SSRI Discontinuation Syndrome - Mechanism

Mechanism

The exact mechanism of SSRI withdrawal syndrome is unknown, and may be due to a variety of factors. Continuing research on discontinuation/withdrawal syndrome has attributed SSRI withdrawal syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor), and electrophysiological changes in the body (nerve growth factor) in the absence of the SSRI, as well as dopamine dependency, and an over-excited immune system.

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. Desired drug effects may be mediated by such compensatory changes which may explain the delayed onset of therapeutic effect of antidepressants. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome. Pharmacodynamic factors explain why withdrawal syndromes are often a class issue and why the administration of a drug in the same class often relieves withdrawal symptoms. Formal studies have not characterized the relative risk.

One theory states that SSRI withdrawal syndrome is associated with a rostral anterior cingulate Cho/Cre metabolite ratio decrease that may reflect dynamics of rostral anterior cingulate cortex (ACC) function. The ACC appears to play a role in a wide variety of autonomic functions, such as regulating heart rate and blood pressure, and is vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion. Neuroscientists indicate the dorsal anterior cingulate cortex is primarily related to rational cognition while the ventral is more related to emotional cognition.

A separate study demonstrated that changes in regional central blood volume of left prefrontal cortex and left caudate nucleus correlate with the emergence of withdrawal symptoms and increased Hamilton Depression Rating Scale after interruption of paroxetine treatment. The findings supported the hypothesis that brain regions implicated in depression, with extensive serotonergic innervation, would exhibit changes in activity associated with emergence of symptoms following drug discontinuation. Cerebral blood volume maps were obtained via dynamic susceptibility functional magnetic resonance imaging (fMRI).

There is speculation concerning the possibility of a temporary deficiency of synaptic serotonin with abrupt withdrawal of an SSRI. This deficiency is compounded by the fact that down-regulated receptors will remain in their relatively hypoactive state for days to weeks. This is believed to result in antidepressant discontinuation syndrome directly or indirectly via downstream effects on other neurotransmitter systems (e.g., norepinephrine, dopamine, and GABA) implicated in depressive and anxiety disorders.

Another possible mechanism is by inhibition of dopaminergic neurotransmission.