Do the pharmacokinetics of statins explain psychiatric symptom improvement from adjunctive statin prescribing in severe mental illness? Three target trial emulation studies

Abstract

Background: Evidence regarding the efficacy of adjunct statins to treat severe mental illness (SMI) is mixed. The varying pharmacokinetic properties of statins mean that specific statin-antipsychotic combinations might improve psychiatric symptoms. Objective: To test whether some statin-antipsychotic/mood stabiliser combinations result in psychiatric symptom improvement in patients with SMI, while others do not, using target trial emulation in observational data. Methods: We identified patients with SMI (schizophrenia, bipolar disorder, ‘other’ psychoses) prescribed antipsychotics/mood stabilisers and statins from 2000 to 2019 in English linked primary care records (Clinical Practice Research Datalink). We defined hypothetical randomised trials and observational emulations: (1) blood-brain barrier (BBB)-penetrant (simvastatin) versus non-penetrant (atorvastatin/pravastatin/rosuvastatin) statins; (2A) P-glycoprotein inhibitors (simvastatin/atorvastatin) versus non-inhibitors (pravastatin) in patients prescribed aripiprazole/risperidone/olanzapine (P-glycoprotein affinity); (2B) high (aripiprazole/risperidone/olanzapine) versus low (quetiapine) P-glycoprotein affinity antipsychotics in patients prescribed P-glycoprotein-inhibiting statins. Findings: We found no reduction in our primary outcomes (12-month psychiatric admissions) in trial 1 (HR 1.07, 95% CI 0.88 to 1.31); trial 2A (HR 0.77, 95% CI 0.28 to 2.15); or trial 2B (HR 0.93, 95% CI 0.79 to 1.09). In trial 2B, we observed lower self-harm events (HR 0.60, 95% CI 0.38 to 0.97) in per-protocol analysis and lower psychiatric admissions in the ‘other’ psychoses subgroup (HR 0.53, 95% CI 0.34 to 0.85). Conclusions: BBB penetrance appears unlikely to be the mechanism by which statins improve SMI symptoms. Interaction with P-glycoprotein may have some effect. Further mechanistic and clinical research is needed to understand statin-antipsychotic interactions and the role of interaction with P-glycoprotein. Clinical implications: There is currently not enough evidence to guide the prescription of statins for psychiatric symptom improvement in patients with SMI. If there is an effect of statins, it may be through specific statin-antipsychotic combinations.