Selective serotonin reuptake inhibitors and manic switch: A pharmacovigilance and pharmacodynamical study

Background: There is still no approved mechanism of manic switch in bipolar disorder, yet many selective serotonin reuptake inhibitors were accused for this important adverse event. Therefore, we aimed to investigate to estimate SSRI' s risk for reporting mania and elevated mood using FEARS database and investigate receptor mechanisms involved. Methods: Mania and relevant side effects approved by FDA were screened in this dataset from the first quarter of 2004 to the third quarter of 2020. Disproportionality analysis were performed to estimate reporting odds ratio (ROR) and linear regressions were conducted to investigate relationship between ROR and Ki values. Receptor occupancy ratios were calculated from in vitro receptor binding profiles. The pharmacodynamical profile was extracted from the International Union of Basic and Clinical Pharmacology and the British Pharmacology Society dataset. Child and adolescent population was also investigated separately. Results: The analysis showed that the odds of a spontaneous report of mania in the FAERS database involving an SSRI were higher than the odds that such a report involved other types of drugs (ROR: 5.324 [CI: 3.773; 7.514]). The largest effect size in this estimation was found in fluvoxamine (ROR: 13.957 [CI: 10.391; 18.747]). Significant effects were found in regression analysis for Ki values of H1 and M1 receptors on ROR. Receptor occupation was not found to have an effect on ROR. Conclusion: Lower degress of Ki values on M1 and H1 may be plausible pharmacological mechanism. Further pharmacological data and clinical assessments may be important to validate this safety signal.