Repurposing HMG-CoA Reductase Inhibitors, L-Type Calcium Channel Antagonists and Biguanides in Serious Mental Illness: A Within-Individual Cohort Study in National Swedish Data

Abstract

Background: Drug repurposing is potentially cost-effective, low-risk and necessary in psychiatric drug development. The availability of large routine datasets provides the opportunity to evaluate the potential for currently used medication to benefit people with severe mental illness (SMI). Methods: We performed several within-individual cohort studies of patients with SMI (bipolar disorder (BPD), schizophrenia or non-affective psychosis (NAP)), in the Swedish population (N=142,691). We compared psychiatric hospitalization and self-harm rates during periods patients were exposed and unexposed to HMG-CoA reductase inhibitors, L-type calcium channel (LTCC) antagonists or biguanides. We adjusted for a number of time-varying covariates. Findings: HMG-CoA reductase inhibitor exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR] 0·86, 95% confidence interval [CI] 0·83-0·89), schizophrenia (aHR 0·75, 95% CI 0·71-0·79) and NAP (aHR 0·80, 95%CI 0·75-0·85) and reduced self-harm rates in BPD and schizophrenia (aHR 0·76, 95%CI 0·66-0·86 and aHR 0·58, 95%CI 0·45-0·74). LTCC antagonists were associated with reduced hospitalization and self-harm in all subgroups (aHR 0·92, 95%CI 0·88-0·96 and aHR 0·81, 95%CI 0·68-0·95 in BPD, aHR 0·80, 95%CI 0·74-0·85 and aHR 0·30, 95%CI 0·18-0·48 in schizophrenia, and aHR 0·89, 95%CI 0·83-0·96 and aHR 0·56, 95%CI 0·42-0·74 in NAP respectively). During biguanide exposure psychiatric hospitalization was reduced in BPD (aHR 0·80, 95%CI 0·77-0·84), schizophrenia (aHR 0·73, 95%CI 0·69-0·77) and NAP (aHR 0·85, 95%CI 0·79-0·92) and self-harm was reduced in BPD (aHR 0·73, 95%CI 0·62-0·84) and schizophrenia (aHR 0·64, 95%CI 0·48-0·85). Interpretation We have provided additional evidence that HMG-CoA reductase inhibitor, LTCC antagonist and biguanide exposure might lead to improved outcomes for people with SMI. Given their well-known adverse event profiles, they should be further investigated as repurposed agents for psychiatric symptoms. Funding: Swedish Research Council and UCLH NIHR Biomedical Research Centre. Conflict of Interests: JFH, AL, GL, DPJO and CD report no conflict of interest. ICKW has received research funding from Bristol-Myers Squibb, Pfizer and Janssen outside the submitted work. JFH, GL and DPJO are supported by the NIHR UCLH Biomedical Research Centre. CD is supported by grant 523-2010-1052 from the Swedish Research Council. Ethical Approval Statement: Ethical approval for the study was obtained via the Regional Ethical Review Board in Stockholm.