imipramine + metyrapone

Imipramine + metyrapone is a combination of two small molecule drugs, imipramine and metyrapone, investigated primarily for their potential synergistic antidepressant effects. Imipramine is a tricyclic antidepressant (TCA) that acts mainly by inhibiting the reuptake of serotonin and norepinephrine, thereby increasing their synaptic concentrations. It also blocks histamine H1 receptors, alpha-1 adrenergic receptors, and muscarinic acetylcholine receptors. Metyrapone is an inhibitor of steroid 11-beta-monooxygenase (CYP11B1), which reduces cortisol synthesis in the adrenal cortex; this leads to increased adrenocorticotropic hormone (ACTH) secretion due to loss of negative feedback. The combination has been shown in preclinical studies to produce more pronounced antidepressant-like effects than either drug alone, possibly through enhanced serotonergic activity involving 5-HT1A and 5-HT2A receptor pathways[1][2][4][5]. This combination has been explored as an augmentation strategy for treatment-resistant depression.