Effect of psychotropic medications on suicide-related outcomes: a systematic review and meta-analysis of observational studies.

BACKGROUND: Psychiatric disorders are associated with increased risk of suicide-related outcomes, and the impact of pharmacological treatments on these outcomes is uncertain. Although randomised controlled trials are the main approach to evaluate efficacy, they may not provide externally valid results for suicide prevention in psychiatric populations. Thus, we aimed to synthesise the evidence on the effect of psychotropic medications on suicide-related outcomes from observational studies. METHODS: In this systematic review and meta-analysis, we systematically searched Ovid (MEDLINE, Embase, APA PsychArticles, AMED, BIOSIS, Global Health, PsycINFO), and Web of Science Core Collection from database inception to 8 December 2025 for pharmacoepidemiological and other observational studies on suicide-related outcomes in people treated with the main types of psychotropic medications: antidepressants, antipsychotics, mood stabilisers (including antiepileptics), and medications for anxiety (anxiolytics), attention deficit and hyperactivity disorder (ADHD), and substance use disorder (SUD). We included primary studies involving adults with common psychiatric diagnoses (schizophrenia spectrum disorders, bipolar disorder, depressive disorders, and personality disorders), who were prescribed medication and a comparison sample with the same diagnosis without prescribed medication (between-individual studies) or the same individuals during a non-prescription period (within-individual studies). We excluded studies that did not report psychiatric diagnoses and from selected samples. Outcomes were suicide attempts/self-harm and suicide mortality. We pooled effect sizes as odds ratios (OR), hazard ratios (HR) or risk ratios (RR) using random-effects models and assessed study quality using NOS and QUIPS tools. Study protocol was registered with PROSPERO, CRD42024515794. FINDINGS: Of 5653 records identified, 48 independent studies from 13 countries based on more than 6 million people (47% male) met inclusion criteria. Across the main diagnostic categories and 70 individual medications examined, associations with reducing risk of suicide mortality were found for second generation antipsychotics in schizophrenia spectrum disorders: clozapine (OR = 0.40; 0.36-0.60; I2 = 60%, moderate certainty), olanzapine (OR = 0.53; 0.39-0.71; I2 = 34%, high certainty), quetiapine (OR = 0.75; 0.58-0.96; I2 = 0%, high certainty), and zuclopenthixol (OR = 0.44; 0.30-0.63; I2 = 0%, high certainty). In schizophrenia, second generation antipsychotics were also associated with reduced risks of suicide attempts: olanzapine (OR = 0.76; 0.60-0.98; I2 = 84%, moderate certainty) and risperidone (OR = 0.61; 0.52-0.72; I2 = 57%, moderate certainty). In bipolar disorder, lithium (OR = 0.38; 0.28-0.50; I2 = 67%, moderate certainty) and valproic acid (OR = 0.66; 0.59-0.75; I2 = 0%, high certainty) were associated with lower suicide risks, and lithium was also associated with lower risks of suicide attempts (OR = 0.60; 0.44-0.82; I2 = 92%, moderate certainty). In depression, associations with lower risk of suicide mortality for selective serotonin reuptake inhibitors (SSRIs) (OR = 0.61; 0.47-0.81; I2 = 23%, high certainty) and tricyclic antidepressants (OR = 0.68; 0.59-0.78; I2 = 0%, high certainty) were found. Benzodiazepines were associated with higher risk of suicide mortality in most diagnostic categories, except depression. There was some evidence for publication bias for lithium in bipolar disorder and clozapine in schizophrenia spectrum disorders, leading to more papers reporting lower risks of suicide-related outcomes. The risk of bias in included studies was low in 47 studies, moderate in one study, and certainty of evidence was moderate. INTERPRETATION: There is evidence of varying effects of psychotropic medication on the risk of suicide-related outcomes across different psychiatric disorders. The appropriate use of prescribed medications in people with high risks of suicide-related outcomes is an important suicide prevention strategy. Findings are not causal, and limitations include the observational nature of included studies, risk of residual confounding, high heterogeneity for some outcomes, and moderate quality of the evidence. FUNDING: University of Oxford (Hill Foundation), NIHR Oxford Health Biomedical Research Centre, Wellcome Trust.