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Atypical antipsychotic agents; Peas in a pod or chalk and cheese? Singh, Ajeet B; Nierenberg, Andrew A; Yatham, Lakshmi N; Berk, Michael Aug 1, 2014

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COMMENTARY Open AccessAtypical antipsychotic ageam, thtyindatrgids ceestwEuropean countries. Interestingly, their data indicate thatonce generic risperidone was available, it was prescribed Differential efficacy profiles of atypical antipsychoticsSingh et al. BMC Medicine 2014, 12:126http://www.biomedcentral.com/1741-7015/12/126PO Box 281, Geelong 3220, AustraliaFull list of author information is available at the end of the articleless (as a proportion of all atypical antipsychotic scripts),and there was a wide variance between countries in theproportion of risperidone scripts that were generic versusbrand name. Furthermore, among newly initiated patientsAtypical antipsychotics are now among the most widelyused agents and the bulk of this use - at least in westerncountries - is for non-psychotic indications, principallymood disorders. The efficacy of individual atypical anti-psychotic agents varies by both condition (schizophreniaor bipolar disorder) and phase of illness (particularly bipo-lar depression). As an exemplar, clozapine has established* Correspondence: a.singh@deakin.edu.au1IMPACT Strategic Research Centre, School of Medicine, Deakin University,allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.Please see related article: http://www.biomedcentral.com/1741-7015/12/98.Keywords: Atypical antipsychotics, Risperidone, Bipolar, Schizophrenia, Generic, Health economicsBackgroundIn an economic climate characterised by rising publicdebt, sluggish economic growth and rapidly expandinghealth care expenditures, there is increasing pressure onrestraining the pace of growth of the health care budget.Pharmaceutical expenditure is a large and growing seg-ment of this budget and an attractive target for cost reduc-tion. In an article recently published in BMC Medicine,Godman and colleagues [1] present data from an inter-national retrospective association study of risperidoneprescribing rates 20 months before and 20 months af-ter cheaper generic brands became available in severalprescribed atypical antipsychotics there was no increasedprescribing of generic risperidone when it may have beena valid treatment option. The authors argue that their datahave significant implications for health care costs andsuggest that health authorities encourage prescribingof cheaper generics versus allowing prescribers to tailortreatment to patient needs based on differential medica-tion side effect and efficacy profiles. We submit that thirdparty payers mandating the use of cheaper generic atypicalantipsychotics as first line agents in schizophrenia and bi-polar disorders raises important but complex issues meri-ting debate.chalk and cheese?Ajeet B Singh1*, Andrew A Nierenberg1,6, Lakshmi N YathAbstractWith escalating health expenditure and a shrinking pursepatented versus generic medications in general, and for aMedicine article, Godman and colleagues presented dataantipsychotic risperidone, arguing for authorities to mandequivalence of atypical antipsychotics. This commentary abetween atypical antipsychotics and important inter-indivAccess to a broad range of atypical antipsychotics enableefficacy and adverse effects profile in order to meet the neffectiveness of treatment. Restriction of agent choice riskpoorer outcomes and greater costs of care. A balance be© 2014 Singh et al.; licensee BioMed Central LCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.nts; Peas in a pod or7 and Michael Berk1,2,3,4,5ere is increased focus on the cost efficacy of stillpical antipsychotics in particular. In a recent BMCicating poor uptake of the off patent atypicale its greater use. This is under the assumption of clinicalues that there are clinically meaningful differencesual heterogeneity in clinical response and tolerability.linicians to tailor care, taking consideration of differentialds of individual patients with improved real worlddetracting from optimal clinical care, with possibleeen encouraging use of cheapest in class agent andtd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Singh et al. BMC Medicine 2014, 12:126 Page 2 of 4http://www.biomedcentral.com/1741-7015/12/126greater symptom efficacy than other atypical antipsycho-tics in the treatment of schizophrenia [2], but due to sideeffect and toxicity profile is not used as a first line agent[3]. Subtle differences in efficacy between other atypicalantipsychotics in the treatment of schizophrenia - particu-larly in improving negative symptoms - arguably exist, butit is unclear whether this is an artefact of methodologicalvariance [2,4]. Importantly, while atypical antipsychoticshave equal efficacy in treating mania, they clearly have dif-ferential efficacy in the depressive phase of bipolar dis-order [5,6], with agents such as quetipine and lurasidonedemonstrating efficacy while aripiprazole, ziprasidone andrisperidone have failed to show consistent benefit and,hence, are not recommended for the management of thedepressive phase of bipolar disorder [6]. Similarly, in uni-polar depression, only quetiapine has been shown to be ef-fective in monotherapy. Atypical antipsychotics are alsowidely used as adjuncts to antidepressants to treat re-fractory unipolar major depression, and here again, whilequetiapine, aripiprazole, risperidone and olanzapine haveefficacy based on meta-analytical data, the number neededto treat for response and remission are much higher andthe number needed to harm are much lower for olanza-pine compared with other atypical antipsychotics [7]. Fur-thermore, another atypical antipsychotic ziprasidone doesnot have demonstrated efficacy [8,9]. Differential efficacyof atypical antipsychotics for other clinical uses has beenless thoroughly investigated, but risperidone may haveutility in dementia associated agitation and obsessive com-pulsive disorder, but poorer efficacy for generalized anx-iety disorder than some other atypical agents, such asquetiapine [10]. Indeed, this inconsistent pattern of effi-cacy of antipsychotic agents in non-psychotic disorders ar-gues strongly against the presence of a class effect. Theseagents, in reality, have markedly divergent pharmaco-dynamics and pharmacokinetics and, while there is con-sensus that activity against dopamine type 2 receptors isnecessary for antipsychotic efficacy [11], there is consider-able uncertainty as to which of the multiplicity of actionsthese agents have may drive their effects in mood disor-ders [12,13].Differential tolerability profiles of atypical antipsychoticsAtypical antipsychotics also have widely differing side ef-fect and tolerability profiles. This is of critical clinicalimportance as tolerability is one factor driving adherence[14], and medication adherence markedly influencesboth clinical course and cost of care [15,16]. In the caseof risperidone, more extrapyramidal side effects, greaterprolactin elevation, and greater weight gain than withsome other atypical antipsychotics have been describedin recent high profile reviews [2,17]. Elevation of prolac-tin appears to be particularly marked with risperidonecompared to other atypical agents [2] and is associatedwith hypogonadism, reproductive dysfunction, gyneco-mastia and bone loss [18]. Osteoporosis and fracturerisk is an adverse effect of diverse psychotropic agentsattracting increasing recent attention, and one wherevery clear between-agent differences are apparent [19,20].Risperidone is, however, less associated with the metabolicsyndrome than other agents, particularly olanzapine, que-tiapine and clozapine [6]. Trend level differences for allcause medication discontinuation have been noted withrisperidone, trending toward greater discontinuation thansome other atypical agents – putatively due to differentialside effect profiles and tolerability [2,17]. As adverseevents are idiosyncratic and unpredictable, the avail-ability of various atypical antipsychotics enables patientand prescriber to tailor treatment based on differentialside effects profile, and this may enhance adherence [21].This clinical need is reflected in international clinical prac-tice guidelines on the management of schizophrenia andbipolar disorder – with several atypical agents consideredfirst line options in patient care [3,6].ConclusionsFinite health resources make cost effective use of phar-maceuticals an important societal issue. Atypical anti-psychotics have differing tolerability and efficacy profiles.Effectiveness in naturalistic settings is highly dependenton subjective efficacy as well as on adherence, which inturn is related to long and short term side effect profiles.While access to cheaper generic atypical antipsychoticsoffers an opportunity for more cost effective care, it isnot without risks. Mandating switching to a generic aty-pical antipsychotic without any corresponding clinicalindication may result in increased risk of relapse, re-duced adherence, poorer outcomes and greater ultimatehealth care costs [22,23]. Reducing access to a range ofatypical agents as first line treatment will hamper tailor-ing of medication to individual patient needs and prefe-rence, reducing clinical effectiveness and making it moredifficult for clinicians to follow current best practiceguidelines [3,6]. Nevertheless, there will be some clinicalinstances where use of a more cost-effective genericatypical agent (either first line or as switch to agent)may be appropriate, and ways for third party payersto encourage such behaviour merit further exploration.In the absence of data, we urge policy makers to strike abalance between tailored effective care (with choice ofatypical antipsychotic agent) versus mandated use ofcheapest in class agent. To obtain the data necessary forevidence-based policy, it would be useful to invest incomparative effectiveness studies that focus on: 1) out-comes of tailored versus mandated care, and 2) suf-ficiently powered cluster-randomized studies of keyatypical antipsychotics. Our patients’ health deserves noless.Singh et al. BMC Medicine 2014, 12:126 Page 3 of 4http://www.biomedcentral.com/1741-7015/12/126Competing interestsAB Singh, is a self-employed psychiatrist and a casual speaker for ServierAustralia, Astra Zeneca Australia, Lilly Australia, Pfizer Australia, LundbeckAustralia. Michael Berk has received Grant/Research Support from the NIH,Cooperative Research Centre, Simons Autism Foundation, Cancer Council ofVictoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue,Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb,Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis,Mayne Pharma, Servier and Woolworths, has been a speaker for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag,Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, andserved as a consultant to Astra Zeneca, Bioadvantex, Bristol Myers Squibb,Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck and Servier. MB issupported by a NHMRC Senior Principal Research Fellowship 1059660.Lakshmi N. Yatham has been a member of the advisory boards/speaker forAstrazeneca, Bristol Myers Squibb, Dinippon Sumamito, GSK, Janssen, Lilly,Lundbeck, Merck, Pfizer, Servier and Sunvion. He has also received researchgrants from Astrazeneca, BMS, DSP, GSK, Janssen, Lilly, Pfizer, Servier, andValeant. Andrew A. Nierenberg. Disclosures June 2014: Consultant: AmericanPsychiatric Association, Appliance Computing Inc. (Mindsite), Basliea, BrainCells, Inc., Brandeis University, Bristol Myers Squibb, Clintara, Corcept, DeyPharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly andCompany, EpiQ, L.P./Mylan Inc., Forest, Genetech, GlaxoSmithKline, HoffmanLaRoche, Infomedic, Lundbeck, Medavante, Merck, Methylation Sciences,Naurex, Novartis, PamLabs, PGx Health, Ridge Diagnostics Shire, Schering-Plough, Sunovion, Takeda Pharmaceuticals, Targacept, and Teva; consultedthrough the MGH Clinical Trials Network and Institute (CTNI) for AstraZeneca, Brain Cells, Inc, Dianippon Sumitomo/Sepracor, Johnson andJohnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire,Schering-Plough, Targacept and Takeda/Lundbeck Pharmaceuticals. Grants/Research support: AHRQ, Brain and Behavior Research Foundation, Cephalon,Elan, Forest, Marriott Foundation, Mylan, NIMH, PamLabs, PCORI, PfizerPharmaceuticals, Shire, and Takeda. Honoraria: Belvoir Publishing, Universityof Texas Southwestern Dallas, Hillside Hospital, American Drug UtilizationReview, American Society for Clinical Psychopharmacology, Baystate MedicalCenter, Columbia University, CRICO, Dartmouth Medical School, IMEDEX,Israel Society for Biological Psychiatry, Johns Hopkins University, MJConsulting, New York State, Medscape, MBL Publishing, National Associationof Continuing Education, Physicians Postgraduate Press, SUNY Buffalo,University of Wisconsin, University of Pisa, University of Michigan, Universityof Miami, APSARD, ISBD, SciMed, Slack Publishing and Wolters KlowerPublishing. Stock: Brain Cells, Inc., Medavante. Copyrights: Clinical PositiveAffect Scale and the MGH Structured Clinical Interview for the MontgomeryAsberg Depression Scale exclusively licensed to the MGH Clinical TrialsNetwork and Institute (CTNI). Speaker Bureaus: none since 2003.Author informationAS – Consultant Psychiatrist, The Geelong Clinic, Australia. Senior ClinicalLecturer and Research Fellow, Impact Strategic Research Centre, School ofMedicine, Deakin University, Australia. AN - Professor of Psychiatry, HarvardMedical School, Co-Director of the Bipolar Clinic and Research Program,and Associate Director of the Depression Clinical and Research Program,Massachusetts General Hospital. LY -Professor of Psychiatry, University ofBritish Columbia; Regional Head, Department of Psychiatry Vancouver CoastalHealth and Providence Health Care; Regional Program Medical DirectorMental Health and Addictions Vancouver Coastal Health and ProvidenceHealth Care. MB – Alfred Deakin Professor of Psychiatry, School of Medicine,Deakin University. Director, IMPACT Strategic Research Centre (Innovation inMental and Physical Health and Clinical Treatment). Professorial ResearchFellow, The Florey Institute of Neuroscience and Mental Health, OrygenResearch Centre and the Department of Psychiatry, University of Melbourne.NHMRC Senior Principal Research Fellow.Authors’ contributionsAll authors contributed to conception of the article, were involved in editingand revision of the manuscript. All authors read and approved the finalmanuscript.Author details1IMPACT Strategic Research Centre, School of Medicine, Deakin University,PO Box 281, Geelong 3220, Australia. 2Orygen Youth Health Research Centre,Centre for Youth Mental Health, University of Melbourne, 35 Poplar Road,Parkville, Victoria 3052, Australia. 3Barwon Health and the Geelong Clinic,Swanston Centre, PO Box 281, Geelong, Victoria 3220, Australia. 4FloreyInstitute for Neuroscience and Mental Health, Kenneth Myer Building, RoyalParade, Parkville, Australia. 5Department of Psychiatry, University ofMelbourne, 3052 Parkville, Australia. 6Bipolar Clinic and Research Program,Massachusetts General Hospital, Harvard Medical School, 50 Staniford Street,Boston, MA 02114-2517, USA. 7Department of Psychiatry, University of BritishColumbia, Vancouver, BC V6T 1Z3, Canada.Received: 10 July 2014 Accepted: 10 July 2014Published: 1 August 2014References1. 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BMC Health Serv Res 2009, 9:32.doi:10.1186/s12916-014-0126-1Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSingh et al. BMC Medicine 2014, 12:126 Page 4 of 4http://www.biomedcentral.com/1741-7015/12/126Cite this article as: Singh et al.: Atypical antipsychotic agents; Peas in apod or chalk and cheese? BMC Medicine 2014 12:126.Submit your manuscript at www.biomedcentral.com/submit


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