## Monoamine Hypothesis of Depression **Key Point:** The monoamine hypothesis is the foundational neurochemical model of depression and underpins the mechanism of action of most antidepressant medications. ### The Monoamine Hypothesis The monoamine hypothesis proposes that **depression results from a deficiency or dysfunction of three key monoamine neurotransmitters:** | Neurotransmitter | Primary Role in Depression | Associated Symptoms | | --- | --- | --- | | **Serotonin (5-HT)** | Mood regulation, emotional processing | Depressed mood, anxiety, sleep disturbance | | **Norepinephrine (NE)** | Attention, arousal, motivation | Anhedonia, fatigue, poor concentration | | **Dopamine (DA)** | Reward, motivation, pleasure | Anhedonia, apathy, psychomotor retardation | ### Historical Context - Proposed in the 1960s–1970s based on observations that reserpine (which depletes monoamines) causes depression. - Tricyclic antidepressants (TCAs) and SSRIs were developed to increase monoamine availability in synapses. - Remains the most widely taught and clinically applied model in psychiatry. ### Limitations of the Monoamine Hypothesis **Clinical Pearl:** While the monoamine hypothesis explains the mechanism of many antidepressants, it does not fully account for: - Why there is a 2–4 week lag before symptom improvement despite immediate neurotransmitter elevation. - Individual variability in treatment response. - The role of neuroplasticity, inflammation, and HPA axis dysfunction in depression. **High-Yield:** The monoamine hypothesis is tested in nearly every NEET PG psychiatry exam. Know the three monoamines and their roles. **Mnemonic:** **SNaD** = **S**erotonin, **N**orepinephrine, **D**opamine (the three monoamines in depression). [cite:Harrison 21e Ch 470]
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