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Clozapine May Best Other Second-Generation Antipsychotics for Schizophrenia, But Concerns Remain

August 14, 2019

By Marilynn Larkin

NEW YORK—Clozapine appears to be more effective for severe schizophrenia than other second- generation antipsychotics (SGAs), but safety concerns remain, a systematic review and meta-analysis suggests.

"Data from 63 cohort studies (with) 109,34 patients indicate that although patients selected for clozapine treatment were more severely ill, they stayed on antipsychotic treatment longer and experienced less hospitalizations than patients selected by clinicians for non-clozapine SGA treatment," Dr. Christoph Correll of Northwell Health in Glen Oaks, New York told Reuters Health.

"While clozapine-treated patients experienced less extrapyramidal symptoms and need for anticholinergic treatment," he said by email, "clozapine treatment was also associated with greater cardiometabolic adverse effects, such as body weight gain, as well as increases in systolic and diastolic blood pressure, triglycerides, glucose, insulin, insulin resistance and diabetes risk."

That said, he added, "Since antipsychotic maintenance treatment has been shown to reduce all-cause mortality as well as mortality due to cardiometabolic reasons, cardiometabolic adverse effects that should be monitored and addressed routinely do not necessarily detract from clozapine's superior effectiveness compared to alternative antipsychotics in patients with insufficient treatment response to non-clozapine antipsychotics."

"Therefore," he continued, "the relatively low utilization of clozapine in patients with schizophrenia in the U.S. and across most of the world needs to be challenged and clinicians should consider clozapine more often in patients with schizophrenia and insufficient treatment outcomes."

Dr. Correll and colleagues searched the literature through 2018 for nonrandomized cohort studies reporting effectiveness and/or safety outcomes when comparing clozapine with SGAs in schizophrenia or schizoaffective disorder.

As reported online July 31 in JAMA Psychiatry and noted by Dr. Correll, 68 articles from 63 cohort studies involving 109, 341 patients were included in the meta-analysis. Patients' mean age was 38.8; 60.3% were men; the mean illness duration was 11 years; and mean study duration was 19.1 months.

Compared with other SGAs and despite greater illness severity (17 studies), clozapine was significantly associated with lower risk of hospitalization (19 studies; RR, 0.817) and all-cause discontinuation (16 studies; RR, 0.732).

Compared with specific SGAs, clozapine was associated with a significantly lower hospitalization risk than quetiapine (RR,0.727) and aripiprazole (RR, 0.698) but not risperidone (RR,0.871), olanzapine (RR,0.936), or amisulpride (RR, 0.777).

For all-cause discontinuation, clozapine was associated with a significantly lower risk than risperidone (RR, 0.702), olanzapine (RR, 0.792), quetiapine (RR,0.654), and amisulpride (RR,0.694) but not aripiprazole (RR, 0.712).

Clozapine was also significantly associated with better overall symptom outcomes (standardized mean difference, −0.302) and Clinical Global Impressions scale severity (SMD, −1.182) compared with other SGAs.

However, clozapine also was significantly associated with increases in body weight (mean difference, 1.70), body mass index (MD, 0.96), and type 2 diabetes (relative risk, 1.777)

The authors state, "In a more generalizable sample of patients with schizophrenia than in randomized trials, clozapine was statistically and clinically associated with better effectiveness outcomes compared with other SGAs, but some concerns about safety require careful monitoring and clinical attention."

Dr. Correll said, "Further studies are needed in order to identify patients who can benefit the most from clozapine or who are most vulnerable to its adverse effects. Moreover, additional research is clearly needed in order to identify alternative treatments that can address partial or full treatment resistance to first line antipsychotics without the severe adverse effect burden that clozapine can be associated with."

Dr. T. Scott Stroup of Columbia University Irving Medical Center in New York City, author of a related editorial, commented by email, "Clozapine is effective as it is actually used - for people diagnosed with schizophrenia who don't do well on standard antipsychotics and have relatively severe illness."

"We need to ensure that this group of people has access to clozapine," he told Reuters Health.

"However, most people diagnosed with schizophrenia will benefit from standard antipsychotics that have fewer medical risks," he said. "Some will do best with long-acting, injectable forms of standard drugs, especially if something is getting in the way of taking the medications regularly."

"Other recent research has provided evidence that there is a legitimate role for combinations of psychotropic medications in schizophrenia," he added. "We still need to know much more about who will do best on which medication or combination of medications."


JAMA Psychiatry 2019.

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