Thirty Years of Clozapine Treatment: Successes, Challenges, and Future Directions

SPRING 2019 SPRING SYNERGIES DEPARTMENT OF PSYCHIATRYDEPARTMENT

CME Credit Deepak K. Sarpal, MD Disclosures: Drs. Sarpal, Gannon, and Chengappa report no relationships with proprietary entities Assistant Professor, Department of Psychiatry producing health care goods and services. Medical Director, Services for the Treatment of Early Psychoses (STEP) Clinic

Instructions: To take the CME evaluation and UPMC Western Psychiatric Hospital receive credit, please visit UPMCPhysician Resources.com/Psychiatry, and click on UPMC Synergies: Spring 2019.

Accreditation Statement: The University of Jessica Gannon, MD Pittsburgh School of Medicine is accredited by Assistant Professor, Department of Psychiatry the Accreditation Council for Continuing Medical Medical Director, Comprehensive Recovery Services (CRS) Clinic Education (ACCME) to provide continuing medical UPMC Western Psychiatric Hospital education for physicians. The University of Pittsburgh School of Medicine designates this enduring material for a maximum of .5 AMA PRA Category 1 Credits™. Each physician should only claim credit commensurate with the extent of their participation in the activity. K.N. Roy Chengappa, MD, FRCPC Other health care professionals are awarded .05 Professor, Department of Psychiatry continuing education units (CEU), which are equivalent to .5 contact hours. Service Line Chief, Comprehensive Recovery Services UPMC Western Psychiatric Hospital

Introduction Clozapine is a unique antipsychotic medication, widely regarded as the most efficacious pharmacologic option available for the treatment of refractory positive symptoms in schizophrenia. Since its approval in 1989, a robust evidence base has characterized clozapine’s superiority for its United States Food and Drug Administration (FDA)-approved indications in persons with schizophrenia or schizoaffective disorder: refractory psychosis and recurrent suicidal behavior. Despite the evidence supporting its use, clozapine remains vastly underutilized in the United States (Figure 1, Page 2). Moreover, recent evidence suggests its use should occur earlier in our treatment algorithms and be expanded to include patients with a partial response to other antipsychotic drugs. Here, we provide an overview of clozapine’s role in our current treatment of psychotic disorders. We first focus on its interesting

UPMC Western Psychiatric Hospital historical context prior to FDA approval, followed by a review of key evidence supporting its use. is a part of UPMC Presbyterian We then review the current state of, and challenges related to, clozapine utilization. Finally, we Shadyside, which is consistently named to the U.S. News & World discuss future directions for clozapine’s place within our treatment algorithms and novel research Report Honor Roll of America’s efforts to develop precision medicine approaches to optimize its use. Best Hospitals. Continued on Page 2

Affiliated with the University of Pittsburgh School of Medicine, UPMC Presbyterian Shadyside is ranked among America’s Best Hospitals by U.S. News & World Report.

19 3

, 2015 REMS Established percent Kane et al., Kane SynergiesArticle *The theoretical theoretical *The 2003

InterSePT Trial Published Trial

Sampling of international Sampling of international 1989 1988 Clozapine Published Kane et al.

FDA Approved FDA Sampling of international utilization rates of of rates utilization international of Sampling

. e lozapin 1954 C Finnish

”Epidemic” Data displayed in purple represent countries that exceed this this exceed that countries represent purple in displayed Data ates of ates R

1956 Timeline of significant events related to the history of clozapine. of clozapine. to the history related events of significant Timeline International Rates of Clozapine. of Clozapine. Rates International

Clozapine Discovered 1954 FDA Approved FDA Chlorpromazine Timeline of Significant Events Related to Clozapine to Related Events of Significant Timeline and Utilization Development The theoretical minimum number of patients who may benefit from clozapine benefit from minimum number of patients who may theoretical The in displayed line. Data with the dotted displayed 25 percent, is approximately this minimum threshold. that exceed countries purple represent tted line. line. tted do the with displayed threshold. minimum Figure1.International schizophrenia. with patients for prescriptions antipsychotic all of out clozapine 25 approximately is clozapine from benefit may who patients of number minimum

Figure 2. Figure In this study, patients underwent a prospective trial of high dose a prospective patients underwent In this study, response and their lack of confirm to haloperidol (60 mg/day) results The or chlorpromazine. clozapine to randomized then were schizophrenia of treatment-resistant that 30 percent demonstrated in had significant improvement clozapine to subjects randomized of subjects 4 percent to compared symptoms and negative positive so were findings efficacy These chlorpromazine. to randomized under clozapine fully approving the FDA led to that they dramatic 2), with blood monitoring in 1989 (Figure name Clozaril the trade findings supporting the following: that clozapine would be used that clozapine following: findings supporting the other medication who had failed only in people with schizophrenia other antipsychotic than better worked trials, and that clozapine medications on the market. and Evidence Trials SupportingKey Efficacy Clozapine’s superior efficacy clozapine’s demonstrated evidence early Though symptoms, psychotic in patients with refractory chlorpromazine over phenomenon. In 1984, this captured had definitively date no trials to (including trial commenced controlled randomized a multicenter, by sponsored Hospital in Pittsburgh), State patients at Mayview published in were of this work In 1988, results Sandoz. trial clozapine pivotal be the landmark and to widely considered symptoms. psychotic refractory supporting its benefit in treating Figure 1. Figure for prescriptions out of all antipsychotic of clozapine rates utilization patients with schizophrenia. *

In a rebuttal to this finding, to In a rebuttal 2 Just four months after clozapine became months after clozapine Just four The Lancet. Lancet. The failed, the FDA asked Sandoz to resubmit an NDA but with research research but with an NDA resubmit to Sandoz asked the FDA failed, changes in the FDA regarding market exclusivity for new drugs new for exclusivity market regarding in the FDA changes a New complete to Efforts marketing. increase to Sandoz spurred by hampered were Sandoz by the FDA to Drug Application (NDA) NDA While the first States. United trials in the a lack of completed results in populations who did not respond to other antipsychotic other antipsychotic to in populations who did not respond results disabling severe had developed drugs, and in those who previously the same time, At disorders. movement neuroleptic-associated amongst clinicians, who noted its unique properties. The reputation reputation The its unique properties. amongst clinicians, who noted not only as an antipsychotic States, in the United grew of clozapine superior show that did not cause EPS, but also as one that seemed to In the United States, while the FDA did not stop the use of clozapine, the use of clozapine, did not stop while the FDA States, In the United the medi and only offered further its development halted Sandoz traction gained clozapine need. Meanwhile, compassionate cation for clozapine was removed from the market in Finland and several other and several in Finland the market from removed was clozapine blood monitoring explore to began Sandoz countries. European neutropenia. for help monitor guidelines to 20 times higher in Finland than in any other country where clozapine clozapine where country other than in any 20 times higher in Finland that, suggested A subsequent review or tested. had been prescribed not significantly was of neutropenia the incidence outside of Finland, Nonetheless, with chlorpromazine. that associated from different disorders, nine of whom died. Eight of these patients, and 16 of the nine of whom died. Eight of these disorders, agranulocytosis. 18, had developed total be to appeared of agranulocytosis that the incidence showed Sandoz Newly blossoming interest in clozapine turned to alarm in 1975, alarm in 1975, turned to in clozapine interest blossoming Newly of Health published concerning National Board when the Finnish findings in blood severe 18 patients developed in Finland, available commercially adopted, and open label trials and the first double blind trial in and open label trials and the first adopted, began. States the United in the United States, discovering there, in early clinical trials, that there, discovering States, in the United orthostatic with severe associated were of clozapine titrations rapid schedule was titration A slow collapse. and even hypotension and Finland, it was not widely adopted into clinical practice. The lack The practice. clinical into not widely adopted it was and Finland, or dystonia, such as Parkinsonism EPS symptoms, of “neuroleptic” of this novel of the promise amongst psychiatrists skepticism led to approval FDA towards started work to Sandoz Regardless, agent. While the cumulative results of these studies were intriguing, and were of these studies results While the cumulative Europe in much of central of clozapine marketing Sandoz’s despite was necessary for antipsychotic action. The international international action. The antipsychotic for necessary was and in 1967 AG Wander acquired giant, Sandoz, pharmaceutical 2,200 patients had been 1970, trials. By conduct to continued results. positive in studies with overall clozapine administered clozapine. Evidence from these early trials suggested that clozapine that clozapine suggested these early trials from Evidence clozapine. a without properties antipsychotic possessed unexpectedly that EPS the belief countering of EPS, significant emergence indicator of antipsychotic drug action. Several experimental trials experimental Several drug action. of antipsychotic indicator in humans effects antipsychotic examine to conducted were had received 1966, 100 subjects and by decade, the next over antidepressant and antipsychotic properties (Figure 2). Clozapine 2). Clozapine (Figure properties and antipsychotic antidepressant in to chlorpromazine profile a similar pharmacologic demonstrated predictive marker a key catalepsy, trials but without signs of rodent in humans and a mechanistic (EPS) symptoms of extrapyramidal Clozapine was developed in the mid-1950s, shortly after in the mid-1950s, developed was Clozapine Wander company pharmaceutical the Swiss by chlorpromazine, dual have a drug that would synthesize to their effort in AG The DrugThat Almost NeverHappened: Clozapine Before Approval FDA

a group a group Taken Taken 28-30 23 Those Those 17 In several In several Patients taking Patients 31 21 Citrome et al., Citrome A 2012 systematic A 2012 systematic 22 s In the seminal International International In the seminal 14,16 In a 2001 trial by In a 2001 trial by 18-20 amelioration of severe psychogenic poly psychogenic of severe amelioration 24,25 ggression and Other ggression and severe treatment-resistant bipolar disorder. treatment-resistant and severe 26,27 Page 2). Given rates of treatment resistance, it is estimated that 25 it is estimated resistance, of treatment rates 2). Given Page be candidates would of patients with schizophrenia 40 percent to countries, across of utilization In published surveys clozapine. for 1, of use (Figure the highest rates show China, and Taiwan Australia, for written prescriptions a quarter of antipsychotic 2), with over Page of antipsychotic 21 percent approximately In Germany, clozapine. clozapine. for were schizophrenia for prescriptions suboptimal treatment response history were randomized to either to randomized were history response suboptimal treatment haloperidol, or clozapine. risperidone, olanzapine, ratings of hostility on decreases significantly greater had clozapine independent of other than patients taking haloperidol or olanzapine, also appear to in aggression Decreases improvements. symptomatic and sedation. be independent of cognition 12 trials, controlled randomized case studies, four of four review studies, and six retrospective studies, 22 noncontrolled prospective in aggression decreases that clozapine animal studies indicated and with than other antipsychotics perhaps better schizophrenia, illness. efficacy in treatment-resistant greater potentially in patients aggression treating in has utility likely clozapine together, although the mechanism spectrum disorders, with schizophrenia this is not clear. for Accumulating been examined. have clozapine uses for Other off-label utility clozapine’s case studies, demonstrates primarily from evidence, in borderline and aggression of self-mutilation the treatment for disorder, personality dipsia, Utilization Clozapine of supporting the superior efficacy of the substantial evidence Despite in individuals with schizophrenia- other antipsychotics over clozapine clozapine symptoms, psychotic and refractory spectrum illnesses 1, (Figure States in the United under-prescribed profoundly remains Suicidality with of individuals the treatment for also is FDA-indicated Clozapine recurrent or with persistent disorder or schizoaffective schizophrenia behavior. self-injurious suicidal or for individuals at high risk (InterSePT), Trial Suicide Prevention or olanzapine. clozapine to randomized were suicidality in suicidal to engage likely less significantly were clozapine receiving suicide prevent to interventions suicide, or require commit behavior, require to likely less also were They (including hospitalization). or anxiolytic medications. with antidepressants treatment adjuvant Uses: A Off-label and is complex and violence schizophrenia between relationship The efficacy of examining Moreover, factors. by numerous influenced illness psychotic to secondary behavior aggressive medications for the risk of Nonetheless, challenges. poses ethical and methodologic or related in patients with schizophrenia and violence aggression medications. antipsychotic by be mitigated may disorders psychotic has been and violence for aggression of clozapine benefits The noting hospitals and other institutional settings by in state reported namely interventions, of psychiatric its impact on the most restrictive and seclusions. restraints and disorder or schizoaffective of patients with schizophrenia

15 showed increased increased showed Similar results were observed observed were Similar results 5

6 Clozapine-treated participants Clozapine-treated clozapine has been developed as has been developed clozapine 11 Rosenheck et al. Rosenheck A recent report from a NIMH from report A recent In a study of high-utilizers of hospital In a study of high-utilizers 4 9,10 Kane et al., Kane and similar data are available in the United in the United available and similar data are 13 In addition to mortality, clozapine treatment has treatment clozapine mortality, In addition to 14 demonstrated greater scores on measures of quality of life. of quality on measures scores greater demonstrated States. Overall mortality was further improved in a large population-based in a large further improved mortality was Overall cohort in Finland, a clear benefit from clozapine on overall mortality over other over mortality overall on clozapine a clear benefit from and cost-per-life. saved of lives on measures agents antipsychotic in relation to patient well-being. Findings from these reports show these reports from Findings patient well-being. to in relation In addition to studies focused on symptomatic improvement, improvement, on symptomatic studies focused In addition to subpopulations of patients across has been evaluated clozapine symptoms, even after a partial response to other antipsychotics. to after a partial response even symptoms, the most treatment-refractory patients but instead could be expanded be expanded could patients but instead the most treatment-refractory psychotic troubling experience to include those who continue to These findings suggested that clozapine should not be restricted to restricted should not be that clozapine findings suggested These were significantly less likely to discontinue for lack of efficacy to discontinue likely significantly less were participants (38 percent). than risperidone-treated (15 percent) beyond refractory illness, and compared its use against risperidone its use against and compared illness, refractory beyond patients. responsive in moderately Jewish Hospital) expanded the scope of clozapine’s effectiveness effectiveness of clozapine’s the scope Hospital) expanded Jewish study conducted in the 1990s by three early adopters of clozapine of clozapine early adopters three in the 1990s by study conducted Island and Hillside-Long UCLA, of Pittsburgh/UPMC, (University Other trials have demonstrated increased efficacy of clozapine efficacy of clozapine increased demonstrated Other trials have olanzapine. over treatment antipsychotic drug after an unsatisfactory therapeutic response. therapeutic drug after an unsatisfactory antipsychotic Trials of Intervention Effectiveness (CATIE) study supported study the (CATIE) Effectiveness of Intervention Trials second-generation a different to a switch over use of clozapine addition, findings from the second phase of the National Institute of the National Institute phase of the second addition, findings from Antipsychotic Clinical multicentric Mental Health (NIMH)-funded improvement in symptoms over the course of one year in patients in patients of one year the course over in symptoms improvement drugs. other antipsychotic at least two to respond to who failed (CUtLASS) found that clozapine treatment resulted in significant resulted treatment that clozapine found (CUtLASS) comparisons with clozapine in several important trials. The Cost Cost important trials. The in several with clozapine comparisons Study Schizophrenia Drugs in Antipsychotic of the Latest Utility starting with risperidone in 1993, and later olanzapine, quetiapine, olanzapine, and later starting in 1993, with risperidone drugs led to of these newer existence The and others. ziprasidone, were developed to treat psychosis, but without the burden of EPS, but without the burden psychosis, treat to developed were Spurred by clozapine’s efficacy, additional second-generation drugs additional second-generation efficacy, clozapine’s by Spurred relative to treatment with haloperidol. treatment to relative patients. hospital of state in a cohort services followed for one year, one year, for followed services effects adverse and fewer hospitalizations, decreased compliance, symptoms of schizophrenia. symptoms trials conducted in the 1990s demonstrated clozapine’s superior superior clozapine’s in the 1990s demonstrated trials conducted negative extent, to a much lesser and, reducing positive efficacy in evidence base consisting of additional trials and several meta- of additional trials and several base consisting evidence drugs, antipsychotic other first-generation to In relation analyses. a gold standard treatment for refractory psychosis by a substantial by psychosis refractory for treatment standard a gold Since the publication of the publication Since no drug,” proved to be one of the barriers to wider use of clozapine wider to one of the barriers be to proved no drug,” market. in the U.S. to monitor absolute neutrophil counts, also known as “no blood, also known counts, neutrophil absolute monitor to parameters put in place, vis-a-vis agranulocytosis. This policy of policy of This agranulocytosis. vis-a-vis in place, put parameters draws weekly blood on contingent prescriptions filling clozapine

. 21

lgorithm

decades.

SynergiesArticle three reatment T

ntipsychotic A the ithin ithin W ). Over time, evidence has supported use of time, evidence ). Over lozapine lozapine A C This is a depiction of the evolving evidence for for evidence is a depiction of the evolving This ). B osition osition of P Changing Position of Clozapine Within the Antipsychotic the Antipsychotic Within of Clozapine Changing Position

Figure 3. Figure Algorithm. Treatment approval, FDA decades. Following the past three use over clozapine other to refractory patients who were to restricted was clozapine ( treatments antipsychotic other to partial and for responders earlier in treatments, clozapine drugs ( antipsychotic common in some Middle Eastern ethnic groups, and also may be and also may ethnic groups, in some Middle Eastern common While the REMS groups. ancestral in other non-European noted the clozapine, receive of who could a broadening for did thus allow increased and pharmacists were providers for requirements reporting without a not dispense clozapine such that pharmacists could only when patients generated (PDA), Authorization Pre-Dispense guidelines and an ANC within clinical registered were and prescribers had patients when given be to was only the PDA on file. Initially, was reliably to yet been able has not on file, but the FDA labs current administrative has increased while this measure this measure; enforce and prescribe responsibly dispensewho wish to all for work clozapine, that were assurances the patient safety undergo a standard, slow retitration onto the medication that helps that the medication onto retitration slow a standard, undergo psychotic to vulnerable the patient orthostasis but can leave prevent at also must obtain labs Patients rebound. and cholinergic relapse not being dispensed these labs risks not obtaining intervals; standard no drug”). “no blood, (i.e., protocol per the REMS clozapine formulation the mandated Starting the FDA 12, 2015, on October the different by be implemented REMS program clozapine of a new host a single would and that they of clozapine, manufacturers several effort combined This of patients taking clozapine. registry After patient safety. ensure and so helped better registries disparate some of the rigorous further relaxed this program early challenges, monitoring, blood cell White clozapine. guidelines for monitoring required, no longer was (ANC), count neutrophil absolute aside from but significantly dropped ANC levels labs when repeating nor were labs after gaps reinitiating for limits. Protocols safe still within were such that monitoring simplified greatly also were in treatment had elapsed, and than 30 days if less as previous continue could patient if the patient had a new as if for proceed would monitoring REMS also helped The than 30 days. more for not been treated with BEN, in individuals use of clozapine the potential expand but than “normal” lab ranges run lower counts neutrophil where be found BEN may infection. to and not prone healthy who remain be relatively Americans, is thought to of African 40 percent in up to Following FDA approval, clozapine was restricted for patients who were refractory to other other to refractory were who patients for restricted was clozapine approval, FDA Following in earlier clozapine of use supported has evidence time, Over (A). treatments antipsychotic drugs (B). antipsychotic other to responders partial for and treatments, This is a depiction of the evolving evidence for clozapine use over the past past the over use clozapine for evidence evolving the of depiction a is This Figure3. Changing

Clinicians Clinicians 34 Interestingly, in Interestingly, There is There 32 35 Adherence tracking is particularly tracking Adherence 36 vigilance for other rare but alarming side but alarming rare other for vigilance 37 The use of clozapine in the United States States in the United use of clozapine The 33 The Substance Abuse and Mental Health Services Abuse and Mental Health Services Substance The 37 even with increasing recognition of benign ethnic recognition with increasing even 36 A focus on patient education and recovery likely will be likely on patient education and recovery A focus 36 prescribing requires coordinated resources to provide patient provide to resources coordinated requires prescribing and medication and education and support, medical consultation, tracking. adherence laboratory must of clozapine than 48 hours more who miss crucial. Patients Clozapine Treatment Monitoring Treatment Clozapine without adequate in environments work physicians Many use. Clozapine support best support to clozapine administrative helpful to empower patients to start patients to clozapine. empower helpful to resident trainees. resident materials training also has developed (SAMHSA) Administration support better to clozapine systems and individual prescribers for use. suicidality, or aggression. A workgroup founded through the National through founded A workgroup or aggression. suicidality, (NASMHD) Directors Mental Health Program of State Association education to improving and recommended these concerns addressed sialorrhea and enuresis, may be troublesome for patients and a for be troublesome may sialorrhea and enuresis, can help prescriber informed use, but the continued barrier to psychosis, target to while continuing these occurrences ameliorate treatment, given their demands for swift and effective clinical and effective swift their demands for given treatment, such as severe effects other serious side for potential actions. The additional require and metabolic syndrome seizures, constipation, like benign side effects, More and measures. questions screening three percent of cases, percent three orthostasis, must also be and severe myocarditis like effects, months of initiating few maintained, particularly in the first shared by physicians who either lack, or perceive that they lack, that they who either lack, or perceive physicians by shared particularly clozapine, prescribe to and skills required knowledge While most clinicians side effects. and treating recognizing to related in up to which occurs of neutropenia, the emergence for monitor potential side effects, and the frequent blood draws set forth by the by set forth draws blood and the frequent side effects, potential and Risk Evaluation of the FDA-mandated requirements stringent might be concerns These monitoring. (REMS) Strategy Mitigation There are many known barriers to broader clozapine use in the use clozapine broader to barriers known many are There about be concerned may and their families Patients States. United further evidence that clozapine may be even more dramatically dramatically more be even may that clozapine further evidence subpopulations, including in African in certain under-prescribed Americans, (BEN). neutropenia 1999, only three percent went toward clozapine in 2008. clozapine toward went percent only three 1999, not a practice polypharmacy, utilize to likely be more fact in may clozapine. than prescribe evidence, supported by of patients with employment, coupled with overall decreased decreased with overall coupled of patients with employment, rates. hospitalization While 11 percent time has been worsening. dismal, and over remains in clozapine by for accounted were prescriptions of all antipsychotic standard practice in most of the rest of the world. of the rest in most of the practice standard 32.8 to 21 percent from increased use clozapine when Zealand, New in numbers noted was an increase 2000 and 2004, between percent thought to be due to an expansion of health insurance to cover other, other, cover to insurance of health an expansion due to be thought to medications, as well antipsychotic second-generation nonclozapine guidelines that mirror prescribing clozapine stringent more as to use was once higher, comprising 40 percent of antipsychotic of antipsychotic 40 percent comprising higher, once use was to this number has dropped years In recent in 2001. prescriptions in western observed higher than numbers which remains percent, 27 been in China has utilization in clozapine decrease The countries. countries in Asia, such as Korea and Singapore, rates of clozapine rates Singapore, and as Korea in Asia, such countries China, clozapine the past decade. In over been increasing use have

the assay the assay 48 While which may 50 46,47 46,47 Moreover, recent work using magnetic work recent Moreover, 49 Early use is argued to outweigh typical delays in delays typical outweigh to Early use is argued 45 In a survey of a first-episode clinic in Australia with a Australia clinic in of a first-episode In a survey 44 the University of Pittsburgh, aim to use methods from functional use methods from aim to of Pittsburgh, the University and treatment clozapine to response characterize to neuroimaging connectivity brain on based outcome of biomarkers prognostic develop this Efforts from ID: NCT03076346). (ClinicalTrials.gov measures the for allowing by with clozapine our treatment optimize may work earlier in from clozapine benefit identification of patients who may remission in quicker and resulting other treatments over their illness outcomes. overall and improved of psychosis this finding has been replicated independently by several studies, by several independently replicated this finding has been has testing HLA-DQB1/HLA-B guided by treatment and clozapine data, in simulated effective be cost to been demonstrated for necessary and specificity sensitivity demonstrated has not yet use. clinical routine of treatment- markers neural examined studies have neuroimaging Few has neuroimaging Structural efficacy. and clozapine illness refractory be associated may volumes matter grey prefrontal that greater shown clozapine. to with response glutamate prefrontal that elevated has shown spectroscopy resonance illness, with treatment-refractory associated are levels be underlying patients who may pathologic differences to be related shed light efforts While these neuroimaging responsive. clozapine glutamatergic to related potentially systems prefrontal on possible unique mechanism of clozapine’s our understanding dysfunction, studies, including at Ongoing unknown. largely of action remains Work from pharmacogenetic studies aim to examine whether examine studies aim to pharmacogenetic from Work clinicians with objective provide could variants genetic inherent personalized in a more utilization clozapine guide to measures help to the potential have assays Pharmacogenetic model. treatment an adverse of developing chance a lower patients have which predict response. for chance a greater or have treatment clozapine from effect is the far, thus effort, finding in this the most promising Arguably antigen polymorphisms in the human leukocyte between association genome-wide reached that have and HLA-B HLA-DQB1 genes agranulocytosis. with clozapine-induced significance two of the trial. In the patients who remained nonresponsive after nonresponsive who remained the patients the trial. In of two remission achieved 28 percent phases, fully an additional both study to olanzapine switching that findings indicated These with clozapine. clozapine to switch and that a second-line outcome did not improve a simple and efficient be an initial trial may to after nonresponse across supports work this meta-analysis A recent adopt. to algorithm as a second- be useful may that clozapine and concludes other trials line drug. of rates and low rates use, high response of clozapine high rate early in patients demonstrating observed were discontinuation illness. refractory after diagnosis often years in treatment, later the clozapine receiving illness. of a schizophrenia-spectrum Biomarkers Treatment with use coincides of clozapine supporting the expansion Evidence responders be exclusive who may determine objectively efforts to the to medicine approach ushering in a precision clozapine, to also may biomarkers Objective disorders. psychotic of treatment likely and identify those more patient populations stratify us to allow medication trials unnecessary preventing clozapine, benefit from to agents. with ineffective

38 40,42 ranging from four percent to 16 to percent four from ranging 36 40,41 Modern conceptualizations of clozapine’s of clozapine’s Modern conceptualizations 11 This includes up to a 10-fold increase in health in increase a 10-fold up to includes This 39 between olanzapine and continued amisulpride treatment in phase amisulpride treatment and continued olanzapine between showed a 56 percent response in the first phase of the study with in the first response a 56 percent showed rates in response no notable difference by amisulpride, followed clozapine for an additional 12 weeks in a third study phase. Results study phase. Results in a third an additional 12 weeks for clozapine amisulpride treatment for six weeks during a second phase. Patients phase. Patients during a second six weeks for amisulpride treatment then given after this phase were nonresponse show to who continued agent for four weeks in the first phase of the study. Those who did not phase of the study. in the first weeks four for agent or continued either olanzapine to assigned randomly were respond schizophrenia who do not respond to an initial treatment choice. an initial treatment to not respond who do schizophrenia as a first-line with amisulpride examined of 446 patients were A total utility of switching an antipsychotic drug in patients with first-episode drug in patients with first-episode an antipsychotic of switching utility A recent report from a large trial with 27 sites in 14 countries (Europe (Europe in 14 countries sites trial with 27 a large from report A recent the examining this question by addressed systematically and Israel) with olanzapine treatment at around 25 percent. at around treatment with olanzapine percent for most drugs and a slightly higher chance for success for and a slightly higher chance most drugs for percent response rate occurs with this switch to a second antipsychotic antipsychotic a second to with this switch occurs rate response failure, treatment following to consideration of clozapine, which is often not recommended until which is often not recommended of clozapine, consideration to low a considerably after However, at least six months of illness. algorithms suggest switching to another antipsychotic agent prior agent another antipsychotic to switching suggest algorithms For the remaining 25 percent of patients who do not respond to to respond of patients who do not 25 percent the remaining For Most do next? to What the question becomes: initial treatment, given to first-episode schizophrenia. It is estimated that up to 75 75 to that up It is estimated schizophrenia. first-episode to given trial. an initial antipsychotic to of these patients will respond percent advocates for clozapine use earlier in our treatment algorithms, algorithms, use earlier in our treatment clozapine for advocates has been attention Recent agent. as a second-line perhaps even place in schizophrenia treatment echo an evolving literature that literature echo an evolving treatment in schizophrenia place its use could be expanded beyond its place as a third-line agent for for agent as a third-line its place beyond be expanded its use could cases deemed refractory. Evidence from work in the 1990s showed that clozapine is efficacious is clozapine that showed 1990s the in work from Evidence that suggesting cases of psychosis, responsive in moderately even nonclozapine antipsychotics, amounting for more than $34 billion in than $34 billion more amounting for antipsychotics, nonclozapine per year. States in the United medical costs psychotic disorders. psychotic to a response demonstrate patients who to relative utilization care treatment-refractory psychosis continues to account for a large a large for account to continues psychosis treatment-refractory with chronic associated utilization health resource of total majority individualized treatments for patients with schizophrenia. Meanwhile, Meanwhile, patients with schizophrenia. for treatments individualized the mechanism of action underlying its uniqueness from a scientific from the mechanism of action underlying its uniqueness of hindering the development unknown, remains perspective has revolutionized the treatment of psychosis, clozapine’s potential potential clozapine’s of psychosis, the treatment has revolutionized of understanding In addition, our realized. impact has not been fully base supporting its superior efficacy in treatment-resistant patients base supportingtreatment-resistant its superior efficacy in Treatment Algorithm Treatment evidence- with the vast combined of clozapine While the availability Clozapine’s Future Place in the Schizophrenia “clozapine clinics” or similar multidisciplinary collaborations to to multidisciplinary collaborations clinics” or similar “clozapine be a challenge. to continues prescribing clozapine facilitate Support for dissemination and implementation of widespread and implementation of widespread dissemination Support for prescribing of clozapine, workgroups have continued to recommend recommend to continued have workgroups of clozapine, prescribing stakeholders. with key the REMS in collaboration to improvement To help address barriers to patient access and psychiatrist psychiatrist and access patient to barriers help address To complicate transitions of care. transitions complicate promoted with the REMS have not come to full fruition. The REMS REMS The full fruition. to come not REMS have with the promoted and collaboration interdisciplinary strain thought to also has been

Int J 2002; 53: 1-6. 2002; Arch Gen Arch J Clin Psychiatry. J Clin Hosp Community Hosp Community 2010:CD006633. 1997; 8: 671-677. 1997; 2001; 52: 1510-1514. 2001; 52: 1995; 152: 183-190. 152: 1995; 2003; 182: 505-508. 182: 2003; Schizophr Res. Schizophr 1998; 59: 103-107. 1998; 59: 1990; 41: 892-897. 1990; 41: Epidemiology. 1992; 53: 395-397. 1992; Psychiatr Serv. Serv. Psychiatr Am J Psychiatry. Am J Psychiatry. Br J Psychiatry. Br J Psychiatry. 2012; 15: 1351-1371. 2008; 28: 485-493. J Clin Psychiatry. J Clin Cochrane Database Syst Rev. Syst Database Cochrane 2016; 77: 628-634. 2016; 77: J Clin Psychiatry. Psychiatry. J Clin 1994; 45: 269-271. 1994; 2003; 60: 82-91. 2003; Hosp Community Psychiatry. Psychiatry. Hosp Community 2009; 374: 620-627. 2009; 374: Neuropsychopharmacol. Neuropsychopharmacol. Borderline Severe of Treatment and Continuation in Acute Clozapine Disorder. Personality in Psychotic and Aggression Self-Mutilation Severe Reduces Disorder. Personality Borderline With Patients 1999; 60: 477-484. Neurocognitive Deficits, and Aggression in Schizophrenic Patients. in Schizophrenic Deficits, and Aggression Neurocognitive Psychopharmacol. J Clin Effects. Anti-aggressive of Clozapine’s of the Evidence Risk-Benefit Assessment. Assessment. Risk-Benefit Krishnan R, G, Islam MZ, Kane J, M, Chouinard Bourgeois Trial Suicide Prevention S, International Potkin JP, Lindenmayer in Schizophrenia: Suicidality for Treatment Study G. Clozapine (InterSePT). Trial Suicide Prevention International Psychiatry. and Clozapine. Hospital. at a State of Seclusion and Restraint Psychiatry. Among Behavior Its Impact on Aggressive Schooler N. Clozapine: Hospital. Psychiatric in a State Patients of Clozapine, Effects JA. M, Lieberman TB, Chakos Cooper J, Among Risperidone, and Haloperidol on Hostility Olanzapine, Schizophrenia. With Patients Schwarz S, Leucht S. Clozapine Versus Other Atypical Antipsychotics Antipsychotics Other Atypical Versus S. Clozapine S, Leucht Schwarz Schizophrenia. for D, H, Umbricht Parepally RW, Baker McMeniman M, WC, Wirshing Refractory Risperidone in Moderately and Kane JM. Clozapine Double-Blind Comparison. A 6-Month Randomized Schizophrenia: Psychiatry. J Clin Treatment-Resistant With on Suicide in Patients of Clozapine in the UK. Schizophrenia of Mortality in Patients Follow-Up 11-year J. A, Haukka Tanskanen (FIN11 Study). Study Cohort A Population-Based Schizophrenia: With Lancet. of Clozapine. Users and Former Schizophrenic of Chronic of Life on the Quality Treatment Clozapine Patients. Impact on Schizophrenia: of Neuroleptic-Resistant Treatment Benedetti F, Sforzini L, Colombo C, Maffei C, Smeraldi E. Low-dose E. Low-dose C, Smeraldi C, Maffei L, Colombo Sforzini Benedetti F, H. Clozapine Parepally J, Kang JS, Levine KN, Ebeling T, Chengappa Krakowski MI, Czobor P, Nolan KA. Atypical Antipsychotics, Antipsychotics, Nolan KA. Atypical P, MI, Czobor Krakowski Review M. A Systematic G, Picchioni Dickens D, C, Taylor Frogley Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, AC, AI, Altamura Alphs L, Green HY, Meltzer Seclusion, K. Restraint, Roebuck-Colgan PD, AR, Roos Mallya on Use of Clozapine Effects McBride D. P, Davidson Chiles JA, R, Gopalani A, Ulrich R, Baker J, Levine J, KN, Vasile Chengappa McEvoy JP, Sheitman B, Lindenmayer P, Czobor J, L, Volavka Citrome Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, F, H, Schmid C, Hunger K, Rummel-Kluge Komossa C, Lobos Asenjo D, G, Ames KN, Petrides SR, Chengappa Marder Schooler NR, R. Modelling the Impact Knapp M, Kerwin J, A, Warner Duggan L, Niskanen T, K, Klaukka Wahlbeck J, Lonnqvist J, Tiihonen Mortality in Current KJ. Rothman F, LL, Arellano AM, Lanza Walker of Six Months of Effects LF. Burnett S, Bastani B, Ramirez HY, Meltzer During Clozapine of Suicidality G. Reduction Okayli HY, Meltzer 24. 25. 22. 23. 17. 18. 19. 20. 21. 10. 11. 12. 13. 14. 15. 16.

2006;

Schizophr Bull. Schizophr 2007; 18: 39-60. 2007; 1988; 45: 789-796. 1996; 32: 683-697. Hist Psychiatry. Hist Psychiatry. 1997; 337: 809-815. 337: 1997; 1975; 2: 611. 1975; 2006; 163: 600-610. Arch Gen Psychiatry. Gen Psychiatry. Arch 2013; 18: 82-89. Lancet. Psychopharmacol Bull. Psychopharmacol 1994; 151: 20-26. 151: 1994; N Engl J Med. Am J Psychiatry. Am J Psychiatry. CNS Spectr. CNS Spectr. Olanzapine in Comparison With Clozapine for Treatment-Resistant Treatment-Resistant for Clozapine With in Comparison Olanzapine and Meta- Review a Systematic From Evidence Schizophrenia: Analyses. Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Chronic With Quetiapine, and Risperidone in Patients Olanzapine, Antipsychotic Atypical Prior to Did Not Respond Who Schizophrenia Treatment. Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, J, CE, Severe RS, Davis Keefe DO, MS, Perkins RA, Swartz Rosenheck Versus of Clozapine Effectiveness C. Hsiao JK, Investigators of Prescription of Clozapine Versus Other Second-Generation Other Second-Generation Versus of Clozapine of Prescription Schizophrenia. Drugs in Resistant Antipsychotic 32: 715-723. Randomized Trial. Trial. Randomized of Effect Trial Controlled H, Jones PB. Randomized A, Lloyd Markwick Schizophrenia. Schizophrenia. a From Hospitals: Results in State Patients for Effectiveness Fye C, Charney D. A Comparison of Clozapine and Haloperidol in of Clozapine A Comparison D. C, Charney Fye Department of Schizophrenia. Refractory With Patients Hospitalized in Refractory on Clozapine Study Group Cooperative Affairs Veterans and Negative Symptoms in Outpatients With Schizophrenia. in Outpatients With Symptoms and Negative Am J Psychiatry. With Chlorpromazine. Chlorpromazine. With on Positive of Clozapine Effects Jr. WT, A, Carpenter Summerfelt and Agranulocytosis. and Agranulocytosis. A Double-blind Comparison Schizophrenic. Treatment-resistant Market: A Review and Analysis. and Analysis. A Review Market: Souza JS, Kayo M, Tassell I, Martins H. Efficacy of CB, Elkis M, Tassell JS, Kayo Souza McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, HY, SM, Meltzer Davis TS, Stroup Lieberman JA, JP, McEvoy Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, KP, RM, Dunn G, Hayhurst L, Murray Barnes TR, Davies SW, Lewis Essock SM, Hargreaves WA, Covell NH, Goethe J. Clozapine’s Clozapine’s NH, Goethe J. Covell WA, Hargreaves SM, Essock Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, Frisman W, Henderson J, Thomas W, Xu J, R, Cramer Rosenheck Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Kirkpatrick B, Davis Buchanan RW, A, Breier Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the for H. Clozapine Meltzer J, G, Singer Honigfeld Kane J, Crilly J. The History of Clozapine and Its Emergence in the U.S. and Its Emergence of Clozapine History The Crilly J. Clozapine I. Letter: Palva M, E, Olkinuora Alhava Idanpaan-Heikkila J, 9. 8. 7. 6. 5. 4. 3. 1. 2. are clozapine-responsive, while also predicting response. response. while also predicting clozapine-responsive, are References based on risk of adverse effects. Efforts to understand the mechanism understand Efforts to effects. based on risk of adverse shedding potentially underway, unique action also are of clozapine’s patients who differentiate that may markers light on neurobiological particularly in the United States. Future challenges for clozapine clozapine for challenges particularly Future States. in the United to a transition utilization, increase to include efforts treatment patients of and stratification agent, use as a second-line clozapine reducing the morbidity that results from untreated psychotic illness. psychotic untreated from results that the morbidity reducing portion of a large for account to continues psychosis Refractory on burden economic resultant and in schizophrenia morbidity underutilized, grossly remains while clozapine systems, health care spectrum illnesses is backed by one of the most formidable evidence- of the most formidable one by is backed spectrum illnesses approval, after its FDA 30 years However bases in psychiatry. for its full potential reaching to close come has not yet clozapine Conclusion schizophrenia- for algorithm within the treatment place Clozapine’s

2017; 2018;

2011;

Nat Commun. Nat Commun. 2015; 18. 2003; 124: 153-161. 124: 2003; Mol Psychiatry. Mol Psychiatry. 2018. Lancet Psychiatry. Psychiatry. Lancet J Clin Psychiatry. Psychiatry. J Clin Psychiatry Res. Res. Psychiatry Pharmacogenomics J. J. Pharmacogenomics 2018; 199: 374-379. Int J Neuropsychopharmacol. Int J Neuropsychopharmacol. 2007; 27: 369-373. 27: 2007; 2018; 138: 281-288. Schizophr Res. Res. Schizophr Glutamatergic Neurometabolites in Clozapine-responsive and in Clozapine-responsive Neurometabolites Glutamatergic Schizophrenia. Resistant Agranulo Clozapine-Induced LF, G, Jorskog AL, Leonenko Richards G, Giegling I, Genovese DA, Collier Chambert C, cytosis KD, MacCabe JH, SA, G, McCarroll Jonasdottir A, Kirov Holmans P, H, Rujescu D, JL, Neale BM, Stefansson K, Moran Mantripragada JTR. Walters MC, O’Donovan MJ, Owen PF, Sullivan MJ, Daly Novel Provides Analysis Variant and Rare Common Genome-wide Neutropenia. Clozapine-associated Insights into 1502-1508. 22: JP, S, Shianna K, Szatkiewicz M, Neale BM, Ripke Huang H, Lek I, Dettling M, Gazit E, Goff DC, Cascorbi EJ, den Oord A, van Tropsha M, Pirmohamed AK, Nielsen J, DL, Malhotra Holden AL, Kelly JL, Lieberman Kennedy RC, DL, Josiassen Levy T, Werge Rujescu D, Is Agranulocytosis Clozapine-induced PF. Sullivan MJ, Daly JA, Alleles. and HLA-B HLA-DQB1 Rare With Associated 2014; 5: 4757. of HLA-DQB1/HLA-B Cost-effectiveness J. Villard Lieberman JA, in US and Bood Monitoring Treatment Pharmacogenetic-guided Clozapine. Taking Patients and M. Anatomical Desco T, C, Palomo Benito J, M, Pascau Aragues in Response Clozapine With Associated Variables Brain Functional Schizophrenia. Treatment-resistant Use of Clozapine for Poorly Responding First-episode Psychosis. First-episode Responding Poorly for Use of Clozapine Psychopharmacol. J Clin First-episode to Approach G. An Algorithm-based Remington Antipsychotic 3 Prospective Over Rates Response Schizophrenia: Analysis. Data a Retrospective With Trials 1439-1444. 72: CM, S, Diaz-Caneja R, Heres Drake P, C, Dazzan M, Arango Leboyer MJC, S, Glenthoj B, Eijkemans M, Galderisi Weiser Rujescu D, Amisulpride OPs. Kapur S, Sommer IE, group WW, Fleischhacker Clozapine With Open-label Treatment by Followed and Olanzapine Disorder and Schizophreniform Schizophrenia in First-episode Study. Switching A Three-phase (OPTiMiSE): 5: 797-807. Treatment Second-line or as a First- Clozapine JJ. Kahn RS, Luykx and Meta-analysis. Review Systematic A in Schizophrenia: Scand. Psychiatr Acta Use in Early O’Donoghue B. Clozapine Ratheesh A, McGorry P, Psychosis. Legge SE, Hamshere ML, Ripke S, Pardinas AF, Goldstein JI, Rees E, JI, Rees Goldstein AF, S, Pardinas ML, Ripke SE, Hamshere Legge D, Fourches A, Duncan L, C, Alfirevic Hilliard LF, JI, Jarskog Goldstein N, Pletscher M, F Samer C, A, Vernaz A, Perrier FR, Poncet Girardin Luque R, J, Artaloytia Francisco Sanz J, F, S, Sarramea Reig Molina V, BR. Russell RR, A, Kydd Pillai VM, ME, Anderson Goldstein Agid O, Remington G, Kapur S, Arenovich T, Zipursky RB. Early Zipursky T, S, Arenovich G, Kapur Remington Agid O, G, RB, Kapur S, Foussias G, Zipursky Sajeev T, Arenovich Agid O, SW, Lewis P, S, McGuire I, Leucht Rossum van Kahn RS, Winter S, Leucht C, Huijsman EAH, Hasan A, Sommer IEC, Okhuijsen-Pfeifer L, M, Downey S, Bardell-Williams M, Eaton Bowtell K, Thien 46. 47. 48. 49. 50. 41. 42. 43. 44. 45.

2018;

2007; 2007;

2014; 2010; Psychiatr Serv. Serv. Psychiatr Psychiatr Serv. Serv. Psychiatr Schizophr Bull. Schizophr Pharmacopsychiatry. Pharmacopsychiatry. Can J Psychiatry. Can J Psychiatry. 2012; 24: 110-113. 2012; 24: 2011; 45: 968-975. Neuropsychopharmacology. Int Clin Psychopharmacol. Psychopharmacol. Int Clin 1999; 11: 86-90. 1995; 56: 411-417. 1995; 1999; 156: 1164-1169. 2000; 157: 982-986. 2000; 157: 2009; 23: 957-965. Aust N Z J Psychiatry. N Z J Psychiatry. Aust Shanghai Arch Psychiatry. Shanghai Arch J Clin Psychiatry. J Clin Am J Psychiatry. Am J Psychiatry. Am J Psychiatry. Clozapine: Re-examining the Evidence. the Evidence. Re-examining Clozapine: 55: 677-684. Social and Economic Burden of Treatment-resistant Schizophrenia: of Treatment-resistant Burden Social and Economic Review. Literature A Systematic 29: 63-76. Schizophrenia PORT Psychopharmacological Treatment Treatment Psychopharmacological PORT Schizophrenia and Summary Statements. Recommendations 2010; 36: 71-93. Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W, W, PR, Keller E, Aquino B, Peterson BA, Himelhoch S, Fang Fischer 2009 The T. Research Outcomes Patient Schizophrenia Addressing the Barriers. 2016; https://nasmhpd.org/sites/default/ the Barriers. Addressing files/Assessment%201_Clozapine%20Underutilization.pdf. to Clozapine Underutilization: A National Effort. A National Effort. Underutilization: Clozapine to 224-227. 69: Long-term Antipsychotic Polypharmacy in the VA Health System: Health System: in the VA Polypharmacy Antipsychotic Long-term Patterns. and Treatment Characteristics Patient 58: 489-495. United States. States. United phrenia Patients With Clozapine Treatment: How Good Does It Get? Good Does It Get? How Treatment: Clozapine With Patients phrenia J Psychopharmacol. Kreyenbuhl JA, Tan CH. Clozapine Use in Schizophrenia: Findings of Findings Use in Schizophrenia: CH. Clozapine Tan JA, Kreyenbuhl Studies From (REAP) Prescription on Asia Psychotropic the Research 2009. 2001 to Shinfuku N, Yang SY, Chong MY, Kua EH, Fujii S, Sim K, Yong MK, S, Sim K, Yong EH, Fujii Kua Chong MY, SY, N, Yang Shinfuku LB, Sartorius N, Dixon KY, Chee P, JK, Chung EK, Udomratn Trivedi Drug Prescription Patterns in Schizophrenia Outpatients: Analysis of Analysis Outpatients: in Schizophrenia Patterns Drug Prescription Fund. Insurance a German Health From Data 2009; 42: 66-71. Disorders. Disorders. Zarate C, Jr., Posener J, Lee H, Dawson R, Richards C, Cole JO, JO, C, Cole Richards R, H, Dawson Lee J, Posener C, Jr., Zarate Psychotic of Refractory in the Treatment Clozapine AF. Schatzberg Mania. Outcome in a Randomized 1-year Trial of Clozapine Versus Treatment Treatment Versus Clozapine of Trial 1-year Randomized a in Outcome and a History Illness Treatment-Resistant With Patients as Usual for of Mania. Schizophrenic Patients With Polydipsia-Hyponatremia Syndrome. Polydipsia-Hyponatremia With Patients Schizophrenic Neurosci. Clin J Neuropsychiatry Can Clozapine Be a New Option? Option? Be a New Can Clozapine 12: 133-138. 1995; Treatment of Polydipsia and Hyponatremia in Psychiatric Patients. Patients. in Psychiatric and Hyponatremia of Polydipsia Treatment Agid O, Foussias G, Singh S, Remington G. Where to Position Position to G. Where G, Singh S, Remington Foussias Agid O, Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The DL, Degtiar I, Hornberger Taylor JL, Altar CA, Kennedy Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Kelly J, Kreyenbuhl Buchanan RW, Love R, Kelly D, Freudenreich O, Sayer M. Clozapine Underutilization: Underutilization: M. Clozapine Sayer O, Freudenreich D, R, Kelly Love Kelly DL, Freudenreich O, Sayer MA, Love RC. Addressing Barriers Addressing RC. MA, Love Sayer O, DL, Freudenreich Kelly Kreyenbuhl JA, Valenstein M, McCarthy JF, Ganoczy D, Blow FC. FC. Blow Ganoczy D, JF, M, McCarthy Valenstein JA, Kreyenbuhl Kelly DL, Wehring HJ, Vyas G. Current Status of Clozapine in the in the Status of Clozapine G. Current Vyas HJ, DL, Wehring Kelly Schizo for G. Outcomes Robinson V, Wheeler A, Humberstone Xiang YT, Wang CY, Si TM, Lee EH, He YL, Ungvari GS, Chiu HF, GS, Chiu HF, Ungvari EH, He YL, Lee Si TM, CY, Wang Xiang YT, Zarate CA, Jr., Tohen M, Baldessarini RJ. Clozapine in Severe Mood in Severe Clozapine RJ. M, Baldessarini Tohen Jr., CA, Zarate CA. G, Gericke R, Juckel Busse T, Stargardt HJ, S, Assion Weinbrenner Green AI, Tohen M, Patel JK, Banov M, DuRand C, Berman I, Chang H, M, JK, Banov M, Patel AI, Tohen Green Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical Clinical H, Rush AJ. Kraemer B, Carmody T, A, Paul Webb Suppes T, Canuso CM, Goldman MB. Clozapine Restores Water Balance in in Balance Water Restores Goldman MB. Clozapine Canuso CM, de Leon J, Verghese C, Stanilla JK, Lawrence T, Simpson GM. Simpson T, JK, Lawrence C, Stanilla Verghese J, de Leon

40. 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. 29. 28. 27. 26. 200 Lothrop St. Pittsburgh, PA 15213-2582 SYNERGIES

UPMC WESTERN PSYCHIATRIC HOSPITAL ADDRESS CORRESPONDENCE TO: UPMC Western Psychiatric Hospital 3811 O‘Hara St. Pittsburgh, PA 15213 Integrating Clinical and Technological Innovation, 1-877-624-4100 Research, and Education David A. Lewis, MD Medical Director and Director of Research, Psychiatric care at UPMC Presbyterian Shadyside has been the province of UPMC Western Psychiatric Hospital UPMC Western Psychiatric Hospital, formerly known as Western Psychiatric Distinguished Professor of Psychiatry Institute and Clinic, since it first opened its doors in 1942. and Neuroscience, and Thomas Detre Chair of Academic Psychiatry UPMC and its academic partner, the Department of Psychiatry of the University of Pittsburgh School of Medicine, constitute one of the leading centers for Chairman, Department of Psychiatry, University of Pittsburgh School research and treatment of individuals who have challenging or particularly of Medicine difficult mental health conditions and/or addictive disorders.

For more than 60 years, the integration of research, academia, and clinical services has infused best-practice research into clinical settings for the individuals who need it most. A $19 billion world-renowned health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, We serve individuals across the lifespan, from young children to aging adults. accountable care. UPMC provides more than $900 million a year in benefits to its communities, including Through our inpatient and outpatient continuum of care, we provide services more care to the region’s most vulnerable citizens than any other health care institution. The largest for more than 400,000 patient contacts each year. nongovernmental employer in Pennsylvania, UPMC integrates 87,000 employees, 40 hospitals, 700 doctors’ offices and outpatient sites, and a 3.5 The Department of Psychiatry is a leading recipient of research funding from million-member Insurance Services Division, the largest medical insurer in western Pennsylvania. the National Institutes of Health (NIH), including research grants from multiple As UPMC works in close collaboration with the University of Pittsburgh Schools of the Health NIH institutes such as the National Institute of Mental Health, the National Sciences, U.S. News & World Report consistently ranks UPMC Presbyterian Shadyside on its annual Institute on Aging, and the National Institute on Drug Abuse. Honor Roll of America’s Best Hospitals. UPMC Enterprises functions as the innovation and commercialization arm of UPMC, and UPMC International provides hands-on health care and management services with partners around the To learn more about the UPMC Department world. For more information, go to UPMC.com. of Psychiatry, please visit UPMCPhysicianResources.com/Psychiatry. USNW510005 AS/MP 2/19 © 2019 UPMC