Neurobiology and Bipolar Disorder: beyond the Synapse*

Affective disorders have hitherto been explained in terms of neurotransmitter deficits or dysfunction. However, research in patients with bipolar disorder shows that, while neurotransmitter dysfunction is clearly important in the presentation of bipolar disorder, it is not the sole explanation for its etiology. Rather than all of the neurotransmitters being independently abnormal in bipolar disorder, perhaps there is something common that regulates all of them? This article will discuss the cellular plasticity and endophenotype models of bipolar disorders as well as the preclinical and clinical research that uses 3 of the most commonly used and effective drugs for bipolar disorder (ie, lithium, valproate, and carbamazepine) to show that bipolar disorder may be a neurologic dysfunction at the cellular level, via anomalies in intracellular signaling. The role of intracellular signaling cascades holds great interest because it may explain why so many neurotransmitter systems are involved in bipolar disorder, the frequent comorbidities with bipolar disorder, some of the physical brain changes observed (also described in this article), why structurally dissimilar drugs can all be effective in treating bipolar disorder, and the lag time between pharmacotherapy initiation and beneficial effect and well as the lag time between treatment cessation and withdrawal effect. Given the complex presentation of mood disorders and the advances in medical research technology, we now are starting to understand the true mechanisms of action of some of our older treatments as we better understand the underlying neurobiology of the disorders. We are on the verge of developing new drugs based on these cellular targets, which, if effective, will allow clinicians to address the fundamental biology of the disorder, rather than the presenting symptoms. (Adv Stud Med. 2006;6(6A):S417-S429)