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 and antidepressants, and carry serious clinical consequences. Since the last cross-class review in 1995, the literature has fragmented into class-specific reviews lacking a shared mechanistic account. I hypothesize 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, I 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. Across 15.4 million post-marketing reports containing 11,698 manic or hypomanic events, which cannot establish incidence or causality, median reported latency ranged from one day (glutamatergic agents) to three to four weeks (antidepressants), a contrast preserved at the drug level. A descriptive temporal-concentration flag identified signals warranting cautious interpretation. Rather than a universal pathway, this untested framework links proximal mechanism to phenotype and time course, generating testable predictions for studies combining exposure measurement, actigraphic sleep monitoring, and repeated activation ratings.