Possible Biological Mechanisms of the Serotonin Reuptake Inhibitor Discontinuation Syndrome

Although the number of documented serotonin reuptake inhibitor (SRI) discontinuation reactionsis increasing, to date no systematic studies have been completed; therefore the mechanism of actionfor these reactions is not clearly understood. However, several hypotheses have been proposed.Researchers have postulated that discontinuation events result from a sudden decrease in the availabilityof synaptic serotonin in the face of down-regulated serotonin receptors. In addition, otherneurotransmitters, such as dopamine, norepinephrine, or gamma-aminobutyric acid (GABA), mayalso be involved, although little research in this area has been published. Individual patient sensitivity,i.e., genetics or cognitive mindset, may also be a factor in SRI discontinuation phenomena. Finally,experts have hypothesized that since some symptoms associated with paroxetine withdrawal are similarto those of tricyclic antidepressant discontinuation, they may be caused by cholinergic rebound.