Christoph U. Correll, MD
Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York; Department of Psychiatry and Molecular Medicine, Donald and Barbara School of Medicine at Hofstra/Northwell, Hempstead, New York; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, New York; and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
John M. Kane, MD
Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York; Department of Psychiatry and Molecular Medicine, Donald and Barbara School of Medicine at Hofstra/Northwell, Hempstead, New York; and The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, New York.
Corresponding Author: Christoph U. Correll, MD, Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd St,
Glen Oaks, NY 11004 (ccorrell@northwell. edu).
Given the numerous randomized clinical trials (RCTs) of antidopaminergic agents for schizophrenia, meta- analyses can help compare their efficacy and safety/ tolerability. Because many medications have never been directly compared, network meta-analyses (NMAs) using direct and indirect effect size estimates via common comparators have been introduced. Because “transitiv- ity” (eg, similar populations, treatment, and measure- ment approaches) is required, changes in patient, ill- ness, treatment, trial design/conduct characteristics, and increasing placebo effects in schizophrenia trials1 chal- lenge the underlying assumptions of NMAs.
Despite these limitations, NMAs can summarize and critically assess the RCT evidence base. The most up- dated NMA of the short-term efficacy of antipsychotics for schizophrenia has recently been published.2 Com- pared with the prior NMA of the same group on the same topic,3 the number of oral antipsychotics used in mono- therapy increased from 15 to 32, RCTs from 212 to 402, participants from 43 049 to 53 463, and outcomes from 7 to 17 (efficacy = 8, safety/tolerability = 9). The meta- analytic approach followed the highest standards. What does this NMA2 add? The median effect size across an- tipsychotics vs placebo remained almost identical (−0.422 vs −0.443), similar to effect sizes for drugs used in general medicine. While this most recent NMA adds more detailed information, the overall conclusions re- main similar: efficacy differences were predominantly nonsignificant, whereas adverse effect differences were often statistically significant and clinically meaningful, leading Huhn et al,2 as well as the authors of this article, to propose a “minimizing harm” approach first.
For overall symptom reduction, clozapine, amisul- pride, zotepine, olanzapine, and risperidone were su- perior to many other antipsychotics. For positive symp- toms, amisulpride, risperidone, olanzapine, paliperidone, and haloperidol were significantly more effective than many other antipsychotics. Conversely, zotepine, olanza- pine, and sertindole had greater weight gain than most drugs, while for agents with sufficient data, ziprasi- done, lurasidone, aripiprazole, brexpiprazole, and cari- prazine were not associated with significantly greater weight gain than placebo. For antiparkinsonian medica- tion use, no differences from placebo were found for clozapine, sertindole, olanzapine, quetiapine, asenap- ine, aripiprazole, amisulpride, iloperidone, and brex- piprazole. Similarly, for akathisia, the following antipsy- chotics did not differ from placebo: clozapine, perazine, sertindole, iloperidone, olanzapine, quetiapine, brex- piprazole, zotepine, and paliperidone. For prolactin lev- els, paliperidone, risperidone, amisulpride, haloperi- dol, sertindole, lurasidone, asenapine, and olanzapine were associated with significantly elevated prolactin
levels, while no difference from placebo was found for clozapine, zotepine, aripiprazole, cariprazine, que- tiapine, brexpiprazole, ziprasidone, iloperidone, and chlorpromazine.
Reassuringly, NMA results were generally consis- tent with pairwise meta-analytic comparisons in which pooled groups were strictly randomized.2 Notably, when reported separately, more patients dropped out for in- efficacy (40%) vs adverse events (20%), underscoring the tolerability, but suboptimal efficacy, of available an- tipsychotics. Most patients consenting to participate in these RCTs had illness for more than a decade and might overrepresent poor/partial responders and/or tolerabil- ity issues. Despite the strengths of the NMA,2 caveats remain. Rankings cannot be extrapolated to pediatric, elderly, or first-episode patients. In first-episode pa- tients, any antipsychotic seems efficacious,4 although second-generation antipsychotics may have small ad- vantages over first-generation antipsychotics for nega- tive symptoms, depression, and cognition.5 Partici- pants with acute illness were not selected for the study if they had predominant negative or depressive symp- toms; therefore, these outcomes must be interpreted cautiously, as improvement in negative and depressive symptoms can be secondary to positive symptom re- ductions. Because trials were short (3-13 weeks), func- tionality/quality of life rankings are tentative. The re- sults were generally consistent across subgroup/ sensitivity analyses.2 However, it is puzzling that although placebo response increased by 12.3 points vs 1.2 points for antipsychotics over 45 years,1 correcting the analyses for placebo effects did not alter the rank- ings for overall symptom improvement. This result raises questions, including whether systematic biases can suf- ficiently be adjusted statistically. Furthermore, the au- thors’ confidence in the evidence was often rated as low.2
The NMA on the short-term efficacy of antipsychot- ics for treating schizophrenia provides 2 overarching con- clusions, ie, that for efficacy, the observed differences were mostly “gradual” and statistically nonsignificant, whereas for adverse effects differences were often larger and statistically significant. Nevertheless, with few ex- ceptions, clozapine, amisulpride, zotepine, olanzapine, and risperidone were significantly more efficacious for the primary outcome of overall symptom improve- ment than other antipsychotics. However, these same medications were also often those with the largest ef- fect sizes regarding relevant adverse effects, highlight- ing the importance of individualized risk:benefit assess- ments when choosing antipsychotics.
Most treatment of schizophrenia involves relapse prevention. In this context, similar efficacy and toler- ability hierarchies emerge across individual antipsychot-
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ics. In longer-term RCTs,6 for overall psychopathology, clozapine, and olanzapine were superior and they and risperidone were superior to several other second-generation antipsychotics regarding all- cause discontinuation. However, like in the NMA for short-term treat- ment effects,2 antipsychotics with slightly greater efficacy ranked more unfavorably for key adverse effects, including weight gain, se- dation, prolactin change.6 Similarly, in a recent meta-analysis of co- hort studies in patients with treatment-resistant schizophrenia or suboptimal treatment response, clozapine was associated with sig- nificantly less hospitalization and greater overall symptom improve- ment than most other second-generation antipsychotics despite pa- tients treated with clozapine having more severe illness. At the same time, clozapine was also associated with significantly greater in- creases in body weight, body mass index, and diabetes risk than other second-generation antipsychotics. Nevertheless, for hospitaliza- tion, risperidone and, in particular, olanzapine were not associated with significantly worse outcomes than clozapine. Conversely, only aripiprazole was not associated with significantly greater all-cause discontinuation than clozapine, a measure in which efficacy and tol- erability/acceptability are merged.7
Taken together, data from short-term2 and longer-term/ maintenance6 RCTs in patients with schizophrenia and from co- hort studies7 of patients with suboptimal responses to antipsy- chotic agents indicate that a few antipsychotics seem to rank some- what higher for efficacy but also rank lower for important adverse events and that efficacy differences are relatively small but toler- ability differences are larger and often significant. Because all anti- psychotics had at least 1 relevant unfavorable adverse effect rank- ing and twice as many patients drop out from short-term trials for inefficacy than intolerability, novel antipsychotics are needed for
which one would not need to compromise between efficacy and tolerability or, at least, between one adverse effect vs another.
Despite progress in the understanding of schizophrenia and ad- vances in psychopharmacology over the past 6 decades, to our knowledge, antidopaminergic agents are currently the only ap- proved medications for schizophrenia. Because currently available antipsychotics vary more regarding adverse effects than efficacy, treatment selection should follow a first “do no harm” approach in that safer agents should be tried first, recognizing that untreated ill- ness generally has greater adverse effects than medications. If af- ter 2 weeks of therapeutic doses not even minimal improvement is observed, switching may be indicated.
However, although RCT antipsychotic-psychotropic medica- tion combinations,8 including antipsychotic polypharmacy,9 have not yielded convincing superiority over antipsychotic monotherapy, na- tionwide, naturalistic database studies suggested the superiority of certain antipsychotic combinations for reducing hospitalization.10 Clearly, a greater understanding of the differences between RCT and real-world evidence and their clinical implications is needed.
Furthermore, more treatment options for different domains of schizophrenia and improving functioning and quality of life are needed, including agents with novel mechanisms that are ideally based on a greater pathophysiological understanding of schizophre- nia or, at least, based on stratifying patient characteristics that in- crease the likelihood of response-therapeutic or adverse. It is hoped that drug choice will have to compromise less between efficacy and tolerability/safety and that novel mechanism agents or novel/ evidence-based combination treatments will become available, es- pecially those that better target the pathophysiology of schizophre- nia in general and of illness subgroups specifically.
Published Online: November 6, 2019. doi:10.1001/jamapsychiatry.2019.3377
Conflict of Interest Disclosures: Dr Correll reported personal fees from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Teva, and Bristol-Myers Squibb and grants and personal fees from Janssen/J&J and Takeda outside the submitted work. Dr Kane reported receiving honoraria from Alkermes, Dainippon Summitomo, Allergan, Lundbeck, Intracellular Therapies, Janssen, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Revivam Roche, Sunovion, Takeda, and Teva; grants from Otsuka, Lundbeck, and Janssen; and royalties from Up to Date and reports being a shareholder in Vanguard Research Group and LB Pharmaceuticals and serving on advisory boards for Alkermes, Dainippon Sumitomo, Intracellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda, and Teva outside the submitted work.
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