Utility of Combination Therapy with Mood Stabilizers and Antipsychotics in Bipolar Disorder
A research group led by Professor Tadashi Kato of Juntendo University and Representative Director Yasuyuki Okumura of the Clinical Epidemiology Research Promotion Organization comprehensively investigated the recurrence prevention effects of monotherapy and combination therapy with mood stabilizers and antipsychotics for bipolar disorder, using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) held by the Ministry of Health, Labour and Welfare. It was revealed that combination therapy, particularly with lithium carbonate and certain other drugs, further reduces hospitalization risk compared to monotherapy.
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- 📰 Published: May 1, 2026 at 03:00
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A research group led by Professor Tadashi Kato of the Department of Psychiatry and Behavioral Sciences, Juntendo University Graduate School of Medicine, and Representative Director Yasuyuki Okumura of the Clinical Epidemiology Research Promotion Organization, comprehensively investigated the recurrence prevention effects of monotherapy and combination therapy with mood stabilizers and antipsychotics used for bipolar disorder*¹, utilizing the National Database of Health Insurance Claims and Specific Health Checkups (NDB) held by the Ministry of Health, Labour and Welfare. This study specifically focused on combination therapies involving lithium carbonate with other mood stabilizers (sodium valproate, lamotrigine, carbamazepine) or antipsychotics, which had not been sufficiently examined previously. The research group identified 315,046 patients with bipolar disorder and systematically investigated the utility of various combination therapies, in addition to confirming the utility of each drug as monotherapy. As a result, lithium carbonate monotherapy was confirmed to be associated with a reduced risk of hospitalization. Furthermore, it was revealed that combination therapy with lithium carbonate and carbamazepine, zotepine, aripiprazole, or sodium valproate was associated with an even lower risk of hospitalization compared to lithium carbonate monotherapy. These findings are expected to provide new clues for drug selection in the treatment of bipolar disorder, especially for cases where monotherapy has not achieved sufficient efficacy.
This paper was published online in the British Journal of Psychiatry on April 30, 2026.
Key Points of This Research Achievement
● Confirmed the recurrence prevention effect of monotherapy, including lithium carbonate, using real-world data*².
● Systematically identified combination drugs associated with a lower hospitalization risk compared to lithium carbonate monotherapy.
● Demonstrated the potential of NDB for bipolar disorder research.
Background
Bipolar disorder (bipolar affective disorder) is a mental illness characterized by mood swings between manic and depressive states. Historically, clinical practice guidelines for bipolar disorder have been primarily based on evidence from clinical trials. However, for older drugs like lithium carbonate, sufficient evidence has not always been accumulated, and clinical trials for combination therapies have been rarely conducted, making treatment selection difficult.
On the other hand, observational studies in Nordic countries have accumulated real-world evidence regarding the utility of bipolar disorder treatments, including lithium carbonate, using national medical databases. However, the utility of combination therapies has not been sufficiently investigated. Therefore, this study comprehensively examined the recurrence prevention effects of monotherapy and combination therapy with mood stabilizers and antipsychotics for bipolar disorder.
Research Content
1. Identification of Patients with Bipolar Disorder
Utilizing the National Database of Health Insurance Claims and Specific Health Checkups (NDB) held by the Ministry of Health, Labour and Welfare, patients with bipolar disorder were identified based on the following criteria. First, 861,016 patients whose medical receipts (medical fee statements) for psychiatric hospitalization or outpatient visits during the inclusion period (April 2013 - March 2022) listed bipolar disorder as the primary diagnosis were identified. Furthermore, applying eligibility criteria such as having received lithium carbonate prescriptions at maintenance doses (200 mg/day) or higher at least twice, not having a diagnosis or treatment history related to dementia, and being 20 years of age or older, the final analytical cohort consisted of 315,046 patients.
Based on this data, the number of bipolar disorder patients receiving medical care in Japan was estimated to be between approximately 310,000 and 860,000. This estimate was close to the value of approximately 740,000 calculated from a preceding web survey (Kato et al., Journal of Affective Disorders, 2021), which estimated the prevalence of bipolar disorder in Japan to be 0.6%.
2. Recurrence Prevention Effect of Monotherapy
These 315,046 patients were followed until May 2023 or their last visit (including death), whichever came first (median follow-up period: 7.1 years). During the follow-up period, 83,621 patients experienced psychiatric hospitalization.
During the follow-up period, an intra-individual comparison design (Figure 1) was used to examine whether the risk of psychiatric hospitalization was lower during periods when mood stabilizers such as lithium carbonate were prescribed as monotherapy compared to periods without mood stabilizer prescriptions. As a result, it was shown that periods of monotherapy with lithium carbonate (adjusted Hazard Ratio [aHR] 0.67, 95% Confidence Interval [CI] 0.66–0.68), sodium valproate (aHR 0.71, 95% CI 0.70–0.73), lamotrigine (aHR 0.72, 95% CI 0.69–0.75), and carbamazepine (aHR 0.74, 95% CI 0.70–0.78) were all associated with a lower risk of psychiatric hospitalization compared to periods when no mood stabilizers were used.
This paper was published online in the British Journal of Psychiatry on April 30, 2026.
Key Points of This Research Achievement
● Confirmed the recurrence prevention effect of monotherapy, including lithium carbonate, using real-world data*².
● Systematically identified combination drugs associated with a lower hospitalization risk compared to lithium carbonate monotherapy.
● Demonstrated the potential of NDB for bipolar disorder research.
Background
Bipolar disorder (bipolar affective disorder) is a mental illness characterized by mood swings between manic and depressive states. Historically, clinical practice guidelines for bipolar disorder have been primarily based on evidence from clinical trials. However, for older drugs like lithium carbonate, sufficient evidence has not always been accumulated, and clinical trials for combination therapies have been rarely conducted, making treatment selection difficult.
On the other hand, observational studies in Nordic countries have accumulated real-world evidence regarding the utility of bipolar disorder treatments, including lithium carbonate, using national medical databases. However, the utility of combination therapies has not been sufficiently investigated. Therefore, this study comprehensively examined the recurrence prevention effects of monotherapy and combination therapy with mood stabilizers and antipsychotics for bipolar disorder.
Research Content
1. Identification of Patients with Bipolar Disorder
Utilizing the National Database of Health Insurance Claims and Specific Health Checkups (NDB) held by the Ministry of Health, Labour and Welfare, patients with bipolar disorder were identified based on the following criteria. First, 861,016 patients whose medical receipts (medical fee statements) for psychiatric hospitalization or outpatient visits during the inclusion period (April 2013 - March 2022) listed bipolar disorder as the primary diagnosis were identified. Furthermore, applying eligibility criteria such as having received lithium carbonate prescriptions at maintenance doses (200 mg/day) or higher at least twice, not having a diagnosis or treatment history related to dementia, and being 20 years of age or older, the final analytical cohort consisted of 315,046 patients.
Based on this data, the number of bipolar disorder patients receiving medical care in Japan was estimated to be between approximately 310,000 and 860,000. This estimate was close to the value of approximately 740,000 calculated from a preceding web survey (Kato et al., Journal of Affective Disorders, 2021), which estimated the prevalence of bipolar disorder in Japan to be 0.6%.
2. Recurrence Prevention Effect of Monotherapy
These 315,046 patients were followed until May 2023 or their last visit (including death), whichever came first (median follow-up period: 7.1 years). During the follow-up period, 83,621 patients experienced psychiatric hospitalization.
During the follow-up period, an intra-individual comparison design (Figure 1) was used to examine whether the risk of psychiatric hospitalization was lower during periods when mood stabilizers such as lithium carbonate were prescribed as monotherapy compared to periods without mood stabilizer prescriptions. As a result, it was shown that periods of monotherapy with lithium carbonate (adjusted Hazard Ratio [aHR] 0.67, 95% Confidence Interval [CI] 0.66–0.68), sodium valproate (aHR 0.71, 95% CI 0.70–0.73), lamotrigine (aHR 0.72, 95% CI 0.69–0.75), and carbamazepine (aHR 0.74, 95% CI 0.70–0.78) were all associated with a lower risk of psychiatric hospitalization compared to periods when no mood stabilizers were used.