Highlight
- Long-term lithium and valproate monotherapy significantly reduce suicide risk in bipolar disorder patients.
- Atypical antipsychotics, when combined with lithium or valproate, further decrease suicide incidence.
- The study utilizes a large nationwide Korean cohort with comprehensive real-world healthcare claims data.
- Findings underscore the importance of optimizing pharmacotherapy to reduce suicide attempts and deaths in bipolar disorder.
Study Background
Bipolar disorder is a chronic psychiatric condition characterized by recurrent mood episodes, including mania and depression, with a well-documented elevated risk of suicide and increased mortality compared to the general population. Suicidal behavior is a leading cause of death in these patients, representing a critical public health concern and an urgent clinical challenge.
Pharmacological mood stabilizers such as lithium and valproate have been foundational in managing bipolar disorder. Lithium, in particular, has been recognized for its potential anti-suicidal properties. Atypical antipsychotics have also been widely adopted as adjunctive or monotherapy options, yet their impact on suicide risk remains less clearly defined.
This study aimed to clarify the long-term effects of lithium, valproate, and various atypical antipsychotics on suicide attempts and completed suicide in a large population of Korean patients diagnosed with bipolar disorder, addressing an important gap in real-world evidence.
Study Design
The investigators conducted a retrospective cohort study utilizing nationwide Korean healthcare claims data spanning from 2002 to 2020. They included 44,694 individuals diagnosed with bipolar disorder (at least two principal diagnoses recorded) who had also received at least two prescriptions of either lithium, valproate, carbamazepine, or one of several atypical antipsychotics including risperidone, quetiapine, olanzapine, aripiprazole, and ziprasidone.
The mean age in the cohort was approximately 31 years, and females comprised 58% of the population. The primary outcomes were incidents of suicide attempts and completed suicides during periods of pharmacotherapy.
The researchers employed Cox proportional hazards regression models to compare suicide risk between treatment periods with the specific agents versus periods without such pharmacotherapy. Both between-individual and within-individual analyses were performed to control for confounding factors.
Key Findings
The study revealed several noteworthy results:
- Treatment with lithium alone was associated with a 39.2% reduction in suicide incidents (hazard ratio [HR] 0.608; 95% confidence interval [CI], 0.434-0.852) compared with periods without lithium, valproate, or atypical antipsychotics.
- Valproate monotherapy correlated with a 26.0% decrease in suicide risk (HR 0.740; 95% CI 0.577-0.949).
- Within-individual analyses demonstrated a marked reduction in suicide risk when lithium was combined with atypical antipsychotics (HR 0.154; 95% CI 0.055-0.428).
- Combination of lithium, valproate, and atypical antipsychotics yielded an HR of 0.235 (95% CI 0.056-0.980), indicating synergistic benefit in reducing suicide risk.
- Valproate combined with atypical antipsychotics also showed reduced risk (HR 0.302; 95% CI 0.152-0.599) compared to no treatment.
Interestingly, carbamazepine was not highlighted as significantly contributing to suicide risk reduction in this study, aligning with its less prominent role in contemporary bipolar disorder management.
The findings affirm that lithium remains a robust agent in decreasing suicide risk, with valproate also offering meaningful benefit. Importantly, atypical antipsychotics appear beneficial primarily when used adjunctively with these mood stabilizers, emphasizing a nuanced role depending on clinical context.
Expert Commentary
This large-scale, real-world observational study strengthens the evidence base surrounding pharmacological suicide risk reduction in bipolar disorder. The significant protective effect of lithium corroborates prior randomized controlled trials and meta-analyses supporting its unique anti-suicidal properties.
While valproate’s effect, albeit smaller, is also clinically relevant, atypical antipsychotics alone did not emerge as protective, highlighting that their utility may be adjunctive, potentially enhancing mood stabilization when combined with traditional mood stabilizers.
Limitations inherent to retrospective cohort studies remain, including potential residual confounding, reliance on diagnostic coding, and lack of detailed clinical parameters such as mood state, medication adherence, and psychosocial interventions.
Furthermore, these findings derive from a Korean population; ethnic and healthcare system differences may influence generalizability. Nonetheless, the large sample size and duration lend credibility and applicability within similar clinical contexts.
From a mechanistic standpoint, lithium’s modulation of neurotransmitter systems, neuroprotective effects, and anti-aggressive properties may underpin its anti-suicide efficacy. Valproate’s mood-stabilizing and anticonvulsant actions might contribute similarly, while atypical antipsychotics’ impact may depend on symptom control synergy.
Conclusion
In summary, this nationwide retrospective cohort study offers compelling evidence that lithium and valproate significantly reduce suicide risk in patients with bipolar disorder during long-term treatment. The addition of atypical antipsychotics further decreases risk when combined with these mood stabilizers, potentially benefiting high-risk patients.
Clinicians treating bipolar disorder should consider lithium and valproate not only for mood stabilization but also for suicide prevention. Personalized treatment strategies incorporating atypical antipsychotics may enhance outcomes in complex cases.
Further prospective studies are warranted to refine pharmacologic protocols, integrate psychosocial approaches, and explore mechanistic insights to optimize suicide prevention in this vulnerable population.
Funding and ClinicalTrials.gov
This study was supported by institutional and governmental research funding in Korea. The original study was retrospective and did not register with ClinicalTrials.gov.
References
- Park SA, Son S, Tae BS, et al. Long-term treatment with lithium, valproate, and atypical antipsychotics on suicide risk in patients with bipolar disorder: A nationwide retrospective cohort study. J Affect Disord. 2026;392:120264. doi:10.1016/j.jad.2025.120264.
- Baldessarini RJ, Tondo L, Viguera AC, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006 Mar;8(3):241-50. doi:10.1111/j.1399-5618.2006.00278.x.
- Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. Oxford University Press; 2007.