Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed class of antidepressants, functioning by selectively blocking the serotonin transporter (SERT) on presynaptic neurons. This prevents serotonin (5-HT) reuptake from the synaptic cleft back into the presynaptic neuron, increasing serotonin availability for postsynaptic receptor activation. The therapeutic delay (2-4 weeks for clinical effect despite immediate SERT blockade) is explained by the desensitization hypothesis: initially, increased serotonin activates presynaptic 5-HT1A autoreceptors on the raphe nuclei, which provide NEGATIVE FEEDBACK reducing serotonin firing. Over 2-4 weeks, these autoreceptors desensitize and downregulate, allowing sustained increased serotonergic transmission. The net effect is enhanced serotonergic signaling in limbic structures (amygdala, hippocampus, prefrontal cortex) modulating mood, anxiety, and emotional processing. SSRIs also promote neuroplasticity and neurogenesis in the hippocampus through brain-derived neurotrophic factor (BDNF) upregulation — this may underlie the long-term antidepressant effect. Side effects correlate with serotonin receptor subtypes: 5-HT2A (sexual dysfunction, insomnia), 5-HT2C (weight changes, anxiety), 5-HT3 (nausea, diarrhea — transient as GI receptors adapt). Six SSRIs are available: fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine.