From Pharmacological Trigger to Manic State: Convergent Neurobiological Mechanisms of Drug-Induced Mania

Manic and hypomanic states are precipitated by pharmacologically diverse agents, including corticosteroids, dopamine agonists, and antidepressants. The last cross-class review of drug-induced mania was published in 1995; the literature has since fragmented into class-specific reviews lacking a shared mechanistic account. We propose that chemically unrelated drugs perturb a few proximal systems — dopaminergic gain, glutamatergic synaptic potentiation, sleep and circadian timing, glucocorticoid signaling, and neuroimmune signaling — that converge on ventral prefrontal–amygdala–striatal circuitry implicated in secondary mania. Inverting the classical lesion-convergence logic, we treat pharmacological exposures as reversible, dose-graded probes of this network, accommodating withdrawal reversibility, dose dependence, and the affected minority. Evidence is appraised by study design rather than drug class, distinguishing experimentally supported associations from case series lacking exposure denominators. We then test the framework against real-world data: 15.4 million deduplicated post-marketing reports containing 11,698 manic or hypomanic events. Median reported latency ordered by mechanistic group from one day to four weeks, and a temporal-concentration flag assessed whether these patterns were more consistent with pharmacology or reporting behavior. Rather than a universal pathway, it links proximal mechanism to phenotype and time course, generating testable predictions for studies combining exposure measurement, actigraphic sleep monitoring, and repeated activation ratings.