Concept article: Antidepressant-induced destabilization in bipolar illness mediated by serotonin 3 receptor (5HT3).

Objectives: Antidepressants used by patients with bipolar disorder have been associated with destabilization with an increase in mania, depression, and cycling. The most commonly proposed mechanism, that antidepressants 'overshoot' their antidepressant effect to create a manic or mixed state, is unlikely since antidepressants have actually been found to be ineffective in treating bipolar depression. Beginning with known bipolar-specific pathophysiologic abnormalities provides the greatest likelihood of insight.

Methods: PubMed was queried with 'bipolar', 'sodium', 'intracellular sodium', 'serotonin 3', '5HT₃', '5-hydroxytryptamine type 3 receptors', and 'antidepressant' either individually or in combination.

Results: Pathologic mood states (both mania and depression) are associated with increased intracellular sodium (Na) concentrations that depolarize the resting membrane potential to increase cellular excitability (mania) or cause depolarization block (depression). Stimulation of the serotonin (5HT) receptors depolarizes the post-synaptic neuron. Stimulation of 5HT₃ may be of particular importance since it is coupled to a cation channel that directly depolarizes the membrane. These effects directly impact the physiology of patients with bipolar disorder to alter neuronal excitability in a fashion that worsens both mania and depression.

Proposed concept: The most consistently observed biological abnormality in individuals going through mania or bipolar depression involves a decline in Na pump activity, with consequent elevation of intracellular Na levels. Antidepressant treatment potentiates this, particularly by activation of 5HT₃. This hypothesis can be tested by coadministering a 5HT₃ antagonist (e.g., vortioxetine or ondansetron) to achieve blockade of that receptor while treating bipolar depression with a serotoninergic antidepressant.