Psychiatric · Medicine Class
Selective inhibition of the serotonin transporter (SERT)
SSRIs selectively block the serotonin transporter (SERT), preventing the reuptake of serotonin (5-HT) from the synaptic cleft back into the presynaptic neuron. This increases serotonin availability at postsynaptic receptors. The full antidepressant effect takes 4–6 weeks, suggesting downstream neuroplasticity changes (BDNF upregulation, hippocampal neurogenesis) are the true therapeutic mechanism rather than simple neurotransmitter elevation.
Sertraline (Zoloft)
Most prescribed antidepressant worldwide. Excellent tolerability. First-line for most indications.
Escitalopram (Lexapro)
Most serotonin-selective SSRI. Minimal medicine interactions. High patient satisfaction.
Fluoxetine (Prozac)
Longest half-life (4–6 days for fluoxetine; 4–16 days for norfluoxetine). No discontinuation syndrome. Safe in pregnancy.
Citalopram (Celexa)
Racemic mixture of escitalopram. FDA dose limit 40mg due to QTc prolongation risk.
Paroxetine (Paxil)
Most anticholinergic SSRI. Significant CYP2D6 inhibition. Severe discontinuation syndrome — short half-life.
Fluvoxamine (Luvox)
Primarily used for OCD. Strong CYP1A2/CYP2C19/CYP3A4 inhibitor — major interaction potential.
MAOIs — ABSOLUTELY CONTRAINDICATED; serotonin syndrome can be fatal. 14-day washout required.
Linezolid and IV methylene blue — serotonergic; contraindicated
Tramadol — increases serotonin syndrome risk
Triptans — potential serotonin syndrome (weaker association, debated)
NSAIDs + SSRIs → increased GI bleeding risk
Anticoagulants + SSRIs → increased bleeding risk
Fluoxetine/paroxetine (CYP2D6 inhibitors) → increase levels of tricyclics, antipsychotics, opioids metabolized by CYP2D6
The general recommendation is to continue antidepressant treatment for 6–12 months after achieving remission for a first depressive episode, to prevent relapse. For patients with 2+ prior episodes or chronic/severe depression, indefinite maintenance therapy is often recommended. Discontinuation should be gradual (over weeks to months) under medical supervision.
SSRIs immediately increase synaptic serotonin from day one. However, the therapeutic effect requires downstream neuroplasticity changes: desensitization of presynaptic 5-HT1A autoreceptors (which initially reduce firing), upregulation of BDNF (brain-derived neurotrophic factor), and hippocampal neurogenesis. These adaptive changes take 4–6 weeks to develop, which is why clinical response is delayed despite immediate pharmacological action.