Brain-penetrant calcium channel blockers showed no significant association with incident schizophrenia (HR 1.05, 95% CI 0.94-1.18), schizoaffective disorder (HR 1.04, 95% CI 0.87-1.23), major depressive disorder (HR 1.02, 95% CI 0.97-1.08), or bipolar disorder (HR 1.04, 95% CI 0.96-1.13) compared to non-brain-penetrant calcium channel blockers.
Cohort (n=10,108,594)
Yes
Does initiating brain-penetrant calcium channel blockers prevent incident neuropsychiatric disorders compared to non-brain-penetrant calcium channel blockers in adults?
There is no evidence of an association between the use of brain-penetrant versus non-brain-penetrant calcium channel blockers and the incidence of neuropsychiatric conditions.
Effect estimate: HR 1.02 for MDD, 1.04 for bipolar disorder, 1.05 for schizophrenia, 1.04 for schizoaffective disorder (95% CI MDD 0.97-1.08, bipolar 0.96-1.13, schizophrenia 0.94-1.18, schizoaffective 0.87-1.23)
Objective To use best practices in pharmacoepidemiology to assess the association between new use of brain-penetrant calcium channel blockers (BP-CCBs) compared with use of non-brain-penetrant CCBs (NP-CCBs) and the incidence of neuropsychiatric outcomes. Design Retrospective comparative cohort study. Setting Secondary data from nine claims and electronic health record databases from across the globe were used. Participants First use of a CCB was the index date. There were 1.2 million BP-CCB patients and 9.3 million NP-CCB patients identified across all databases, with 881 758 matched in each group. Interventions Patients were categorised as either initiating BP-CCBs or NP-CCBs. On-treatment and intention-to-treat analyses were conducted. Large-scale propensity models were used to match cohorts and control for observed confounding. Cox models were used to analyse the time to incident neuropsychiatric disorders. Negative control outcomes were used to calibrate estimates, CIs and p values to account for residual confounding. Diagnostics were used to assess the validity of the analysis. Primary and secondary outcome measures The time to first diagnosis of schizophrenia, schizoaffective disorder, major depressive disorder (MDD) and bipolar disorder was assessed independently. HRs compared the BP-CCB group to the NP-CCB group. Results For the outcome of incident MDD in the intention-to-treat design, the meta-analytic HR (95% CI) was 1.02 (0.97, 1.08). Meta-analytic HRs for bipolar disorder (1.04 (0.96, 1.13)), schizophrenia (1.05 (0.94, 1.18)) and schizoaffective disorder (1.04 (0.87, 1.23)) showed similar null effects. The on-treatment analysis was largely consistent: MDD (1.01 (0.96, 1.06)), bipolar (1.05 (0.86, 1.27)), schizophrenia (1.09 (0.87, 1.38)) and schizoaffective (1.00 (0.71, 1.40)). Conclusions There was no evidence of an association with any of the neuropsychiatric conditions of interest between use of BP-CCB and NP-CCB. This does not rule out the potential beneficial effect of CCB formulations and doses targeted specifically for the brain rather than the cardiovascular system.
Kern et al. (2026) conducted a cohort in Adults (≥18 years) initiating calcium channel blockers without prior neuropsychiatric diagnosis (n=10,108,594). Brain-penetrant calcium channel blockers (felodipine, isradipine, nifedipine, nitrendipine) vs. Non-brain-penetrant calcium channel blockers (amlodipine, lacidipine, levamlodipine) was evaluated on Time to first diagnosis of schizophrenia, schizoaffective disorder, major depressive disorder, and bipolar disorder (HR 1.02 for MDD, 1.04 for bipolar disorder, 1.05 for schizophrenia, 1.04 for schizoaffective disorder, 95% CI MDD 0.97-1.08, bipolar 0.96-1.13, schizophrenia 0.94-1.18, schizoaffective 0.87-1.23). Brain-penetrant calcium channel blockers showed no significant association with incident schizophrenia (HR 1.05, 95% CI 0.94-1.18), schizoaffective disorder (HR 1.04, 95% CI 0.87-1.23), major depressive disorder (HR 1.02, 95% CI 0.97-1.08), or bipolar disorder (HR 1.04, 95% CI 0.96-1.13) compared to non-brain-penetrant calcium channel blockers.