## Monoamine Hypothesis of Depression **Key Point:** The **monoamine hypothesis** proposes that depression results from deficiency of monoamine neurotransmitters—primarily serotonin (5-HT), norepinephrine (NE), and dopamine (DA). SSRIs directly support this hypothesis by increasing synaptic serotonin. ### Mechanism of SSRIs and the Monoamine Hypothesis | Feature | Details | |---------|----------| | **SSRI Mechanism** | Inhibit serotonin reuptake at the presynaptic terminal → ↑ synaptic 5-HT | | **Hypothesis Prediction** | ↑ Synaptic monoamines → restoration of normal mood signaling | | **Clinical Outcome** | Symptom improvement supports the monoamine deficit model | | **Timeline** | Immediate increase in synaptic 5-HT, but clinical response takes 2–4 weeks (suggests downstream neuroadaptation) | ### Historical Context The monoamine hypothesis emerged from: 1. Observation that reserpine (depletes monoamines) causes depression 2. Discovery that tricyclic antidepressants block monoamine reuptake 3. Development of SSRIs as selective 5-HT reuptake inhibitors **High-Yield:** The **monoamine hypothesis** is the foundational neurobiological model for antidepressant drug development. All first-line antidepressants (SSRIs, SNRIs, TCAs) work by increasing monoamine availability. **Clinical Pearl:** The 2–4 week lag between SSRI initiation and symptom improvement suggests that simple monoamine increase is insufficient; downstream neuroadaptation (receptor desensitization, gene expression changes, neuroplasticity) is required for therapeutic effect. **Warning:** The monoamine hypothesis is a useful model but likely incomplete—it does not fully explain depression's etiology (genetics, stress, inflammation, HPA axis dysfunction also play roles). [cite:Harrison 21e Ch 470]
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