REVIEW OF: Nomura N et al, Lancet Psychiatry 2025;12(4):266–275

STUDY TYPE: Meta-analysis of RCTs

Sedation is a frequent side effect of antipsychotics, potentially impacting both adherence and quality of life. Although we often assume patients develop tolerance, solid evidence about when sedation starts and how long it lasts is lacking. How do we know when to wait it out, adjust the dose, or switch medications? This meta-analysis examined the course of sedation in patients on various antipsychotics.

The researchers pooled individual patient data from 19 RCTs of antipsychotic monotherapy for acute schizophrenia or schizoaffective disorder, totaling 6,791 participants. Studies included in the meta-analysis encompassed several oral formulations: paliperidone, risperidone, olanzapine, haloperidol, and placebo, as well as three long-acting injectable (LAI) formulations: paliperidone, risperidone, and placebo. Nearly 50% of participants were prescribed either the oral or LAI formulation of paliperidone, and this study did not include aripiprazole, which is generally considered less sedating. The researchers tracked sedation-related side effects using terms like sedation, somnolence, and fatigue, but specific assessments of sedation were not conducted.

LAIs and oral formulations had similar risks. Eighty-three percent of sedating effects started within the first two weeks of treatment. Most cases resolved quickly: half within a week and 75% within a month. About a quarter of patients reporting sedation continued to experience it after four weeks. Risk of sedation varied by antipsychotic, with oral quetiapine carrying the greatest risk (23.3%) and LAI paliperidone carrying the lowest (4.4%).

CARLAT TAKE
Three out of four times, antipsychotic-related sedation resolved within a month. If it lasts longer than that in your patient, consider other contributing factors (eg, concomitant medications, sleep disturbances, or other medical conditions) before assuming tolerance will eventually develop. In such cases, a dose adjustment or a switch to a less sedating antipsychotic may be warranted.