Impact of adjunctive dihydropyridine calcium channel blockers on mental health outcomes in people with severe mental illness: A target trial emulation in English electronic health records
Naomi Launders, Alvin Richards-Belle, Stephanie M. Wu, Kenneth K. C. Man, Ian C. K. Wong, David P. J. Osborn, Joseph F. HayesBackground:
Dihydropyridine calcium channel blockers have been implicated in both symptom improvement and exacerbation in pre-existing severe mental illness (SMI). We aimed to test the hypothesis that blood-brain barrier penetrant dihydropyridines (DHPs) reduce rates of mental health hospitalisation and self-harm compared to non-penetrant DHPs.
Methods:
We used English electronic health records (Clinical Practice Research Datalink) to conduct a target trial emulation study in people with schizophrenia, bipolar disorder or other psychosis. We compared admissions for mental health and self-harm in those prescribed blood-brain barrier penetrant (intervention) and non-penetrant DHPs (control). Our primary endpoint was a 12-month intention-to-treat analysis using covariate adjustment. We additionally completed overlap weighting, per-protocol analyses and negative outcome controls.
Results:
We included 918 people prescribed blood-brain barrier penetrant DHPs and 3384 prescribed amlodipine (control). In the primary covariate-adjusted intention-to-treat analysis, there was no clear evidence of a difference in rates of combined mental health admissions and self-harm events (adjusted hazard ratio (HR): 1.22; 95% confidence interval (CI): 0.78–1.91 at 12 months). In a pre-specified sensitivity analysis using overlap weighting, self-harm event rates were elevated in the intervention group at 12 months (HR: 2.10; 95% CI: 1.13–3.94); however, the equivalent covariate-adjusted estimate showed no clear difference (HR: 1.81; 95% CI: 0.52–6.26).
Conclusion:
In people with SMI, blood-brain barrier penetrant DHPs were not associated with reduced mental health hospitalisations or self-harm events compared to those treated with amlodipine, though estimates were imprecise. This active comparator design cannot distinguish between absence of effect or equivalent benefit of both drug classes. There are peripheral pathways through which DHPs may impact psychiatric symptoms and these require further exploration.