Which of the following is the PRIMARY mechanism of action of selective serotonin reuptake inhibitors (SSRIs)?

Explanation

## Mechanism of Action of SSRIs **Key Point:** SSRIs selectively block the serotonin reuptake transporter (SERT), a sodium-dependent symporter on the presynaptic nerve terminal, thereby increasing synaptic serotonin concentration. ### SSRI Mechanism: Step-by-Step 1. Serotonin is released into the synaptic cleft from presynaptic neurons. 2. SERT normally recycles ~90% of released serotonin back into the presynaptic terminal. 3. SSRIs competitively inhibit SERT, blocking reuptake. 4. Synaptic serotonin accumulates, increasing postsynaptic receptor activation. 5. Antidepressant effect develops over 2–4 weeks (not immediate). **High-Yield:** SSRIs are **selective** for serotonin reuptake; they do NOT significantly block norepinephrine or dopamine reuptake (unlike SNRIs or TCAs). This selectivity accounts for their favorable side-effect profile. **Clinical Pearl:** The delay in clinical response (2–4 weeks) despite immediate SERT blockade is thought to involve downstream neuroadaptation, including desensitization of autoreceptors and altered gene expression — not just acute serotonin elevation. **Mnemonic:** **SERT** = Serotonin Transporter; **SSRIs block SERT** = Selective Serotonin Reuptake Inhibitors. ### Comparison with Other Antidepressant Classes | Class | Primary Target | Secondary Targets | Examples | |-------|----------------|-------------------|----------| | **SSRI** | SERT (serotonin) | None | Fluoxetine, Sertraline, Paroxetine | | **SNRI** | SERT + NET | Dopamine (at high doses) | Venlafaxine, Duloxetine | | **TCA** | SERT + NET | Muscarinic, H1, α1 | Amitriptyline, Imipramine | | **MAOI** | MAO enzyme | — | Phenelzine, Tranylcypromine |