Neurocircuitry of Mood Disorders

One of the first neurochemical theories of depression was the monoamine deficiency hypothesis (139,143,153). Over the past 30 years, this hypothesis has been the most scrutinized of any theories regarding the biology of depression. Unfortunately, the biology of depression remains an elusive issue, despite intense biological research. It is widely held that most, if not all, antidepressant drug treatments produce their therapeutic antidepressant effects, at least in part, by modulating monoamine systems (noradrenergic, serotonergic, and dopaminergic); however, less is known about the neurochemical pathology of these monoamine systems in depression. Early attempts to evaluate monoamine systems in depressive disorders led to diverse and not clearly integrated findings. As a result, many other neurochemical theories have been generated in efforts to explain the biological basis of depression. These theories include HPA axis hyperactivity (111), the GABA hypothesis (132), the galanin hypothesis (186), the substance P hypothesis (82), the glutamate hypothesis (162), the neurotrophin hypothesis (39), and many others. A substantial portion of the evidence supporting these ‘‘other neurotransmitter’’ theories derives from studies of the pharmacologic and behavioral effects of antidepressant drugs in laboratory animals. Of course, these antidepressant drugs have prominent actions on norepinephrine (NE), serotonin (5HT), and to a lesser extent, dopamine (DA). Hence, originators of new hypotheses are continuously forced to place new theories in the context of the old monoamines. The principal reason for this is that, despite years of pharmaceutical development, drugs with primary actions on monoamine systems remain the mainstay of treatment for depressive disorders. In fact, evidence that there has been an improvement of medication over the