Switching to Hypomania and Mania: Differential Neurochemical, Neuropsychological, and Pharmacologic Triggers and Their Mechanisms

Current data suggest that monoamines, acetylcholine, amino acids, cortisol, thyroid hormones, and melatonin may be involved in the pathophysiology of bipolar disorder (BPD). Any neuropsychological or pharmacologic factor causing a disturbance in these neurochemicals may trigger manic/hypomanic switching. Antidepressants, stimulants, anticholinergics, steroids, and thyroid hormone have been reported to cause treatment-emergent mania (TEM) in BPD, but only recently have the traditional antidepressants been systematically studied. Paroxetine, 20 mg/d, monotherapy in treatment of acute, relatively pure bipolar I and II depression, and fluoxetine monotherapy in bipolar II depression conferred a similar risk as placebo for TEM. Paroxetine or bupropion adjunctive therapy to mood stabilizer(s) had a similar risk as placebo for treatment of TEM in real world patients with bipolar depression during continuation treatment. Venlafaxine was shown to have an increased risk of TEM compared with bupropion and sertraline. The evolving literature continues to support the role of mood stabilizers in preventing future mood episodes of BPD.