Anxiety: First-Line SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for all major anxiety disorders (GAD, panic disorder, social anxiety disorder, OCD, PTSD). SSRIs selectively block the serotonin transporter (SERT) on presynaptic neurons, preventing reuptake of serotonin (5-HT) from the synaptic cleft. Acutely, this increases synaptic 5-HT levels, but the anxiolytic effect requires 4-6 weeks because of a complex cascade of receptor adaptations. Initially, increased 5-HT activates inhibitory 5-HT1A autoreceptors on raphe nuclei neurons, paradoxically reducing serotonergic firing and potentially worsening anxiety. Over 2-4 weeks, these autoreceptors desensitize (downregulate), allowing restoration of normal firing rates with enhanced net serotonergic transmission. Simultaneously, postsynaptic 5-HT receptors in the amygdala and prefrontal cortex undergo adaptive changes that restore inhibitory modulation of fear circuits. Chronic SSRI treatment also increases brain-derived neurotrophic factor (BDNF) and promotes hippocampal neurogenesis, counteracting stress-induced hippocampal atrophy. Individual SSRIs differ in selectivity for SERT, secondary receptor binding profiles, CYP450 metabolism, half-life, and side effect profiles, guiding NP prescribing decisions.