The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence

THE OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL PSYCHOPHARMACOLOGY SUPPLEMENT VOLUME 77 • 2016 • SUPPLEMENT 3 SUPPLEMENT TO THE JOURNAL OF CLINICAL PSYCHIATRY

Part 1: Efficacy and Safety of LAIs ��4 Part 2: Practical Considerations and Recommendations Regarding LAI Use ��16 Date Release/Review ofOriginal How to Credit Obtain Credit Designation Accreditation Statement Target Audience Statement ofNeed andPurpose CME Objectives Overview SupportedbyeducationalgrantsfromJanssenPharmaceuticals,Inc.,administeredScientificAffairs,LLC,andAlkermes. Financial Support J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ CME Information How to Credit Obtain The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence It isIt illegal to post this copyrighted PDF on any website. to lessfrequent dosingschedules. should claim only the credit commensurate with the extent of their participation intheactivity. participation their should claimonlythecredit commensurate with the extent of The latest review of this material was June2016. this The latest review of medication. improved relationships withphysicians cangreatly facilitate patients’ to necessity consistently takeschizophreniathe understandingof antipsychotics and lacktraining inusingthem. in relapses misunderstanding of LAIs have limited the use of this approach. this have limited theuseof LAIs misunderstanding of This supplement was publishedinSeptember 2016 andiseligible 1Credits for Category 1.25AMAPRA will beissuedto you within4–6weeks viae-mail. evaluation,ofcompletion acertificate activity the posttest (grade of70%orhigher)andsubmission the Upon successful completion of for completing thisactivity, pleasecomplete theposttest andevaluation onhttp://programs.rmei.com/SZ/Assessment/posttest.html. Green CMEby Einstein offering College supports your ofMedicine forAlbert Request Credit online. you If wishto receive acknowledgment Einstein 1Credits for College Category designatesThe amaximum of1.25AMAPRA ofMedicine Albert activity thisenduring Education, LLC. Einstein College isaccredited ofMedicine Albert by theACCME to provide continuing medicaleducation for physicians. Council for Continuing Education Medical (ACCME) through Einstein thejoint providership College andRMEIMedical ofMedicine ofAlbert hasbeenplannedandimplemented Accreditation inaccordanceThis activity the withtheaccreditation requirements andpolicies of isdesigned to educateThis activity psychiatrists andothermental healthcare professionals whomanagepatients withschizophrenia. hasbeensignificantly correlatedhospitalization withadherence andgapsinantipsychotic medication use.The of risk Schizophrenia treatment hascome alongway withtheinitialdevelopment ofantipsychotics antipsychotics. andthenatypical After completing thiseducational initiative, you shouldbeableto: and experience for allstakeholders. cost outcomes; andprovides guidance onwhento consider LAItreatment aswell that asbestclinicalpractices canmaximize acceptability antipsychotics, andamongLAIs;reviews theeffectofLAItreatment oneffectiveness, patient-centered delivery, service andhealthcare antipsychotics injectable (LAIs)versus evaluates placebo, theefficacy,This CMEactivity long-acting versus safety, oral andtolerability of However, effective symptom management stillremains aproblem inalarge numberofpatients withschizophrenia. with apersonwhohasnomedication gaps. comparedeffect ofmedication gapsreveals hospitalization that even missing1to 10days ofmedication theoddsof leadsto twice nearly occurrence, dueto often lapsesinmedication adherence. increase insuicide attempt rate antipsychotic whenatypical therapy isinterrupted. Expiration Date: September30,2017 Date:Release September 30,2016 http://programs.rmei.com/SZ/Assessment/posttest.html • • • 15. 14. 13. Psychiatry Mol BL. Roth JA, ray 12. 11. 10. 1. 9. 8. 7. 6. 5. 4. 3. 2. I S E

nstitute collaborative discussionswithpatients that includeincorporating LAIsasapotential management option

P K L C K Z O K H A C G Blackwell; 1995:949–500. Blackwell; K H W valuate andinterpret efficacy, safety, andoutcomes data for LAIsfor schizophrenia elect themostappropriateelect patients for LAIintervention eucht C, Heres S, Kane JM, et al. Schizophr Res al. et JM, Kane S, Heres C, eucht atel MX, Haddad PM, Chaudhry IB, et al. J Psychopharmacol al. et IB, Chaudhry PM, Haddad MX, atel J Clin Psychiatry JClin JM. Kane SJ, eith ipursky RB, Menezes NM, Streiner DL. Schizophr Res DL. Streiner NM, Menezes RB, ipursky CNS Spectr CNS JM. ane 2007;12(suppl Spectr. CNS JM. ane 17):21–26. J Clin Psychiatry JClin al. et M, Borenstein M, T,ishimoto Nitta J Clin Psychiatry CU. JClin orrell arpenter WT, Koenig JI. Neuropsychopharmacology. 2008;33(9):2061–2079. doi:10.1038/sj.npp.1301639 Neuropsychopharmacology. JI. WT,Koenig arpenter PubMed Evid Based Ment Health Ment Based Evid G. O, Remington gid irsch S, Barnes T. The clinical treatment of schizophrenia with antipsychotic medication. In: Hirsch S, Weinberger D, eds. Schizophrenia D, eds. Weinberger S, Hirsch In: medication. antipsychotic with schizophrenia of treatment T. clinical The Barnes S, irsch erings Erkens RM, JA. J Nerv Ment Dis Ment JNerv al. et CA, D, Boyer Mechanic M, lfson eiden PJ, Kozma C, Grogg A, et al. Psychiatr Serv al. et A, PJ, Grogg eiden C, Kozma 13 5 andhospitalizations, doi:10.1017/S1092852900025852 PubMed . 2006;11(suppl 14):1–7, doi:10.1017/S1092852900025852 7–8. quiz Pharmacoepidemiol Drug Saf . 2013;74(8):e16.. doi:10.1038/sj.mp.4002062 PubMed 2007;12(10):904–922.. doi:10.1038/sj.mp.4002062 12 10,11 and reduce risk of hospitalization compared withoralhospitalization antipsychotics. andreduce of risk . 2003;64(11):1308–1315. doi:10.4088/JCP.v64n1105 PubMed 2003;64(11):1308–1315. . Their usecanimprove schizophrenia outcomes, includingsymptom reduction doi:10.4088/JCP.12117tx3c 7 The ofrelapse risk increases withmore timespent offanantipsychotic. doi:10.1136/ebmental-2012-100906 PubMed . 2012;15(4):92. doi:10.1136/ebmental-2012-100906 PubMed . 2011;127(1–3):83–92.. doi:10.1016/j.schres.2010.11.020 PubMed . 2004;55(8):886–891. doi:10.1176/appi.ps.55.8.886. 2004;55(8):886–891. PubMed doi:10.1002/pds.837 PubMed doi:10.1002/pds.837 2003;12(5):423–424. . . 2014;152(2–3):408–414. doi:10.1016/j.schres.2013.08.001 PubMed 2014;152(2–3):408–414. . . 1999;187(12):721–729. doi:10.1097/00005053-199912000-00003 1999;187(12):721–729. . PubMed . 2013;74(10):957–965. doi:10.4088/JCP.13r08440 2013;74(10):957–965. . PubMed 4 Patient education regarding theneedfor consistent medication iscritical, and doi:10.1177/0269881109104882 PubMed 2010;24(10):1473–1482.. doi:10.1177/0269881109104882 Education andPlannerProviders and Albert Einstein College ofMedicine.and Albert isjointly providedThis by activity Education, RMEIMedical LLC, 15 LAIusecanalsobelimited becausecliniciansare unfamiliarwithLAI © 2016Copyright Physicians Postgraduate Press, Inc. 9 Injectable medications canincrease adherence, Injectable due ™ through September2017. 14 However, stigma and 8 3 12 There isalsoan Relapse isacommon Relapse 6 and reduction andreduction Looking at Looking the ™ . Physicians 1,2 . Oxford, UK: UK: . Oxford,

1 It is illegal to post this copyrighted PDF on any website. 2 For [email protected]. reprints orpermissions, contact ♦ Acknowledgments Disclaimer Disclosure Use ofUnlabeled Financial Disclosure Faculty The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence It isIt illegal to post this copyrighted PDF on any website. Einstein CME Reviewer:Einstein CME Victor B. Hatcher, PhD, Associate and Director for Dean CME, Professor andMicrobiology, ofMedicine Einstein Peer Reviewer: Bruce J., Professor MD Schwartz, ofClinicalPsychiatry, ofPsychiatry andBehavioral Sciences, Department have given to their written permission benamed. (RMEI) for theirassistance and editing thismanuscript. inwriting nopotentialThe ofinterest individualsmentioned conflicts report and (Beaver County Psychiatric Services). P.The authorsthankMark Bowes, PhD; Jacqueline Brooks, MBBCh,MRCPsych (RMEI);andAmy Reeve Discussion contribution at the roundtable was provided by Stephen M. Calloway (MO HealthNet Division) and Suzanne Vogel-Scibilia, MD manufacturer’s information, product andcomparison withrecommendations of otherauthorities. patient’stheir conditions andpossiblecontraindicationsclinicians withoutevaluation of ondangersinuse, review ofany applicable Any procedures, medications, orothercourses ofdiagnosis ortreatment shouldnotbeusedby discussedorsuggested inthisactivity professional development. The information asaguidelinefor isnotmeant presented to patient serve management. inthisactivity Participants have animpliedresponsibility to use thenewlyacquired information to enhance patient outcomes andtheirown contraindications, andwarnings. 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Any presenter whosedisclosed The “Conflict ofInterest Disclosure Policy” Einstein College inany requires ofMedicine CMEactivity ofAlbert participating that faculty Faculty: Leslie Citrome, MD, ofPsychiatry andBehavioral Sciences, MPH,Department New York College, Medical Valhalla, New York Christoph U.Chair: ofMedicine, School Correll, ofPsychiatry Shore-LIJ Medicine, andMolecular Hofstra MD,Department North Mark P.Mark Bowes, PhD, hasnoaffiliations to discloserelevant to theactivity. MD, BeaverSuzanne Vogel-Scibilia, County Psychiatric (Non-CME/CE hasaffiliations withNAMI ( Speakers’ Services, Bureau ) andOtsuka Stephen M.Calloway hasnoaffiliations to discloserelevant to theactivity. Amy Reeve Education,, RMEIMedical LLC, hasnoaffiliations to discloserelevant to theactivity. Jacqueline Brooks, MBBCh, MRCPsych Education,, RMEIMedical LLC, hasnoaffiliations to discloserelevant to theactivity. Victor B. Hatcher, PhD, hasnoaffiliations to discloserelevant to theactivity. (Consulting ). Bruce J. MD,hasaffiliations withOtsuka Schwartz, John M.Kane, MD,hasaffiliations withAlkermes, EliLilly, FORUM,Forest, Genentech, Lundbeck, Intra-Cellular Therapies, Janssen/J&J, Olfson,Mark MD,). MPH,hasaffiliations withSunovion (Salary (Consulting andJanssen( Research); Alkermes John Lauriello,). Benckiser MD,hasaffiliations withReckitt Peter Quantum, and M.Haddad, MD,hasaffiliations withJanssen,Lundbeck, Otsuka, Teva (Consulting); Janssen,Lundbeck, andOtsuka Leslie Citrome, MD, MPH,hasaffiliations withAlexza, Alkermes, Bristol-Myers Squibb, Allergan, Ingelheim, Boehringer EliLilly, FORUM, Montefiore Center, Medical Bronx, New York Albert Einstein College ofMedicine,Albert Montefiore Center, Medical Bronx, New York IslandJewishHealthSystem, Shore-Long North ofBehavioral HealthServices, John M.Kane, MD,Department JeffersonStephen M.Calloway City, Services, ofSocial , MOHealthNetDivision,Department Missouri. Olfson,Mark MD, ofPsychiatry, MPH,Department Columbia University, New York, New York John Lauriello, ofPsychiatry, MD,Department Columbia, Missouri University ofMissouri, Peter M.Haddad, MD,University ofManchester, Salford, United Kingdom Christoph U. Correll, MD,hasaffiliations withAcadia, Actavis, Alkermes, EliLilly, FORUM,Genentech,Lehrman Gerson Group, Hempstead, New York, andRecognition andPrevention Program, (RAP) The Hospital, Zucker Hillside GlenOaks, New York

). Services Vanguard). Research Group (Ownership Reviva,Roche, Sunovion, and Otsuka, TevaHonorarium ( ); MedAvante (Consulting); Janssen,Genentech, Lundbeck, andOtsuka and ). Services (Non-CME/CE Pfizer,Otsuka, Shire, Sunovion, Takeda, and Teva (Speakers’ Bureau ); Bristol-Myers Squibb, EliLilly,). J&J, andPfizer (Ownership Merck, Sunovion, Takeda, Teva,(Consulting); Alkermes,Vandaand Valeant, Allergan, AstraZeneca, Novartis, Janssen,Jazz,Lundbeck, Merck, Pfizer, Noven, Novartis, Medivation, Mylan, Genentech, Janssen,Jazz,Lundbeck, Merck, Otsuka, Benckiser, Reckitt Reviva,Shire, ). Services (Non-CME/CE Sunovion, Supernus, Takeda, and Teva Pfizer, (Consulting); FORUM,Janssen/J&J, Lundbeck, Otsuka, ProPhase, Sunovion, and Takeda Intra-Cellular Lundbeck, MedAvante, Pfizer,Therapies, Medscape, Otsuka, Janssen/Johnson&Johnson(J&J), ProPhase, Reviva, Roche, ofPsychiatry,and Department The Hospital, Zucker Hillside NewHyde Park, New York © 2016Copyright Physicians Postgraduate Press, Inc. J ClinPsychiatry 2016;77(suppl 3)

It is illegal to post this copyrighted PDF on any website. G they remain practice.they inclinical underutilized are among most the treatments effective in psychiatry, yet ence and relapse, long-acting injectable antipsychotics (LAIs) role of LAIs treatmentin the of schizophrenia in order to roundtable was to examine current regarding evidence the roundtable this that was31,2015.The of held goal October therapy among patients, families, and providers. and access to treatment, and negative perceptions of injectable sicians, inaccurate perceptions about safety and efficacy, cost many reasons, including lack of familiarity among many phy- supplementthis demonstrate, will LAIs for may underused be therapy and reduce relapse progression.risk and disease As important treatment option for helping patients remain on remission or recovery. functional psychotic therapy, few are able to attain long-lasting symptom ofepisode psychosis often respond well to anti initial very - or schizophrenia.first-episode Although patients with a first of LAIs inearly-phase on efficacy the inparticular focused history of treatment poor adherence. Recent research has may with a patients benefit those beyond population the of and occupational disabilities. However, it is likely that LAIs havewho frequent relapses accompanied by marked social inpatientstraditionally used been with chronic schizophrenia J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. This supplement was developed from aconsensus antipsychotics and strong the nonadher between link iven of frequency high the suboptimal adherence to oral families, payers, andotherstakeholdersto better characterize therole ofLAIsinthetreatment ofschizophrenia. functioning. This evidence review, recommendations may discussion,andsummary helpclinicians, patients, medication dosing, fear of needles, and the potential for patient due to harm relapses and associated loss of ment, easeofuse, substance misuse, access patient andcost, autonomy, stigma, socialsupport, control over weighing theuseofLAItherapy, includingmedication adherence, relapse andseverity, risk cognitive impair and cost issues. that shouldbeconsidered alsoidentified anumberofadditionalfactors The when participants negative attitudes about LAIs,knowledge, and resource LAI use in current practice, including clinician lack of inhealthcarereductions utilization oroverall costs withLAIs. panelidentified several toThe barriers expert differences studies, Some but notall, canbeusedto helpguideLAIselection. have demonstrated significant effects, includingweight gain,metaboliceffects, extrapyramidal symptoms, elevation, andprolactin andthese of LAIs in early-phase schizophrenia patients.considerably adverse in their propensity to LAIs vary cause certain ofLAIsversus oral antipsychotics,efficacy butrecent database andrandomized controlled studiesfavor theuse similar to oneanotherinterms ofschizophrenia relapse prevention. thedemonstrated Study design impacts are to superior placebo for acute andmaintenance treatment ofschizophrenia and, ingeneral, appearto be groups: patients, healthcare professionals, families, andpayers. The evidence review demonstrated that LAIs whenchoosinganLAIversus anoralacteristics antipsychotic, from of4different theperspectives stakeholder and unmetneedsrelated to LAIs. Participants were alsoaskedto ofseveral rate patient theimportance char and cost-effectiveness ofLAIsandto develop recommendations practical regarding theclinicaluse, education, on themanagement ofschizophrenia andLAIsmetto evaluate theevidence surrounding theefficacy, safety, treatment strategy for2015,agroup disease. October patients of8 experts In withearly-phaseorfirst-episode patients withchronic schizophrenia, recent research hassuggested that theymay alsoprovide aneffective remain underutilized in clinical practice. Although LAIs are used to maintain typically treatment adherence in The Use of Long-Acting Injectable Antipsychotics Long-acting injectable antipsychoticsLong-acting injectable (LAIs)are amongthemosteffective treatments inpsychiatry, yet they Mark Olfson, MD, MPH; Leslie Citrome, MD, MPH; Peter M.Haddad, MD; Lauriello, MD; John in Schizophrenia: Evaluatingin Schizophrenia: theEvidence 5 LAIs may provide an Christoph U.Correll, MD (Chair); 1–4 © Copyright 2016 by Physicians Postgraduate Press, Inc. Press, Postgraduate 2016 Physicians by © Copyright LAIs have Stephen M.Calloway; - importance of each characteristic and stakeholder group was patients, care health professionals, families, and payers. The teristic from of perspectives 4different the stakeholder groups: oral antipsychotic. rated They importance the of eachcharac- patienteral characteristics choosing when an versus LAI an develop recommendations for treatment, research, and policy. information the cussed presented information and the used to patient and selection, optimizing use.Participants LAI dis- siderations value design, and in clinical trial cost-effectiveness, presentations related to LAIs, including efficacy, safety, con- mercial insurance company. Six attendees provided brief settings, National the Alliance on Mental Illness, and acom- representatives from and academic community psychiatry unmet research related needs to LAIs. Attendees included recommendations regarding use, education, clinical the and and LAIs met to evaluate and evidence the to develop of aset to improve appropriate implementation of LAIs. schizophrenia as well as care health and education policy goals additional research to better is needed understand for use LAI practice.in clinical The panel areasidentified also in which develop recommendations practical specific, for their use METHODS Participants were asked also to rate importance the - of sev A group on of management the 8experts of schizophrenia © 2016Copyright Physicians Postgraduate Press, Inc. (J 2016;77[suppl3]:1–24) ClinPsychiatry and John M.Kane, MDand John dx.doi.org/10.4088/JCP.15032su1 - -

3 It is illegal to post this copyrighted PDF on any website. and standard deviation of the pooled ratings. pooled and standardthe deviation of andscenario stakeholder group was presented with mean an The consensus LAI. opinion on value the of LAIs for each that deciding when other trumps aspects all extremely inappropriate characteristic or acharacteristic therapy, given enhanced attention as compared to usual an impact onhad adherence toparticipation oral itself Correll etal ill patients.ill symptoms administered when as first-line therapy inacutely controlled (RCTs) trials show that agents these reduce also 4 For [email protected]. reprints orpermissions, contact ♦ demonstrating efficacy. discontinued prematurely on basis of the interim analyses 4weeks 6weeks). oror 881mg 882every every 4weeks), and aripiprazole(400 mg every lauroxil (441,662, 4weeks),weeks aripiprazole or 405mg every monohydrate 3months),every olanzapine pamoate 2 (150or 300mg every peridone palmitate 4weeks or 273–819mg (39–156mg every 3months, tobiweekly once every including of intervals - pali second-generation antipsychotics (SGAs) administered at reduction in relapses with long-acting formulations of schizophrenia, advocated for relapse prevention inpatients with chronic Oral Antipsychotics, andAmong LAIs ofLAIs Efficacy Versus Placebo, Versus P other deciding when all to aspects an and use LAI 1 important characteristic or acharacteristic that trumps evaluated using a 10-point in 10 which scale, adherent to oral antipsychotics. LAIs care, inclinical were and also they more likely to be treatment were likely less severely receiving than those ill importantly, patients randomized to willing be to blinded hadwho received antipsychotics for months or years. Most RCTs enrolled chronically patients ill with schizophrenia criteria and ways the relapse inwhich Most was defined. tain limitations. The studies inpatient varied enrollment thatrecognized meta-analysis the was associated with cer appeared similarfor LAIs and oral therapy, it should be analysis suggestthis that resultsthe treatment of outcomes with older studies of first-generation antipsychotics (FGAs). 1year), (eg, as was moretime for typical alonger of period patientswould had all followed have been observed been underestimate magnitude true the of improvement that treated with LAIs versus oral antipsychotics. rates of relapse and all-cause discontinuation for patients A meta-analysisnia. of 21 RCTs (N antipsychotics for treatment the of patients with schizophre - meta-analyses have of versus compared LAI oral efficacy the with schizophrenia are summarized inTable 1. have compared antipsychotics LAI with inpatients placebo It isIt illegal to post this copyrighted PDF on any website. art Notably, newer studies of SGALAIs were sometimes Placebo-controlled RCTs have demonstrated also placebo. versus LAIs Although LAIs are typically LAIs versus oral versus LAIs antipsychotics.

1:E 7–9 fficacy 6 data from placebo-controlled, randomized

and 11,17 This early discontinuation may S afe 18,19 ty It likely is also that trial Many and several trials =

5,176) found similar of L AI = 10,11 against an extremely 7–9,11–17 18 s Although Although RCTs that using

an - for therapy. LAI dations for identifying patients should who considered be research. Finally, supplement the concludes with recommen- LAIs for patients and providers, and additional topics for regarding treatment and patient education selection, about ofissues recommendations use. Aseries inLAI is provided and safety of examines second LAIs, the part practical while risperidone, or haloperidol; n zole, olanzapine, quetiapine, paliperidone extended-release, versus investigator’s choice of oral antipsychotic (aripipra - antipsychotic agents are summarized inTable 2. practice. The results of studies that compared LAIs to oral also Supplementaryalso eTable 1at ing to LAIs found can be in references 48 through 72(see studies that compared outcomes before and after switch- discussed later Implicationsdiscussed (see of Study Design). than RCTs, have they drawbacks, are which methodological mirror-image studies assess more representative patients form (hazard ratio, 0.36;P =.007). pitalization compared same with the antipsychotics inoral were associated with a significantly reduced risk of rehos anoate, haloperidol decanoate, or decanoate) perphenazine depot antipsychotics (risperidone depot, zuclopenthixol- dec nationwide cohort study conducted inFinland (N were lower also (14.8% vs 20.9%; palmitate than to oral antipsychotics (P significantly longer for patients randomized to paliperidone psychiatric hospitalization. that LAIs were superior to oral antipsychotics for preventing A meta-analysis of 25mirror-image studies (N psychotics, with as each his patient or her own serving control. patients receive LAIs after an treatment initial with oral antipsychotics is demonstrated by mirror-image studies, inwhich Table 3. that compared one versus LAI another are summarized in of one versus LAI efficacy another. The results of studies (relativerisperidone reduction, risk 84.7%;P randomized to an antipsychotic LAI versus 33% with oral or exacerbation of psychosis was noted for 5%of patients a 12-month study of patients, 86first-episode relapse and/ of LAIsdence for inearly-phase efficacy schizophrenia. In nonadherence. Two recently published RCTs provided- evi patients,sode apopulation that is characterized by frequent rater-blinded treatment with paliperidone palmitate (n schizophrenia were randomized to up to 2years of open-label, another study, recently (≥ diagnosed antispsychotics Table (see 2). open-label studyized showed no advantage for LAIs over oral rates are generally similar with different LAIs, differences The first portion of this supplement this efficacy the reviews The first portion of Strong for evidence superiority the of LAIs over oral anti- There LAIs. is little versus LAIs for evidence superior in early-phaseLAIs useful may or especially first-epi be - © 2016Copyright Physicians Postgraduate Press, Inc. 76–80 Although symptom improvement and relapse J ClinPsychiatry 2016;77(suppl 3) 47 39 The results of mirror-image = PSYCHIATRIST 363). P 75 = A very recent Avery random- 1–5 years) patients with .032). In a prospective, 74 .0191); relapse rates relapse =.0191); Time to relapse was . COM =

4,066) found < 20–46 ). Although .001). 73 = 2,588), = 43 352) 352) In In - It is illegal to post this copyrighted PDF on any website. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 1. Long-Acting Injectable Antipsychotics vs Placebo: Randomized Controlled Trials Study/ Study Duration Definition of Relapse- % % Hp Country N Design (wk) Inclusion Criteria Related Outcome Mean Age, y Male at BL Chronicity Drug Tx n Dosing Efficacy Safety Kane et al12 554 DB, PC 12 SCZ Change in PANSS total 38 75 About 76% Dx RIS LAI 400 25, 50, or 75 mg/ Clinical improvement 47%, AEs similar in all groups 2003/USA score 50 paranoid 2 wk 48%, and 39%, respectively SCZ vs PBO OLA 404 210 or 300 mg/ Lauriello 466 DB, PC 8 SCZ w/PANSS- Mean change in PANSS 40 72 100 74% Mean decreases in PANSS Sedation, increased LAI et al13 derived BPRS total score concomitant 2 wk or total scores significantly appetite more frequent BZD use w/300 mg/2 wk vs PBO 2008/Int. score ≥30 405 mg/4 wk greater for all 3 OLA LAI vs PBO Time-to-relapse favored PP No new safety signals 39 53 NR Mean no. of PP 410 IM PP (50 mg eq) Hough (1) Hp, (2) increase in (P < .0001, log rank test) at 951 DB, PC, 63 SCZ w/PANSS Hps= 3 weekly; then 25, et al14 OL total score <120 PANSS total score, (3) 50, or 100 mg eq, interim and final analysis 2010/Int. deliberate self-injury, flexibly dosed, aggressive behavior, once monthly suicidal/homicidal ideation Kramer 266 DB, PC 9 SCZ w/PANSS Mean change in PANSS 38 41 100 67% had PP 247 50 or 100 mg eq Mean PANSS total scores More parkinsonism- improved for 50 and et al15 total score total score ≥ 3 Hps fixed doses on related disorders in LAI 2010/Int. 70–120, days 1, 8, and 36 100 mg eq groups vs PBO vs PBO BMI 15–35 kg/m2 Nasrallah 620 DB, PC 13 SCZ w/PANSS Change in PANSS total 41 67 100 45% had PP 518 IM fixed doses PANSS total scores improvedLocally and systemically tolerated et al16 total score score ≥ 4 Hps (25, 50, or for all dose groups 2010/Int. 70–120, 100 mg eq) on BMI> 15.0 kg/m2 days 1 and 8, then days 36 and 64 Pandina 855 DB, PC 13 Acutely Definition not given 39 67 100 NR PP 652 50, 100, or 150 mg PANSS total scores improvedAEs w/PP injection-site et al pain, dizziness, sedation, 7 exacerbated SCZ IM on day 1, day 8, (P ≤ .034) in all PP dose and then monthly groups vs PBO pain in the extremity, and 2010/Int. myalgia

© 2016Copyright Physicians Postgraduate Press, Inc. Kane et al LAI 40.1; Insomnia, tremor, and AntipsychoticsLong-Acting inSchizophrenia Injectable 17 843 DB, PC 52 SCZ, history of CGI-C and PANSS total LAI NR NR ARI 843 300 and 400 mg Relapse delayed and headache 2012/Int. relapse without Txscore increases, Hp, PBO 41.7 60.2; IM- monthly improvements in CGI-C and risk of suicide, violent (range, PBO depot PANSS total scores w/Tx vs behavior PBO 18–60) 79 Meltzer Most common AEs: 848 DB, PC 12 SCZ w/acute Defined by changes in 39 68 NR NR ARI 623 441 or 882 mg Significant (P≤ .004) et al insomnia, akathisia, 9 exacerbation PANSS total score lauroxil monthly improvements in both active Tx groups headache, and anxiety 2015/Int. Kane et al 8 506 DB, PC 12 SCZ w/acute Defined by PANSS total IM 42, 79 NR Mean age at ARI IM 340 400 mg monthly Improvement in PANSS total AEs vs PBO: increased weight (16.8% vs 7.0%), 2014/Int. psychotic episodescore PBO 43 Dx was 24 y score at all time points w/ARI vs PBO headache (14.4% vs 16.3%), and akathisia (11.4% vs 3.5%) Berwaerts 38 75 0 92% had Most frequent AEs vs PBO: 620 DB, PC 60 SCZ w/PANSS Hp, increase PANSS PP 305 175, 263, 350, or Time-to-first-relapse et al significantly higher in headache (9% vs 4%), 11 total score lower total score, deliberate at least 1 525 mg eq or PBO self-injury or violent PP group weight increased (9% vs 2015/Int. than 120 prior Hp once every 3 mo behavior, suicidal/ 3%), nasopharyngitis homicidal ideation (6% vs 1%), and akathisia (4% vs 1%)

Abbreviations: AE= adverse event, ARI= aripiprazole, BL= baseline, BMI= body mass index, BPRS= Brief Psychiatric Rating Scale, BZD= benzodiazepine, CGI-C= Clinical Global Impressions-Change score, DB= double-blind, Dx = diagnosis, eq = equivalent, Hp = hospitalization, IM = intramuscular, Int. = international, LAI = long-acting injectable antipsychotic, N = study population, n = randomized number, NR = not reported, OL = open label,

OLA = olanzapine, PANSS = Positive and Negative Syndrome Scale, PBO = placebo, PC = placebo-controlled, PP = paliperidone palmitate, RIS = risperidone, SCZ = schizophrenia, Tx = treatment, USA = United States of America,

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Table 2. Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range) % Male at BL Chronicity Medication n (Range) Efficacy Safety First-Generation Long-Acting Injectables Fluphenazine Depot NR NR 29 0 NR FPZ decanoate 14 Same dose as Discontinuation Withdrawal: Crawford and 31 DBDD 40 Stable and (20–65) before the trial rate favored FPZ 20 termination due to Forrest cooperative OPs Trifluoperazine 17 10 mg/d (fixed) decanoate but did significant Sx that 1974/UK w/SCZ, adherent to not reach statistical warranted unblinding medication, attending significance Tx clinic del Giudice 88 DBDD/ 69 IPs w/SCZ, responded Re-Hp NR 100 0 48.8% had FPZ enanthate 27 25 mg/2 wk Median time to AEs were uncommon et al21 RMa to oral FPZ, were (20–50) 5–10 Hps in (fixed) re-Hp: 420 d w/both Txs discharged 1975/USA the past FPZ 61 21.7 mg w/depot injection (5–80 mg) vs 100 d w/oral FPZ (P < .001) Rifkin et al22 73b DBDD 52 Stable OPsc on FPZ Relapse: clinical 23.7 67 0 Mean no. of FPZ decanoate 23 NR No difference 35% of Pts receiving FPZ decanoate 1977/USA depot or oral for deterioration (17–38) Hps in the (0.5–2 mL/2 wk) in relapse rates past: 1.79 FPZ 28 NR (5–20 mg) between the 2 developed severe 4 wk, no or minor w/marked social akinesia AEs, cooperative and impairment medications compliant Falloon et al 39 45 0 81% had AEs were similar 23 53 DBDD 52 SCZ Pts returning Relapse: SCZ features FPZ decanoate NR 25 mg/2 wkd Relapse/ that led to withdrawal (17–60) between the 2 drugs 1978/UK to the community ≥ 2 Hps in (flexible) deterioration: from the trial, Pimozide NR 8 mg/d following Hp for an the past d 40% FPZ vs 23% acute episode regardless of re-Hp w/pimozide e (flexible) (not statistically significant) 34.2 46 0 88% had © 2016Copyright Physicians Postgraduate Press, Inc. Hogarty et al24 105 DBDD 104 Pts w/SCZ received Relapse: unequivocal FPZ decanoate 55 34 mg/2 wk Similar relapse rates NR clinical deterioration (18–55) 1979/USA major neuroleptic ≥1 Hp in (12.5–125 mg/ w/FPZ decanoate of such magnitude Tx during the Hp; the past 2 wk) and oral FPZ discharged that Hp appeared imminent; or suicide FPZ 50 9.9 mg/d (2.5–40 mg/d) 29 59 100/0 Schooler et al25 290 DBDD 52 Pts w/SCZ dischargedRelapse: deterioration f 100% FPZ decanoate 143 34.2 mg/3 wk No differences NR (18–55) 1980/USA after acute-phase Tx that could not be new Hps (12.5–100 mg/ between the 2 Txs managed after in community 3 wk) adjustment of dosage FPZ 147 24.8 mg/d

J ClinPsychiatry 2016;77(suppl 3) NR (2.5–60 mg/d) Similar rates of 49.5 50 0 ≥ 77.8% FPZ decanoate 19 Same dose as 26 Relapse: marked relapse, withdrawal, Barnes et al 36 DBDD 52 OPs w/SCZ regularly (NR) have social before the trial exacerbation of and study 1983/UK receiving depot FPZ performance Pimozide 17 Dose equivalent psychotic features completion between for ≥6 mo limitations before the trial requiring increased groups medication and re-Hp Kaneno et al FPZ decanoate 130 12.6–50 mg/ 27 263 DBDD 24 Chronic SCZ needing Discontinuation 90% of 65 NR 81% had FPZ superior to No significant duration of between-group 1991/Japan long-term Tx due to worsening of Pts were 4 wkd (up to HAL on Hp rate, illness ≥10 y differences in AEs psychiatric Sx 30–59 75 mg/4 wk) measures of global years improvement HAL 133 3.1–12.0 mg/dd old (up to 18 mg/d) (continued)

Table 2 (continued). Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range) % Male at BL Chronicity Medication n (Range) Efficacy Safety Haloperidol Depot EPS rates low in 42.3 80 0 Mean duration HAL decanoate 14 170 mg/4 wk Glick and 35 OL 48 OPs w/SCZ or SzAD No longer No between- both groups; QUE 28 of illness: (Target dose: Marder needing long-term Txexacerbation-free (NR) group differences associated w/less 16.5 y in Pts remaining 2005/USA QUE 21 493200 mg/dmg/4 wk) rigidity, akathisia exacerbation-free; QUE more effective (Target dose: for negative Sx 500 mg/d) (P < .05)

Zuclopenthixol Depot 26 233 mg/ Arango et al29 46 RM 52 Pts w/SCZ, violent Hp 34 83 0 NR Zuclopenthixol Lower incidence of NR depot 2006/Spain episode in previous (NR) 2 wk (NR)e violent acts in depot year, score ≥3 on Zuclopenthixol 20 35 mg/d (NR)e group physical aggression subscale of OAS Second-Generation Long-Acting Injectables Olanzapine LAI OLA LAI 599 150 mg/2 wk, Psychotic exacerbation: 38.9 65 0 Mean duration No clinically Kane et al30 1,065g DBDD 24 Clinically stable Pts increased BPRS-P, Hp as(18–75) of illness: 24-wk exacerbation-important differences 2010/Int. w/SCZ, OP status the result of worsening 13.3 y 405 mg/4 wk, free rate was 93% in safety parameters for ≥4 wk, BPRS-P of positive psychotic Sx 300 mg/2 wk w/oral OLA and ≤4 on the following 95%, 90%, and 84% 36.9% had OLA 322 14.3(fixed) mg/d items: conceptual w/high, medium, © 2016Copyright Physicians Postgraduate Press, Inc. ≥ 2 psychotic and low LAI doses, disorganization, AntipsychoticsLong-Acting inSchizophrenia Injectable episodes or suspiciousness, (10, 15, 20 mg/d)respectively exacerbations hallucinatory in last 24 mo behavior, and unusual thought content 40.9 67 0 Mean duration No clinically Relapse: Hp, increase 31 (18–65) of illness: No differences in significant group Detke et al 524 OL 104 OPs w/SCZ, no acute in PANSS total score OLA LAI 264 386.6 mg/4 wk 2011/Int. Hp in 8 wk prior, (15–405 mg/ discontinuation differences in AEs or CGI-S, deliberate or relapse rate; PANSS total score Mean14.7 y OLA 260 12.74 wk) mg/d injury to self or others, mean duration of < 70, CGI-S score 4≤ psychotic discontinuation due to Hp significantly at visits 1 and 2, 2≥ episodes in worsening Sx (5–20 mg/d) longer for oral than episodes of clinical last 24 mo: 2.7 LAI, 1.80 vs 0.43 d, worsening in the (P=.02) past 2 y

Risperidone LAI Most AEs were rated 32 40 64 NR Mean no. of RIS LAI 319 25–75 mg Both Txs showed Chue et al 779 DBDD 12 SCZ w/PANSS total PANSS total score Oral RIS 321 2–6 mg mild/moderate: Hps in past: comparable efficacy 2005/Int. score ≥50 change from DB insomnia, anxiety, about 5 in PANSS total scores baseline headache, psychosis (continued)

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Table 2 (continued). Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range)35.2 % 57Male at44 BL MeanChronicity duration RISMedication LAI 253n 40.7(Range) mg/2 wk RIS LAIEfficacy was not DiscontinuationSafety due Significant Keks et al33 629 OL 53 IPs/OPs w/SCZ or of illness: 8.6 y (25, 50 mg/2 wk)inferior to oral OLA to AEs: 3% w/RIS LAI, deterioration: (≥ 18) SzADh OLA 310 14.6 mg/d 4% w/OLA 2007/Int. who had acute 1. Hp for Sx exacerbation in the exacerbation past 2 mo, additional 2. need for an (5–20 mg/d) acute exacerbation in the past 2 y, PANSS increased level of care and ≥2-point total score ≥50, increase in CGI-S BMI ≤40 3. self-injury, suicidal/ homicidal ideation or violent behavior Relapse: definition not 46.4 50 100 Mean duration RIS LAI 25 Equivalent to Bai et al34 50 RM 48 Stable SCZ on oral given (18–65) of Hp stay: oral 5.0 mg/d No significant RIS LAI group had (25, 37.5, lower scores on rating 2007/Taiwan RIS for ≥3 mo, PANSS 127.9 mo differences in PANSS scales of side effects total score <80, total scores between (P = .048), motor Sx PANSS conceptual i the 2 Txs 50 mg/2 wk) (P=.028), prolactin disorganization, RIS 25 4.0 mg/d (same hallucinatory dose as before levels (P= .046) behavior, the trial) suspiciousness, unusual thought © 2016Copyright Physicians Postgraduate Press, Inc. content <4, CGI-I screening visit and baseline were same Potapov et al EPS rate: PANSS total score 35 41 OL 52 OPs w/SCZ (ICD-10), Relapse: ≥5-point 34.9 58 0 NR RIS LAI 20 41.7 mg/2 wk decreased in PANSS total score 60≥ increase in CGI-S and (18–65) (NR) 2008/Russia both groups from 40% w/RIS LAI, ≥20% in PANSS total OLA 21 15.9 mg/d (NR) baseline but did not 35% w/OLA score compared to differ significantly previous from one another

J ClinPsychiatry 2016;77(suppl 3) Rates of AEs and RIS LAI was not 42.7 62 28 Mean duration RIS LAI 153 32.3 mg/2 wk discontinuations due Kamijima 205 OL 24 IPs/OPs w/SCZ, takingTx discontinuation inferior to RIS 36 of illness: (25, 37.5, to AEs were similar et al RIS ≤6 mg/d, due to worsening of (≥ 20) tablets on several 14.9 y 50 mg/2 wk) for the 2 Txs 2009/Japan PANSS total score psychiatric Sx RIS 52 3.4 mg/d outcomes, including (2–6 mg/d) ≥ 60 to <120 PANSS and CGI-C from baseline (continued)

Table 2 (continued). Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range)41.6 % 58Male atNR BL MeanChronicity duration Medication n (Range) Efficacy Safety Both agents Gaebel et al37 710j OL 104 Stable IPs and OPs w/Relapse: (≥ 18) of illness: RIS LAI 355 33.6 mg/2 wk Time-to-relapse 1. psychiatric Hp well tolerated; 2010/Int. SCZ or SzADk; stable (up to 50 mg/ significantly longer 2. increase in level of hyperprolactinemia dose of RIS, OLA, or 10.0 y; mean QUE, ARI 401 2QUE: wk) 413.4 mg/dw/RIS LAI than QUE care and PANSS total was reported in FGA; living in the no. of Hps in (P < .0001); relapse score 13.1% w/RIS LAI same residence for the past: 5.3 occurred in 16.5% and 1.5% w/QUE; 3. deliberate self-injury (up to > 30 d; candidates for of Pts w/RIS LAI and somnolence in 2% 4. clinically significant switching Tx 750 mg/d) 31.3% w/QUE of Pts w/RIS LAI and suicidal/homicidal ARI: 15.1 mg/d 11% w/QUE ideation (10–30 mg/d) 5. violent behavior resulting in significant injury to another person or property 6. CGI-C≥ 6 7. exceeding registered drug dose The study was 37.9 60 0 Mean duration RIS LAI 179 41.8 mg/2 wk No significant discontinued before differences between completing 2 y by Macfadden 355 RM 104 SCZ, ≥2 psychotic Relapse: (≥ 18) of illness: 9.9 y ARI 176 (25–5019.9 mg/d mg/2 wk) RIS LAI and ARI about 29% of Pts in et al38 relapses in the past 1. worsening of (10–30 mg/d) groups in time-to- each group 2 y, stabilized for psychiatric Sx 2010/Int. relapse or time-in- ≥2 mo 2. increased PANSS remission. Relapse total score rates 45.8% and 3. deliberate self-injury, 43.6% for RIS LAI and clinically significant ARI, respectively suicidal/homicidal © 2016Copyright Physicians Postgraduate Press, Inc.

ideation, or violent AntipsychoticsLong-Acting inSchizophrenia Injectable behavior 4. drug discontinuation or addition of another AP for 1> wk because of lack of efficacy 5. dosage beyond recommended Malla et al dosage

22.7 84 NR Mean duration RIS LAI 44 NR RIS LAI and oral 39 85 OL 104 IPs/OPs; early- Relapse: Similar (18–30) of illness: 2.1 y agents had similar onset SCZ, SzAD, or 1. psychiatric Hp improvements in 2016/Canada (25–50 mg/2 wk) safety profiles schizophreniform 2. increased PANSS Oral SGA 41 NR PANSS total score except CLO disorder,l PANSS total score and and CGI-S for both psychiatric care (flexible dose) Tx groups total scores ≥60 and 3. self-injury, suicidal/ ≤ 120, currently on homicidal ideation, monotherapy atypical or violence AP or Tx naïve; 4. CGI-C≥ 6 Pts stable within 18 wk entered the maintenance phase

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Table 2 (continued). Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range) % Male at BL Chronicity Medication n (Range) Efficacy Safety Rosenheck 382 RM 104 SCZ or SzAD, at risk Hp 51 91 40 Mean duration RIS LAI 190 40.9 mg/1.5 wk Hp rate was similar RIS LAI was associated et al40 of Hp (≥ 18) of illness: (25, 37.5, 50 for RIS LAI (39%) and 2011/USA 23.4 y mg/2 wk) oral APs (45%) w/more injection-site Any oral AP 192 NR (flexible) Anorexiareactions significantlyand EPS RIS 153 33.6 mg/2 wk Psychotic Sx and lower in oral than RIS 38.2 71 NR Mean duration except CLO microsphere (12.5–75 mg/ BPRS improved arm; other AEs similar 41 m Relapse: masked of illness: Buckley et al 305 RM 74–130 OPs w/SCZ or SzAD (18–65) 2 wk) more in the RIS between Txs committee, Hp for 15.9 y; mean Oral SGA 152 NR (flexible) 2015/USA (32%), exacerbation group, but relapse psychosis, increases no. of Hps in within 12 mo, CGI 4,≥ and Hp rates were in level of care, the past: 11.0 in community 4≥ wk, similar substantial clinical ≥1 mo since the most deterioration (BPRS), recent exacerbation and deliberate self-injury or violent Green et al behavior

Heavy drinking 79% had AEs; most 42 95 Proof of 24 SCZ or SzAD and 42 77 NR Mean lifetime RIS LAI 49 ≤ 50 mg every Heavy drinking in the oral group common were pain, 2015/USA concept current alcohol (≥ 5 drinks/d), intensity Hps: 7.5 Oral RIS 46 62 mg/dwk worsened over time upper respiratory use disorder, at of drinking (no. of tract infection, (P = .024) community mental drinks/wk) drooling, nausea or health and VA clinics stomach discomfort, diarrhea, vomiting, other digestive, or hepatic problems Subotnik et al Oral RIS 43 2 mg/d Psychotic

© 2016Copyright Physicians Postgraduate Press, Inc. 22 78 NR First major Increases in the BPRS 43 266 RCT 52 Recent onset psychotic exacerbation, Oral RIS Pts more items unusual thought SCZ, SczAD episode within relapse rate, frequently prescribed 2015/USA content, hallucinations, RIS LAI 43 25 mg/2 wk depressed type, or the past 2 y hallucinations/ AE medication or conceptual schizophreniform delusions lower disorganization disorder

w/RIS LAI vs oral Paliperidone Palmitate LAI Injection-site pain, Time-to-relapse was 33 58 32.4 Dx within nasopharyngitis, Schreiner 775 OL 24 SCZ, PANSS total Hp; increase in PANSS PP LAI 376 150 mg eq significantly longer increase in weight, et al44 score of 70–120 total score, deliberate 1–5 y; on day 1, in the PP group J ClinPsychiatry 2016;77(suppl 3) self-injury, suicidal/ 100 mg eq on headache, tremor, 2015/Int. ≥ 2 Hps in than oral AP group homicidal ideation, day 8, 75 mg eq anxiety, insomnia, the preceding (P = .0191) violent behavior, on day 38, then SCZ, suicidal ideation 24 mo clinical deterioration monthly w/ (CGI-S) flexible dosing 388 Varied ARI, QUE, OLA, 25–150 mg eq paliperidone extended- release, RIS, or HAL (continued)

It is illegal to post this copyrighted PDF on any website. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 2 (continued). Long-Acting Injectable vs Oral Antipsychotics: Randomized Controlled Trials Definition of Mean Study/ Study Duration Relapse-Related Age, y % Hp Mean Dose Country N Design (wk) Inclusion Criteria Outcome (Range) % Male at BL Chronicity Medication n (Range) PP delayedEfficacy time to CommonSafety AEs for PP: 38 86 0 Mean no. of PP LAI 230 234 mg on day injection site pain, 45 Arrest/incarceration, first Tx failure vs oral Alphs et al 693 OL 60 SCZ with a history of Hps >5 1 and 156 mg insomnia, weight Hp, suicide, Tx AP (P= .011) 2015/USA incarceration on day 8 (±4 d), increased, akathisia, discontinuation or and PR then monthly anxiety supplementation, 50–150 mg eq increased psychiatric 220 startedDosage on day 38 services Oral AP (ARI, determined by HAL, OLA, package insert paliperidone, perphenazine, QUE, RIS) Aripiprazole LAI Fleischhacker

42 60.4% NR ≥ 3 y ARI LAI 265 400 mg/mo Impending relapse ARI once monthly: 1,118 DB 38 SCZ Increased CGI-S or 41 63.2% NR ARI oral 266 10–30 mg/d rates at week 26 insomnia, akathisia, 46 PANSS total score; et al were 7.12% for headache, and Hp; violent behavior 40 59.5% NR ARI LAI 131 50 mg/mo 2014/Int. weight decrease/ resulting in clinically 41 60.0% PP LAI 147 50–150 mg/mo ARI once monthly increase reported by relevant self-injury, [EU and Canada] 400 mg and 7.76% 9%–12% of Pts injury to self or another or 78–234 for oral ARI; ARI once person, or property monthly was not damage mg/mo [USA] inferior to oral ARI

aRaters were masked for 3 arms, but DBDD were applied to 2 arms.bPatients allocated to placebo arm are not included in the analysis.c100% schizophrenia by clinical diagnosis but included 15% nonschizophrenia when assessed by research psychiatrists.d Most common dosing.e Accurate safety/efficacy evaluation information not found.f100% during intensive treatment phase; 0% in maintenance phase.gVery low dose (OLA LAI 45 mg/4 wks) group is not included in the analysis.h SzAD = 17.3%. iDepot dose based on prior oral dose.jIncluding exploratory arm (ARI), randomized:= n 45, efficacy: n= 44. kSzAD = 17.7%. lSzAD = 6.5%, schizophreniform= 3.9%. mFull study period ranged between 17–30 months depending on enrollment date. Abbreviations: AE= adverse event, AP= antipsychotic, ARI= aripiprazole, BL= baseline, BMI= body mass index, BPRS= Brief Psychiatric Rating Scale, BPRS-P= Brief Psychiatric Rating Scale-Positive, CGI-C= Clinical Global Impressions- © 2016Copyright Physicians Postgraduate Press, Inc.

Change score, CGI-I= Clinical Global Impressions-Improvement scale, CGI-S= Clinical Global Impressions-Severity of Illness scale, CLO= clozapine, DB= double-blind, DBDD= double-blind double-dummy, Dx= diagnosis, AntipsychoticsLong-Acting inSchizophrenia Injectable EPS = extrapyramidal side effects, eq= equivalent, EU= European Union, FGA= first-generation antipsychotic, FPZ= fluphenazine, HAL= haloperidol, Hp= hospital/hospitalization, ICD= International Classification of Diseases, Int. = International, IP= inpatient, LAI= long-acting injectable antipsychotic, =N study population, n= randomized number, NR= not reported, OAS= Overt Aggression Scale, OL= open label, OLA= olanzapine, OP= outpatient, PANSS= Positive and Negative Syndrome Scale, PP= paliperidone palmitate, PR= Puerto Rico, Pt = patient, QUE= quetiapine, RCT= randomized controlled trial, RIS= risperidone, RM= rater masked, SCZ= schizophrenia, SGA = second-generation antipsychotic, Sx= symptom(s), SzAD= schizoaffective disorder, Tx= treatment, UK= United Kingdom, USA= United States of America, VA= US Department of Veterans Affairs, w/= with. summarized in Table 4. FGAand oftics SGALAIs selected are younger patients (≤ was driven effect the by differences in paliperidone palmitate (P with once monthly aripiprazole than significantly for higher patients treated total scorelife was onbaseline quality of 28-week study, mean the change from with schizophrenia. and functioninglife inpatients quality of mitate once monthly on arating of scale monthly 400 mg- with paliperidone pal (N example, arecently published study measures. Forsome other efficacy LAIsbetween have reported for been propensity to cause range awide of chotics. Antipsychotics intheir differ consideration antipsy selecting when - and Among LAIs Placebo, Versus Oral Antipsychotics, and Safety Tolerability ofLAIs Versus domains have reported. been vention, although differences in other one another interms of relapse pre- In general, LAIs appear similar toto be tative of care usual patients and practices. studies that arguably are more represen- ics is most pronounced in mirror-image Superiority of LAIs over oral antipsychot- tenance treatment of schizophrenia. superior to for placebo acute and main- delirium and sedation. due to potentialtion period postinjection requires- a 3-hour postinjection observa differentthe agents. Olanzapine pamoate centration varies considerably among Time to reach steady-state plasma con and aripiprazole lauroxil (3weeks). (3 weeks), aripiprazole (2weeks), LAI medications, including risperidone LAI treatment with some first few weeks of supplementation is required during the with paliperidone palmitate Oral LAI. lauroxil 882mg, 3months and once every most agents, to 6weeks with aripiprazole 2to 4weeksonce (or monthly) every with SGA LAIs. from Injection vary intervals inject than water-based formulations of mulations, may which more be to painful decanoate) are supplied for inoil-based (fluphenazine decanoate, haloperidol Characteristics of Characteris LAIs. - Characteristics Side effect liabilitySide effect is an important and conclusions. Summary = 295) compared aripiprazole once 35 years). 80 At the end of the Atthe end the of 89 10,81–88

= 06, and .036), FGA LAIs LAIs are

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Table 3. Long-Acting Injectable vs Long-Acting Injectable: Randomized Controlled Trials Study/ Duration Definition of Relapse- Mean % % Hp Country N Study Design (wk) Inclusion Criteria Related Outcome Age, y Male at BL Chronicity Medication n Dosing Efficacy Safety Pandina 1,220 DBDD 13 SCZ, PANSS total Defined by a change 39 58 NR NR PP LAI+ PBO 607 150 mg eq on day 1, PP was not inferior The tolerability and et al76 score 60–120, in the PANSS total 100 mg eq on day 8, to RIS LAI (primary safety of PP was 2011/ BMI≥ 17.0 kg/m2 and score and monthly flexible analysis) generally similar to dosing on days 36 RIS LAI w/no new Int. <40 kg/m2 safety or tolerability and 64; oral PBO findings (days 1–28) RIS LAI+ oral 613 Days 8 and 22 (25 mg), RIS days 36 and 50 (25 or 37.5 mg), and days 64 and 78 (25, 37.5 or 50 mg); oral RIS supplementation

1–6 mg/d (days 1–28) Most common AEs 77 13 SCZ, acute Sx, PANSS 32 38 NR NR PP LAI 229 50–150 mg eq, flexiblyPP was not inferior Li et al 452 OL, rater Determined by were akathisia, total score 60–120, dosed, without to RIS LAI 2011/ blinded changes in PANSS tremor, and China BMI≥ 17.0 kg/m2 total scores oral paliperidone supplementation insomnia 32 42 RIS LAI 223 25–50 mg, flexibly dosed, w/oral RIS supplementation 68.0% PP Pts vs No statistically McEvoy 43 73.1 16.6 PP LAI 145 325 mg mean dose on 59.9% HAL reported Efficacy failure: significant 311 DB 52–104 SCZ or SzAD, at risk days 1 and 8; 129–169 at least 1 moderate/ psychiatric Hp, difference in the 78 of efficacy failure mg/mo thereafter severe AE; 1 death et al crisis stabilization, rate of efficacy (history of medication from unknown 2014/ increased outpatient 45 75.9 19.3 HAL LAI 145 94 mg mean dose on failure for PP noncompliance causes USA visits, inability to days 1 and 8; 67–83 compared to HAL

NR 4,532 Retrospective 260 SCZ, filling ≥1 Hp 39 56 7 Mean FGA LAIsa 2,454 Varied RIS LAI was et al79 cohort outpatient LAI years similar to FGA 2015/ prescription Dx = 9 LAIs re time to Denmark hospitalization and 36 60 6 RIS LAI 2,078 NR time to all-cause J ClinPsychiatry 2016;77(suppl 3) discontinuation Naber AEs were more 295 OL 28 SCZ; stable, not QLS scores 43 69 NR NR ARI LAI 148 400 mg/mo QLS total score 41 60 PP LAI 147 50–150 mg/mo frequent w/PP; 80 acutely psychotic; confirmed et al [EU and Canada] or most common were inadequate response, noninferiority 2015/ 78–234 mg [USA] increased weight, Int. poor tolerability, or and established psychotic disorder, lack of adherence superiority of ARI and insomnia once monthly w/current oral AP aZuclopenthixol decanoate, haloperidol decanoate, perphenazine decanoate, fluphenazine decanoate, and flupenthixol decanoate. Abbreviations: AE = adverse event, AP = antipsychotic, ARI = aripiprazole, BL = baseline, BMI = body mass index, DB = double-blind, DBDD = double-blind double-dummy, Dx = diagnosis, eq = equivalent, EU = European Union, FGA = first-generation antipsychotic, HAL = haloperidol, Hp = hospitalization, Int. = international, LAI = long-acting injectable antipsychotic, N = study population, n = randomized number, NR = not reported, OL = open label, PANSS = Positive and Negative Syndrome Scale, PBO = placebo, PP = paliperidone palmitate, = patient,Pt QLS = Quality of Life Scale, re = regarding, RIS = risperidone, SCZ = schizophrenia, SzAD = schizoaffective disorder, Sx = symptom(s), USA = United States of America, w/ = with.

It is illegal to post this copyrighted PDF on any website. decanoate Fluphenazine ery that patientsery can achieve. and may they limit maximal level the of recov functional - treatment adherence and increased long-term morbidity, advocated. Adverse events may (AEs) contribute to poor simplistic and misleading, although past inthe it was in terms profiles of sideeffect is today as generally seen LAI Paliperidone palmitate LAI Paliperidone palmitate J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ adverse events among antipsychotics elevation). Results indicated to large small differences in (sedation, EPSs, weight gain, prolactin elevation, and QTc antipsychotics were ranked by 5different AEdomains large meta-analysis of 15antipsychotics inschizophrenia, oralfollow molecule. In athe known the AEprofiles of psychotic associated AEs with drugs. LAIs generally elevation. (EPSs), weight gain, metabolic disturbance, and prolactin includingside effects sedation, extrapyramidal symptoms a (Invega Trinza) (Invega Sustenna) (Zyprexa Relprevv) microspheres Risperidone (Haldol andothers) Antipsychotic United States ofAmerica Table First-Generation 4.Characteristics Antipsychotics ofSelected Long-Acting andSecond-Generation inthe Injectable (LAI) (Aristada) Olanzapine pamoate (Risperdal Consta) approach. through shared decision-making and psychoeducational issues should addressed be these safety and of risk. All AEand how patientthe affects this objectivethe of severity by whereas clinicians sideeffects, more typically focus on more likely to respond to subjective the distress produced of The roundtable AEs. participants felt that patients are physicians importance maythe perceptions intheir differ of Aripiprazole lauroxil (Abilify Maintena) Haloperidol decanoateHaloperidol and prolactin change (lower with LAIs). lipoprotein cholesterol change, anxiety with (higher LAIs), did not significantly, differ aside from low-density akinesia, 119 reported adverse events, LAIs and oral antipsychotics recent meta-analysis of 16RCTs (n into consideration choosing when among also LAIs. Amore monohydrate Aripiprazole It isIt illegal to post this copyrighted PDF on any website. Data from package inserts ofeachantipsychotic andCitrome. inserts Data from package 86 85 Comparison of adverse events associated with anti associated with ofComparison adverse events - 81 90 93 83 87 However, asimple division of FGAs and SGAs

88 84

82 Water Water Water Water Water Water Base Oil Oil a 2 or4wk Monthly Monthly Monthly Monthly 882 mg) Interval weekly: weekly: Varies every every Once Dose Dose 3 mo 91,92 4 wk 2 wk (or 6 Importantly, patients and

= ampoules 50 and100mg/mL prefilled syringes 273, 410,546,819mg vial kits 25, 37.5,50mg ampoules/vials/syringes 25 and100mg/mL vial kits 210, 300,405mg prefilled syringes 78, 117,156,234mg prefilled syringes 441, 662,882mg chamber syringe anddual- vial kits 300, 400mg 90 4,902) showed that of that should taken be Strengths/Forms 93a Dosage Dosage 10

(day 8) 100 mg (day 1)+ 2 wk 50 mg Varies, monthly dose on once- Depending 25 mg 12.5 mg Varies, up to 300mg/ Varies, 150 mg 441–882 mg Varies, 400 mg Starting Dose Starting

LAIs are summarized inSupplementary eTable 3. each of has which strengths and limitations. strategies—RCTs, mirror-image studies, and cohort studies— Implications ofStudy Design of selection guide the LAIs. and prolactin elevation. This information to help used can be to cause adverse including certain effects, weight gain, EPSs, data suggest that considerably LAIs vary propensity intheir comparisons and spontaneously reported The AEs. available event differences among LAIs comes largely from indirect can help among inselecting LAIs are summarized inTable 5. versus same the oral agent. similar forbeen patients treated antipsychotics with LAI clinical practice. frequently seen to be thatAEs inday-to-day expected can be for medication versus placebo denote potentially common that you would like to avoid?” In general, NNHvalues < towould encounter expect one additional outcome of interest treat with Intervention A instead of Intervention B before you answers question the “How many patients would you to need quantifiedbe using number to harm (NNH).NNH needed atypical antipsychotics. as weight gain to encountercan expect important adverse outcomes such NNH versus can placebo help to determine how often we

LAIs have examined study using been several design and conclusions. Summary in choosingConsiderations issues Practical that an LAI. treatmentOverall, discontinuation rates have generally Differences inAErates antipsychotic between may drugs (25–150 mg) 75 mg 2 wk up to 300mg/ Varies, 300 mg Varies, 273–819 mg Varies, (25–50 mg) 25 mg 12.5–100 mg Varies, 441–882 mg Varies, (300–400 mg) 400 mg Maintenance © 2016Copyright Physicians Postgraduate Press, Inc. Dose Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia Injectable ≥

Supplementation 7%, somnolence, or akathisia with different 94–96 As shown in Supplementary eTable 2, 3 wk 3 wk 2 wk Oral No No No No No 97,98 99 The most common with AEs 30–33 d Time to 4–6 wk Information about adverse 6–7 d 2–4 d 5–7 d Peak 13 d 4 d 4 d at equivalent 400: 4–8mo; Steady State 300: 3–4mo steady state Continues 1.5–2 mo 7–11 mo 2–3 mo 2–3 mo 4–6 mo 3 mo dose 18,73,77 82–88 Postinjection Observation At least3 hours No No No No No No No

13 10 97

It is illegal to post this copyrighted PDF on any website. studies found that as study designs toward shift real-world for confounding factors. One analysis of outcomes from LAI support.cial Therefore, it is important to and identify adjust greater of severity and illness less insight illness or psychoso- treatedthan those with oral antipsychotics, including having with LAIs in cohort studies may categorically be different adherence. More importantly, patients for selected treatment medication inopen studies may introduce bias by improving pared with other study However, types. of selection the changing(eg, hospitalization practices over time). subject to isThis potential also design or time cohort effects studies have examined reversing switching this sequence. have switched been from oral antipsychotics to LAIs, but no mainthe outcome. In mirror-image studies of LAIs, patients inherent of design inthe amirror-image study and may affect tive of practice than clinical actual an RCT. bias Expectation is with posttreatment is study This more design periods. - reflec from one medication to another, comparing pretreatment medication,free and on, so can impact adherence rates. more comprehensive assessments, payments for participation, In itself, addition, with reminders trial the for appointments, intypical practice. seen thanthose manysevere disease of comply with instructions. RCT patients may have also less ways, including levels higher of motivation or to willingness may from differ general the patient population inimportant potential adherence benefits, as patients enrolled in RCTs approach may not way best the be to study interventions with expectations about different the treatments. However, this on of part the investigators,biases elimination of including of RCTs include objective rating of patient outcomes and the for comparison the of LAIs with oral antipsychotics. Strengths explanatory RCTs are most likely not optimal the study design and safety of differentparing efficacy the treatments. However, Correll etal 14 For [email protected]. reprints orpermissions, contact ♦ Table 5.Considerations Antipsychotic ofaLong-Acting Injectable inSelection It isIt illegal to post this copyrighted PDF on any website. health care facility, pharmacy? Olanzapine Pamoate Patient Care Program: patient, prescriber, following peopleorentities notenrolledthe inthe Are any of concern? Is cost theprimary elevationIs prolactin aclinicalconcern for thisindividualpatient? individual patient? Are weight gainandmetabolicadverse effects aconcern for this using oral medications? Is thepatient beingtreated acutely, andisthepatient averse to olanzapine, oraripiprazole? on oral fluphenazine, haloperidol, risperidone, paliperidone, Is thepatient demonstrating andtolerability adequate efficacy Consideration In cohort studies, patient bias selection is reduced com- Mirror-image studies examine patients are who switched RCTs are usually considered “gold the standard” for com-

• • • • • • • • • • Olanzapine pamoate cannotbeused First-generation LAIantipsychotics may betheonlyoption LAI antipsychotics Avoid palmitate, paliperidone microspheres, risperidone orfirst-generation Consider aripiprazole LAI A first-generation LAIantipsychotic may alsobeconsidered inthiscase microspheres amongthesecond-generation antipsychotics, inthat order Consider aripiprazole palmitate, LAI,paliperidone orrisperidone palmitatepaliperidone orolanzapinepamoate) where have theclinicaltrials demonstrated (either acute efficacy Consider LAIantipsychotics that donotrequire oral supplementation, cognitive functions adds complexity to theregimen andother andmay interfere withmemory anticholinergic agents for themanagement ofmotor adverse effects, which disadvantages shouldbeweighted for usingconcomitant oral For patients receiving oral fluphenazineorhaloperidol, potential considered for convenience For patients receiving oral risperidone, palmitate paliperidone may be Switching to thecorresponding LAIformulation is relatively simple are followed over time. For example, inastudy importantly, nonadherence patients is when even higher macy records,macy or antipsychotic blood level tests. using quantitative techniques, such as pill counting, phar judgment may markedly be lower than adherence measured and adherence by assessed patient self-report or physician of nonadherence is practice inclinical often challenging, varies overalso long-term the treatment course. Detection This suggests that medication adherence is suboptimal but patients. study wasthe noted the for 4years all 18%of of tion possession ratio < nonadherence as an was defined entire year- with amedica nonadherent at some point during 4-year the study, where adherent inany one year, but more than 60%of patients were Health Administration, approximately one-third were non- than 34,000patients with schizophrenia Veterans inthe family members, other caregivers, or clinicians. istime, this evaluated whether using reports from patients, schizophrenia are poorly adherent to oral medications at any demonstrated that approximately one-third of patients with onAdherence ofLAIs Effect andCosts differentthese angles. of LAIs,effects creating picture afull only from viewed when anddesign interpretation of studies clinical examining the different issues methodological must considered be in the haswhich its own strengths and limitations. Therefore, RCTs, mirror-image studies, and cohort studies, each of hospitalizations, and all-cause discontinuation. nitude of improvement on outcomes, such as relapses, patient populations, LAIs are associated with alarger mag- changes, addition of concomitant medications, and labeling ence antipsychotic include unnecessary medication or dosage consequencesclinical of medicationundetected nonadher Medication nonadherence in schizophrenia. Studies have and conclusions. Summary Selecting a Long-Acting Injectable Antipsychotic aLong-Acting (LAI) Injectable Selecting © 2016Copyright Physicians Postgraduate Press, Inc. 0.8. Consistent nonadherence across J ClinPsychiatry 2016;77(suppl 3) LAIs have studied in been 100 106 101–104 105 Potential of more more of More More - - It is illegal to post this copyrighted PDF on any website. examined in several internationalexamined inseveral studies. Amirror-image comes inpatients were with observed Medicare coverage. LAIs versus $2,562with oral agents (P ( respectively $134 versus $568for and LAI the oral antipsychotic groups, antipsychotics (P increased by a mean of $758 for patients received who oral bycosts decreased amean of group LAI $5,981inthe and commercially insured patients. Schizophrenia-related hospital oral antipsychotics (n patients with schizophrenia initiated who (n LAI world care health costs and medication adherence between vs 7.8%),and substance misuse (31.1%vs21.5%). behaviors of (15.1% acrime victim the (10.8%vs4.8%),being emergency care (10% vs 6%), arrest (8.4% vs 3.5%), violent 14.1% for nonadherent vsadherent patients, respectively), outcomes, including psychiatric hospitalization (26.8% vs that nonadherent patients had rates higher adverse of several treatment adherence inpatients with schizophrenia found phrenia. One study LAIs overall affects care health cost of patients with- schizo adherence. LAIs, there evenwhen of is evidence recent treatment poor that fewer than 20% of patients with schizophrenia receive indication clinical mary for use, yet LAI studies have reported of patients as “treatment resistant.” $13,980; two the significantly treatmentsdiffer between ($14,916vs ($1,913; patients randomized ($3,028)than to oral LAI medication mean quarterly outpatient medication costs were for higher sician’s choice of an oral antipsychotic (n randomized to either (n risperidone LAI with schizophrenia or schizoaffective disorder were who study may increase over and time. Lin colleagues group, suggesting that economic the of benefit therapy LAI long-termin the group LAI short-term inthe than LAI those stay. Mean total hospital payments were 26%lower for patients hospitalizations hospital mean number and of mean length of lower levels of some care health utilization measures, including n days; n on short-durationbeen treatment LAI as 30–79 (defined costs for hospitalized patients with schizophrenia had who United States compared carehealth utilization and treatment total care health costs. age inpatient costs, average higher costs, pharmacy and similar compared to oral antipsychotics had significantly lower aver 12-monththe follow-up patients period, treated with LAI initiatedwho of use either or LAI oral antipsychotics. During schizophrenia Veterans inthe Health Administration system comparedbeen among propensity score–matched adults with J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. = The impact on of use care health LAI costs been has also A recent Medicaid health care utilization study Health care costs. Studies have examined how of use the Poor treatment adherence is usually considered pri the - 2,838). The longer-term patients LAI had significantly 108 = that examined outcomes functional associated with 2,856) versus longer-term treatment LAI (≥ P P

= 40,109 = .73). Health care utilization and costs have also .003), although total treatment costs didnot P = .023). The cost mean was $4,132with drug

< .001). Mean outpatient cost increased by 110 = compared treatment costs for patients 111 2,610) using medical claims2,610) using medical data from 106,107 A3-year, prospective 01. iia out - Similar <.001). = 113 187) or phy the - = compared real- 182). Overall, = 108 394) versus 112 180 days; in the the in - study conducted United inthe Kingdom, during treatment LAI the By contrast, period. amirror-image tient department and costs pharmacy significantly increased driven largely by lower hospitalization costs, although outpa- was associated with significantly lower total costs medical study conducted inTaiwan as awhole, compared with other antipsychotic strategies. cost-effective but cost-saving also for care health the system zapine for LAI patients with relapses was considered not only A strategy of paliperidone palmitate followed LAI by olan- costs than strategies that included oral antipsychotic therapy. strategies that LAIs used had lower total 1-year treatment care,medical institutional care, and indirect costs. Treatment or oral antipsychotics, including total costs associated with per-patient of sequences costs associated LAI with several conducted inCanada patientsthe treated with oral antipsychotics. Finally, astudy treated by incurred with LAIs werethose only one-half of total schizophrenia-related patients treatmentthe costs of agents (39%)during 18-month the follow-up The period. tion adherent initiated who (55%)than those FGAoral FGA LAIs were significantly more likely medica to be previously medication nonadherent, initiated who those ings related therapy. to LAI Among outpatients were who countries provides additional support for health care sav- followed adults with schizophrenia from 10European Hong KongHong study with performed patients treated in public hospitals in outpatient(eg, psychiatry, medication costs). Amirror-image other butvices, nonmedication for increased services) others mean for costs decreased some outcomes inpatient (eg, ser therapy.LAI After aswitch from oral antipsychotics, to LAI claimsmedical data during 1year before and after initiating and showed cost-neutrality or evengreater cost. although other studies have not demonstrated effects these demonstratedbeen insome studies of antipsychotics, LAI care utilization or costs associated with schizophrenia have herent patients receive Significant them. reductions inhealth treatment adherence, only aminority of medication nonad- Although LAIs may provide one to help method improve with schizophrenia is common to detect. and difficult P < .001). year; ($27,234 vs$16,987for preinitiation the postinitiation vsthe tion were significantly lower after aswitch therapy to LAI 1-year costs associatedOverall with care health utiliza- 1,992 patients with schizophrenia or disorder. schizoaffective during 1 year before and after initiation of treatment LAI in In astudy conducted inSweden, tion of study patients therapy LAI started who as inpatients. large inthe level ofhigh reflected propor severity illness results unexpected These explained may by partially be the days, although number the of inpatient admissions declined. care costs significantly increased along with inpatient bed yearin the following therapy LAI initiation, total health predominantly patients with schizophrenia, reported that A prospective study observational Summary and conclusions. Summary © 2016Copyright Physicians Postgraduate Press, Inc. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia Injectable 114 found that switching from oral therapy to LAI 118 compared care health resource use 48 examined treatment costs from Nonadherence inpatients 116 investigators modeled 117 that recruited and 115 which included which

15 - - - It is illegal to post this copyrighted PDF on any website. health carehealth providers. United inthe In asurvey Kingdom, Correll etal 16 For [email protected]. reprints orpermissions, contact ♦ cian attitudes use. Physicians to may LAI abarrier be also among other misconceptions about treatment. LAI - Clini associated with agreater burden sideeffect than oral agents, FGA LAIs. Many clinicians mistakenly that believe LAIs are Younger members staff may have little or with no experience an injection or has persistent symptoms after starting therapy. pharmacokinetics, and what to apatient dowhen is late for issues of use tical inthe LAIs, including selection, dose inrelapsedecrease rate of 10%compared with oral therapy. most favored an only LAI if it was associated with an absolute agents. For example, of psychiatrists, 106German inasurvey clearly can be shown superior tothey be to oral chotics only if psychiatrists say that are they interested inusing antipsy LAI - chiatrists remain reluctant antipsychotics. to LAI use Most adherence among patients with schizophrenia, many psy- ratehigh of nonadherence and consequences the of poor prescribe and monitor than oral medication. compromising of patient autonomy, or more bothersome to likely than psychiatrists the to characterize LAIs as coercive, Unitedin the Kingdom, nurses the were significantly more datathese were compared to data of from nurses asurvey ated with more favorable attitudes (r =0.39, psychiatrists’ knowledge about LAIs was positively associ antipsychoticsLAI are less acceptable to patients. However, that depot medications are stigmatizing, and 69%believed and prevent relapse (94%);however, despite 48%felt this, as oral medications and improve patient adherence (81%) most psychiatrists (91%) felt that LAIs were as efficacious patient.the repeated schizophrenia relapses oris preferred LAI when by only nonadherence when to oral medication has resulted in Association, recognize LAIs as atreatment option but usually ment guidelines, including by those American the Psychiatric Patient andSelection Eligibility When to Consider LAI Treatment: P dom. schizophrenia or schizoaffective disorder United in the King- Similar findings were reported inastudy of outpatients with that patients are more likely to favor current their treatment. (n was 73%among patients were who current users of LAIs shortly before hospital discharge, acceptance of therapy LAI attitudes about LAIs among patients with schizophrenia related to previous and current of In experiences. asurvey degree on provider and patient attitudes, are which closely ofThe use LAIs practice may inclinical to depend alarge patients may not aware be that LAIs are available. mend LAIs as an option ifpreferred by patient, the many among LAI-naive patients (n It isIt illegal to post this copyrighted PDF on any website. art = In addition, many clinicians lack knowledge about prac- Why are psychiatrists reluctant Despite LAIs? to use the schizophreniaGuidelines Several manage use. for LAI - Patient and mental health of LAIs. perceptions provider 60), 45%among past users of LAIs (n

124 2:P Perceptions about may use LAI differ among also 119–122 l ractica However, guidelines when even recom- C onsiderations = 145). 123 These data These show 01. When P <.001). 126 =

95), and 23% and R ecommendations 125 127 -

inappropriate for patients. first-episode cians have shown that many psychiatrists regard LAIs as from learning that LAIs are apotential option. cian and beliefs perceptions about LAIs may prevent patients LAIs in schizophrenia,first-episode including demonstrate who those intolerance to or inefficacy patients with schizophrenia: factors may Several favoruse? of therapy use the LAI in coercion. about stigmatizationbeliefs to patients their or of because patients, and may they have concerns about suggesting LAIs often overestimate treatment the own their adherence of tions accepted (33%)being by patients. a negative light, resulting inonly 11of recommenda 33LAI - at 10health clinics, psychiatrists generally presented LAIs in of LAIs made by psychiatrists to patients with schizophrenia example, inastudy of communication patterns offer inthe inappropriate for afirst episode. approximately 70%of psychiatrists thought that LAIs were ate for first-episode patients, whereas study inaGerman of psychiatrists thought that LAIs were always inappropri- conducted United inthe Kingdom, approximately one-third with treating illness). the cian and payer failure to consider total the costs associated unless there is clear documentation of nonadherence, clini- acquisition higher (eg, costs, payer reluctance to cover LAIs ister maintenance treatment) LAI and barriers financial consider care with primary partnering providers to admin- lack of community nurses to administer injections, failure to treatment. LAI ing to try changed mind, their stating- that would actually will they be 28 patients recommendation initial declined the (96%)who a more positive light and with more information,the 27of a postvisit interview, during LAIs which were presented in Although several studiesAlthough several suggested possible of benefits Conversely, LAIs may less suitable be for some patients, What patient and illness LAI factors should influence Other obstacles to LAI use include service barriers (eg, (eg, barriers obstacles includeOther use to LAI service • • • • • • © 2016Copyright Physicians Postgraduate Press, Inc. Preference of by LAI patient the violence nerability, self-harm, or aggression or of ahistory such as of ahistory psychosis associated- with vul relapse is associated with significant risk, clinical Factors that suggest risk of ahigh relapse and that substance misuse, or lack of insight of adherence, poor such as younger age, comorbid Risk factors that are associated with increased risk ofA history nonadherence with oral medication interms(eg, of education or employment) in remission and most the through to lose relapse patients usually have most the to gain by remaining Early-phase or schizophrenia, first-episode as these Willingness by clinicians to consider treatment LAI 125,128 R egarding 123,125 J ClinPsychiatry 2016;77(suppl 3) L AI U 128,129 43,74,75 se In many physi cases, - 132 128,129 However, during surveys of clini - surveys In astudy 130,131 For For

It is illegal to post this copyrighted PDF on any website. side effects using dataside effects from RCTs of oral antipsychotics. Meta-analysis has quantified relative the risk of arange of extrapolate from same drug. oral the formulationthe of ing safety the profiles of different LAIs, it is reasonable to scores.interviewer-ratedlife quality of discontinuations and significantly greater improvement in ated with numerically fewer adverse events and treatment schizophrenia, reporting that aripiprazole- was associ LAI of aripiprazole and inpatients LAI paliperidone LAI with ment groups. Finally, Naber and colleagues overallin the rate of EPSwere two the treat similar between - althoughLAI, changes and inglucose lipid parameters and and prolactin elevation but less akathisia with paliperidone in patients with schizophrenia, reporting greater weight gain colleagues ence to asubstance management use plan. McEvoy and Positivethe and Negative Syndrome and better adher Scale associated with fewer EPSsas well as more improvement on 6monthsmisuse. Over of follow-up, was risperidone LAI decanoate in patients with schizophrenia and substance J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ stakeholder groups, including family and employers, friends, only for patients and physicians but for also many additional and Experience for Stakeholders PracticesBest to Acceptability Maximize LAI potential for significant consequences associated with relapse. adherence, risk of high nonadherence, lack of insight, and the coursein the of psychosis as well as patients with known poor from LAIs include patients first-episode and patients early LAIs, resource issues, and might cost. who Those benefit clinicians’ andknowledge negative lack attitudes of about incurrentfor use to use. Barriers LAI practice include LAI with oral antipsychotic agents as most the important reasons guidelines generally emphasize nonadherence and relapse wasthis available. ment for using same the antipsychotic form, in LAI assuming adverse Innew effects. such there cases, would an be argu- formulationLAI might associated with be arisk of relapse or one oral medication, switching to adifferent medication ina an important patient consideration.the is well stabilized on If FGA LAIs. Finally, patient’s the current oral regimen is also tion, with acquisition costs of SGALAIs of than higher those is oftenCost an important consideration intreatment- selec colleagues different LAIs treatment inthe of schizophrenia. Rubio and ever, few studies have directly compared profiles sideeffect of are often a key consideration anHow LAI. selecting when - of differentcacy LAIs is generally similar, profiles sideeffect settings. considerations may limit access to LAIs states incertain or require chronic anticoagulation therapy. Furthermore, cost oral therapy, have astrong preference for oral therapy, or with parent the compound, establish adherence good with It isIt illegal to post this copyrighted PDF on any website. In absence the of an extensive of body research compar The appropriate of use antipsychotics is aconcern not and conclusions. Summary - AsWhat effi the selection? LAI factors should influence 78 133 compared and haloperidol LAI paliperidone LAI compared and risperidone LAI zuclopenthixol Schizophrenia treatment 80 examined use 90 - -

team. providedshould be also to clinicians and care health the and prevention of relapses and suicide. includealso aplan to improve adherence, management, crisis treatment developmentin the the plan. Education of should expert” by and experience that patient the should involved be tion should reinforce also concept the that patient the is “an in making decisions about of use the LAIs. Psychoeduca- process andthis important may especially be of part critical phrenia and and benefits the risks of its treatment is clearly a psychiatrists (81%)or family members (80%). medication outweigh (61% of bad the patients) than were phrenia were less likely to agree that things about good the of perceptions about medication use, patients with- schizo have differing interests and concerns. For example, inasurvey as awhole.and In society stakeholder some cases, groups may court-appointed guardians, law enforcement and judiciary, the cal issuescal associated with dosing the and switching of LAIs and families their about treatment this option. LAIs may improve outcomes and to educate patients those often first line the of contact to patients identify for whom therapy and its most appropriate Team uses. members are of LAIs should followed be by education detailed about LAI and benefits limitationsaboutthe using LAIs. of An overview step educational inthis process is to acknowledge concerns and address issues that patients have about LAIs. The first decisions. empowering patients and family members to make effective emphasis with particular on services, health their ation of involvedbe of planning, aspects inall delivery, and- evalu oras friends close clergy. Patients should encouraged be to other caregivers as well as abroader support network, such provider,the patient, the patient’s the family members, and Patient-centered care relies heavily on collaboration between not clinically indicated or that could result inpatient harm. ever, clinician the should not agree to atreatment plan that is to make sure patient the has avoice inhis or her care. How- cian should flexible, adjusting be treatment appropriate when to developingcritical treatmenta successful plan. The clini- patient’s past positive and negative treatment is experiences knownher views and to ask questions.the Consideration of and The patient beliefs. should given be to time make his or thorough and history listen carefully to patient’s the account patientbetween and provider. The clinician should take a steps may helptreatment to goals maximize alignment of cian, and to and consider economic social factors. patient,the rather and needs the than concerns physi the of - Patient-centered to attention medicine focus seeks first on concerns and considerations of patients and physicians. optimize treatment LAI the and between abalance find centered medicine provides one approach that can help such as medication cost, access to care, and reimbursement. groups may attitudes intheir differ also toward other issues, Likewise, educationLikewise, about potential the of benefits LAIs Education. There to aneed educate is also clinicians regarding practi- Patient-centered medicine. 136 © 2016Copyright Physicians Postgraduate Press, Inc. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia Injectable Health care providers should able be to anticipate 135 Psychoeducation for patients about schizo- The concept of patient- 130 Stakeholder 134 Several Several

It is illegal to post this copyrighted PDF on any website. of LAIs. The roundtable recommended experts that patients therapy may not criteria meet for insurance reimbursement treatment for patients adherence. with poor vations suggest that LAIs should simply not viewed be as a but fail then to medication. the take Together, obser these treatmentcator adherence. Patients of may aprescription fill medicationthe possession ratio alone is not asufficient indi- with schizophrenia. Although often inresearch used studies, future nonadherence, iswhich always a possibility for patients LAIs, since antherapy important should to prevent be of goal current medication adherence should not preclude of use the In addition, nonadherence is frequently unrecognized, and do not they because accept chronic the illness. naturethe of of psychosis, likely may to especially discontinue be treatment ence. a population that is associated rate with a high of nonadher have demonstrated of benefits LAIs patients, infirst-episode psychotics generally has similar inRCTs, been some studies families,their providers, and payers. impact multiple different stakeholders, including patients and sidered weighing of when therapy. use the LAI factors These anumberdiscussed of additional factors that should con be - Additional Considerations LAI carehealth home, or possibly patient’s eveninthe own home. tion at physician’s the or office clinic, pharmacy, in the at a might which LAI, include administrathe - administration of and provider should arrive also at arrangement aflexible for goals, andmeeting these offering anifindicated. LAI Patient therapy, goals of a discussion is helpful use of LAI whether for phrenia, shared this vision might include agreement about the to arrive at ashared vision of care. For patients with- schizo patientinvolves andthe provider the priorities the aligning of thatso access is more broadly assured. “value-based” approach to payment for and pricing of drugs more, payers and should industry encouraged be to atake helpfulwithin systems health be regard. inthis will Further mendations to help as well make analyses case as financial this hospitalizations, relapses, Researchlife. recom and- quality of cost and consider potential the long-term of benefits reduced beyondlook short-term the decisions financial around drug appointment. patienttionsthe misseshis or for her injection what to doif flexibility indosing and intervals, has recommenda each LAI - adjusted on based clinical presentation. There some is also with oral the version; dosage may titrated to need be and appropriate informed can be dose by previous experiences for oral coverage). or loading doses necessary the Selecting initiated test (eg, dosing using oral the counterpart, need the The clinician to needs understand how should eachLAI be rently available each have and unique specific characteristics. and what to do should adverse emerge. effects The LAIs cur Correll etal 18 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Currently, patients are who adherent to antipsychotic Nonadherence. and safety data for efficacy Beyond LAIs, panel the and conclusions. Summary Finally, payers educated to be need and also encouraged to 44,75

First-episode patients, or patients early course in the Although efficacy of LAIs and Although oral efficacy anti- Patient-centered medicine - - - - levels are not always obtained inroutine practice. clinical not receiving an adequate medication although dose, these understanding relapses whether patients because occur are on therapy.while LAI antipsychotic Blood levels may help in optimalthe approach to patients with relapsing schizophrenia or another and LAI), more research to is better needed define orLAI how to switch from to another LAI antipsychotic (oral may unsure be of what to a patient do when relapses on an has examined why patients relapse on medication. Clinicians reason the cases, for a relapse is unknown, and scant research homedrugs, care, or other environmental factors. In many effectiveness but of because changes also of use inthe other relapse. therapy, of evenfor donot who those yet have of ahistory oflikelihood future relapses should an be important goal individual,etal, biological, and Preventing psychosocial. the produce at detrimental effects many levels, including- soci medications before becoming eligible for LAIs. Relapses should not have to first prove that have they relapsed on oral Patients and families should understand that longer injection administrations may even more be convenient for patients. day.cation every LAIs that offer longer between intervals even 12weeks rather than required being to oral take - medi may simply prefer to receive 2, 4, 6, or a single injection every patients of benefit the improved convenience. Some patients or safety of versus LAI oral formulations, LAIs offer many ting on antipsychotic adherence. asked. LAIs are choice agood to reduce impact the of forget- overestimatealso own their adherence to treatment when remembering to medication take as prescribed, and may they tive impairment or problems memory may have difficulty informed consent process might delay randomization. departmentgency at may some difficult facilities, be and the patient’s treatment patient the while history is emer inthe treatment with oral antipsychotics. However, accessing the ward to treatment with an versus LAI home or in-hospital with emergency the department or as as possible soon after could investigate randomization at of time the contact initial could provide more data regarding relapse. trial Aclinical patients with LAIs emergency inthe beginning room, which relapse associated with violence, self-harm, or self-neglect. considered desirable especially there when is a history of example, continuous coverage treatment with LAI may be weighingwhen potential the of benefits treatment. LAI For ofhistory relapse may important be also considerations leave hospital the with antipsychotic effective coverage. tant strategy to help bridge gap this and ensure that patients acutely patients ill suggest that agents these provide an impor discharge. The observations that LAIs reduce relapse risk in for an acute and episode transition the to outpatient care after Unitedin the States is gap the in-hospital between treatment PatientsRelapses. of may drug lack relapse because of Aside of from use. issuesEase of comparative efficacy Cognitive and problems. Patients memory - with cogni Very little research on has treatment the focused of or relapse. The patient’s of episode Severity and type most importantthe issues inschizophrenia One of care © 2016Copyright Physicians Postgraduate Press, Inc. J ClinPsychiatry 2016;77(suppl 3) 137 - - - It is illegal to post this copyrighted PDF on any website. overall treatment costs with LAIs. antipsychotics found that most studies demonstrated lower that examined carehealth costs associated with LAIs or oral reduced relapses or hospitalizations. of Areview 28studies may save money across entire the continuum of care due to areucts acquisition associated with drug higher costs, they from health system the although prodperspective, LAI - state. to state significant be differencesalso in access therapy to LAI from of 2-way or video other telemedicine approaches. There may possible to improve patient access to care through use the inmental with It experience health. those cially might be regions by are care health underserved professionals,- espe patients have copayments or deductibles. In addition, many region. by state vary issues will or geographicthese manyfact, of provider, insurers, and care health the system as awhole. In patient,from many the the including perspectives, of those compared to an oral antipsychotic. that patients these are more likely to from benefit an LAI groups are who often excluded from studies, clinical suggest patients with substance misuse problems among other patient Demonstrating Effectiveness (PRIDE) study, included which RCTs. Data from Paliperidonethe Palmitate Research in yet patients with substance misuse are often excluded from label. product injection as early as 14days after first, according the to the lauroxil, there is an opportunity to administer second the larger than that of aconventional With needle. aripiprazole internal with bore,injection amodified needles is which spheres and paliperidone palmitate require specialized among available the LAIs. For example, risperidone micro- schedule of follow-up appointments. up visits and that injection the schedule is distinct from the know that patient the continue will to have regular follow- physician or other mental team health members; should they donotintervals mean that patient the by not seen the will be been on treatmentbeen time. for longer of periods that of benefits the LAIs are greater for patients have who utilization, and analyses hoc haveservice post demonstrated short to adequately evaluate of LAIs effects the on quality and as ameasureused of care quality, may too be period time this States. Although 30-day hospital readmission rate is often There is aclear for need alarge-scale cost study United inthe common reasons for adherence poor to antipsychotics, mg without doses) needing to restart oral supplementation. against alate injection (up to amonth on 662mg the or 882 shown on asystem-wide basis inCanada requiredhospitalization. Potential days of cost savings were cine acquisition by costs offset can changes be small inthe days,hospital andnumber substantially even of greater- medi States, cost-effectiveness analyses are largely by influenced J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. The cost of LAIs presents to use. However, their abarrier An important that access to is fact the LAI barrier many Access and cost. For providers, there may differences of be inease use Substance misuse. Substance 88 This LAI also provides also This LAI longer coverage Issues of access and cost may viewed be Substance misuse is one of the most Substancethe misuse is one of 139 45 In studies United inthe 118 and Sweden. 140,141 138 116

worsened. ishment or that as asign patient or the ill has recently is very physician’s recommendation of therapy LAI as aform of pun- adherence to medication. Patients or families may the view patients with schizophrenia have who of ahistory poor de improve confidence among providers regarding use. their may reduce perceived the associated stigma with LAIs and disciplines. Exposure to using LAIs in aresidency setting that should communicated be to professionals indifferent Moreover, of it use to keyLAI aspects the is identify critical includingals, workers, social nurses, counselors. and peer is an urgent for need training of mental profession health - significant influence on perception of therapy. LAI There mostthe with time patients and family and may have a tant role inpatient attitudes toward LAIs. with patient care. Nurses may inparticular play an impor pharmacists, workers, social and others are who charged about of use the LAIs, including physicians, nursing staff, care process that care health all providers are knowledgeable ability of this treatmentthis option.ability of and may unwilling be to inform patients about avail the - havealso negative attitudes agents these toward of use the to patients and families. their Many care health professionals ofto type program this from state vary to state. Laws about pharmacist-administered injections and access may obtaining less when stigma experience injection. the other conditions, including standard vaccinations, patients pharmacy might receiving be injections for any number of come to physician’s the other people inthe Because office. injections directly from apharmacist, without needing to on indefinitely. In some regions, patients may receive LAI rather than astime something that patient the remain will to present LAIs as atool that of for might used be aperiod pumps for patients with diabetes. It preferable might be also areas of medicine, such as rheumatoid or arthritis infusion treatmentacting strategies are increasingly common in other When to patients, talking it may help also to note that long- associated stigma with nonadherence.the reduce some of make patient’s the life simpler. This approach may help to is at fault for not medication, taking but simply as away to physician is not recommending patient the an because LAI many experience dailyotherwise stressors. In way, this the for true may patients especially be work who night or shifts thatbenefit reduces to daily need take the medication. This respond favorably to suggestion the as of alifestyle use LAI Patients with distracted or insight-based nonadherence may bility-based nonadherence lack (eg, of insurance coverage). an or illness that requires illness the medication) or accessi - adherence (ie, patient the not does that believe he or she has disorganization. patients Other exhibit insight-based non- resultswhich from issues such as cognitive impairment or what might referred be to as “distracted nonadherence,” many different of types nonadherence. Some patients exhibit stigmatize nonadherence. It is sufficiently common across Stigma. LAIs are most frequently recommended for Finally, it important is also to emphasize to need the Stigma about of antipsychotics use the LAI is not limited © 2016Copyright Physicians Postgraduate Press, Inc. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia Injectable 124 However, it should that recognized be there are 125,126,129 It to is the critical 120 Nurses spend

19 - It is illegal to post this copyrighted PDF on any website. Correll etal 20 For [email protected]. reprints orpermissions, contact ♦ patients and providers. One potential advantage of LAIs is adherence can become asource of ongoing between conflict example, aloved when one relapses and insight. loses mightwho themselves find police, the for needing to call and disturbing consequences of relapse. are They ones the family members are suffer often immediate who the those rolethe of LAIs in schizophrenia treatment. In addition, ensure that patients have an advocate is who educated about themselves. Including families discussion inthe can help to for difficult patientsbe with schizophrenia to advocate for help patients to LAIs use appropriate. when In addition, it can therefore,bers, may have akey role as advocates inacting to ensure that are they adherent to medications. Family mem- well as patients, and family members often help patients to nature, not behavior.” “bad ofhumanall nonadherence medicine to view of as an aspect It isIt illegal to post this copyrighted PDF on any website. Conflict over and fear of nonadherence. of and fear over Conflict of support. social Level

a Treatment Table ofCharacteristics 6.Importance When Antipsychotic Choosing orNotChoosing Long-Acting Injectable (LAI) Characteristics orderedCharacteristics by meanscores across theratings for patients, healthcare professionals, familymembers, andpayers. Patient hadneuroleptic malignant syndrome onanantipsychotic Patient isafraid ofneedles First-episode/early-phase illness Wish to beableto stop treatment abruptlyifneeded Access to/cost of treatment Access to/cost of Level ofnonadherence withLAImedications Coercion/diminished patient autonomy Patient isonchronic blood-thinningtherapy Injection site pain Injection Wish to beableto adjustdosequickly Stigma associated withtreatment Level impairment ofcognitive/memory Degree of lack ofsocialsupport lack Degree of Comorbid substance abuse/dependence Potential for lossoffunction Ease of use of the treatment the Ease ofuse Family over conflict patient’s adherence Recency of last relapse(s) last of Recency Severity ofepisodes/relapse(s)Severity Number of prior relapsesNumber ofprior Level ofnonadherence withoral medications Danger to relapse(s) selforothersduring Characteristic 1 2–3 4–5 6–7 8–9 10 PLEASE RATE FOREACH CELLGIVING YOUR BESTESTIMATE: to participants: Instructions whendecidingwhethertocharacteristic prescribe anLAImedication. Values shown are mean(SD) basedonthegroup responses. (psychiatrists) wereSix ofthe8participants askedto rate onascalefrom ofeach 1to 10theirbestestimate ontheimportance = = Extremely inappropriate: whendecidingagainstusinganLAI. Extremely that trumpsallotheraspects characteristic = = = = Extremely important: characteristic that trumps all other aspects whendecidingonusinganLAI. that trumpsallotheraspects characteristic important: Extremely Usually inappropriate: among the most important characteristics forUsually characteristics inappropriate: thestakeholdernotto consider anLAI. amongthemostimportant Equivocal thestakeholderwould againstLAI:characteristic sometimesconsider whendecidingagainstanLAI. Equivocal for thestakeholderwould LAI:characteristic sometimesconsider whendecidingfor anLAI. for characteristics thestakeholderto consider. amongthemostimportant Usually important: a Poor adherence families affects as Medication Total Mean need toneed adjust than during would dose the case the acute be as amaintenanceused treatment, there is likely less to be to adjustficult or control medication the As dose. LAIs are months, some patients or providers may that believe it is dif- treatment is administered only few weeks or once every not patient. the patient.the The is goal to control on of part the illness, the ing therapy to LAI not does involve asurrender of autonomy patientthe voluntarily agrees to receive each injection. Agree- tion. However, it should stressed that be of case inthe LAIs, similar to injecting asedative for apatient with acute agita- patient autonomy. Some may perceive an injection of as LAI family members, and clinicians even that LAIs diminish patient-provider relationship. are approached and possibly discussed, strengthening the source of bythis conflict changing removalthe how of LAIs Scores 3.0 3.6 3.8 4.0 4.2 4.2 4.2 4.2 4.4 4.5 4.5 5.9 6.2 6.4 6.5 6.6 6.9 7.1 7.6 7.6 7.6 7.9 Wish to control treatment and dosing. LAI Because Autonomy. © 2016Copyright Physicians Postgraduate Press, Inc. Mean (SD)Mean Patients, 2.8 (1.8) 2.5 (1.5) 3.0 (5.7) 3.3 (1.0) 4.4 (1.0) 3.8 (2.1) 3.0 (0.9) 4.3 (1.7) 3.2 (1.2) 4.3 (0.8) 3.9 (1.1) 5.4 (1.4) 5.5 (1.0) 5.3 (2.2) 5.7 (2.3) 7.0 (1.4) 6.0 (2.1) 6.7 (1.2) 7.2 (1.5) 6.5 (2.0) 6.0 (1.9) 6.7 (1.5) There is sometimes aconcern among patients, Professionals, Health Care Mean (SD)Mean 2.7 (1.6) 3.8 (1.2) 4.8 (1.3) 3.7 (1.2) 4.2 (0.8) 4.3 (1.5) 4.5 (0.5) 4.1 (1.7) 4.8 (0.4) 4.0 (1.1) 4.8 (0.9) 6.4 (1.1) 6.7 (1.4) 7.3 (1.4) 6.8 (1.7) 6.0 (2.1) 7.5 (1.2) 7.2 (1.9) 8.0 (2.0) 8.5 (1.4) 8.7 (1.9) 8.5 (1.9) J ClinPsychiatry 2016;77(suppl 3) Mean (SD)Mean 2.5 (1.5) 3.3 (1.5) 4.1 (1.2) 4.0 (0.9) 4.3 (0.9) 4.7 (1.3) 4.3 (0.5) 4.3 (1.7) 4.5 (0.8) 4.8 (0.4) 4.3 (1.1) 6.3 (1.1) 6.5 (1.2) 7.2 (1.5) 7.3 (2.0) 7.5 (1.6) 8.0 (1.1) 7.7 (1.6) 7.8 (1.6) 7.8 (1.2) 8.3 (1.0) 8.5 (2.1) Family, Mean (SD)Mean 3.8 (2.1) 4.8 (0.9) 3.3 (1.3) 5.1 (0.2) 3.7 (1.6) 3.8 (0.8) 4.9 (0.8) 4.1 (1.8) 5.1 (0.2) 4.8 (0.4) 5.1 (0.2) 5.6 (1.0) 6.0 (0.9) 5.8 (1.5) 6.2 (2.0) 5.9 (2.1) 6.0 (0.9) 6.8 (1.8) 7.3 (1.9) 7.5 (2.2) 7.3 (2.1) 7.7 (2.2) Payers,

It is illegal to post this copyrighted PDF on any website. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Table 7.Concluding Recommendations • • • • • • • • • andPolicyGuidelines • • • • • • Patient and Eligibility Treatment Selection • • • • and TrainingEducation • • • • • • • • • Research Recommendations companies to identify value-based pricing andpayment pricing companies strategies to identify value-based for LAIs. As analternative to current approaches, market-based drugpricing payers may withpharmaceutical consider working potential long-term benefitsofreduced hospitalizations, relapses, issues. and quality-of-life Payers shouldbestrongly encouraged financial decisionsaround to lookbeyond drugcost andconsider the short-term the patients andinsurance providers. The long-term benefitsandcost savings associated withLAI useandroutine healthmonitoring shouldbeemphasized to levels shouldbestreamlined. behaviorsIncentives could beprovided for guideline-consistent for clinicians, andreimbursement at theinstitutional andstate considered. and theinvolvement care. Optionsoutsideofthemedicaloffice, orat home, of primary shouldbe suchasat thepharmacy shouldbeputinplace to facilitate theadministration support sites ofLAIs,Institutional orclinics whichincludesinjection improving, whoare nonadherent, orwhoare oftime. hospitalized periods repeatedly orwithinshort Guidelines shouldbecreated for cliniciansto assessthepotential for LAIusefor oral antipsychotics patients taking whoare not LAI usepatterns across large systems ofcare. leaderstoClaims-based tools track shouldbedeveloped mental healthdirectors that Medicaid andotherclinicalpolicy permit claimsinformation in pharmacy “real time.” Information systems shouldbedeveloped that allow patients to voluntarily theirtreating permit cliniciansto access their annual antipsychotic medication possessionratio of< shouldbedeveloped metric to ofadultswithschizophreniaA quality measure theproportion inahealthplanthat have an LAIs shouldnotbeviewed asthefinalchoice for patients whoare consistently nonadherent. Clinicians, patients, andfamilyshould allbeinvolved inapatient-centered approach indecidingwhetheranLAIisindicated. should beconsidered. anLAI,theacquisition costWhen andtheeffectiveness selecting oftheoral antipsychotic usedintheacute treatment phase When relapse ispredicted to beassociated or withhighrisks “a lotto lose,” theargument for LAIuseisstronger. Previous pooradherence andthepresence for factors ofrisk future nonadherence increase theargument for LAIuse. tolerability concerns, including extrapyramidal elevations sideeffects, weight inprolactin, akathisia, gain,andsedation. ofaspecificLAIshouldconsider anindividualpatient’sSelection preferences to specific ofsensitivity history andprior Even patients onLAIscanbecome isrequired. nonadherent, soongoingeducation andsupport improve confidence, experience, withtheseagents. and familiarity Residents (andpotentially allproviders intraining) shouldberequired to beexposed to theirtraining using LAIsduring to physicians, nursepractitioners, nurses, physician assistants, pharmacists, socialworkers, residents, peercounselors, andothers. Tailored education aboutLAIsshouldbedeveloped for different groups ofprofessionals whointeract withpatients, including All patients shouldbeinformed oftheoptionanLAIandpros andcons ofLAIversus oral medication discussed. LAI useasaninstrumental variable shouldalsobeconsidered. analysis that comparesAn observational outcomes ofschizophrenia patients across clinicsandthat useshistorical clinicrate of groups) for introducing LAIsto schizophrenia outcome patients, ofLAIacceptance. withtheprimary shouldbeconsideredA clinicaltrial that compares different strategies (eg, motivational interviewing, familyeducation, peer increased utilization. Greater shouldbepursuedto helpdrive choices intervals methods, interms ofspecificmolecules, andinjection delivery financial analyses withinhealthsystems. will increase. Acompelling to healtheconomics sway studymay reimbursement benecessary inmany states, including As more attention isgiven to reducing avoidable hospitalizations andtheirassociated ofsuchstudies costs, theimportance examine outcomes withdifferent schizophrenia treatment strategies. considerations andtherecent toward efforts healthcare reform andreducing costs, to larger shouldbeperformed trials contrast withotherareas ofmedicine, there are large few RCTs very inthetreatment ofschizophrenia. Given thepublichealth antipsychotic adherence andhospitaladmissionsmay bethemostappropriate methodfor ofLAIs. In assessing theimpact offer/no offer ofLAIonthecourse ofillnessinyoung adultswithschizophrenia whoare followed through claimsrecords for Pragmatic (large are simple)trials likelyto bethemostinformative andgeneralizable. Alarge that simple trial compares not betheappropriate goldstandard inthiscontext. Different studydesigns are associated withdivergent findingsregarding relative benefitsofLAIsvs oral medications; RCTs may are neededto more accurately assessdifferences amongLAIsinterms ofadverse event frequency. Appropriately powered randomized head-to-head cont 0.80. © 2016Copyright Physicians Postgraduate Press, Inc. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia Injectable

It is illegal to post this copyrighted PDF on any website. Correll etal 22 For [email protected]. reprints orpermissions, contact ♦ Supplementary material: Consta). risperidone (Risperdal and others), risperidone microspheres (Risperdal others), and (Seroquel quetiapine (Orap), Trinza), pimozide Invega Sustenna, (Invega palmitate paliperidone Relprevv), (Zyprexa pamoate olanzapine others), and (Zyprexa olanzapine others), and (Haldol haloperidol others), aripiprazole monohydrate (Abilify Maintena), clozapine (Clozaril, FazaClo, and lauroxil (Abilify), (Aristada), aripiprazole aripiprazole names: Drug marized inTable 7. Concluding Recommendations members, and payers. making by patients, health care professionals, family of LAIs and how factors these might decision- influence ing importance the factorsof clinical several selection in the PatientsSchizophrenia With Recommending LAI Therapy for schizophrenia. with employment that jeopardized could be by a relapse of away from usual their source of care/support, or individuals a first psychotic and episode to treatment need take while dents living away from home have who recently experienced consequences for patient. the Examples include college stu- functioning associated with arelapse could have important important option potential the when for loss of normal reduce discomfort the associated with LAIs. choosing agents with longer injection may intervals also agents Selecting this. injection with smaller volumes or LAIs, although no head-to-head studies have investigated more discomfort than aqueous the solution with newer used psychotics vehicles that oil-based used were associated with suggestsLAIs. experience that Clinical older the depot anti- concerned about potential the for pain or discomfort with 29or 30days. every optimal plasma concentration drug might treated be once Conversely, apatient is who thought at to be ahigher-than- treated at asomewhat shorter 25days). (eg, dosing interval just below a therapeutic plasma concentration drug may be vidual patient by is who believed his or her physician to be label recommends 26 to 28 days, injections an every indi - or lower concentrations. plasma drug Forthe example, if uling injection visits to at attain interval a specific higher adjust dosing through LAI of use the calendars and- sched state. suggests experience that Clinical it possible is to also ficient has time elapsed for to reach LAI the steady anew supplementation can subsequently withdrawn be once suf- patient’sthe If LAI. the symptoms respond, oral the then antipsychotic and simultaneously increasing of dose the can often most be rapidly achieved by coprescribing an oral relapse during treatment, LAI occur symptom then control of enabling doses, adjustment. dose Finally, if symptoms of treatment. In addition, many LAIs are available inarange © Copyright 2016 by Physicians Postgraduate Press, Inc. Press, 2016 Postgraduate Physicians © Copyright by It isIt illegal to post this copyrighted PDF on any website. Concluding recommendations from panel the are sum- Table 6summarizes opinions the of participants regard - Potential for of loss functioning. LAIs may offer an Fear of needles and pain. Some patients are especially

Available at at Available PSYCHIATRIST . COM . 12 11 10 9. 8. 7. 6. 5. 4. 3. 2. 1. 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 REFERENCES ......

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It is illegal to post this copyrighted PDF on any website. Supplementary Material

Article Title: The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence

Author(s): Christoph U. Correll, MD (Chair); Leslie Citrome, MD, MPH; Peter M. Haddad, MD; John Lauriello, MD; Mark Olfson, MD, MPH; Stephen M. Calloway; John M. Kane, MD DOI Number: dx.doi.org/10.4088/JCP.15032SU1

List of Supplementary Material for the Supplement

1. eTable 1 Summary of Mirror-Image Studies

2. eTable 2 Comparison by Antipsychotic of Number Needed to Harm for Weight Gain ≥ 7%, Somnolence, or Akathisia

3. eTable 3 Adverse Events (%) Occurring in at Least 5% of Patients Treated With Long-Acting Injectable Antipsychotics (LAIs)

Disclaimer This Supplementary Material has been provided by the author(s) as an enhancement to the published article. It has been approved by peer review; however, it has undergone neither editing nor formatting by in-house editorial staff. The material is presented in the manner supplied by the author.

© Copyright 2016 Physicians Postgraduate Press, Inc. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Supplementary eTable 1. Summary of Mirror-Image Studies Medication Follow-Up Study/ Duration, mo Age, y LAI (n)b Dose, mg Country Na Data Source LAI Phase Oral AP/LAI Inclusion Criteria Reported Outcome(mean ± SD) % Male Chronicity Oral AP (n)b (mean ± SD) Key Outcomes Chang et al48 184 Medical Retrospective, 12/12 SCZ (ICD-9), started RLAI, # Hps 36–55d 50.5 DOI ≥6 y in RLAI (184)otal t 177/3 mo Reduction of 34% dropouts followed ≥ # Outpatient visits 2012/Taiwan claims data, 1 y before and 77.2% CLO (7) NR and 32% of total excluded # ER visits nationwide after RLAI initiation, treated RIS (80) inpatient services % Hps regularly with RLAI c Other SGA (50) costs and inpatient # Hp days Oral FGA (91) nonmedication costs, respectively (P # Relapse < .005) Cost Overall psychiatric service costs increased 40.2 26% # Experienced Hps Rosa et al49 6/6 SCZ/SzAD (DSM-IV), e e 98 Multinational Prospective, # Experienced Hps ± 14.0 77.1 Mean DOI: RLAI (79) 32.6 ± 7.1/ Significant efficacy nonacute, previously e 2012/Int. dropouts due to psychotic 13.5 y 2 wk changes vs baseline excluded treated with OLA (stable OLA (79) 16.2 were observed for dose) and willing to switch disease ± 5.6 # Experienced PANSS, CGI-S, and GAF to RLAI, not known as RIS (all P nonresponder relapses < .0001) # Hp days TEAEs were similar with 1

Psychopathology wk and 3 wk OLA taper AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables Social functioning (40.0% and 46.5%, Safety measures respectively) TEAEs were generally mild (34.5%) or moderate (49.0%) in intensity 41.9 Crivera et al50 435 Multicenter Prospective, 12/1f SCZ (DSM-IV), appropriate # Hps ± 12.6 66.7ean M ± SD RLAI (435, 343) 25/2 wknnual A number of Hps 2011/USA dropouts for RLAI initiation # Psychiatric Hps DOI: (for any reason and # ER visits NR (435, 343) NR © 2016Copyright Physicians Postgraduate Press, Inc. included 17.6 ± 12.1 y psychiatric Hps) and % Psychiatric Hps ER visits decreased significantly after initiation of RLAI (all P values < .0001) Ren et al51 924 VA, Retrospective, 12/12 SCZ (ICD-9), started RLAI, # Psychiatric Hps 51 ± 11 94 NR RLAI (924) ± 38.9 13.0/ Initiation of RLAI 2011/USA multicenter dropouts and had ≥ 4 RLAI injections % Psychiatric Hps 2 wk associated with NR (924) NR included % ≥ 2 Psychiatric Hps significant reductions # Hp days in number of Length of stay psychiatric Hps, % of patients hospitalized, # Hp days, and length of stay Peng et al 42.6 52 147 Commercial Retrospective, 6/6 SCZ (ICD-9), started any # Hps ± 14.7 53.7 NR RLAI (38) NR Psychiatric Hps depot, but without depot 2011/USA claims data, dropouts % Hps HAL (69) decreased from 49.7% injection in the 6 mo before multicenter included % Psychiatric Hps FP before depot initiation baseline, ≥ Z (40) 2 outpatient % Hps for SCZ NR (147) NR to 22.4% after depot # Hp days visits or ≥ 1 Hp within 180 d initiation # Psychiatric Hp days Decreases also noted for # Hp days for SCZ total Hps, SCZ-related Hps, and total health

care costs

e1 (continued)

It is illegal to post this copyrighted PDF on any website. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables e2 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Supplementary eTable 1 (continued). Summary of Mirror-Image Studies

Medication Follow-Up b Study/ Duration, mo Age, y LAI (n) Dose, mg Country Na Data Source LAI Phase Oral AP/LAI Inclusion Criteria Reported Outcome(mean ± SD) % Male Chronicity Oral AP (n)b (mean ± SD) Key O utcomes # Hps 35.9 Carswell et al53 443 Multicenter Retrospective, 12/12 SCZ (DSM-IV), nonadherent ±12.4 64.3ean M ±SD RLAI (427) 41.5/2 gwk The mean number of # Hp days dropouts to oral AP (or preferred 2010/New Zealand (5 centers) # Days of compulsory DOI: Hp admissions was included RLAI), intensive treatment 11.7 significantly lower treatment order ± 9.9 y NR (427) NR in the year prior to post-RLAI than pre- switching to RLAI Cost RLAI (1.38 vs 0.61, P < .001), although mean length of stay was longer and mean costs were also lower Girardi et al54 88 Multicenter Prospective, 6/6 (24)f SCZ/SzAD (DSM-IV), with % Hps 41.2 ± 10.6 64.8ean M ± SD RLAI (88) 47.4 ± 10.1/ Transition to RLAI was 2010/Italy no dropouts clinically inadequate Response rate DOI: 18 ± 5.0 2NR wk associated with OLA (29) during the response to ≥ 2 oral APs Psychopathology y, improvement on all CLO (26) 6-month within 3 mo, BPRS total Safety Mean±SD outcomes studied, QUE (21) phase score ≥ 65 # Hp: including BPRS scores HAL (13) and hospitalization 8.26 ± 2.79 ARI (9) AEs were reduced by RIS (2) 2.5- to 7.4-fold during 18 mo of follow-up with RLAI Su et al 55 108 Medical Retrospective, 12/12 SCZ (ICD-9), regularly # Hps 42.0 ± 10.4 50 NR RLAI (108) 175.4± 54.5/ Switching to RLAI 2009/Taiwan claims data, dropouts treated with RLAI for # ER visits 3 mo was associated with excluded ≥ # Hp days nationwide 1 y, ≥ 1 y data in pre-RLAI RIS (17) NR significant reductions # Relapses in the total annual periods, had <90 d Hps Other SGA (41) numbers of acute

© 2016Copyright Physicians Postgraduate Press, Inc. FGA (27) hospital admissions FGA + RIS (10) (55% reduction, FGA + other P SGA (5) = .0003), Hp days None (8) (48% reduction, P = .0021), and elapsesr (54% reduction, P = .0005) Lam et al56 2,300 Multinational Prospective, 12/12 SCZ who participated in % Hps 38.4 NR Mean DOI: RLAI (1,748) NR 12-mo Hp rate was 44.5% 2009/15 countries dropouts RLAI clinical trials All cause 10.3 y on oral AP vs 16.4% on OAP (1,748) NR RLAI (P J ClinPsychiatry 2016;77(suppl 3) included discontinuation < .001) Psychopathology

Fuller et al57 106 VA (Ohio), Retrospective, 10.2 ± 6.4/ SCZ/SzAD (ICD-9) at any # Psychiatric Hps 51.9 ± 10.2 93 NR RLAI (106) 35.5/ Fewer patients had 2009/USA multicenter dropout 10.2 ± 6.4 time of the study period % Psychiatric Hps 2 wk (end) psychiatric Hps after (5 centers) included (1/2003 to 1/2006), with % ≥ 26.3 switch to RLAI (75% vs (mean ± SD) 2 Psychiatric Hps ARI (7) ± 4.9 continuous enrolment 42%, P # Psychiatric Hp days OLA (19) 15.1 ± 7.1 < .001) throughout the study # Psychiatric Hp days/ QUE (30) Post-switch patients also period, ≥ 423.5 ± 275.5 months RIS (57) 4 injections of 3.8 ± 1.9 had significantly lower # Psychiatric-related ZIP (8) mean number and RLAI 107.7 ± 45.1 outpatient visits duration of Hps Compliance Cost (continued)

1998/France dropouts 69.6 ± 38.4 # Hp days OAP (48) NR higher during depot AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables excluded (mean ± SD) treatment than during treatment with oral APs (4.8 vs 7.2 Hps), as was the mean number of Hps per year (0.93 vs 1.25) Svestka et al Clopenthixol 169.5/3.7 wk Lower Hp risk while on 60 34 Single center Prospective, 10.3/10.3 SCZ, in remission % Hps 37.4 23.5 Mean DOI: 9.2 y, decanoate (34) LAI than on oral AP (risk 1984/Czech dropouts ratio © 2016Copyright Physicians Postgraduate Press, Inc. included # Hps in = 0.43,P < .0001). lifetime: NR NR 1–12 # Hps NR 27.7 Duration ofFPZ (65) 17.7/3 wk Lower number of Waldmann and 65 Single centerRetrospective, 31.2/31.2 SCZ/SzAD, outpatients and treatment: Hps while on LAI Neumann61 dropouts patients in day hospital 1–9 y than on oral AP 1984/Germany excluded who were receiving FPZ NR (65) NR decanoate (rate ratio = 0.0201, P < .0001). # Hp days 25–44 Michel et al62 112 Single centerRetrospective, 12–17/12–17 SCZ, on depot when study h 67.9 NR FPZ NR 93% of patients had was conducted NR NR 1981/Chile dropouts (range) less medical resource excluded use (eg, nursing consultations, injections, use of concomitant medications) after switching to LAI FPZ, and 96% of patients had fewer consultations after switching (continued)

It is illegal to post this copyrighted PDF on any website. Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables e4 For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website. Supplementary eTable 1 (continued). Summary of Mirror-Image Studies

Medication Follow-Up b Study/ Duration, mo Age, y LAI (n) Dose, mg Country Na Data Source LAI Phase Oral AP/LAI Inclusion Criteria Reported Outcome(mean ± SD) % Male Chronicity Oral AP (n)b (mean ± SD) Key O utcomes Tan et al63 127 Multicenter Retrospective, 24/24 SCZ, DOI 8 ≤ y, # Hps 32.5 ± 8.8 61.4 6–8 yZ FP (127) 25/mo Of 127 patients, 105 had 1981/Singapore (6 centers) dropouts ≥ 24 mo treatment # Hp days NR (127) NR reductions in relapses excluded before and after the Compliance requiring readmission institution of FPZ depot after switching to depot FPZ. Relapses increased in 19 patients and were unchanged in 3.

Arató and Erdós64 51 Single centerRetrospective, 44/26 SCZ/SzAD, ≥1 y on depot,# Hps 34 100 Mean DOI: Mixed FGA FPZ During LAI treatment, 1979/Hungary dropouts ≥2 Hps in the past # Patients who 7.2 y (12.5–25 mg/ patients had lower excluded experienced Hps 4 wk), incidence of Hp (risk Flupenthixol ratio = 0.204,P < .0001) (20 mg/3 wk) and # Hps (rate ratio = NR NR 0.106, P < .0001) # Hps 18–39 65 12/12 SCZ spectrum disorders, i Devito et al 122 Single centerRetrospective, % Hps 50.8 NR FPZ (61) 37.5 mg/ Hp readmission rate was treated in the same 1978/USA dropouts Length of stay 3–4 wk 25% with FPZ vs 44% inpatient program and excluded # Hps per patient NR (61) NR with oral AP. referred for outpatient FPZ group also had treatment in the FPZ shorter mean length of program stay (7 vs 20 d) Polonowita and 43 Single centerRetrospective, 13/13 SCZ (ICD-8), started FPZ # Hps NR 67.4 NR FPZ decanoate NR FPZ associated with James66 dropouts depot # Hp days (43) significantly fewer 1976/New Zealand included Hps (total of 60 vs 22 NR (43) NR admissions for oral AP

© 2016Copyright Physicians Postgraduate Press, Inc. vs FPZ groups, P < .004) and a lower mean # Hp days (1,463 vs 327, P < .00005) 107 mg Mean # Hps per year Lindholm67 24 Multicenter Retrospective, 26.9/26.9 SCZ, administered # Hps 44.9 25.0 Mean DOI: Perphenazine enanthate (24) decreased from 1.31 1975/Sweden (2 centers) dropouts perphenazine enanthate % Hps 6.8 y during the control excluded for > # Hp days 1 y NR (24) NR period to 0.59 Concomitant during treatment antiparkinson with perphenazine J ClinPsychiatry 2016;77(suppl 3) medication enanthate (P < .05). Perphenazine enthanate was also associated with fewer total Hp FPZ decanoate 40/2 wk as a Significantdays. reduction # Relapses requiring NR NR Patients (58) general rule, in relapse frequency Gottfries and 58 Single centerRetrospective, NR SCZ, discharged, treated Hp started (range, after switching from Green68 dropouts with flupenthixol LAI during % Hps 20–60 mg) oral APs FPZ decanoate excluded decanoate during Hp and 1974/Sweden # Hp days (P observation period later were Length of stay transferred All cause NR (58) NR < .005) to ambulant Patients also had fewer discontinuation treatment Hps and shorter duration of stay after switching (continued) It is illegal to post this copyrighted PDF on any website. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ It isIt illegal to post this copyrighted PDF on any website.

Supplementary eTable 1 (continued). Summary of Mirror-Image Studies Medication Follow-Up b Study/ Duration, mo Age, y LAI (n) Dose, mg Country Na Data Source LAI Phase Oral AP/LAI Inclusion Criteria Reported Outcome(mean ± SD) % Male Chronicity Oral AP (n)b (mean ± SD) Key O utcomes NR 42.4 NR FPZ decanoate NR Among 33 patients, the Morritt69 33 Single centerRetrospective, 12/12 SCZ, administered FPZ # Hps decanoate and with 1 y % Hps (33) total number of Hp 1974/UK dropouts NR (33) NR excluded record pre/post FPZ depot # Hp days admissions was 60 before FPZ decanoate vs 12 after FPZ decanoate. Total number of days Hp decreased from 2,379 to 801. Johnson and 12.5/5 wk to After 1 y, FPZ was Freeman 126y Single center Retrospective, 12/12 SCZ, administered FPZ % Hp NR NR NR FPZ enanthate 25/10 d associated with a 70 dropouts depot and with follow-up Hp days or decanoate (126) 57% decrease in Hp 1972/UK excluded record of 1 or 2 y NR (126) NR admissions and a 48% AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables decrease in length of stay After 2 y, Hp admissions decreased 74%, and length of stay decreased 48% Denham and 38.5 55.3 Chronic FPZ (103) FPZ enanthateReduction in Hp SCZ, receiving FPZ depot, # Hps Adamson 103 Single centerRetrospective, 24.8/24.8 % Hps (6.25–50 mg/ admission rate and 71 (mean) ≥12-mo follow-up record

© 2016Copyright Physicians Postgraduate Press, Inc. dropouts 2 wk) or inpatient time after after injection, with # Hp days 1971/UK excluded # Hps due to specific decanoate transition to depot completely documented agent previous history reasons (12.5–37.5 mg/ # Hp days due to 2 wk) specific reasons NR (103) NR Malm # Hps NR 100 Chronic FGA mix (44) NR Lower number of Hps 72 44 Single centerRetrospective, 36/36 SCZ, chronic, known # Hp days during LAI than dropouts to have difficulty with 1971/Denmark NR (44) NR during oral AP (rate excluded adherence to AP oral medication ratio = 0.294,P < .0001) aOriginal study sample size.b Number of patients analyzed.c Obtained directly from author.d Majority (60.3%) were from 36–55 years old.eBased on patients who received at least 4 doses of RLAI = (n 96). fAnalyzed pre- vs post-LAI phase (6 months each), but study had 18-month extension follow-up phase.gDose at 12 months. h Majority (65.2%) were between 25–44 years old.iHalf of the participants were assessed in a mirror-image setting. Abbreviations: AE = adverse event, AP = antipsychotic, ARI = aripiprazole, BPRS = Brief Psychiatric Rating Scale, CGI-S = Clinical Global Impressions-Severity of Illness scale, CLO = clozapine, DOI = duration of illness, DSM- IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, = ER emergency room, FGA = first-generation antipsychotic, FPZ = fluphenazine, GAF = Global Assessment of Functioning, HAL = haloperidol, Hp = hospital/hospitalization, ICD = International Classification of Diseases, Int. = international, LAI = long-acting injectable, NR = not reported, PANSS = Positive and Negative Syndrome Scale, OLA = olanzapine, QUE = quetiapine, RIS = risperidone, RLAI = risperidone long-acting injectable, SCZ = schizophrenia, SzAD = schizoaffective disorder, SGA = second-generation antipsychotic, TEAE = treatment-emergent adverse event, UK = United Kingdom, USA = United States of America, VA = Department of Veterans Affairs, ZIP = ziprasidone. Symbol: # = number/number of.

It is illegal to post this copyrighted PDF on any website. Cariprazine Brexpiprazole Lurasidone Asenapine Iloperidone Paliperidone Aripiprazole Ziprasidone XR Quetiapine Quetiapine IR Quetiapine Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables e6 For [email protected]. reprints orpermissions, contact ♦ b a Antipsychotic or Akathisia Number Neededto Harmfor Weight ≥ Gain eTableSupplementary 2.Comparison by Antipsychotic of Olanzapine Risperidone Abbreviations: IR It isIt illegal to post this copyrighted PDF on any website. Updated from Citrome L.CNSDrugs. 2013;27:879–911andCitrome L.IntJClin Number neededto values harm < be expected every 10patients treated every be expected withlurasidone versus placebo. versus placebo; and1additionalpatient can withcomplaint ofakathisia 7patients treated every witholanzapine orquetiapineXR is observed treated witholanzapineorquetiapineIRversus placebo; somnolence 1 additionaloutcome ofweight gain Pract XR

. 2015;69:978–997. extended release.extended

immediate release, ND Weight Gain ≥ 34 17 67 35 10 35 20 16 22 18

7% 6 6

Number Neededto Harm 10 are boldedinthetable. For example, ≥

7% is observed every 6patients every 7% isobserved Adverse Event S

= omnolence

no difference from placebo, 100 50 11 17 16 42 20 15 10 13 7 7

It is illegal to post this copyrighted PDF on any website. J ClinPsychiatry 2016;77(suppl 3) For [email protected]. reprints orpermissions, contact ♦ Supplementary eTable 3. Adverse Events (%) Occurring in at Least 5% of Patients Treated With Long-Acting Injectable Antipsychotics (LAIs)a isIt illegal to post this copyrighted PDF on any website. Paliperidone Haloperidol Risperidone LAI Olanzapine Pamoate Paliperidone Palmitate LAI Palmitate LAI Aripiprazole LAI Aripiprazole Lauroxil Decanoate (Risperdal Consta) (Zyprexa Relprevv) (Invega Sustenna) (Invega Trinza) (Abilify Maintena) (Aristada) (Haldol) 405/ 210/ 300/ 234/ 234/ 234/ Adverse Event 25 mg 50 mg 4 wk 2 wk 2 wk 39 mg 78 mg 156 mg39 mg 156 mg 234 mg 273–819 mg 400 (300) mg 441 mg 882 mg Gastrointestinal disorders Constipation 5 7 ……………………… … 10 …… 2 Diarrhea ……275032122 … 3 …… … Dry mouth 07264310111 … 4 …… 3.4 Dyspepsia 6 6 ……………………… … … …… … Nausea 34554443222 … — …… … Vomiting ……612542322 … 3 …… … General disorders and administration site conditions Fatigue 39423122121 … … …… … Injection-site reaction … … … … … 0 4 6 9 7 10 3 … …… 1.2 Injection-site pain …… 232……………… … 5 3 4 … Infections and infestations Nasopharyngitis ……361022422 … … …… … Long-Acting Injectable AntipsychoticsLong-Acting inSchizophrenia: Injectable Supplementary Tables Upper respiratory tract infection 20314222124 10 4 …… … Investigations Weight increased 54567441112 9 17 2 2 2.9 Metabolism and nutrition disorders Increased appetite …… 146……………… … … …… … Musculoskeletal and connective tissue disorders Pain in extremity 62………022230 … … …… … © 2016Copyright Physicians Postgraduate Press, Inc. Back pain ……435213111 … 4 …… … Muscle rigidity … … 1 4 4 1 1 < < 1 1 1 2 … … …… 6.1 Nervous system disorders Headache 15 21 13 15 18 11 11 15 11 7 6 9 … 3 5 … Parkinsonism 8 15 8 14 20 12 10 6 … … … 4 … 3 4 7.3 Dizziness 7 11 4 4 1 6 2 4 1 4 2 … 4 …… … Akathisia 4 11 5 11 10 5 6 5 … 5 6 5 11 11 11 3.4 Sedation/somnolence 5 6 13 8 13 5 7 4 1 5 5 … 5 …… 4.9 Extrapyramidal disorder ……………523100 … … … … 13.6 Dyskinesia ……021464……… 3 … …… < 1 Tremor 03 301……………… … 3 …… 8 Psychiatric system disorders Agitation … … … … … 10 5 9 8 5 4 … … …… … Anxiety ……………853566 … … …… … Respiratory, thoracic, and mediastinal disorders Cough 42…59231011 … … …… … Nasal congestion 20 217……………… … 2 …… … a

These data are derived from product labeling and not from randomized, head-to-head clinical studies comparing LAI antipsychotics. Comparisons must be made with caution, as they reflect different methods of assessment and

adverse event definitions across studies.* Rates with placebo, which differ from label to label, are not shown. e7 *Hamer S, Haddad PM. Adverse effects of antipsychotics as outcome measures. Br J Psychiatry Suppl. 2007;191(50):s64–s70. Symbol: … = event not reported. It is illegal to post this copyrighted PDF on any website.