d e p r e s s i o n s c r e e n i n g p r o t o c o l that c o u l d b e u s e d to i d e n t i f y l o n g - t e r m care patients w i t h s y m p t o m s o f d e p r e s s i o n . T h e u s e f u l n e s s a n d i m p a c t o f the d e p r e s s i o n s c r e e n i n g p r o t o c o l w a s e v a l u a t e d w i t h t w o r e l a t e d studies: a t w o - p h a s e c l i n i c a l s c r e e n i n g s t u d y a n d a f o l l o w - u p therapeutic o u t c o m e s study. T h e c a s e - f i n d i n g p h a s e o f the c l i n i c a l s c r e e n i n g study u s e d a two-step d e p r e s s i o n s c r e e n i n g p r o t o c o l , i n w h i c h p a t i e n t s n o t s c r e e n e d o u t b y p e r c e i v e d cognitive impairment o r other e x c l u s i o n criteria w e r e initially administered the G e r i a t r i c D e p r e s s i o n S c a l e ( G D S ) . T h o s e p a t i e n t s w h o m e t the G D S c r i t e r i o n o f > 13 w e r e t h e n a d m i n i s t e r e d the M i n i - M e n t a l State E x a m ( M M S E ) . T h e s e c o n d p h a s e o f the c l i n i c a l s c r e e n i n g study, the eight-week r a n d o m i z e d c l i n i c a l trial phase, a s s e s s e d the effect o f the d e p r e s s i o n s c r e e n i n g p r o t o c o l o n p h y s i c i a n c l i n i c a l d e c i s i o n m a k i n g a n d response. A n i n i t i a l letter o f n o t i f i c a t i o n w a s sent to the p r i m a r y c a r e p h y s i c i a n o f e a c h p a t i e n t w h o s c o r e d 13 o r m o r e o n the G D S a n d 19 o r m o r e o n the M M S E . I n the letter, the p h y s i c i a n w a s i n f o r m e d o f the G D S a n d M M S E s c o r e s a n d p r o v i d e d w i t h a n i n t e r p r e t a t i o n o f the s c o r e s i n t e r m s o f the p o s i t i v e p r e d i c t i v e v a l u e f o r s y m p t o m s c o n s i s t e n t w i t h m a j o r d e p r e s s i v e d i s o r d e r . A s a r e m i n d e r , a f o l l o w - u p letter w a s sent to the p h y s i c i a n 4 w e e k s later. A f t e r c o m p l e t i o n o f the c l i n i c a l s c r e e n i n g study, the f o l l o w - u p 2 6 w e e k o b s e r v a t i o n a l s t u d y assessed therapeutic o u t c o m e s f o r patients w i t h s y m p t o m s o f d e p r e s s i o n w h o w e r e either n e w l y treated w i t h antidepressants o r w e r e untreated. T h e s e q u e n c e o f the c l i n i c a l s c r e e n i n g s t u d y a n d t h e therapeutic o u t c o m e s s t u d y i s o u t l i n e d i n t h e f l o w chart o f patient p a r t i c i p a t i o n i n F i g u r e 2. 2.1.1  Ethics approval  T h e Ph.D. r e s e a r c h study w a s a p p r o v e d b y the C l i n i c a l S c r e e n i n g C o m m i t t e e f o r R e s e a r c h a n d O t h e r S t u d i e s I n v o l v i n g H u m a n Subjects at the U n i v e r s i t y o f B r i t i s h C o l u m b i a , a n d the  48 Figure 2 F l o w chart o f l o n g - t e r m care patient p a r t i c i p a t i o n i n the t w o - p h a s e c l i n i c a l s c r e e n i n g  study a n d the f o l l o w - u p therapeutic o u t c o m e s study  CLINICAL SCREENING STUDY 1 i i i  Case-finding phase:  Case-finding phase:  LTC p a t i e n t s Baseline  Case-finding phase:  Case-finding phase:  LTC p a t i e n t s  LTC patients administered G D S and M M S E  excluded a s G D S < 13  o r M M S E < 19  LTC patients  m e t exclusion c r i t e r i a  Case-finding phase:  LTC patients w i t h M M S E > 19 G D S > 13  RCT  phase:  RCT  phase:  LTC p a t i e n t s g a v e informed consent physician randomization  R a n d o m i z e d clinical screening study 8 weeks  THERAPEUTIC OUTCOMES STUDY  Therapeutic outcomes study:  Therapeutic outcomes study:  N e w antidepressant therapy 6, 12 a n d 2 6 w e e k s  Observational group 26 weeks  C e r t i f i c a t e o f A p p r o v a l is attached ( A p p e n d i x 1).  49 A request f o r ethical r e v i e w w a s a l s o s u b m i t t e d  to the B e h a v i o r a l R e s e a r c h E t h i c s B o a r d at the U n i v e r s i t y o f B r i t i s h C o l u m b i a to p r o v i d e a n e v a l u a t i o n o f p h y s i c i a n r a n d o m i z a t i o n to a n e a r l y ( e x p e r i m e n t a l ) a n d a d e l a y e d ( c o n t r o l ) group. M e m b e r s o f the B e h a v i o r a l R e s e a r c h E t h i c s B o a r d felt that the f o u r - w e e k w a i t i n g p e r i o d p r i o r to n o t i f i c a t i o n o f p h y s i c i a n s i n the d e l a y e d g r o u p o f the results o f the s c r e e n i n g w a s appropriate, g i v e n the i n s i d i o u s nature o f d e p r e s s i o n a n d the n o r m a l pattern o f p h y s i c i a n visits to l o n g - t e r m care facilities. T h e C e r t i f i c a t e o f A p p r o v a l f r o m the B e h a v i o r a l R e s e a r c h E t h i c s B o a r d is attached (Appendix 2.1.2  2).  Long-term care facility approval  T h e M e d i c a t i o n A d v i s o r y C o m m i t t e e o f e a c h l o n g - t e r m care f a c i l i t y p a r t i c i p a t i n g i n the study a p p r o v e d the r e s e a r c h p r o t o c o l . T h e facility a d m i n i s t r a t o r p r o v i d e d a f o r m a l letter o f a p p r o v a l to D r . M a r c L e v i n e at the U n i v e r s i t y o f B r i t i s h C o l u m b i a ( A p p e n d i x 3), a n d g r a n t e d s t u d y p e r s o n n e l t e m p o r a r y p r i v i l e g e s as c l i n i c a l researchers f o r the d u r a t i o n o f the project. F a c i l i t y administrators a l s o i n f o r m e d the M e n t a l H e a l t h t e a m i n the C o n t i n u i n g C a r e D i v i s i o n o f the l o c a l P r o v i n c i a l H e a l t h U n i t o f t h e i r p a r t i c i p a t i o n i n the project. P r i o r to initiation o f the c a s e - f i n d i n g p h a s e o f the study, p r i m a r y care p h y s i c i a n s attending patients i n the p a r t i c i p a t i n g l o n g - t e r m care facility w e r e sent a p e r s o n a l letter d e s c r i b i n g the c l i n i c a l r e s e a r c h ( A p p e n d i x 4).  Information  p r o v i d e d to facilities a n d i n the letters to p h y s i c i a n s w a s p r o v i d e d i n s u c h a m a n n e r that the ability to assess the i m p a c t o f the p r o t o c o l o n p h y s i c i a n s ' d e c i s i o n m a k i n g w a s not c o m p r o m i s e d . P h y s i c i a n s w e r e g i v e n the o p p o r t u n i t y to request that s p e c i f i c patients not be a p p r o a c h e d to participate i n the study. T h e p h y s i c i a n s w e r e a l s o i n f o r m e d that the researchers w e r e a v a i l a b l e to a n s w e r a n y study-related q u e s t i o n s that he o r she m i g h t have. A l l patients s i g n e d a n i n f o r m e d c o n s e n t p r i o r to p a r t i c i p a t i n g i n the r a n d o m i z e d c l i n i c a l trial o r t h e r a p e u t i c o u t c o m e s study ( A p p e n d i c e s 5, 6).  50 2.2  CLINICAL SCREENING STUDY  2.2.1  PHASE A: Case-finding component A l l patients o v e r the age o f 65 y e a r s r e s i d i n g i n a p a r t i c i p a t i n g l o n g - t e r m care facility o n a  s p e c i f i e d census d a y w e r e e l i g i b l e f o r the initial c a s e - f i n d i n g p h a s e o f the s t u d y ( F i g u r e 3). A d m i n i s t r a t o r s , nurses a n d care-aides at e a c h facility w e r e o r i e n t e d to the r e s e a r c h i n a w o r k s h o p that p r o v i d e d staff w i t h sufficient i n f o r m a t i o n o n the s t u d y w i t h o u t c o m p r o m i s i n g  the results  obtained. T h e essence o f the w o r k s h o p is s u m m a r i z e d i n the i n t r o d u c t o r y letter sent to p h y s i c i a n s p r i o r to initiation o f the study ( A p p e n d i x 4). A s a c o m p o n e n t o f s c r e e n i n g , f a c i l i t y s t a f f a d v i s e d r e s e a r c h e r s w h i c h p a t i e n t s s h o u l d n o t b e a s s e s s e d o n the d e p r e s s i o n - s c r e e n i n g i n s t r u m e n t s , b a s e d o n their k n o w l e d g e o f patients' c o g n i t i v e i m p a i r m e n t o r the p r e s e n c e o f o t h e r e x c l u s i o n criteria i n the m e d i c a l chart (see M e t h o d s 2.2.1.2). E x p e r i e n c e d care-aides w e r e t r a i n e d on-site to a d m i n i s t e r the G D S  v e r b a l l y to patients i n a consistent m a n n e r , a n d to r e c o r d h i s o r h e r responses onto the  G D S form. F o u r e x p e r i e n c e d r e s e a r c h assistants s c o r e d the G D S , a n d w i t h i n 1 w e e k a d m i n i s t e r e d the M M S E to those patients w i t h a G D S score > 13. T h e r e s e a r c h assistants w e r e a w a r e o f aspects o f the study d e s i g n as d o c u m e n t e d i n the c o n s e n t form, b u t d i d n o t h a v e s u f f i c i e n t i n f o r m a t i o n that their i n v o l v e m e n t w i t h the patient w o u l d c o m p r o m i s e the results o f the study.  The research  assistants d i s c u s s e d the s t u d y w i t h the patients w h o m e t the entry criteria. T h e y o b t a i n e d the patient's s i g n e d i n f o r m e d consent after a s c e r t a i n i n g that the patient u n d e r s t o o d the p u r p o s e o f the research, was able to w e i g h the risks a n d benefits o f participation, a n d u n d e r s t o o d that he o r she c o u l d w i t h d r a w at a n y time. T h i s c a s e - f i n d i n g p h a s e o f the s t u d y h a d b e e n s u c c e s s f u l l y p i l o t e d i n p r e v i o u s r e s e a r c h i n a s i m i l a r s a m p l e o f l o n g - t e r m care patients ( S o o n , 1994a).  51 Figure 3 F l o w chart o f the c a s e - f i n d i n g p h a s e o f the c l i n i c a l s c r e e n i n g s t u d y  22 L T C f a c i l i t i e s s e l e c t e d U  Physicians and staff oriented to the c l i n i c a l s t u d y  P a t i e n t s w e r e s c r e e n e d o u t b a s e d o n e x c l u s i o n criteria i n the m e d i c a l c h a r t o r the a d v i c e o f f a c i l i t y s t a f f o f c o g n i t i v e i m p a i r m e n t o r o t h e r e x c l u s i o n criteria  u  C a r e a i d e s a d m i n i s t e r e d the G D S to r e m a i n i n g p a t i e n t s  u R e s e a r c h assistants a d m i n i s t e r e d the M M S E to p a t i e n t s w i t h G D S s c o r e > 13  I f G D S s c o r e > 13 a n d M M S E s c o r e > 19, t h e n the p a t i e n t m e t e n t r y c r i t e r i a for the r a n d o m i z e d c l i n i c a l trial  u Informed consent was obtained P a t i e n t e n r o l l e d i n the r a n d o m i z e d c l i n i c a l trial  u P a t i e n t a s s i g n e d to e a r l y o r d e l a y e d g r o u p b a s e d o n p h y s i c i a n r a n d o m i z a t i o n  52 2.2.1.1 Study sample  T h e s t u d y s a m p l e c h o s e n to investigate the d e p r e s s i o n s c r e e n i n g p r o t o c o l w a s c o m p r i s e d o f 2  3  patients r e s i d i n g i n i n t e r m e d i a t e a n d m u l t i - l e v e l l o n g - t e r m care facilities i n s o u t h w e s t B r i t i s h C o l u m b i a . A s d e t a i l e d i n M e t h o d s 2.2.2.5.3, w e e s t i m a t e d that it w a s n e c e s s a r y to e n r o l l 100 patients i n the r a n d o m i z e d c l i n i c a l trial, b a s e d o n the s a m p l e s i z e c a l c u l a t i o n s f o r the p r i m a r y o u t c o m e . I n p r e v i o u s r e s e a r c h , w e r e p o r t e d that s c r e e n i n g 3 1 5 l o n g - t e r m care p a t i e n t s f o r d e p r e s s i o n r e s u l t e d i n the i d e n t i f i c a t i o n o f a b o u t 2 0 p a t i e n t s w h o m e t e n t r y c r i t e r i a s i m i l a r to t h o s e o f the p r e s e n t s t u d y ( S o o n , 1994a). T h e r e f o r e , w e e s t i m a t e d that at least 1575 l o n g - t e r m care p a t i e n t s w o u l d b e n e e d e d to p a r t i c i p a t e i n the c a s e - f i n d i n g p h a s e o f the s t u d y to a c h i e v e a n e n r o l m e n t o f 100 p a t i e n t s i n t o the r a n d o m i z e d c l i n i c a l trial. T o ensure that the n u r s i n g h o m e s r e p r e s e n t e d t y p i c a l geriatric facilities w i t h r e g i s t e r e d n u r s i n g staff, f a c i l i t y e n t r y criteria w e r e s i m i l a r to those u s e d b y B e e r s et al. ( B e e r s et al., 1988). F a c i l i t i e s w i t h f e w e r t h a n 34 a n d m o r e t h a n 150 i n t e r m e d i a t e - c a r e b e d s w e r e e x c l u d e d , as w e r e those w i t h m o r e t h a n 2 0 % o f their patients a d m i t t e d f r o m tertiary-referral p s y c h i a t r i c hospitals. F a c i l i t i e s i n the city o f V a n c o u v e r w e r e e x c l u d e d , s i n c e m a n y o f t h o s e l o n g - t e r m care facilities a c t i v e l y p a r t i c i p a t e i n u n i v e r s i t y - b a s e d a c a d e m i c r e s e a r c h a n d as t e a c h i n g sites f o r h e a l t h p r o f e s s i o n a l s . Patients r e s i d i n g i n d e s i g n a t e d A l z h e i m e r ' s U n i t s a n d i n short-term respite accommodation were also excluded. T w e n t y - t w o l o n g - t e r m care f a c i l i t i e s w i t h 1602 p a t i e n t s p a r t i c i p a t e d i n the c a s e - f i n d i n g p h a s e o f the study. T h e s u p e r v i s o r a n d s t u d y i n v e s t i g a t o r s e l e c t e d f a c i l i t i e s b a s e d o n their a b i l i t y to m e e t the s t u d y c r i t e r i a o f f a c i l i t y size, s o u r c e o f patients, a n d g e o g r a p h i c a l l o c a t i o n . F a c i l i t i e s intermediate-care (IC) facilities provide continuous supervision by non-professional personnel with individual professional/ non-professional attention ranging from 75 minutes/day for IC 1 to 120 minutes/day for IC 3 (British Columbia Ministry of Health and Ministry Responsible for Seniors, 1999). 2  multi-level care facilities admit individuals requiring intermediate-care and those requiring more than 120 minutes/day of individual professional and non-professional attention (British Columbia Ministry of Health and Ministry Responsible for Seniors, 1999). 3  f r o m 11 d i f f e r e n t c o m m u n i t i e s  53 i n s o u t h - w e s t e r n B r i t i s h C o l u m b i a p a r t i c i p a t e d i n the p r o j e c t :  Abbotsford, Aldergrove, Burnaby, Chilliwack, Delta, Langley, M a p l e Ridge, Mission, Port Coquitlam, Surrey, and W h i t e Rock. T o m i n i m i z e overlap w h e n m o r e than 1 facility  was  e n r o l l e d i n a c o m m u n i t y , the facilities w e r e n o t e n r o l l e d s e q u e n t i a l l y . D e p e n d i n g o n the l o c a l p o p u l a t i o n o f the area, 1 to 4 facilities i n a s p e c i f i c c o m m u n i t y p a r t i c i p a t e d i n the study. A p a t i e n t c o u l d be e n r o l l e d o n l y once, at the first f a c i l i t y i n w h i c h h e o r she w a s p r e s e n t o n c e n s u s day. P a t i e n t s w e r e g e n e r a l l y a d m i t t e d to the facilities f r o m the s u r r o u n d i n g c o m m u n i t i e s ,  which  were predominantly white and middle-class. T h e 22 s t u d y facilities i n c l u d e d 9 % o f the l i c e n s e d l o n g - t e r m care b e d s i n the p r o v i n c e ( T a b l e 1). F o u r t e e n d i f f e r e n t p h a r m a c y p r o v i d e r s , r e p r e s e n t i n g 1 2 % o f l o n g - t e r m care p h a r m a c y s u p p l i e r s i n the p r o v i n c e , s e r v i c e d the p a r t i c i p a t i n g f a c i l i t i e s . T h e p h a r m a c i e s p r o v i d i n g the 4  long-term  care s e r v i c e s i n c l u d e d 3 i n d e p e n d e n t  c o m m u n i t y pharmacies,  2  independent  p h a r m a c i e s s p e c i a l i z i n g i n l o n g - t e r m care, 4 f r a n c h i s e c h a i n p h a r m a c i e s , a n d 6 c o r p o r a t e c h a i n pharmacies.  Study facilities were representative o f British C o l u m b i a facilities i n general with  r e g a r d to t y p e o f f a c i l i t y ( 9 1 % i n t e r m e d i a t e - c a r e , 9 % m u l t i - l e v e l care), a c c r e d i t a t i o n status ( 1 4 % accredited), pattern o f ownership ( 4 4 % for-profit corporations), and m e a n ± S D n u m b e r o f beds 73 ± 32. T h e r e w a s a m e a n ± S D o f 29.8 ± 9.8 a t t e n d i n g p r i m a r y c a r e p h y s i c i a n s p e r l o n g - t e r m care f a c i l i t y e n r o l l e d i n the study. 2.2.1.2 Exclusion and inclusion criteria  E l i g i b i l i t y c r i t e r i a f o r p a r t i c i p a t i o n i n the r a n d o m i z e d provide a sample o f patients who  c l i n i c a l t r i a l w e r e d e s i g n e d to  w o u l d b e g e n e r a l l y r e p r e s e n t a t i v e o f m i l d to m o d e r a t e l y  d e p r e s s e d e l d e r l y i n d i v i d u a l s i n the l o n g - t e r m care p o p u l a t i o n w h o w e r e n o t b e i n g t r e a t e d f o r  In British Columbia, pharmacy services to a long-term care facility are supplied by a single community pharmacy, which is reimbursed by B.C. Pharmacare for prescription costs and a per diem based on number of beds serviced. 4  Table 1  D e m o g r a p h i c c h a r a c t e r i s t i c s o f the 2 2 l o n g - t e r m c a r e f a c i l i t i e s i n s o u t h w e s t B r i t i s h C o l u m b i a that p a r t i c i p a t e d i n the c l i n i c a l s c r e e n i n g a n d t h e r a p e u t i c o u t c o m e s studies  D e m o g r a p h i c c h a r a c t e r i s t i c s o f L T C facilities  N u m b e r in study (%)  N u m b e r o f f a c i l i t i e s w i t h > 33 L T C b e d s N u m b e r o f p h a r m a c i e s s e r v i c i n g > 33 L T C b e d s N u m b e r of licensed L T C beds -  Patients i n L T C facilities on census day  E m p t y b e d s i n L T C facilities o n c e n s u s d a y Special A l z h e i m e r Care Unit beds T y p e of L T C facility Intermediate care - Multi-level care Accreditation status Non-accredited facility - A c c r e d i t e d facility Type of ownership - Non-profit society beds - For-profit corporation beds N u m b e r o f L T C patients M e a n number of patients/LTC facility ± S D R a n g e o f patients/LTC facility N u m b e r of primary care physicians M e a n number of p h y s i c i a n s / L T C facility ± S D - R a n g e of number of p h y s i c i a n s / L T C facility  22 14 1875  1602  Total number in B.C. ( % ) 210 113 20,843 3  46 227  4  2 0 (90.9) 2( 9.1)  185 (88.3) 2 5 (11.7)  19 (86.4) 3 (13.6)  165 (78.6) 4 5 (21.4)  5  6  7  4 5 6 7  8 9 0 (55.6) 7 1 2 (44.4)  13,756(66.7) 6,878 (33.3)  72.9 ± 32.3 3 4 - 145 3 8 7 ( 9.5) 29.8 ± 9 . 8 16-53  74.0 ± 29.3 34-150 4,086 N o t available  S o u r c e : E x t r a c t e d f r o m B.C. P h a r m a c a r e r e c o r d s A p r i l 1, 1 9 9 6 S o u r c e : S a l l y H a m i l t o n , A c u t e a n d C o n t i n u i n g C a r e , B.C. M i n i s t r y o f H e a l t h , J u l y 13, 1 9 9 8 S o u r c e : C e c i l e L a c h a p e l l e , C a n a d i a n C o u n c i l o n H e a l t h S e r v i c e s A c c r e d i t a t i o n , J u l y 27, 1998 S o u r c e : E d H e l f r i c h , B.C. A s s o c i a t i o n o f P r i v a t e C a r e , M a r c h 16, 1 9 9 8 S o u r c e : 1 9 9 4 / 1 9 9 5 M e d i c a l S e r v i c e P l a n - p r i m a r y c a r e p h y s i c i a n s ( W e s t et al., 1 9 9 6 )  55 d e p r e s s i o n . A l l p a t i e n t s a d m i t t e d p r i o r to a f a c i l i t y - s p e c i f i c c e n s u s d a y w e r e e l i g i b l e f o r the i n i t i a l c a s e - f i n d i n g p h a s e o f the study. Patients w e r e s c r e e n e d out b a s e d o n the p r e s e n c e o f e x c l u s i o n criteria d o c u m e n t e d i n the m e d i c a l chart o r the a d v i c e o f f a c i l i t y s t a f f b a s e d o n their c l i n i c a l j u d g e m e n t o f c o g n i t i v e i m p a i r m e n t o r the p r e s e n c e o f o t h e r e x c l u s i o n criteria, i n c l u d i n g communication difficulty. EXCLUSION CRITERIA: 1. 2. 3. 4. 5. 6. 7. 8.  Perceived low cognitive function Seriously or terminally ill, or i n hospital P r o f o u n d deafness Severe aphasia L a n g u a g e barrier R e f u s a l to participate A d m i t t e d to l o n g - t e r m care < 2 w e e k s A c t i v e m e n t a l h e a l t h referral (e.g. a c t i v e l y s u i c i d a l )  9.  R e c e i v i n g antidepressant m e d i c a t i o n ( i n c l u d i n g h e r b a l t h e r a p y e.g. St. John's W o r t )  INCLUSION CRITERIA: 1. 2. 3.  A t least 65 years o f age, m a l e o r f e m a l e G e r i a t r i c D e p r e s s i o n S c a l e s c o r e > 13 at b a s e l i n e M i n i - M e n t a l State E x a m i n a t i o n s c o r e > 19 at b a s e l i n e  4.  Patient understood and signed informed consent  P a t i e n t s w e r e e l i g i b l e f o r i n c l u s i o n i n the c a s e - f i n d i n g p h a s e i f t h e y w e r e o v e r the a g e o f 65 y e a r s o n the c e n s u s d a y f o r their f a c i l i t y . T h i s l o w e r l i m i t o f p a t i e n t a g e is arbitrary, b u t c o n s i s t e n t w i t h s i m i l a r c l i n i c a l r e s e a r c h i n e l d e r l y l o n g - t e r m c a r e s a m p l e s ( G a r r a r d et al., 1992; K a f o n e k et a l , 1989). A c l i n i c i a n - a d m i n i s t e r e d a s s e s s m e n t i n s t r u m e n t , s u c h as the H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H A M - D ) , is c o m m o n l y u s e d as a n e n t r y c r i t e r i o n i n a n t i d e p r e s s a n t c l i n i c a l trials w i t h g e r i a t r i c p a t i e n t s to d o c u m e n t the s e v e r i t y o f d e p r e s s i o n ( K a t z et al., 1990; T o l l e f s o n et al., 1993). P s y c h i a t r i s t s a l s o r o u t i n e l y e s t a b l i s h that p o t e n t i a l c l i n i c a l trial p a t i e n t s m e e t Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ( A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n , 1994) c r i t e r i a f o r m a j o r d e p r e s s i v e d i s o r d e r , u n i p o l a r s u b t y p e ( R o o s e et al., 1998). H o w e v e r , i n r o u t i n e c l i n i c a l p r a c t i c e p r i m a r y c a r e p h y s i c i a n s r a r e l y assess l o n g - t e r m  care patients with the H A M - D o r according to D S M - I V criteria guidelines.  56 Physicians  c o m m o n l y m a k e t r e a t m e n t a n d r e f e r r a l d e c i s i o n s b a s e d o n i n f o r m a t i o n that i s r e a d i l y a v a i l a b l e f r o m l o n g - t e r m c a r e f a c i l i t y s t a f f a n d f a m i l y m e m b e r s . S i n c e this trial w a s d e s i g n e d t o use a s c r e e n i n g i n s t r u m e n t that w o u l d b e p r a c t i c a l t o u s e i n c l i n i c a l p r a c t i c e i n l o n g - t e r m c a r e facilities, t h e G D S w a s d e s i g n a t e d as the r e s e a r c h e n t r y c r i t e r i o n f o r s e v e r i t y o f d e p r e s s i o n . P r e v i o u s r e s e a r c h ( S o o n , 1 9 9 4 a ) a n d that o f G e r e t y et al. ( G e r e t y et al., 1 9 9 4 b ) e s t a b l i s h e d that a G D S c r i t e r i o n o f > 13 w a s a s e n s i t i v e a n d s p e c i f i c p r e d i c t o r u s e f u l f o r i d e n t i f y i n g e l d e r l y l o n g term care patients with depression.  O n c e the patient h a d signed the informed consent to  p a r t i c i p a t e i n the r a n d o m i z e d c l i n i c a l trial, the H A M - D w a s a d m i n i s t e r e d to d e t e r m i n e the l e v e l o f s e v e r i t y o f d e p r e s s i o n . A M M S E s c o r e o f > 19 a s a n i n c l u s i o n c r i t e r i o n p r o v i d e d a m i n i m u m l e v e l o f c o g n i t i v e f u n c t i o n at s t u d y b a s e l i n e t o e n s u r e that the l o n g - t e r m c a r e p a t i e n t s w e r e c a p a b l e o f u n d e r s t a n d i n g the p u r p o s e o f the study, a n d w e r e c o m p e t e n t to s i g n the c o n s e n t f o r m . I n a d d i t i o n , there is e v i d e n c e that the u s e o f the G D S i s v a l i d f o r p a t i e n t s w i t h M M S E s c o r e s > 15 ( G e r e t y et al., 1 9 9 4 b ; M c G i v n e y et al., 1994). T h e e x c l u s i o n criteria w e r e d e s i g n e d to e x c l u d e patients f o r w h o m the c l i n i c a l trial w o u l d create u n a c c e p t a b l e r i s k s ( s e r i o u s l y o r t e r m i n a l l y i l l ) , patients w h o w e r e u n a b l e t o c o m p l e t e the G D S q u e s t i o n n a i r e ( l o w c o g n i t i v e f u n c t i o n , p r o f o u n d deafness, s e v e r e aphasia, l a n g u a g e barrier), patients w h o r e f u s e d to participate, a n d patients f o r w h o m m e n t a l h e a l t h s e r v i c e s o r antidepressant t h e r a p y h a d a l r e a d y b e e n initiated . L o n g - t e r m care patients w e r e e l i g i b l e f o r the study 2 w e e k s 5  after a d m i s s i o n , c o n s i s t e n t w i t h t h e m e t h o d o l o g y o f c o m p a r a b l e  l o n g - t e r m care r e s e a r c h  i n v e s t i g a t i o n s ( M c G i v n e y et al., 1994). Patients w e r e s c r e e n e d out b a s e d o n i n f o r m a t i o n i n their m e d i c a l r e c o r d s a n d o n c l i n i c a l j u d g e m e n t p r o v i d e d b y facility nurses o r care-aides. T h e reasons for each instance o f exclusion were documented. Physicians of patients receiving antidepressant therapy were sent a questionnaire requesting that they note the indication for use of the agent and then return the questionnaire to the study investigator.  5  57 C o n s i s t e n t w i t h a c t u a l c l i n i c a l p r a c t i c e i n l o n g - t e r m care facilities, there w e r e n o restrictions o n the use o f c o n c o m i t a n t p r e s c r i p t i o n o r over-the-counter m e d i c a t i o n s . P a t i e n t s w e r e not e x c l u d e d due to c o m o r b i d m e d i c a l illness, a n d b a s e l i n e l a b o r a t o r y tests w e r e n o t r e q u i r e d p r i o r to enrollment. 2.2.1.3 Rating instruments  2.2.1.3.1 G e r i a t r i c D e p r e s s i o n S c a l e ( G D S ) A d e p r e s s i o n c a s e - f i n d i n g instrument suitable f o r u s e i n the l o n g - t e r m care setting s h o u l d be brief, e a s y to administer, s i m p l e to understand, a b l e to e f f i c i e n t l y i d e n t i f y patients w i t h s y m p t o m s o f depression, a n d h a v e k n o w n reliability a n d v a l i d i t y i n the f r a i l , e l d e r l y p o p u l a t i o n . W h i l e n u m e r o u s c a s e - f i n d i n g instruments h a v e b e e n d e v e l o p e d to i d e n t i f y c o m m u n i t y - d w e l l i n g  elderly with a high  p r o b a b i l i t y o f d e p r e s s i o n , s o m e o f these r a t i n g scales are n o t a p p r o p r i a t e f o r use w i t h frail e l d e r l y l o n g - t e r m care patients. T h e r e are a n u m b e r o f c a s e - f i n d i n g instruments that c a n b e u s e d to s c r e e n l o n g - t e r m care patients, a n d a m o n g t h e m the G D S has b e e n s e l e c t e d f o r use i n the p r e s e n t study. T h e G D S is a 30i t e m d e p r e s s i o n r a t i n g s c a l e d e s i g n e d f o r a d m i n i s t r a t i o n to e l d e r l y i n d i v i d u a l s ( Y e s a v a g e et al., 1983) ( A p p e n d i x 7). T h e i n s t r u m e n t was s p e c i f i c a l l y d e v e l o p e d to a v o i d q u e s t i o n s that m i g h t increase the d e f e n s i v e n e s s o f e l d e r l y subjects o r r e d u c e c o o p e r a t i o n a n d r a p p o r t ( Y e s a v a g e et al., 1983).  I n a d d i t i o n , q u e s t i o n s o n s o m a t i c s y m p t o m s o f d e p r e s s i o n s u c h as sleep disturbances,  constipation, a n d p a i n d i s c o m f o r t that are c o m m o n i n n o n d e p r e s s e d elderly, w e r e m i n i m i z e d .  The  instrument w a s d e s i g n e d to be s i m p l e to a d m i n i s t e r b y a n i n d i v i d u a l w h o i s not a t r a i n e d i n t e r v i e w e r ( Y e s a v a g e et al., 1983), a n d d i f f e r e n c e s i n i n s t r u c t i o n p r o v i d e d d o not a p p e a r to s i g n i f i c a n t l y alter the results ( D u n n et al., 1988). T h e r e appears to be n o r e l a t i o n b e t w e e n the t e n d e n c y o f the patient to r e s p o n d to items i n a s o c i a l l y d e s i r a b l e m a n n e r a n d the G D S score, s u g g e s t i n g that o l d e r adults d o n o t s y s t e m a t i c a l l y under-report d e p r e s s i v e s y m p t o m s b e c a u s e o f a d e f e n s i v e attitude about a d m i t t i n g s o c i a l l y i n a p p r o p r i a t e attitudes a n d b e h a v i o r s ( C a p p e l i e z , 1989).  T h e yes/no f o r m a t  p r o v i d e s a s i m p l e task f o r e l d e r l y patients, a n d r e q u i r e s less c o g n i t i v e effort f o r p r o c e s s i n g questions  58 than a m u l t i p l e - c h o i c e format. T h e G D S h a s b e e n v a l i d a t e d i n n u r s i n g h o m e patients w i t h a M i n i M e n t a l State E x a m i n a t i o n ( M M S E ) s c o r e o f > 15 u s i n g D S M III-R criteria f o r m a j o r d e p r e s s i o n ; sensitivity w a s 8 4 % a n d s p e c i f i c i t y w a s 9 1 % ( M c G i v n e y et al., 1994). T h e G D S r e q u i r e s less than 10 m i n u t e s t o c o m p l e t e i n this p o p u l a t i o n ( S o o n , 1994a).  Investigators h a v e a c c e p t e d u p t o 2 0 %  m i s s i n g data (6 items) o n the G D S , a n d t h e n adjusted the total s c o r e to a p p r o x i m a t e a 30-point s c a l e ( P a r m e l e e et al., 1989a). A s the entry criterion f o r o u r s t u d y r e q u i r e d a h i g h e r l e v e l o f c o g n i t i v e f u n c t i o n ( M M S E s c o r e o f > 19), w e c h o s e to b e c o n s e r v a t i v e a n d o n l y a c c e p t e d u p to 1 0 % m i s s i n g data (3 items). T h e m a x i m u m score o n the G D S is 30; 0 - 10 is c o n s i d e r e d to i n d i c a t e n o d e p r e s s i o n ; 11 17 t o i n d i c a t e p o s s i b l e m i n o r d e p r e s s i o n ; a n d > 18 i s c o n s i d e r e d t o i n d i c a t e p o s s i b l e m a j o r d e p r e s s i o n ( P a r m e l e e et al., 1989a; Y e s a v a g e et al., 1983). T h e r e l i a b i l i t y a n d sensitivity o f the G D S h a s b e e n e s t a b l i s h e d i n e l d e r l y i n d i v i d u a l s w h o are c o m m u n i t y - d w e l l i n g  ( B r i n k et al., 1982;  Y e s a v a g e et al., 1983), i n acute care h o s p i t a l s ( K o e n i g et al., 1992b), a n d i n n u r s i n g h o m e s ( G e r e t y et al., 1994b; L e s h e r , 1986; M c G i v n e y et al., 1994).  T h e G D S has also been validated f o r  a d m i n i s t r a t i o n b y self-report ( Y e s a v a g e et a l , 1983), b y i n t e r v i e w e r ( P a r m e l e e et al., 1 9 8 9 b ) a n d b y t e l e p h o n e ( B u r k e et al., 1995). Y e s a v a g e et al. ( Y e s a v a g e et al., 1 9 8 3 ) f o u n d a h i g h degree o f internal c o n s i s t e n c y f o r the G D S ; a n d test-retest reliability c o r r e l a t i o n o v e r the p e r i o d o f 1 m o n t h was 0.94 i n n u r s i n g h o m e patients (Lesher, 1986). T h e sensitivity o f the G D S t o treatment-related change, h o w e v e r , r e q u i r e s further e v a l u a t i o n ( M o n t o r i o et al., 1996). U s i n g t h e H A M - D as t h e " g o l d standard", t h e sensitivity a n d s p e c i f i c i t y o f the G D S i n n u r s i n g h o m e patients are 8 9 % a n d 6 8 % , r e s p e c t i v e l y , w i t h a traditional c u t - o f f o f 11 ( G e r e t y et al., 1994b).  W h e n t h e o p t i m a l t h r e s h o l d score o f 13 w a s used, t h e sensitivity w a s 8 6 % a n d t h e  s p e c i f i c i t y w a s 7 7 % ( G e r e t y et al., 1994b). T h e s e results w e r e o b t a i n e d i n n u r s i n g h o m e patients w i t h M M S E s c o r e s o f > 15. O u r p r e v i o u s r e s e a r c h i n the l o n g - t e r m c a r e s a m p l e u s e d a M M S E  59 s c o r e > 19 as a n e n t r y criterion, restricting the s t u d y to those patients w i t h intact o r m i l d c o g n i t i v e i m p a i r m e n t . W e f o u n d that u s i n g a c u t - o f f o f 11 r e s u l t e d i n a sensitivity a n d s p e c i f i c i t y o f 1 0 0 % a n d 6 4 % , r e s p e c t i v e l y , w h i l e u s i n g a c u t - o f f o f 13 r e s u l t e d i n a sensitivity a n d s p e c i f i c i t y o f 1 0 0 % a n d 8 1 % , r e s p e c t i v e l y ( S o o n , 1994a). S i n c e b o t h the G e r e t y et al. s t u d y ( G e r e t y et al., 1 9 9 4 b ) a n d o u r p r e v i o u s w o r k ( S o o n , 1994a) i n d i c a t e d that u s e o f the " o p t i m a l " c u t - o f f o f 13 i n c r e a s e d s p e c i f i c i t y w h i l e k e e p i n g the sensitivity about the same, w e c h o s e to u s e the c u t - o f f o f 13 f o r the present study. T h e i n c r e a s e i n s p e c i f i c i t y m e a n s that there is a r e d u c t i o n i n the n u m b e r o f patients w i t h false-positive results o n the c a s e - f i n d i n g instrument. A shorter, e m b e d d e d 15-item v e r s i o n o f the G D S has b e e n v a l i d a t e d ( B u r k e et al., 1 9 9 1 ; G e r e t y et al., 1994b; H e r r m a n n et al., 1996; S h e i k h et al., 1986), a n d has s l i g h t l y l o w e r sensitivity a n d s p e c i f i c i t y ( G e r e t y et al., 1994b). W e c h o s e to u s e the o r i g i n a l 3 0 - i t e m G D S f o r the study, d u e to m o r e d e s i r a b l e o p e r a t i n g characteristics a n d m i n i m a l d i f f e r e n c e i n a d m i n i s t r a t i o n time. 2.2.1.3.2 M i n i - M e n t a l State E x a m i n a t i o n ( M M S E ) C o g n i t i v e f u n c t i o n i n e l d e r l y i n d i v i d u a l s c a n b e a s s e s s e d b y u n s t r u c t u r e d mental-status e x a m i n a t i o n s a d m i n i s t e r e d b y c l i n i c i a n s , self-rated q u e s t i o n n a i r e s , o b s e r v e r ratings, a n d f o r m a l p s y c h o l o g i c a l tests ( K a n e et al., 1981a). I n l o n g - t e r m care patients, m e a s u r e s that assess c o g n i t i v e f u n c t i o n n e e d to b e brief, objective, s i m p l e to a d m i n i s t e r a n d understand, a b l e to q u a n t i f y c o g n i t i v e c h a n g e o v e r time, a n d h a v e k n o w n reliability a n d v a l i d i t y i n the f r a i l , e l d e r l y p o p u l a t i o n . O f the v a r i o u s t o o l s a v a i l a b l e to assess m e n t a l status, the M i n i - M e n t a l State E x a m i n a t i o n b y F o l s t e i n et al. ( F o l s t e i n et al., 1975) w a s selected f o r use i n this s t u d y ( A p p e n d i x 8). T h e M M S E is a brief, but t h o r o u g h , s c r e e n i n g test that q u a n t i t a t i v e l y assesses the severity o f c o g n i t i v e i m p a i r m e n t a n d d o c u m e n t s c o g n i t i v e c h a n g e s o c c u r r i n g o v e r t i m e ( T o m b a u g h et al., 1992). T h e 3 0 - i t e m i n s t r u m e n t w a s d e s i g n e d to b e a d m i n i s t e r e d i n less t h a n 10 m i n u t e s b y h e a l t h p r o f e s s i o n a l s o r l a y p e r s o n n e l w i t h m i n i m a l t r a i n i n g ( F o l s t e i n et al., 1975). T h e M M S E c o n t a i n s 11 questions, s e p a r a t e d i n t o t w o sections. T h e first s e c t i o n has a m a x i m u m s c o r e o f 21 a n d evaluates  60 o r i e n t a t i o n to t i m e a n d place, short-term m e m o r y a n d c o n c e n t r a t i o n . T h e r e s p o n s e s i n this s e c t i o n are v e r b a l . T h e s e c o n d s e c t i o n h a s a m a x i m u m s c o r e o f 9, a n d assesses l a n g u a g e skills. T h e questions test t h e patient's ability t o f o l l o w v e r b a l a n d w r i t t e n c o m m a n d s , t o w r i t e a sentence spontaneously, a n d t o c o p y a c o m p l e x i n t e r s e c t i n g p o l y g o n . S e v e r i t y o f c o g n i t i v e i m p a i r m e n t is c l a s s i f i e d into 3 l e v e l s ( T o m b a u g h et al., 1992): 0 - 17 (severe c o g n i t i v e i m p a i r m e n t ) ; 18 - 2 3 ( m i l d c o g n i t i v e impairment); a n d 2 4 - 3 0 ( n o c o g n i t i v e impairment). T h e M M S E is c o n s i d e r e d t o h a v e l i m i t e d v a l u e i n e l d e r l y patients w h o a r e f u n c t i o n a l l y illiterate, h a v e p r o f o u n d deafness, o r h a v e l i m i t e d E n g l i s h f l u e n c y ( D r a n c e , 1991). T h e p s y c h o m e t r i c p r o p e r t i e s a n d utility o f t h e M M S E h a v e b e e n r e v i e w e d e x t e n s i v e l y ( T o m b a u g h et al., 1992). Internal c o n s i s t e n c y is h i g h , a n d w h e n the test-retest interval is 2 m o n t h s o r less, the reliability c o e f f i c i e n t s f o r b o t h c o g n i t i v e l y intact a n d i m p a i r e d subjects are b e t w e e n 0.80 a n d 0.95 ( T o m b a u g h et al., 1992). I n a n u r s i n g h o m e p o p u l a t i o n , the M M S E h a s b e e n r e p o r t e d t o c o r r e c t l y i d e n t i f y 8 1 % o f patients c l a s s i f i e d as c o g n i t i v e l y i m p a i r e d b y D S M - I I I criteria (sensitivity) a n d 8 3 % o f patients c l a s s i f i e d as c o g n i t i v e l y intact ( s p e c i f i c i t y ) ( K a f o n e k et al., 1989). T h e m e a s u r e m e n t t o o l is appropriate f o r use as b o t h a n initial assessment a n d f o r serial assessments o v e r t i m e s i n c e there appears t o b e l i t t l e p r a c t i c e e f f e c t ( F o l s t e i n et al., 1975). T h e M M S E h a s b e e n i n c l u d e d i n t h e D i a g n o s t i c I n t e r v i e w S c h e d u l e u s e d i n the E p i d e m i o l o g i c C a t c h m e n t A r e a study s p o n s o r e d b y t h e N a t i o n a l Institute o f M e n t a l H e a l t h ( R o b i n s , 1985). T h e M M S E h a s a l s o b e e n a d o p t e d as a standard c o m p o n e n t o f long-term care assessments b y the D i v i s i o n o f C o n t i n u i n g C a r e o f B r i t i s h C o l u m b i a (Drance, 1991). A d m i n i s t r a t i o n o f the M M S E w a s s t a n d a r d i z e d t o c o n s i s t e n t l y u s e "apple, table, p e n n y " to test r e c a l l ( T o m b a u g h et al., 1992), a n d t o u s e " s p e l l W O R L D b a c k w a r d s " t o test c o n c e n t r a t i o n ( M o r r i s et al., 1988). E a c h q u e s t i o n w a s a s k e d as s p e c i f i e d i n t h e M M S E , a n d w a s repeated a m a x i m u m o f 3 times i f the patient h a d d i f f i c u l t y w i t h the question. F o r q u e s t i o n s that the patient w a s u n a b l e t o r e s p o n d to, t h e i n t e r v i e w e r assessed t h e patient's p h y s i c a l a b i l i t y t o c o m p l e t e the  61 question. I f the patient w a s p h y s i c a l l y able to a n s w e r the q u e s t i o n , b u t w a s n o t a b l e to p r o v i d e the c o r r e c t answer, t h e n t h e s c o r e w a s r e c o r d e d as zero. I f t h e patient w a s p h y s i c a l l y unable t o c o m p l e t e a n i t e m d u e to v i s u a l o r m o t o r i m p a i r m e n t , t h e n the i t e m w a s s c o r e d " p h y s i c a l l y u n a b l e " a n d r e c o r d e d as a "blank". T h e M M S E w a s p r o r a t e d i f v i s u a l o r m o t o r i m p a i r m e n t p r e v e n t e d patients f r o m c o m p l e t i n g items, c o n s i s t e n t w i t h the m e t h o d f o l l o w e d b y G e r e t y et al. ( G e r e t y et al., 1994b). T h e patient's c o r r e c t responses w e r e s u m m e d , d i v i d e d b y 3 0 m i n u s the n u m b e r o f items u n a b l e to b e assessed, a n d t h e n the result w a s m u l t i p l i e d b y 3 0 to g i v e the total p r o r a t e d score. C o g n i t i v e i m p a i r m e n t m a y m a k e it d i f f i c u l t f o r patients t o p r o v i d e a c c u r a t e a n d consistent i n f o r m a t i o n ( P h i l l i p s et al., 1993). A l t h o u g h the G D S has b e e n v a l i d a t e d f o r patients w i t h a M M S E score o f > 15 ( M c G i v n e y et a l , 1994), a n d " m i l d c o g n i t i v e i m p a i r m e n t " i n c l u d e s M M S E scores o f 18-23  ( T o m b a u g h et al., 1992), w e c h o s e t o select a c o n s e r v a t i v e M M S E s c o r e o f > 19 as the  study entry c r i t e r i o n to e n h a n c e patient c o m p r e h e n s i o n . 2.2.1.3.3 C o n s i s t e n c y o f G D S a n d M M S E a d m i n i s t r a t i o n T o facilitate c o n s i s t e n c y i n the a d m i n i s t r a t i o n o f the G D S , t h e s t u d y i n v e s t i g a t o r o r i e n t e d e x p e r i e n c e d care-aides a n d the r e s e a r c h assistants to the study at a n i n s e r v i c e w o r k s h o p , w h e r e the aides a n d assistants w e r e taught to v e r b a l l y a d m i n i s t e r the q u e s t i o n n a i r e i n a s t a n d a r d i z e d m a n n e r . T h e q u e s t i o n s w e r e r e a d a l o u d to the patient, a n d repeated a m a x i m u m o f 3 times. T h e a n s w e r w a s r e c o r d e d a s yes, no, o r n o t attempted. T h e r e s e a r c h assistants s c o r e d a l l t h e G D S questionnaires: those w i t h m o r e than 1 0 % m i s s i n g data (3 items) w e r e e x c l u d e d . T o facilitate inter-rater reliability w i t h t h e M M S E , t h e s t u d y i n v e s t i g a t o r a n d r e s e a r c h assistants r e v i e w e d the instructions f o r a d m i n i s t r a t i o n a n d s c o r i n g o f the i n s t r u m e n t f r o m F o l s t e i n et al. ( F o l s t e i n et al., 1 9 7 5 ) a n d f r o m t h e B . C . M i n i s t r y o f H e a l t h M a n u a l o n Assessing Difficult Behaviour in the Elderly ( D r a n c e , 1991). T h e first 2 patients a s s e s s e d w i t h t h e M M S E b y e a c h  r e s e a r c h nurse w e r e i n t e r v i e w e d j o i n t l y w i t h t h e study i n v e s t i g a t o r . T h e M M S E w a s rated  62 i n d e p e n d e n t l y a n d t h e n the s c o r i n g o f the q u e s t i o n n a i r e w a s r e v i e w e d a n d c o n s e n s u s was reached. R e s e a r c h assistants r o u t i n e l y s c o r e d the M M S E d u r i n g the c a s e - f i n d i n g p h a s e o f the study. 2.2.1.4 Baseline data collection  2.2.1.4.1 D e m o g r a p h i c i n f o r m a t i o n B a s e l i n e d e m o g r a p h i c data o n age, gender, p h y s i c i a n , race, language, intermediate-care level, a n d d u r a t i o n o f stay w e r e o b t a i n e d b y the study i n v e s t i g a t o r f r o m the m e d i c a l chart o n census day, a n d r e c o r d e d o n a s t a n d a r d i z e d data c o l l e c t i o n f o r m . A l t h o u g h patients less than 65 y e a r s o f age w e r e not e l i g i b l e f o r the r a n d o m i z e d c l i n i c a l trial p h a s e o f the study, their d e m o g r a p h i c i n f o r m a t i o n w a s c o l l e c t e d to p e r m i t c h a r a c t e r i z a t i o n o f the total l o n g - t e r m care s a m p l e . 2.2.1.4.2 M e d i c a l d i a g n o s e s T h e m e d i c a l d i a g n o s e s w e r e extracted f r o m the patient's m e d i c a l chart u t i l i z i n g i n f o r m a t i o n r e c o r d e d o n the l o n g - t e r m care a d m i s s i o n h i s t o r y f r o m the p h y s i c i a n , the M i n i s t r y o f H e a l t h C o n t i n u i n g C a r e assessment p r i o r to l o n g - t e r m care a d m i s s i o n , the d i s c h a r g e d i a g n o s e s f r o m recent acute care h o s p i t a l a d m i s s i o n s , a n d the M e d i c a t i o n A d m i n i s t r a t i o n R e c o r d . 2.2.1.4.3 C o n c o m i t a n t d r u g t h e r a p y M e d i c a t i o n use i n l o n g - t e r m care patients has b e e n s t u d i e d b y B e e r s et a l . ( B e e r s et al., 1988) a n d T o b i a s a n d P u l l i a m ( T o b i a s et al., 1997), a n d m e t h o d o l o g y c o n s i s t e n t w i t h these t w o studies was f o l l o w e d i n the present research. M e d i c a t i o n use w a s d e t e r m i n e d f r o m the M e d i c a t i o n Administration Record (MAR)  o n the census d a y at the facility.  The following medication  i n f o r m a t i o n w a s r e c o r d e d f o r e a c h patient: the n u m b e r o f r e g u l a r l y a d m i n i s t e r e d orders, w h e t h e r the patient r e c e i v e d > 9 r o u t i n e orders p e r day, the n u m b e r o f P R N (as n e e d e d ) orders, a n d the n u m b e r of PRN  orders that w e r e a d m i n i s t e r e d 4 o r m o r e t i m e s i n the past m o n t h .  Ophthalmologic  p r e p a r a t i o n s a n d n i t r o g l y c e r i n e o i n t m e n t a n d patches w e r e r e c o r d e d i f n o t e d o n the M A R .  Other  t o p i c a l p r e p a r a t i o n s w e r e not counted. C o n t i n g e n c y (standing) P R N o r d e r s w e r e c o u n t e d o n l y i f n o t e d o n the M A R .  T i m e - s p e c i f i e d orders (e.g. short-term antibiotic o r steroid orders) w e r e  63 i t e m i z e d s e p a r a t e l y f r o m r e g u l a r a n d P R N orders, a n d w e r e not i n c l u d e d i n patient totals. I f the same drug appeared on two regular or two P R N  orders (e.g. d i m e n h y d r i n a t e P R N n a u s e a a n d  d i m e n h y d r i n a t e P R N sleep), t h e n the o r d e r w a s c o u n t e d once. S i m i l a r l y , i f the s a m e d r u g a p p e a r e d o n the M A R  i n 2 different dosages (e.g. o x a z p a m 5 m g at n o o n a n d 10 m g at b e d t i m e ) , t h e n the  o r d e r was c o u n t e d once. H o w e v e r , i f a d r u g w a s p r e s c r i b e d as b o t h a r o u t i n e a n d a P R N o r d e r (e.g. acetaminophen), t h e n the patient w a s c o u n t e d as h a v i n g 2 orders. A d d i t i o n a l i n f o r m a t i o n was r e c o r d e d o n p s y c h o t h e r a p e u t i c m e d i c a t i o n use i n f o u r g e n e r a l categories: a n t i p s y c h o t i c , a n x i o l y t i c , h y p n o t i c a n d antidepressant.  P a t i e n t - s p e c i f i c data w e r e  r e c o r d e d o n the n u m b e r o f r o u t i n e a n d P R N orders i n e a c h o f the a n t i p s y c h o t i c , a n x i o l y t i c , h y p n o t i c a n d antidepressant categories. D r u g s w e r e c o u n t e d i n a p s y c h o t h e r a p e u t i c c a t e g o r y b a s e d o n i n d i c a t i o n f o r use (e.g. o n l y w h e n p r e s c r i b e d f o r b e h a v i o u r o r m o o d changes). A s a n e x a m p l e , a p r e s c r i p t i o n f o r a b e n z o d i a z e p i n e that was p r e s c r i b e d t w i c e a d a y a n d at b e d t i m e w a s d o c u m e n t e d b o t h as a n a n x i o l y t i c a n d as a h y p n o t i c , c o n s i s t e n t w i t h m e t h o d o l o g y  developed by Tobias and  P u l l i a m ( T o b i a s et al., 1997). 2.2.1.5 Clinical trial considerations in long-term care patients  " S t u d y i n g d e p r e s s e d patients, p a r t i c u l a r l y t h o s e w h o are v e r y o l d , is h a r d work." ( A n s t e y e t a l . , 1995) S e v e r a l p r a c t i c a l a n d l o g i s t i c c h a l l e n g e s m u s t b e a d d r e s s e d to s u c c e s s f u l l y c o n d u c t c l i n i c a l trials i n e l d e r l y l o n g - t e r m c a r e p a t i e n t s ( Z i m m e r et a l . , 1985). P a t i e n t r e c r u i t m e n t f o r studies i n the e l d e r l y c a n b e s u b s t a n t i a l l y m o r e t i m e c o n s u m i n g  t h a n f o r trials i n y o u n g e r  patients, a n d e x t r a time, m o n e y and/or p e r s o n n e l m a y n e e d to b e b u d g e t e d f o r r e c r u i t i n g s u b j e c t s w i t h the a p p r o p r i a t e i n c l u s i o n criteria w h o  are w i l l i n g to p a r t i c i p a t e ( V o g t et al., 1986).  T r e a t m e n t o u t c o m e s n e e d to be r e l e v a n t f o r f r a i l , a g e d p a t i e n t s ( B o w e s et a l . , 1990), a n d s h o u l d g e n e r a l l y f o c u s o n the i m p r o v e m e n t i n the q u a l i t y o f l i f e a n d the a b i l i t y to p e r f o r m activities o f d a i l y l i v i n g r a t h e r t h a n i m p r o v e d s u r v i v a l . T o b e s u i t a b l e f o r u s e i n the f r a i l , a g e d patient,  64 assessment tools should m i n i m i z e inconvenience a n d discomfort to the patient, be relevant to activities o f d a i l y l i v i n g , a n d b e s e n s i t i v e e n o u g h t o d o c u m e n t e v e n s m a l l t h e r a p e u t i c r e s p o n s e s ( B o w e s et al., 1990). S i n c e the o n s e t o f f a t i g u e m a y c a u s e the p a t i e n t t o t e r m i n a t e t h e i n t e r v i e w i n f r u s t r a t i o n o r t o g i v e i n a c c u r a t e a n d u n r e l i a b l e i n f o r m a t i o n ( K e l s e y et al., 1989), a p i l o t s t u d y u s i n g the a c t u a l s t u d y s a m p l e is e s s e n t i a l t o p r o v i d e i n f o r m a t i o n o n the t i m e i n v o l v e d t o c o n d u c t a s s e s s m e n t i n t e r v i e w s . A p p l e g a t e a n d C u r b ( A p p l e g a t e et al., 1 9 9 0 ) n o t e that t h e greatest b o n d i n g b e t w e e n s t u d y s t a f f a n d p a r t i c i p a n t s tends t o o c c u r i n the e a r l y stages o f e n r o l l m e n t , a n d e m p h a s i z e that c o n t i n u e d p a t i e n t p a r t i c i p a t i o n is e n h a n c e d b y p r o v i d i n g a p l e a s a n t , s u p p o r t i v e , unhurried study environment. O b t a i n i n g true i n f o r m e d c o n s e n t is a n i m p o r t a n t a s p e c t o f the e n r o l l m e n t p e r i o d o f a trial, as c o n s e n t t o p a r t i c i p a t e i n r e s e a r c h c a n b e g i v e n o n l y b y a p e r s o n w h o i s f u l l y i n f o r m e d a b o u t the r e s e a r c h , c a p a b l e o f u n d e r s t a n d i n g t h e c o n s e n t d o c u m e n t , w e i g h i n g r i s k s a n d benefits, a n d a b l e t o p a r t i c i p a t e v o l u n t a r i l y ( A n n a s et al., 1986).  Investigators are encouraged to provide  elderly patients with informed consent documents written i n very simple language i n large b o l d print a n d to provide research staff with a checklist o f the critical elements o f the i n f o r m e d c o n s e n t t o r e v i e w w i t h patients. S i n c e s o m e e l d e r l y s u b j e c t s m a y w a n t t o h a v e f a m i l y m e m b e r s or friends i n v o l v e d i n the informed consent a n d decision-making process, investigators are e n c o u r a g e d t o d i s c u s s t h e s t u d y w i t h these i n d i v i d u a l s t o o b t a i n t h e i r o n g o i n g  support  ( A p p l e g a t e e t a l . , 1990). 2.2.1.6 Research personnel  T h e f o u r r e s e a r c h assistants w h o a s s i s t e d t h e s t u d y i n v e s t i g a t o r w e r e m a t u r e n u r s e s w i t h e x t e n s i v e g e r i a t r i c e x p e r i e n c e i n l o n g - t e r m care and/or h o m e s u p p o r t n u r s i n g . T h e i r t h o r o u g h k n o w l e d g e o f the l o n g - t e r m c a r e e n v i r o n m e n t a n d s e n s i t i v i t y t o t h e n e e d s o f the f r a i l e l d e r l y h e l p e d t o p r o m o t e a p r o f e s s i o n a l , y e t s u p p o r t i v e s t u d y s e t t i n g f o r p a t i e n t s a n d f a c i l i t y staff. M s . Lorna Adair, Ms. Katherine Davies, Ms. Paula Jakeman, and Ms. Jacquelin Liebe were trained  65 on-site i n d a t a c o l l e c t i o n m e t h o d s f o r the p u r p o s e o f f a c i l i t a t i n g d a t a c o n s i s t e n c y a n d r e d u c i n g inter-rater v a r i a b i l i t y . T h e r e s e a r c h assistants w e r e u n a w a r e o f c r i t i c a l f e a t u r e s o f s t u d y d e s i g n , i n c l u d i n g the r a n d o m i z a t i o n o f p h y s i c i a n s a n d a s s i g n m e n t s o f p a t i e n t s t o g r o u p s , a n d o f the H A M - D a n d C l i n i c a l G l o b a l I m p r e s s i o n ( C G I ) scores, s o that their i n v o l v e m e n t w i t h the patient w o u l d not c o m p r o m i s e the results o f the study. D u r i n g the c a s e - f i n d i n g p h a s e o f the study, the r e s p o n s i b i l i t i e s o f the r e s e a r c h assistants i n c l u d e d a d m i n i s t r a t i o n o f the G D S a n d the M M S E , a n d o b t a i n i n g i n f o r m e d c o n s e n t f r o m patients. D u r i n g t h e r a n d o m i z e d  c l i n i c a l trial a n d  t h e r a p e u t i c o u t c o m e s study, t h e r e s e a r c h assistants a l s o a d m i n i s t e r e d t h e S i c k n e s s I m p a c t P r o f i l e - N u r s i n g H o m e ( S I P - N H ) , the P h y s i c a l P e r f o r m a n c e T e s t ( P P T ) , a n d the B a r t h e l I n d e x (BI).  W h i l e the majority o f i n d i v i d u a l patient assessments w e r e completed i n 1 day, the  assistants a n d the i n v e s t i g a t o r r e t u r n e d the f o l l o w i n g d a y to c o m p l e t e the i n t e r v i e w i f the p a t i e n t b e c a m e u n d u l y fatigued. E x p e r i e n c e d care aides at each facility were trained on-site b y M s . S o o n to v e r b a l l y a d m i n i s t e r the G D S i n a c o n s i s t e n t m a n n e r , a n d to r e c o r d the r e s p o n s e o f the p a t i e n t o n t o the G D S a n s w e r f o r m . M s . J u d i t h S o o n c o o r d i n a t e d a n d c o n d u c t e d the s t u d y i n the l o n g - t e r m care facilities, u n d e r t h e d i r e c t s u p e r v i s i o n o f M a r c L e v i n e , P h D . , a P r o f e s s o r i n t h e U.B.C. F a c u l t y o f P h a r m a c e u t i c a l S c i e n c e s . M s . S o o n w a s s o l e l y r e s p o n s i b l e f o r the c o l l e c t i o n o f d e m o g r a p h i c i n f o r m a t i o n , m e d i c a l d i a g n o s e s , c o n c o m i t a n t d r u g therapy, a n d m o r t a l i t y status. S h e w a s a l s o s o l e l y r e s p o n s i b l e f o r the a d m i n i s t r a t i o n o f the H A M - D , C G I , a n d the U K U S i d e E f f e c t s R a t i n g S c a l e , a n d a d m i n i s t e r e d o t h e r a s s e s s m e n t t o o l s a s n e c e s s a r y . S h e w a s u n a w a r e o f s c o r e s o n the G D S , w h i c h w e r e a s s e s s e d a n d r e t a i n e d b y the r e s e a r c h a s s i s t a n t s u n t i l e v a l u a t i o n s at the f a c i l i t y w e r e c o m p l e t e . D a t a w e r e c o l l e c t e d , e n t e r e d i n t o the database, a n d a n a l y z e d b y M s . S o o n . F o r the p u r p o s e o f this thesis, M s . S o o n is r e f e r r e d t o a s the s t u d y investigator a n d D r . L e v i n e is r e f e r r e d to as the s t u d y supervisor.  66 2.2.1.7 Statistical analysis of the case-finding component  A M i c r o s o f t A c c e s s 9 7 ® r e l a t i o n a l d a t a b a s e w a s d e s i g n e d t o store a n d v a l i d a t e p a t i e n t data, a n d E x c e l 9 7 ® w a s u s e d t o p r e p a r e spreadsheets, charts, a n d d e s c r i p t i v e statistics. D e m o g r a p h i c c h a r a c t e r i s t i c s o f the l o n g - t e r m c a r e facilities, p r i m a r y c a r e p h y s i c i a n s a n d l o n g t e r m c a r e p a t i e n t s i n the s t u d y w e r e c o m p i l e d a n d d e s c r i b e d f o r the c a s e - f i n d i n g p h a s e o f the study, u s i n g p e r c e n t , m e a n s , r a n g e s a n d s t a n d a r d d e v i a t i o n s ( + S D ) w h e r e a p p r o p r i a t e . T h e estimated prevalence (+ 9 5 % CI) o f patients w i t h s y m p t o m s o f untreated depression w a s the p r o p o r t i o n w h o m e t the c r i t e r i a f o r s y m p t o m s o f d e p r e s s i o n ( G D S s c o r e > 13, M M S E s c o r e > 19). 2.2.2  PHASE B: Randomized clinical trial component  2.2.2.1 Design of the randomized clinical trial  A p a t i e n t w a s e l i g i b l e f o r p a r t i c i p a t i o n i n the r a n d o m i z e d c l i n i c a l trial i f h e o r she w a s a s s e s s e d to h a v e a G D S s c o r e > 13 a n d a M M S E s c o r e > 19, s i g n e d the i n f o r m e d consent, a n d d i d n o t m e e t a n y e x c l u s i o n c r i t e r i a f r o m t h e c a s e - f i n d i n g p h a s e o f the study.  A t baseline,  physicians were randomized into a n early (experimental) group o r a delayed (control) group w h e n t h e i r first p a t i e n t w a s e n r o l l e d i n the s t u d y ( F i g u r e 4); a l l s u b s e q u e n t p a t i e n t s a t t e n d e d b y the s a m e p h y s i c i a n w e r e a l l o c a t e d t o the s a m e r a n d o m i z e d g r o u p . F o l l o w i n g r a n d o m i z a t i o n , p h y s i c i a n s i n the e a r l y g r o u p w e r e i n f o r m e d o f the G D S a n d M M S E r e s u l t s o f the s c r e e n b y a letter o f n o t i f i c a t i o n  ( A p p e n d i x 9 ) a n d b y notes i n the m e d i c a l c h a r t a t the l o n g - t e r m c a r e  f a c i l i t y . T h e n o t i f i c a t i o n letter w a s h a n d - d e l i v e r e d to the p r i m a r y c a r e p h y s i c i a n ' s m a i l b o x at the acute c a r e h o s p i t a l i n w h i c h h e o r she h a d a t t e n d i n g p r i v i l e g e s . A n i n t e r p r e t a t i o n o f the r e s u l t s w a s p r o v i d e d i n t e r m s o f the p o s i t i v e p r e d i c t i v e v a l u e f o r major depressive disorder, based o n o u r previous data (Soon, 1994a) a n d those o f other r e s e a r c h e r s ( L e s h e r , 1986; S n o w d o n et al., 1986). T h e letter e m p h a s i z e d :  67 "Please consider the screening information in your ongoing management of the patient. The choice to assess, refer, treat, and monitor your patient's clinical condition remains entirely up to you."  Patients' m e d i c a l records w e r e m o n i t o r e d w e e k l y b y the i n v e s t i g a t o r f o r p h y s i c i a n response to the letter o f notification. T h e p h y s i c i a n w a s d e e m e d to h a v e r e s p o n d e d i f he o r she either p r e s c r i b e d a n t i d e p r e s s a n t d r u g therapy, o r r e q u e s t e d a c o n s u l t f r o m a p s y c h i a t r i s t o r the m e n t a l h e a l t h t e a m . T h e p r i m a r y e n d p o i n t was a c o m p a r i s o n o f the f r e q u e n c y o f p h y s i c i a n responses (antidepressant p r e s c r i p t i o n or referral to m e n t a l h e a l t h services) i n the e a r l y g r o u p w i t h that i n the d e l a y e d g r o u p ( F i g u r e 4). O u r h y p o t h e s i s w a s that at 4 w e e k s after r a n d o m i z a t i o n , the p r o p o r t i o n o f patients f o r w h o m a p h y s i c i a n r e s p o n s e was i n i t i a t e d w o u l d be s i g n i f i c a n t l y greater f o r p a t i e n t s i n the e a r l y g r o u p c o m p a r e d w i t h the d e l a y e d g r o u p . F o u r w e e k s w a s s e l e c t e d as a r e a s o n a b l e t i m e f r a m e f o r a r e s p o n s e b y the p h y s i c i a n , b a s e d o n k n o w l e d g e o f the p r i m a r y c a r e p h y s i c i a n s ' p a t t e r n o f f a c i l i t y v i s i t a t i o n s . In B r i t i s h C o l u m b i a , a t t e n d i n g p h y s i c i a n s are r e q u i r e d to v i s i t t h e i r l o n g - t e r m c a r e patients e v e r y 6 m o n t h s . S i n c e d e p r e s s i o n w o u l d n o t b e c o n s i d e r e d a n acute o r l i f e t h r e a t e n i n g c o n d i t i o n , the p r i m a r y care p h y s i c i a n w o u l d l i k e l y v i s i t the p a t i e n t at h i s o r h e r c o n v e n i e n c e , p e r h a p s s e v e r a l w e e k s after the i n i t i a l letter o f n o t i f i c a t i o n . It w a s felt that r e s p o n s e at a later t i m e m i g h t h a v e b e e n i n f l u e n c e d b y other u n k n o w n f a c t o r s i n a d d i t i o n to the letter. D u r i n g the d e s i g n p h a s e , w e r e c o g n i z e d that the f r e q u e n c y o f p h y s i c i a n r e s p o n s e w a s n o t l i k e l y to b e m a x i m a l at 4 w e e k s . W e  therefore used a two-step screening protocol with  p h y s i c i a n s b y s e n d i n g a f o l l o w - u p letter 4 w e e k s after the i n i t i a l letter o f n o t i f i c a t i o n h a d b e e n d e l i v e r e d . T h u s , 4 w e e k s after r a n d o m i z e d g r o u p a s s i g n m e n t s , p h y s i c i a n s i n the e a r l y g r o u p r e c e i v e d a f o l l o w - u p ( f e e d b a c k ) letter, w h i l e p h y s i c i a n s i n the d e l a y e d g r o u p r e c e i v e d t h e i r first letter o f n o t i f i c a t i o n ( A p p e n d i x  10). S i m i l a r l y , 8 w e e k s after r a n d o m i z e d g r o u p  assignments,  p h y s i c i a n s i n the d e l a y e d g r o u p r e c e i v e d the f o l l o w - u p letter o f n o t i f i c a t i o n . T h e r a t i o n a l e f o r the f o l l o w - u p letter w a s to p r o v i d e a r e m i n d e r to the p h y s i c i a n that the p a t i e n t h a d b e e n assessed.  68 Figure  4 F l o w c h a r t o f the p r i m a r y o u t c o m e f o r the r a n d o m i z e d c l i n i c a l trial p h a s e o f the  clinical screening study  First Letter  Follow-up Letter  Endof 8 weeks  Week 4  Week 8  Early  Case-finding phase  w  Screened positive  randomization Delayed  Baseline N o letter  F i r s t letter  t Primary outcome  Follow-up letter  W e e k 12 Endof 8 weeks  69 T h e letter a l s o e n c o u r a g e d the p h y s i c i a n to take the t i m e to t h i n k t h r o u g h w h a t the initial d e c i s i o n h a d b e e n o r s h o u l d be i n a g i v e n case. T h e s e o b j e c t i v e s w e r e a c c o m p l i s h e d i n the f o l l o w - u p letter b y p r o v i d i n g the p h y s i c i a n w i t h the s a m e initial i n f o r m a t i o n o n the G D S ,  MMSE  a n d p r o b a b i l i t y o f m a j o r d e p r e s s i o n as o n the initial letter. I n a d d i t i o n , the p h y s i c i a n w a s r e q u e s t e d to p r o v i d e f e e d b a c k to the r e s e a r c h t e a m o n the i n i t i a l d e c i s i o n a n d to p r o v i d e s u g g e s t i o n s to i m p r o v e the u s e f u l n e s s o f the s c r e e n i n g p r o g r a m . B e c a u s e o f the staggered start time, patients i n the e a r l y g r o u p c o m p l e t e d the trial at 8 w e e k s after r a n d o m i z a t i o n w h i l e patients i n the d e l a y e d g r o u p c o m p l e t e d at 12 w e e k s after r a n d o m i z a t i o n . T h e o v e r a l l i n t e r v e n t i o n rates at 4 w e e k s a n d 8 w e e k s after p h y s i c i a n s r e c e i v e d t h e i r initial letter o f n o t i f i c a t i o n w e r e the s e c o n d a r y endpoints f o r the trial ( F i g u r e 5). O u r e x p e c t a t i o n w a s that the p h y s i c i a n r e s p o n s e rate w o u l d be the s a m e f o r b o t h g r o u p s at these t i m e i n t e r v a l s , as p h y s i c i a n s i n e a c h g r o u p w o u l d h a v e h a d the letters o f n o t i f i c a t i o n f o r the s a m e l e n g t h o f time.  The  s e q u e n c i n g o f the a s s e s s m e n t s a n d p r o v i s i o n o f i n f o r m a t i o n w e r e s t a g g e r e d s u c h that m e d i c a l a n d n u r s i n g s t a f f w e r e u n a w a r e o f the e x i s t e n c e o f g r o u p  assignments.  P h y s i c i a n s w e r e a b l e to p r e s c r i b e , w i t h o u t r e s t r i c t i o n , the 20 a n t i d e p r e s s a n t  agents  a v a i l a b l e i n B r i t i s h C o l u m b i a d u r i n g the s t u d y p e r i o d . T h e c h o i c e o f a n t i d e p r e s s a n t d r u g a n d dosage regimen  r e f l e c t e d the p h y s i c i a n s ' u s u a l c l i n i c a l p r a c t i c e .  a n t i d e p r e s s a n t s , the initial a n d  For newly prescribed  8 w e e k antidepressant drug, dosage,  and  directions for  a d m i n i s t r a t i o n w e r e d o c u m e n t e d from the P h y s i c i a n ' s O r d e r F o r m o n the patient's m e d i c a l chart. The W o r l d Health Organization unit o f measure Defined D a i l y D o s e ( D D D )  w a s u t i l i z e d to  facilitate the c o m p a r i s o n b e t w e e n d o s a g e s o f d i f f e r e n t c l a s s e s o f a n t i d e p r e s s a n t s p r e s c r i b e d to s t u d y s u b j e c t s ( W e r t h e i m e r , 1986). T h e D D D  is a t e c h n i c a l u n i t o f m e a s u r e m e n t e s t a b l i s h e d o n  the b a s i s o f the a s s u m e d a v e r a g e d a i l y m a i n t e n a n c e d o s e f o r the target drug's m a i n i n d i c a t i o n i n adults, a n d a s s u m e s p a t i e n t s are c o m p l i a n t . T h e d a i l y d o s e (mg) p r e s c r i b e d f o r e a c h p a t i e n t was  70 Figure  5 F l o w c h a r t o f the s e c o n d a r y o u t c o m e s f o r the r a n d o m i z e d c l i n i c a l trial p h a s e o f the clinical screening study  First Letter  Case-finding phase  w  Follow-up Letter  End of 8 weeks  Screened positive  N o letter  F i r s t letter  Follow-up letter Secondary outcomes  End of 8 weeks  d i v i d e d b y the W o r l d H e a l t h O r g a n i z a t i o n D D D  r e p o r t e d i n the A T C  O r g a n i z a t i o n , 1999), to d e t e r m i n e the p r o p o r t i o n o f the D D D  71 Index ( W o r l d Health  p r e s c r i b e d p e r p a t i e n t p e r day.  2.2.2.2 Implementation  E n r o l l m e n t i n the r a n d o m i z e d c l i n i c a l trial b e g a n i n N o v e m b e r 1996, w h e n letters o f n o t i f i c a t i o n w e r e sent to the p r i m a r y c a r e p h y s i c i a n s i n the first 2 l o n g - t e r m c a r e facilities. A n 8w e e k p i l o t s t u d y w a s c o n d u c t e d w i t h the 140 p a t i e n t s at the 2 f a c i l i t i e s to p e r m i t a m o r e a c c u r a t e e s t i m a t i o n o f p h y s i c i a n c l u s t e r s i z e a n d s a m p l e s i z e (see M e t h o d s 2.2.2.5.4). F e e d b a c k  was  s o l i c i t e d f r o m f a c i l i t y M e d i c a l D i r e c t o r s s a n d n u r s i n g s t a f f r e g a r d i n g the letters o f n o t i f i c a t i o n u s e d i n the s t u d y to c o m m u n i c a t e w i t h p r i m a r y c a r e p h y s i c i a n s .  Since no substantive  m o d i f i c a t i o n s w e r e m a d e to the s t u d y p r o t o c o l f o l l o w i n g the p i l o t study, p a t i e n t s e n r o l l e d i n the first 2 f a c i l i t i e s w e r e r e t a i n e d i n the f i n a l study. A d d i t i o n a l l o n g - t e r m care f a c i l i t i e s w e r e t h e n s e q u e n t i a l l y e n r o l l e d i n the study. T h e rate o f e n r o l l m e n t w a s b a s e d o n the a v a i l a b i l i t y o f r e s e a r c h a s s i s t a n t s a n d the a b i l i t y to a r r a n g e a m u t u a l l y c o n v e n i e n t t i m e f o r f a c i l i t y o r i e n t a t i o n a n d t r a i n i n g o f e x p e r i e n c e d c a r e a i d e s to a d m i n i s t e r the G D S .  F a c i l i t y e n r o l l m e n t w a s c o m p l e t e d i n N o v e m b e r 1997, 1 y e a r after the  study began. 2.2.2.3 Evaluation ofphysician response to the  letters of notification  T h e p r i m a r y o u t c o m e o f p h y s i c i a n response w a s d e e m e d to h a v e o c c u r r e d i f the p h y s i c i a n p r e s c r i b e d a n antidepressant f o r d e p r e s s i o n o r r e f e r r e d the patient f o r a p s y c h i a t r i c o r m e n t a l h e a l t h c o n s u l t a t i o n w i t h i n 4 w e e k s o f r a n d o m i z a t i o n to the e a r l y group. T h e p h y s i c i a n r e s p o n s e rates f o r b o t h the e a r l y a n d d e l a y e d g r o u p s w e r e a l s o e v a l u a t e d at 4 w e e k s a n d 8 w e e k s after the initial letter, to d e t e r m i n e w h e t h e r the f r e q u e n c y o f i n t e r v e n t i o n was e v e n t u a l l y the s a m e i n the t w o groups.  The  o v e r a l l p h y s i c i a n r e s p o n s e rate o f the two-stage p r o t o c o l a n d the 9 5 % c o n f i d e n c e interval was a l s o estimated.  I n f o r m a t i o n o n d e m o g r a p h i c s , diagnoses, m e d i c a t i o n usage, c o - m o r b i d i t y , G D S  72 score,  M M S E score, H A M - D score, p h y s i c i a n data a n d m o r t a l i t y w e r e c o m p a r e d f o r patients w i t h a n d w i t h o u t a p h y s i c i a n r e s p o n s e 8 w e e k s after the initial letter to c h a r a c t e r i z e a n y d i f f e r e n c e s b e t w e e n the groups. D o c u m e n t a t i o n f r o m the patient's m e d i c a l r e c o r d i n the f a c i l i t y w a s u s e d to d e t e r m i n e the t i m e u n t i l p h y s i c i a n response, the t y p e o f a c t i o n t a k e n b y p h y s i c i a n s w h o v i s i t e d their patients, the r e s p o n s e to the f o l l o w - u p letter, a n d the pattern o f a n t i d e p r e s s a n t d o s i n g initially a n d 8 w e e k s after r a n d o m i z a t i o n . 2.2.2.4 Cluster randomization and  group assignments ofpatients  Patients w h o s c r e e n e d p o s i t i v e f o r p o s s i b l e m a j o r d e p r e s s i o n a n d p r o v i d e d i n f o r m e d c o n s e n t w e r e a s s i g n e d to 1 o f 2 r a n d o m i z e d groups: e a r l y ( e x p e r i m e n t a l ) o r d e l a y e d (control). T h e nature o f this s t u d y m a d e cluster r a n d o m i z a t i o n a m o r e a p p r o p r i a t e m e t h o d to use t h a n s i m p l e r a n d o m i z a t i o n . I n s i m p l e r a n d o m i z a t i o n f o r c l i n i c a l trials, e a c h s u b j e c t i n the s t u d y is a s s i g n e d at r a n d o m to a n e x p e r i m e n t a l o r c o n t r o l group. R a n d o m i z a t i o n r e d u c e s the l i k e l i h o o d that the e x p e r i m e n t a l a n d the c o n t r o l g r o u p w i l l differ w i t h r e s p e c t to a n i m p o r t a n t p r o g n o s t i c factor, w h e t h e r k n o w n o r u n k n o w n ( H e n n e k e n s et a l , 1987). W i t h s i m p l e r a n d o m i z a t i o n , the i n d i v i d u a l p a t i e n t is b o t h the u n i t o f r a n d o m i z a t i o n a n d the u n i t o f analysis. I n s o m e studies, h o w e v e r , the u n i t o f a n a l y s i s r e m a i n s the i n d i v i d u a l subject, b u t i t is either statistically u n d e s i r a b l e o r i m p r a c t i c a l to r a n d o m i z e i n d i v i d u a l s ( D o r m e r et al., 1981; H a u c k et al., 1991). I n these situations, it has b e c o m e c o m m o n to r a n d o m i z e b y g r o u p s o r clusters, s u c h as f a m i l y units, c o m m u n i t i e s , o r m e d i c a l p r a c t i c e s . T h e r e are a n u m b e r o f r e a s o n s w h y c l u s t e r r a n d o m i z a t i o n m a y b e preferred. O n e o f the reasons m a y b e f o r a d m i n i s t r a t i v e c o n v e n i e n c e , s u c h as r a n d o m i z i n g b y h o s p i t a l or b y p h y s i c i a n p r a c t i c e ( B u c k et al., 1982). A s e c o n d r e a s o n m a y b e to m i n i m i z e c o n t a m i n a t i o n , s u c h as i n trials w h e r e i t m a y n o t b e p o s s i b l e to k e e p e x p e r i m e n t a l a n d c o n t r o l patients separate ( D o r m e r et al., 1981). A n o t h e r r e a s o n f o r cluster r a n d o m i z a t i o n m a y b e to e n h a n c e a d h e r e n c e to a b e h a v i o r a l m o d i f i c a t i o n intervention, w h e r e b y a n entire f a m i l y w o u l d f o r m  73 the c l u s t e r ( H a u c k et al., 1991). A f u r t h e r r e a s o n to use c l u s t e r r a n d o m i z a t i o n m a y b e to a v o i d ethical d i l e m m a s , s u c h as w h e n p h y s i c i a n s m a y n o t b e w i l l i n g to treat s o m e patients d i f f e r e n t l y t h a n others ( H a u c k et a l , 1991). D u r i n g the d e s i g n p h a s e o f the p r e s e n t study, i t was r e c o g n i z e d that s o m e p h y s i c i a n s m i g h t b e r e s p o n s i b l e f o r m a n a g i n g the m e d i c a l care o f m o r e t h a n 1 p a t i e n t w h o m e t the entry criteria. C o n f o u n d i n g c o u l d o c c u r i f a p h y s i c i a n was to h a v e patients i n b o t h the e a r l y a n d the d e l a y e d group. I n addition, p h y s i c i a n s m a y h a v e a t e n d e n c y to a p p r o a c h the treatment o f d e p r e s s i o n i n their e l d e r l y patients i n a s i m i l a r m a n n e r b a s e d o n their t r a i n i n g a n d e x p e r i e n c e ( H a u c k et al., 1991). A s w e l l , the p h y s i c i a n s m a y h a v e patients w i t h s i m i l a r characteristics w h o h a v e s e l e c t i v e l y c h o s e n a s p e c i f i c t y p e o f m e d i c a l practice. T h e s e t e n d e n c i e s w o u l d result i n a c o r r e l a t i o n b e t w e e n treatment d e c i s i o n s w i t h i n the physician's practice. It is i n situations l i k e this that cluster r a n d o m i z a t i o n is m o r e appropriate than simple randomization. P h y s i c i a n p r a c t i c e s i n the present study w e r e r a n d o m i z e d to either the e a r l y o r the d e l a y e d g r o u p w h e n the first p a t i e n t o f that p h y s i c i a n s c r e e n e d p o s i t i v e a n d c o n s e n t e d to participate i n the trial. A n y s u b s e q u e n t patients o f that p h y s i c i a n w h o m e t the entry criteria f o r the trial w e r e a s s i g n e d to the s a m e cluster. T h e c o m p u t e r - g e n e r a t e d r a n d o m i z a t i o n s c h e d u l e f o r e a r l y a n d d e l a y e d p h y s i c i a n s was p r e p a r e d i n v a r i a b l e b l o c k s b y the s t u d y s u p e r v i s o r . P h y s i c i a n s at e a c h f a c i l i t y w e r e r a n d o m i z e d i n d e p e n d e n t l y , due to the s t a g g e r e d entry t i m e o f the facilities i n t o the study. T h e stratified r a n d o m i z a t i o n b y facility b a l a n c e d f o r s u c h potential inter-facility d i f f e r e n c e s as patient l e v e l o f care, staffing levels, f a m i l y support, s o c i o - e c o n o m i c status o f patients, a n d e t h n i c b a c k g r o u n d . 2,2.2.5 Sample size estimate  2.2.2.5.1 A priori estimates o f base rate a n d p h y s i c i a n r e s p o n s e rate T h e r e are n o g o o d estimates i n the literature o f the i n c i d e n c e o f n e w antidepressant p r e s c r i p t i o n s o r p s y c h i a t r i c c o n s u l t a t i o n s i n p o t e n t i a l l y d e p r e s s e d l o n g - t e r m care patients. T o  74 estimate a n e x p e c t e d b a s e rate o f n e w antidepressant orders a n d m e n t a l h e a l t h referral i n n e w l y treated long-term care patients, the m e d i c a l r e c o r d s o f 2 l o n g - t e r m care facilities w e r e r e v i e w e d retrospectively. T h e 8 9 patients i n the first facility r e c e i v e d 6 n e w antidepressant orders i n a p e r i o d o f 142 days, w h i c h w a s e q u i v a l e n t to 1 . 3 % p e r 4 w e e k s . T h e 51 patients i n the s e c o n d facility r e c e i v e d 4 n e w antidepressant orders i n a p e r i o d o f 3 0 4 days, w h i c h w a s e q u i v a l e n t to 0 . 7 % p e r 4 w e e k s . N o n e w m e n t a l health referrals w e r e n o t e d i n the m e d i c a l r e c o r d s d u r i n g the p e r i o d o f t i m e o f the retrospective review.  B a s e d o n the results o f this assessment, p r i m a r y care p h y s i c i a n s  r o u t i n e l y p r e s c r i b e d n e w antidepressant m e d i c a t i o n to a p p r o x i m a t e l y 1 % t o 2 % o f the long-term care patients d u r i n g a f o u r - w e e k period.  S i n c e t h e c o g n i t i v e f u n c t i o n o f those patients w a s  u n k n o w n , it is p o s s i b l e that the b a s e rate f o r patients w i t h o n l y m i l d c o g n i t i v e f u n c t i o n (e.g. M M S E score > 19) c o u l d b e h i g h e r than the 1 % t o 2 % range. I n a d d i t i o n , p h y s i c i a n s a n d n u r s i n g staff w o u l d b e a w a r e that a study w a s b e i n g c o n d u c t e d i n the facility a n d m i g h t b e alerted i n d i r e c t l y t o a patient's s y m p t o m s o f depression.  C o n s e q u e n t l y , f o r s a m p l e size estimation, t h e f r e q u e n c y o f  p h y s i c i a n response i n the d e l a y e d (control) g r o u p (base rate) w a s c o n s e r v a t i v e l y estimated to b e 3 % i n the 4 w e e k p e r i o d p r i o r to r e c e i v i n g the letter o f notification. A priori, w e d e c i d e d that it w a s c l i n i c a l l y important t o d e t e r m i n e w h e t h e r the s c r e e n i n g  p r o t o c o l l e d t o a p h y s i c i a n response w i t h i n 4 w e e k s i n > 2 0 % o f patients i d e n t i f i e d as h a v i n g s y m p t o m s o f depression. T h i s rate w a s b a s e d o n t w o c o n s i d e r a t i o n s . T h e first c o n s i d e r a t i o n w a s that the m e a n p o s i t i v e p r e d i c t i v e v a l u e o f the G D S to i d e n t i f y patients w i t h m a j o r d e p r e s s i o n w a s about 7 0 % , as p r e v i o u s l y e s t a b l i s h e d i n o u r r e s e a r c h c o m p a r i n g the G D S a n d H A M - D i n a s i m i l a r long-term care s a m p l e (Soon, 1994a). T h e s e c o n d c o n s i d e r a t i o n w a s that s i n c e p h y s i c i a n s are n o t r e q u i r e d to visit patients i n long-term care facilities m o r e f r e q u e n t l y than e v e r y 6 m o n t h s , it w a s a n t i c i p a t e d that p h y s i c i a n s w o u l d assess n o m o r e than a p p r o x i m a t e l y o n e - t h i r d ( 3 3 % ) o f the patients w i t h i n the first 4 w e e k s after notification. T h e r e f o r e , the f r e q u e n c y o f p h y s i c i a n response d u r i n g the first 4 w e e k s after r a n d o m i z a t i o n i n the e a r l y g r o u p w a s estimated t o b e about 2 3 % (chance o f  depression: 7 0 % x c h a n c e o f b e i n g s e e n b y p h y s i c i a n : 3 3 % ) .  A conservative figure o f 2 0 %  75 was  selected as the e x p e c t e d p h y s i c i a n r e s p o n s e rate to ensure that an a d e q u a t e s a m p l e size w o u l d be enrolled. 2.2.2.5.2 S a m p l e size estimate f o r s i m p l e  randomization  S a m p l e size estimates f o r s i m p l e r a n d o m i z a t i o n  were calculated for a range o f levels o f  s i g n i f i c a n c e ( a ) , p o w e r (1 - P), a n d differences i n p h y s i c i a n r e s p o n s e rate b e t w e e n the e a r l y a n d d e l a y e d g r o u p s 4 w e e k s after the initial letter was sent to the e x p e r i m e n t a l g r o u p ( T a b l e 2). T h e c a l c u l a t i o n s w e r e b a s e d o n the f o r m u l a f o r c o m p a r i n g two p r o p o r t i o n s ( D a w s o n - S a u n d e r s et al., 1990): n = [ z V 2n (l-7t ) - zp V n (l-7t ) + n (1-7X ) ] a  c  c  t  t  c  2  C  Tic  w h e r e n = s a m p l e s i z e i n each g r o u p , z = t w o - t a i l e d z v a l u e r e l a t e d to the n u l l h y p o t h e s i s , zp = l o w e r o n e - t a i l e d z v a l u e r e l a t e d to the a l t e r n a t i v e h y p o t h e s i s , n = p r o p o r t i o n i n treatment group, n = proportion in control group a  c  t  A c o n s e r v a t i v e s a m p l e size o f 37 subjects/group was c h o s e n f o r the e s t i m a t i o n u s i n g cluster randomization, b a s e d o n a=0.05, p o w e r = 9 0 % , a n d a d i f f e r e n c e o f 1 7 % . 2.2.2.5.3 S a m p l e s i z e a d j u s t m e n t f o r c l u s t e r  randomization  C l u s t e r r a n d o m i z a t i o n r e d u c e s the e f f e c t i v e s a m p l e size i n a c l i n i c a l trial. T h e m a g n i t u d e o f the r e d u c t i o n is related to the intracluster c o r r e l a t i o n K, as d e s c r i b e d i n the f o l l o w i n g  formula  ( D o r m e r et al., 1981; H a u c k et a l , 1991): Effective Sample Size (ESS) = (Kn)/[1 + (n - 1 ) K]  w h e r e K = n u m b e r o f r a n d o m i z e d clusters, n = m e a n cluster size, K= intracluster c o r r e l a t i o n T h e intracluster c o r r e l a t i o n is a quantitative a s s e s s m e n t o f the o b s e r v e d s i m i l a r i t y o f r e s p o n s e s w i t h i n clusters ( H a u c k et al., 1991). W h e n the o u t c o m e o f interest is d i c h o t o m o u s , s u c h as p r e s e n c e or a b s e n c e o f p h y s i c i a n r e s p o n s e i n the present study, the i n t r a c l u s t e r c o r r e l a t i o n  76 Table 2 E s t i m a t e s o f s a m p l e s i z e r e q u i r e d t o detect a d i f f e r e n c e b e t w e e n e a r l y ( e x p e r i m e n t a l ) a n d d e l a y e d ( c o n t r o l ) g r o u p u s i n g simple r a n d o m i z a t i o n  Power Level o f significance D i f f e r e n c e : TIT - Tic 25-5 25-3 25-1 20-5  Power=90% a = 0.05  power=90% a = 0.01  power=95% a = 0.05  Power=95% a = 0.01  38 24 13 63  20-3  37  20-1  24  51 31 16 84 48 29  49 32 18 82 49 35  64 40 21 106 62 40  1  S a m p l e s i z e p e r g r o u p c h o s e n f o r e s t i m a t i o n u s i n g cluster r a n d o m i z a t i o n  77 p a r a m e t e r o f interest i s K ( D o n n e r et a l , 1981). F o r c o n t i n u o u s r e s p o n s e s , t h e a n a l a g o u s i n t r a c l u s t e r c o r r e l a t i o n p a r a m e t e r is p ( D o n n e r et al., 1981). I f a l l m e m b e r s o f a cluster are treated o r r e s p o n d t o a treatment alike, t h e n n o additional i n f o r m a t i o n is g a i n e d b y a n a l y z i n g m o r e t h a n 1 subject per group, a n d the intracluster correlation K is 1 ( E S S = K ) . I f i n d i v i d u a l m e m b e r s o f a cluster are as d i s s i m i l a r i n r e s p o n s e as if he o r she w a s a m e m b e r o f different g r o u p s , t h e n the intracluster correlation K is 0 ( E S S = K n ) . Unfortunately, t h e intracluster c o r r e l a t i o n o b s e r v e d i n various research settings is n o t w e l l d o c u m e n t e d . It is k n o w n that n o n f a m i l i a l clusters, s u c h as m e d i c a l practice units, t e n d to h a v e s m a l l v a l u e s o f K i n the 0.01 0.05 r a n g e ( H a u c k et al., 1991). A s w e l l , larger clusters t e n d t o h a v e s m a l l e r i n t r a c l u s t e r c o r r e l a t i o n s ( H a u c k et al., 1991). W h e n t h e c l u s t e r is a h o u s e h o l d o r a f a m i l y , t h e intracluster c o r r e l a t i o n t e n d s t o b e h i g h e r ( B u c k et al., 1982). T h e m a g n i t u d e o f the intracluster correlation K f o r t h e p r e s e n t s t u d y w a s u n k n o w n . T h e effects o f a K v a l u e r a n g i n g f r o m 0.01 t o 0.75 o n the s a m p l e s i z e w a s e x p l o r e d ( T a b l e 3). B a s e d o n t h e i n f o r m a t i o n a v a i l a b l e , w e c o n s e r v a t i v e l y s e l e c t e d a K v a l u e o f 0.75 t o e s t i m a t e a total s a m p l e s i z e o f 96 patients f o r the t w o g r o u p s . T o s u m m a r i z e the a priori s a m p l e s i z e estimation: Assuming a 17% difference exists between the early (20%) and delayed (3%) groups in the prescription of an antidepressant or referral to mental health services at 4 weeks from randomization, 96 subjects would provide power of 90% to detect a difference this large at a two-sided alpha of 0.05.  A conservative  total s a m p l e s i z e o f 1 0 0 patients w a s c h o s e n , w i t h patients t o b e  r a n d o m i z e d i n clusters t o t h e t w o g r o u p s . P r e v i o u s r e s e a r c h i n a s i m i l a r s a m p l e e s t a b l i s h e d that 20 o f 3 1 5 l o n g - t e r m care patients m e t t h e s t u d y entry c r i t e r i a w i t h a G D S s c o r e o f > 13 a n d a M M S E s c o r e o f > 19 ( S o o n , 1994a). B a s e d o n this i n f o r m a t i o n , it w a s e s t i m a t e d that a n initial s a m p l e o f a b o u t 1,575 patients w o u l d b e n e c e s s a r y t o i d e n t i f y 1 0 0 patients w h o m e t t h e casef i n d i n g entry criteria.  78 Table 3 R e l a t i o n b e t w e e n i n t r a c l u s t e r c o r r e l a t i o n , i n f l a t i o n factor, e f f e c t i v e s a m p l e size, a n d t h e s a m p l e s i z e u s i n g b o t h simple a n d cluster r a n d o m i z a t i o n  K a p p a (K)  Inflation Factor 1+ (n-1) K  Effective sample size (ESS)  S a m p l e size  ( 2 N ) f o r simple  randomization  (Kn/l+(n-l)K)  74  S a m p l e size for  cluster  randomization 2N[l+(n-l)Kl  0.0 0.01 0.03 0.05 0.1 0.5  1.0 1.004 1.012 1.02 1.04 1.2  74 74 73 73 71 62  74 75 75 76 77 89  0.75  1.3  57  96  1.0  1.4  53  104  cc=0.05, p o w e r (1 - (5) = 9 0 % , d i f f e r e n c e i n p r o p o r t i o n s nj - no. = 2 0 - 3 , c l u s t e r s i z e n = 1.4, K = 0.75, N = s a m p l e s i z e o f e a c h g r o u p  79 2.2.2.5.4 P i l o t s t u d y i n t w o l o n g - t e r m care facilities to v e r i f y the p h y s i c i a n r e s p o n s e rate f o r n e w antidepressant orders o r referral to m e n t a l h e a l t h services, a n d p h y s i c i a n cluster s i z e T o s u p p o r t the e s t i m a t e d 2 0 % p h y s i c i a n r e s p o n s e rate f o l l o w i n g n o t i f i c a t i o n a n d 3 % b a s e rate, a n e i g h t - w e e k p i l o t s t u d y w a s c o n d u c t e d i n 2 l o n g - t e r m c a r e f a c i l i t i e s w i t h a total o f 1 4 0 patients. S e v e n t e e n p a t i e n t s s c r e e n e d p o s i t i v e , w i t h a p h y s i c i a n r e s p o n s e rate o f 2 4 % at 4 w e e k s a n d 3 5 % at 8 w e e k s . N o n e o f the p a t i e n t s r a n d o m i z e d to the d e l a y e d ( c o n t r o l ) g r o u p r e c e i v e d a n antidepressant order o r mental health referral during the four-week interval f o l l o w i n g r a n d o m i z a t i o n a n d p r i o r to p h y s i c i a n n o t i f i c a t i o n . T w e l v e p h y s i c i a n s w e r e r e s p o n s i b l e f o r the m a n a g e m e n t o f the 17 p a t i e n t s e n r o l l e d i n t h e trial, y i e l d i n g a m e a n c l u s t e r s i z e o f 1.4 p a t i e n t s / p h y s i c i a n . S i n c e the p i l o t s t u d y s u p p o r t e d the e s t i m a t e d b a s e rate, p h y s i c i a n r e s p o n s e rate, a n d c l u s t e r s i z e c a l c u l a t e d a priori, p a t i e n t s i n the r e m a i n i n g l o n g - t e r m c a r e facilities w e r e s c r e e n e d a n d t h e n e n r o l l e d i n the r a n d o m i z e d c l i n i c a l trial as o r i g i n a l l y d e s i g n e d . 2.2.2.6 Rating instruments  B a s e l i n e assessments f o r the r a n d o m i z e d c l i n i c a l trial w e r e c o m p l e t e d w i t h i n 1 w e e k o f the c a s e - f i n d i n g p h a s e o f the s t u d y i n e a c h facility, after the p a t i e n t h a d s i g n e d the i n f o r m e d c o n s e n t a n d p r i o r to r a n d o m i z a t i o n i n t o the trial. T h e b a s e l i n e assessment i n s t r u m e n t s f o r the r a n d o m i z e d c l i n i c a l trial w e r e the G D S , the M M S E , a n d the H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H A M - D ) . U s e o f the G D S a n d M M S E h a s b e e n p r e v i o u s l y d e s c r i b e d i n M e t h o d s 2.2.1.3. T h e s t u d y investigator a d m i n i s t e r e d the H A M - D to patients e n r o l l e d i n the r a n d o m i z e d trial, but w a s u n a w a r e o f the a c t u a l s c o r e o n t h e r e s e a r c h n u r s e - a d m i n i s t e r e d G D S u n t i l a l l assessments h a d b e e n c o m p l e t e d at the facility. T h i s s a f e g u a r d p r o t e c t e d the i n d e p e n d e n c e o f the assessment o f s y m p t o m s o f d e p r e s s i o n as m u c h as p o s s i b l e . A l l patient assessments w e r e c o n d u c t e d b e t w e e n 1000 a n d 1 6 0 0 h o u r s s i n c e patient m o o d s a n d c o g n i t i v e f u n c t i o n m a y e x p e r i e n c e d i u r n a l f l u c t u a t i o n s ( K o e n i g et al., 1992b).  80 2.2.2.6.1 H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H A M - D ) T h e H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H A M - D ) is the standard c l i n i c i a n - r a t e d scale f o r the e v a l u a t i o n o f d e p r e s s i o n ( C a r r o l l et al., 1973; E n d i c o t t et al., 1981; Y e s a v a g e et al., 1983). T h e H A M - D has b e e n s h o w n to b e u s e f u l as a d i a g n o s t i c t o o l ( S c h n u r r et al., 1976), a n d has b e e n u s e d e x t e n s i v e l y f o r patient s e l e c t i o n a n d f o l l o w - u p i n r e s e a r c h studies o n d e p r e s s i o n ( B e c h et al., 1993; W i l l i a m s , 1988).  Studies h a v e suggested that a d m i n i s t r a t i o n o f the H A M - D is l e a r n e d r a p i d l y  ( H a m i l t o n , 1967; W i l l i a m s , 1988), a n d that it is a reliable a n d v a l i d i n d i c a t o r o f b o t h s e v e r i t y o f d e p r e s s i o n a n d c h a n g e d u r i n g treatment ( H a m i l t o n , 1967; K n e s e v i c h et al., 1977). T h e H A M - D has b e e n u s e d w i d e l y t o d i s t i n g u i s h b e t w e e n d i f f e r e n t degrees o f d e p r e s s i o n ( C a r r o l l et al., 1 9 7 3 ; K n e s e v i c h et al., 1977) i n antidepressant c l i n i c a l trials, i n c l u d i n g those i n v o l v i n g e l d e r l y subjects ( G e o r g o t a s et al., 1989b; K a t z et al., 1990; R o o s e et a l , 1998).  W h i l e the H A M - D w a s not  d e s i g n e d w i t h r e f e r e n c e to standard r e s e a r c h criteria f o r d e p r e s s i o n s u c h as the D S M - I I I o r R e s e a r c h D i a g n o s t i c C r i t e r i a ( G a l l a g h e r , 1986)), items from the H A M - D are i n c l u d e d i n the S c h e d u l e f o r A f f e c t i v e D i s o r d e r s a n d S c h i z o p h r e n i a ( E n d i c o t t et al., 1981). T h e reliability a n d v a l i d i t y o f the H A M - D h a v e b e e n e s t a b l i s h e d i n e l d e r l y patients w i t h c o g n i t i v e i m p a i r m e n t a n d c o m o r b i d p h y s i c a l illness, w h e n u s e d w i t h i n f o r m a t i o n from r e l i a b l e i n f o r m a n t s ( M u l s a n t et al., 1994). S i n c e the scale e m p h a s i z e s s o m a t i c s y m p t o m s , i n t e r v i e w e r s m u s t be t r a i n e d to differentiate b e t w e e n s o m a t i c s y m p t o m s from c o m o r b i d m e d i c a l illness a n d those o f a p s y c h o g e n i c o r i g i n ( G a l l a g h e r , 1986). T o m a x i m i z e the reliability o f the instrument, the structured i n t e r v i e w g u i d e f o r the H A M - D ( W i l l i a m s , 1988) w a s u s e d c o n s i s t e n t l y b y the i n v e s t i g a t o r d u r i n g the s t u d y ( A p p e n d i x 11). T r a i n i n g to a d m i n i s t e r the H A M - D c o n s i s t e d o f d i d a c t i c sessions a n d o b s e r v a t i o n o f patient i n t e r v i e w s b y s e n i o r geriatric p s y c h i a t r y s t a f f at 2 p s y c h o g e r i a t r i c r e f e r r a l hospitals. T h e m e a n t i m e to a d m i n i s t e r the structured H A M - D is less than 3 0 m i n u t e s ( G a l l a g h e r , 1986; S o o n , 1994a; W i l l i a m s , 1988).  81 T h e o r i g i n a l H A M - D scale c o n t a i n e d 2 1 items, a l t h o u g h H a m i l t o n r e c o m m e n d e d that o n l y the first 17 items that r e l a t e d to d e p r e s s i o n b e u s e d i n c a l c u l a t i n g the total s c o r e ( H a m i l t o n , 1960). T h e 17-item v e r s i o n o f the H A M - D is t h e m o s t frequently u s e d i n c l i n i c a l r e s e a r c h ( G a l l a g h e r , 1986; S o n g et al., 1993). W h e n a s s i g n i n g the i t e m a r a t i n g score, i n t e r v i e w e r s m u s t c o n s i d e r b o t h the i n t e n s i t y a n d frequency o f a s y m p t o m ( W i l l i a m s , 1988). N i n e i t e m s a r e s c o r e d o n a 3-point scale a n d 8 items a r e s c o r e d o n a 5-point scale, w i t h h i g h e r v a l u e s r e f l e c t i n g m o r e severe symptomatology.  T h e m a x i m u m total score o n the 17-item r a t i n g s c a l e is 5 2 ( C a r r o l l et al., 1973).  In t h e e l d e r l y , i n v e s t i g a t o r s h a v e n o t e d that q u e s t i o n s about s e x u a l i t y o f t e n m a k e t h e i n d i v i d u a l b e c o m e d e f e n s i v e a n d m a y n o t a p p r o p r i a t e ( Y e s a v a g e et al., 1983). O n the r e c o m m e n d a t i o n  of a  c o n s u l t a n t geriatric psychiatrist, a n d c o n s i s t e n t w i t h other n u r s i n g h o m e studies ( K a t z et al., 1990), the t w o - p o i n t i t e m o n s e x u a l i t y a n d g e n i t a l s y m p t o m s w a s o m i t t e d a n d s c o r e d a s zero. T h e r e f o r e , i n t h e present study, t h e m a x i m u m score o n the structured H A M - D w a s 50. W h i l e v a r i o u s g u i d e l i n e s are u s e d to interpret the total H A M - D s c o r e ( F a n k h a u s e r et al., 1987), the c u t - o f f scores employed  i n this s t u d y w e r e t h e f o l l o w i n g : n o t d e p r e s s e d ( 0 - 6); m i l d l y d e p r e s s e d (7-17);  m o d e r a t e l y d e p r e s s e d (18 - 24); a n d s e v e r e l y d e p r e s s e d (> 25) ( E n d i c o t t et al., 1981). In c l i n i c a l d r u g trials, the m o s t c o m m o n l y u s e d m e a s u r e o f i m p r o v e m e n t is a r e d u c t i o n o f > 5 0 % o f the total H A M - D s c o r e ( B e c h et al., 1993). T h e n u m b e r o f patients w h o b e c o m e s y m p t o m free d u r i n g the c o u r s e o f a c l i n i c a l study is t y p i c a l l y d e s i g n a t e d as those patients w i t h a f i n a l H A M D s c o r e o f 7 o r less ( B e c h et al., 1993). 2.2.2.7 Statistical analysis of the randomized clinical trial component  D e m o g r a p h i c characteristics o f the patients a n d the primary care physicians i n the randomized  c l i n i c a l trial w e r e c o m p i l e d a n d d e s c r i b e d , u s i n g p e r c e n t , m e a n s , r a n g e s a n d  standard deviations (± S D ) where appropriate. Concomitant medication use, antidepressant p r e s c r i b i n g patterns, p h y s i c i a n r e s p o n s e  to the follow-up  questionnaire, reasons f o r  antidepressant  discontinuation, and reasons  82 f o r e x c l u s i o n o f p a t i e n t s f r o m the 2 6 - w e e k  assessment were also tabulated and analyzed descriptively. T h e p r i m a r y o u t c o m e w a s the d i f f e r e n c e i n the f r e q u e n c y o f p h y s i c i a n r e s p o n s e b e t w e e n the e a r l y a n d d e l a y e d g r o u p s o f patients 4 w e e k s after the i n i t i a l letter o f n o t i f i c a t i o n was d e l i v e r e d to p h y s i c i a n s i n the e a r l y g r o u p . T h e intent-to-treat a n a l y s i s i n c l u d e d a l l patients w h o s e p h y s i c i a n r e c e i v e d a letter o f n o t i f i c a t i o n o f the d e p r e s s i o n s c r e e n i n g results. C h i - s q u a r e tests, a d j u s t e d f o r c l u s t e r r a n d o m i z a t i o n ( D o n n e r et al., 1994), c o m p a r e d the p r o p o r t i o n o f e a r l y a n d d e l a y e d patients w i t h a response, u s i n g a t w o - t a i l e d a l p h a o f 0.05 A d j u s t e d c h i - s q u a r e tests w e r e a l s o c a l c u l a t e d f o r the s e c o n d a r y  (see M e t h o d s 2.2.2.5). o u t c o m e s , the d i f f e r e n c e  between groups at 4 a n d at 8 w e e k s after p h y s i c i a n n o t i f i c a t i o n . S t a t i s t i c a l a n a l y s e s  were  c o n d u c t e d u s i n g Statistical software b y Statsoft. U n i v a r i a t e logistic r e g r e s s i o n was c o n d u c t e d to e x p l o r e patient, p h y s i c i a n a n d  long-term  care f a c i l i t y characteristics p o s s i b l y a s s o c i a t e d w i t h the p h y s i c i a n s ' c l i n i c a l d e c i s i o n s to intervene f o l l o w i n g r e c e i p t o f the letters o f n o t i f i c a t i o n . T h e d e p e n d e n t v a r i a b l e , p h y s i c i a n response,  was  c o d e d as " 1 " (antidepressant order o r referral to m e n t a l h e a l t h s e r v i c e s w i t h i n 8 w e e k s o f p h y s i c i a n n o t i f i c a t i o n ) o r as " 0 " (no response w i t h i n 8 w e e k t i m e p e r i o d ) . T h e u n i v a r i a t e analyses u s e d the W a l d test f o r c o n t i n u o u s a n d o r d i n a l variables, a n d the chi-square test f o r d i c h o t o m o u s v a r i a b l e s ( H o s m e r Jr. et al., 1989). V a r i a b l e s w i t h a u n i v a r i a t e P-value o f < 0.15 ( H o s m e r Jr. et al., 1989) a n d a d d i t i o n a l c l i n i c a l l y important v a r i a b l e s w o u l d be c o n s i d e r e d as p o s s i b l e candidate v a r i a b l e s f o r future m u l t i v a r i a b l e l o g i s t i c r e g r e s s i o n m o d e l l i n g . L o g i s t i c r e g r e s s i o n was c o n d u c t e d u s i n g SPSS 8.0 for Social Sciences).  Windows ( S t a t i s t i c a l P a c k a g e f o r 0  83 2.3  THERAPEUTIC OUTCOMES STUDY  2.3.1 D e s i g n o f t h e t h e r a p e u t i c o u t c o m e s s t u d y T h e p r i m a r y g o a l o f the therapeutic o u t c o m e s study was to assess the b e n e f i t s o f d r u g therapy w i t h r e g a r d to s y m p t o m s o f depression, p h y s i c a l f u n c t i o n a n d other m e a s u r e s o f q u a l i t y o f life i n a g r o u p o f n e w l y treated l o n g - t e r m care patients w i t h s y m p t o m s o f d e p r e s s i o n , a n d a s i m i l a r g r o u p o f untreated patients. T h e o u t c o m e s s t u d y w a s a p r o s p e c t i v e o b s e r v a t i o n a l m u l t i c e n t r e open-label study o f antidepressant medication prescribed b y primary care physicians and a d m i n i s t e r e d c o n t i n u o u s l y f o r at least 4 w e e k s . S i n c e the s t u d y was d e s i g n e d to c o r r e s p o n d to actual c l i n i c a l p r a c t i c e i n l o n g - t e r m care facilities, the p r i m a r y care p h y s i c i a n w a s able to change, d i s c o n t i n u e , o r adjust the d o s a g e o f the antidepressant d u r i n g the 2 6 - w e e k s t u d y a c c o r d i n g to h i s o r her assessment o f the c l i n i c a l n e e d s o f the patient. T h e s t u d y s c h e d u l e i n v o l v e d a n  assessment  p e r i o d o f 2 6 - w e e k s d u r a t i o n , w i t h c l i n i c a l a s s e s s m e n t o f p a t i e n t o u t c o m e s at 6, 12 a n d 2 6 w e e k s for t r e a t e d p a t i e n t s a n d at 2 6 w e e k s f o r u n t r e a t e d patients. T r e a t e d patients w e r e r e c r u i t e d f r o m a m o n g those w h o p a r t i c i p a t e d i n the  randomized  c l i n i c a l trial. In a d d i t i o n , patients not i n the r a n d o m i z e d c l i n i c a l trial, but w h o w e r e initiated o n antidepressant therapy a n d met entry criteria w e r e a l s o r e c r u i t e d . Patients w h o d i d not r e c e i v e n e w l y p r e s c r i b e d antidepressant therapy f r o m their p h y s i c i a n d u r i n g the r a n d o m i z e d c l i n i c a l trial w e r e e n r o l l e d i n the untreated g r o u p f o r the therapeutic o u t c o m e s study. T h e s e patients w e r e i n h e r e n t l