Clozapine is Associated with Lower Odds of Insomnia in Patients with Schizophrenia

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Clozapine treatment may offer the added benefit of improved sleep in patients with schizophrenia, according to a meta-analysis.

A study led by Brian Miller from the Department of Psychiatry and Health Behavior at Augusta University provided evidence to support the use of clozapine treatment in patients with schizophrenia to reduce the risk of insomnia, a common symptom in this population.1

According to Batalla-Martín et al., the prevalence of insomnia fluctuates depending on the diagnostic criteria; however, the schizophrenic population shows high prevalence in some clinical characteristics.2

Additionally, insomnia is a risk factor for suicidal behavior, making it crucial to manage this symptom effectively in patients with schizophrenia. Investigators performed a meta-analysis to evaluate the association between clozapine and insomnia by comparing patients treated with clozapine and those treated with alternative antipsychotics.1

Insomnia is known to be linked with a debilitating cluster of symptoms, metabolic dysfunction, and adverse outcomes in schizophrenia. Specifically, the study cited previous evidence from Assimakopoulos et al., that stated Polymorphisms of the MTRN1 gene (melatonin receptor 1) could possibly be associated with increased insomnia in patients with schizophrenia.3

The current results revealed patients treated with clozapine had significantly lower odds of insomnia compared with those treated with other antipsychotics. According to the investigation, this could suggest the improvement in sleep quality may be a potential mechanism underlying clozapine's anti-suicidal properties.1

The meta-analysis included randomized controlled trials (RCTs) to provide robust evidence for the relationship between clozapine and insomnia in this patient population.

Investigators conducted a systematic search in PubMed, PsycINFO, and Web of Science databases to identify RCTs in English that provided data on the occurrence of insomnia in patients with schizophrenia who had been treated with antipsychotics.

Data from the selected studies were pooled using a random effects model. The primary outcome measure was the odds ratio (OR) of insomnia in patients treated with clozapine compared with other antipsychotics.

Results of the analysis exhibited 8 RCTs were included, involving a total of 1952 patients. Of those patients, 922 were treated with clozapine, and 1030 were treated with other antipsychotics.

Investigators found significantly higher odds of insomnia among patients who were treated with other antipsychotics as compared with those treated with clozapine (22.3% vs. 12.4%, OR = 2.20, 95% CI = 1.64–2.94, p < 0.01).

More specifically, subgroup analyses revealed that olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significantly increased odds of insomnia compared with clozapine.

Investigators observed no significant associations between clozapine dose, publication year, sex, trial duration, and study quality score with the association between clozapine and insomnia in the meta-regression analyses. A significant association was identified when assessing age, where older patients had a greater likelihood of insomnia.

“We found a significant, 2.2-fold increased odds of insomnia in patients with schizophrenia treated with other antipsychotics compared to clozapine (22.3 % versus 12.4 % prevalence, respectively),” the team wrote.

However, further research is needed to elucidate the underlying mechanisms and explore the clinical implications of these findings. Investigators made a call for clinicians to consider clozapine as a preferred treatment option in patients with schizophrenia who have comorbid insomnia.


  1. Miller BJ, McEvoy JP, McCall WV. Meta-analysis of clozapine and insomnia in schizophrenia. Schizophrenia Research. 2023;252:208-15.
  2. Batalla-Martín D, Belzunegui-Eraso A, Miralles Garijo E, et al. Insomnia in Schizophrenia Patients: Prevalence and Quality of Life. Int J Environ Res Public Health. 2020;17(4):1350.
  3. Assimakopoulos K, Karaivazoglou K, Skokou M, et al. Genetic Variations Associated with Sleep Disorders in Patients with Schizophrenia: A Systematic Review. Medicines (Basel). 2018;5(2):27.