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Clozapine tied to better effectiveness outcomes than other second-generation antipsychotics
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Clozapine was linked to an 18% lower risk for hospitalization and 27% lower risk for all-cause discontinuation compared with nonclozapine second-generation antipsychotics, despite greater illness severity in patients with schizophrenia receiving clozapine, according to findings from a meta-analysis of cohort studies.
However, clozapine use was also associated with a higher risk for cardiometabolic-related outcomes, researchers reported in JAMA Psychiatry.
“Clozapine is the criterion standard medication for [treatment-resistant schizophrenia], whose superior effectiveness is supported by a network meta-analysis of acute treatment associations, although the population was not specifically treatment resistant,” Christoph U. Correll, MD, from the department of psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, and colleagues wrote. “However, recent meta-analyses of masked randomized clinical trials (RCTs) comparing clozapine with other oral nonclozapine second-generation antipsychotics inconsistent results.”
To test the real-world effectiveness of clozapine beyond RCTs, researchers conducted a systematic review and meta-analysis to compare various outcomes of clozapine vs. oral nonclozapine second-generation antipsychotics in cohort studies.
Correll and colleagues examined hospitalization and all-cause discontinuation (coprimary outcomes) and all effectiveness and safety outcomes (secondary outcomes). Nonrandomized cohort studies that reported effectiveness and/or safety outcomes comparing clozapine with nonclozapine second-generation antipsychotics in schizophrenia or schizoaffective disorder were included.
Analysis included 63 cohort studies encompassing 109,341 patients with schizophrenia.
Despite having more severe illness, patients taking clozapine were at lower risk for hospitalization (RR = 0.817; 95% CI, 0.725-0.92) and all-cause discontinuation (RR = 0.732; 95% CI, 0.639-0.838) compared with patients taking nonclozapine-second-generation antipsychotics, according to the results.
After assessing effectiveness-related analyses, Correll and colleagues also found that clozapine use was linked to a significant reduction in overall symptoms (SMD = –0.302; 95% CI, –0.572 to –0.032), cognitive symptoms (SMD = –0.124; 95% CI, –0.235 to –0.014) and Clinical Global Impressions scale severity (SMD = –1.182; 95% CI, –2.243 to –0.122;). In addition, clozapine use was significantly linked to greater body weight (mean difference [MD] = 1.7; 95% CI, 0.31-3.08 kg), BMI (MD = 0.96; 95% CI, 0.24-1.68) and risk for type 2 diabetes (RR = 1.777; 95% CI, 1.229-2.57).
“Careful risk-benefit evaluation is needed before initiating clozapine, and cardiometabolic parameters (body weight, fasting glucose and lipid levels, and glycated hemoglobin levels) should be monitored regularly,” the investigators wrote. “Because cohort studies have inherent biases, large pragmatic RCTs with broad inclusion and minimal exclusion criteria that better reflect real-world practice are needed.”
Because there doesn’t seem to be new drug treatments for schizophrenia on the horizon, it’s important to find ways to use current treatments better, T. Scott Stroup, MD, MPH, from the department of psychiatry, Columbia University Irving Medical Center and New York State Psychiatric Institute, wrote in a related editorial.
“Although RCTs are the gold standard for research evidence, they are expensive, slow, and not feasible for answering all worthwhile questions. Using cohort studies to learn from what clinicians do in routine practice is an important and efficient approach to this,” he wrote. “The meta-analysis of cohort studies by Masuda et al supports evidence that clozapine is effective as it is used in the real world. That clozapine remains the focus of so much attention, in spite of its serious drawbacks, highlights the need for continued research and innovation.” – by Savannah Demko
Disclosures: Please see the study for all authors’ relevant financial disclosures. Stroup reports personal fees from Intracellular Therapies.