Mania: not the opposite of depression, but an extension? Neuronal plasticity and polarity

Abstract

What underlies bipolar disorder? What pathophysiologic process can produce symptoms that are apparently polar opposites? Recent studies of neuronal plasticity suggest a mechanism. Both zinc deficiency and social isolation impair neuronal plasticity; both are associated with major depression. Yet when zinc deficiency and social isolation occur together, they are associated with aggression, not with depression. On that basis, and according to additional findings in rats reported herein, it was inferred that moderate impairment of neuronal plasticity induces a depressive state, but that further impairment of neuronal plasticity induces not more depression, but a manic state. However, not only neuronal plasticity, but also some kind of load toward neuronal function can influence polarity or symptoms of mood disorder. Our hypothesis is that mania is an extension of depression from the perspective of neuronal plasticity, and that multiaxial evaluation by neuronal plasticity and neuronal load is useful to elucidate the pathophysiology of mood disorder. Using this hypothesis, many clinical aspects that have been heretofore difficult to interpret can be understood. A mood stabilizer or electric convulsive therapy is often used for the treatment of mood disorder, but it has remained unclear why such therapies are useful for both mania and depression. This hypothesis can explain how mood stabilizers or electric convulsive therapy can improve both mania and depression through the recovery of neuronal plasticity. It is difficult to explain the pathophysiology of manic switching by antidepressants solely from the perspective of the impairment of neuronal plasticity. To interpret this phenomenon, the action of antidepressants to neuronal load should be regarded as the other axis from neuronal plasticity. Based on this hypothesis, it is expected that the pathophysiology of mood disorder and clinical mechanism of mood stabilizers and antidepressants can be understood in an integrated manner.