Calcium-Channel Blocker and Adenosine Modulator Use and Risk of Hospitalization in Bipolar Disorder

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CASE VIGNETTE

“Mr Amir” is a 48-year-old male from the Balkans with a 17-year history of bipolar I disorder with psychotic features. He was last hospitalized for affective symptoms at age 35. He has chronic insomnia, low energy, impaired concentration, and suspiciousness. He also has episodic irritability and anger. He has been on a stable psychotropic regimen of quetiapine 100 mg in the morning and 400 mg at bedtime, and valproic acid 750 mg daily. Mr Amir was diagnosed with comorbid hypertension after multiple elevated readings at his outpatient psychiatry visits. He does not have a primary care physician, so his psychiatrist started him on amlodipine, which was titrated to 10 mg daily. His blood pressure control subsequently improved, without any change in his psychiatric symptoms.

Inadequate response and treatment resistance remain issues in bipolar disorder.¹ One approach to identifying novel treatments is drug repurposing, whereby a drug approved for 1 disease is investigated for its potential for a new indication. Previous reviews include the adenosine modulator allopurinol² and calcium-channel blockers (CCBs)³ for potential repurposing in bipolar disorder, although evidence for the latter has been inconclusive. Allopurinol and dipyridamole are adenosine modulators that may have potential in the treatment of bipolar disorder and other severe mental illnesses.⁴ Allopurinol is a xanthine oxidase inhibitor used to treat gout and hyperuricemia.⁴ Dipyridamole is an antithrombotic and vasodilator that inhibits adenosine reuptake.⁵

The Current Study

Lintunen and colleagues⁶ investigated the risk of psychiatric hospitalization associated with CCBs (dihydropyridines, verapamil, diltiazem) and adenosine modulators (allopurinol, dipyridamole) in a nationwide Finnish cohort of individuals with bipolar disorder. They identified individuals diagnosed with bipolar disorder between 1987 and 2018 from inpatient, specialized outpatient, sickness absence, and disability pension registers. Follow-up started on January 1, 1996, or at the date of diagnosis, and ended at death, diagnosis of schizophrenia, or on December 31, 2018 (whichever occurred first).

The primary exposures were use of CCBs and adenosine modulators. Thiazide diuretics were used as a negative control. Information on medication use was obtained from the Prescription Register and modeled with PRE2DUP method, which predicts periods of use and non-use.⁷ The primary outcome was hospitalization due to affective symptoms, based on the Hospital Discharge register. Secondary outcomes were hospitalization due to manic or depressive symptoms or any psychiatric hospitalization. The risk of non-psychiatric hospitalization was also analyzed to consider potential adverse somatic effects of CCBs or adenosine modulators.

Data were analyzed using within-individual models, where individuals act as their own control, based on periods of exposure and non-exposure, using stratified Cox regression. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for hospitalization-based outcomes comparing periods when the individual was using versus no using the medication. Models were adjusted for use of antipsychotics, mood stabilizers, benzodiazepines and Z-drugs, antidepressants, temporal order of treatments, and time since cohort entry.

The study cohort included 60,045 individuals, with a median follow-up of 8.4 years. Approximately 9056 individuals (15%) used primary dihydropyridines (91%). The most commonly used dihydropyridine was amlodipine (64%). Approximately 2967 individuals (5%) used adenosine modulators (57% allopurinol and 43% dipyridamole). Thiazides were used by 1286 individuals (2%).

Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.83, 95% CI 0.78-0.88). The beneficial effect was associated with diltiazem and dihydropyridines, but not verapamil. Results were similar for hospitalization due to depressive symptoms or any reason. However, verapamil and dihydropyridines—but not diltiazem—were associated with decreased risk of hospitalization due to mania.

Use of adenosine modulators was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.87, 95% CI 0.79-0.96). Effects were similar for both allopurinol and dipyridamole. Results were similar for any psychiatric hospitalization. Allopurinol, but not dipyridamole, was associated with a decreased risk of hospitalization due to depressive symptoms. There was no association between adenosine modulators and hospitalization due to manic symptoms. Allopurinol was associated with an increased risk of non-psychiatric hospitalization (aHR=1.10, 95% CI 1.03-1.17). The decrease in risk of hospitalization with these medications was greater in individuals under versus over 40 years of age.

Study Conclusions

The authors found that CCBs and adenosine modulators were associated with a decreased risk of hospitalization due to affective symptoms in individuals with bipolar disorder. Study strengths include the large nationwide cohort, long follow-up period, and use of within-individual models, which control for time-invariant factors (eg, genetics). Study limitations include the absence of ratings of symptom severity, the fact that the authors did not adjust for psychosocial treatments, and the potential for selection bias in observational studies.

The Bottom Line

Findings support potential roles for calcium, the purinergic system, and adenosine modulators in the pathophysiology of bipolar disorder. CCBs and adenosine modulators warrant further study in these individuals.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times^TM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry. 2006;11(3):227-240.

2. Bartoli F, Cavaleri D, Bachi B, et al. Repurposed drugs as adjunctive treatments for mania and bipolar depression: a meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials. J Psychiatr Res. 2021;143:230-238.

3. Cipriani A, Saunders K, Attenburrow MJ, et al. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol Psychiatry. 2016;21(10):1324-1332.

4. Hirota T, Kishi T. Adenosine hypothesis in schizophrenia and bipolar disorder: a systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators. Schizophr Res. 2013;149(1-3):88-95.

5. Gamboa A, Abraham R, Diedrich A, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke. 2005;36(10):2170-2175.

6. Lintunen J, Lähteenvuo M, Tanskanen A, et al. Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder - a nationwide cohort study. J Affect Disord. 2022;313:43-48.

7. Taipale H, Tanskanen A, Koponen M, et al. Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons. Clin Epidemiol. 2016;8:363-371.