MOOD STABILIZERS, ATYPICAL ANTIPSYCHOTICS TREATMENT AND SUICIDE RISK IN PATIENTS WITH BIPOLAR DISORDER IN KOREA - A NATIONWIDE RETROSPECTIVE COHORT STUDY

Abstract Background Patients with bipolar disorder show higher suicide rate and mortality rate of suicidal behavior than the general population. Although several studies have revealed that lithium and some mood stabilizers might prevent suicide in bipolar disorder, it is difficult to clearly confirm the treatment effect on suicide due to the relatively short study period and low suicide rate. Aims & Objectives This study is aimed to examine and compare the long-term effects of mood stabilizers such as lithium and valproate and atypical antipsychotics on suicide attempt and suicide (hereinafter referred to as suicide incidents) in a large cohort of bipolar patients in Korea. Method This retrospective cohort study drawn from Korean national health insurance claims database included 44,694 individuals aged 15-50 years who had at least two main diagnoses of bipolar disorder and at least two prescriptions for lithium, valproate, carbamazepine or atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole) within one year of a diagnosis between January 1, 2002 and December 31, 2020. We examined the hazard ratios of suicide attempts, identified by an emergency room diagnosis, and suicide, confirmed by linking the cause of death data, during treatment periods with each drug by using Cox proportional regression. Suicide incidents were repeatedly measured by using between-individual and within-individual analyses. Medication was regarded as a time-dependent variable, contributing to the estimation of suicide-related risk of each medication when changed. Results When exposure periods by each medication were considered, the lowest rate of suicide incidents occurred when lithium alone was prescribed, followed by lithium plus valproate and valproate alone. The risk of suicide incidents was significantly reduced by 39.2% and 26.0%, respectively during treatment with lithium alone and valproate alone compared to the period without lithium, valproate or atypical antipsychotics treatment after adjustment for age, sex, income status, past history of suicide attempts, comorbid medical and psychiatric diseases, and concurrent other psychotropic medications in between- individual analysis. In within-individual analysis controlling for time-invariant confounders, the risk of suicide incidents was most significantly reduced during the combination of lithium and atypical antipsychotics by 0.154 times. When lithium, valproate, and atypical antipsychotics were combined, the risk was significantly reduced by 0.235 times compared to the period without lithium, valproate or atypical antipsychotics treatment. Valproate showed 0.251-fold decrease in the risk of suicide incidents, and there was 0.302-fold decrease in combination therapy with atypical antipsychotics. Discussion & Conclusion In patients with bipolar disorder, risk of suicide incidents is reduced during the treatment period with lithium alone and valproate alone compared to the period when none of lithium, valproate, or atypical antipsychotics was prescribed. In subjects with suicide incidents, atypical antipsychotics might have protective effect against suicide incidents when combined with lithium and valproate.