The Bipolar Switching Mystery: Closer to an Explanation

Researchers review evidence pointing to catecholaminergic—cholinergic imbalance as the factor that influences cycling between affective states.

Bipolar disorder’s cyclical switching has mystified researchers. Opposite symptoms—depression and mania—are present in the same patient. Since the early 1970s, researchers have believed that bipolar disorders result from adrenergic—cholinergic imbalance. Mania seemed to be associated with high adrenergic activity, and depression with high cholinergic activity.

In a new article published in the August 2014 issue of the European Journal of Pharmacology, a multinational team of researchers discusses a new hypothesis. They review evidence pointing to a catecholaminergic—cholinergic hypothesis for this often life-threatening mental illness.

In addition to walking readers through the historical basis for the adrenergic—cholinergic theory, the researchers review mounting evidence supporting this newer theory. The accumulated evidence includes neuroimaging studies, neuropharmacological interventions, and genetic associations. Drug studies, for example, indicate that the muscarinic antagonist scopolamine relieves depression.

Targeting nicotinic receptors may also alleviate depression (although studies have found mixed results). Nicotinic receptors’ role in depression may also explain why patients with affective disorders are more likely to smoke (and smoke heavily) than others and often experience new or aggravated depression when they try to quit.

From these studies, the researchers document that increased cholinergic functioning at both muscarinic and nicotinic acetylcholine receptors appears to underlie depression. Once cholinergic function returns to normal levels, the patient becomes euthymic. On the other hand, increased catecholamine (dopamine and norepinephrine) activation may affect dopamine reuptake transporter receptor expression and functioning, leading to mania.

This theory is still young, although studies in both animals and humans seem to be directing researchers’ attention in its direction. Evidence of causative neurotransmitters at the extremes of mood—depression and mania—is clear. One piece of the hypothesis is still unclear: no one has been able to establish how the 2 neurotransmitter systems interact to cause cycling between states of depression and mania.

The researchers note that environmental stimuli and genetic susceptibilities may be the puzzle pieces that explain the cycling between affective states. More research is clearly needed.