Mechanisms of SSRI Therapy and Discontinuation

SSRIs are one of the most widely used drug therapies in primary care and psychiatry, and central to the management of the most common mental health problems in today's society. Despite this, SSRIs suffer from a slow onset of therapeutic effect and relatively poor efficacy as well as adverse effects, with recent concerns being focused on a disabling SSRI discontinuation syndrome. The mechanism underpinning their therapeutic effect has long shifted away from thinking that SSRIs act simply by increasing 5-HT in the synapse. Rather, a current popular view is that increased 5-HT is just the beginning of a series of complex downstream signalling events, which trigger changes in neural plasticity at the functional and structural level. These changes in plasticity are then thought to interact with neuropsychological processes to enhance re-learning of emotional experiences that ultimately brings about changes in mood. This compelling view of SSRI action is underpinning attempts to understand fast-acting antidepressants, such as ketamine and psychedelic drugs, and aid the development of future therapies. An important gap in the theory is evidence that changes in plasticity are causally linked to relevant behavioural effects. Also, predictions that the SSRI-induced neural plasticity might have applicability in other areas of medicine have not yet been borne out. In contrast to the sophisticated view of the antidepressant action of SSRIs, the mechanism underpinning SSRI discontinuation is little explored. Nevertheless, evidence of rebound increases in 5-HT neuron excitability immediately on cessation of SSRI treatment provide a starting point for future investigation. Indeed, this evidence allows formulation of a mechanistic explanation of SSRI discontinuation which draws on parallels with the withdrawal states of other psychotropic drugs.