Mania: a rational neurobiology

A cohesive picture has emerged over the last decade regarding the pathophysiology and treatment of bipolar disorder, a serious mental disorder that cycles between mania and depression. Mania is associated with overactive PKC intracellular signaling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Overactive PKC signaling in the prefrontal cortex may explain many of the symptoms of mania. Functional imaging studies have shown reduced activity in the right prefrontal cortex during the manic state. Dysfunction of the right prefrontal cortex is known to lead to a disinhibited profile, including poor impulse control, risk-taking, distractibility, poor sustained attention and delusions, which resemble the symptoms of mania. Structural imaging studies have further shown a loss of prefrontal volume in untreated patients with bipolar disorder. This loss of function and gray matter in the prefrontal cortex may arise from abnormal signaling cascades, notably PKC signaling. Studies in animals have shown that elevated PKC activity markedly and rapidly impairs the functioning of the prefrontal cortex, providing a link to the the loss of prefrontal regulation of thought and emotion during the manic state. Sustained elevation in PKC signaling may also lead to loss of gray matter in the prefrontal cortex, which can be protected by PKC inhibitors. Importantly, the current mainstays in the treatment of mania, lithium (a monovalent cation) and valproate (a small fatty acid), indirectly inhibit PKC. Proof-of-principle studies with the antiestrogenic PKC inhibitor tamoxifen have shown rapid antimanic effects. Recent evidence suggests that lithium may also protect prefrontal gray matter in patients. These data indicate that new, direct PKC inhibitors are needed as potential new treatments for bipolar disorder.