Which neurotransmitter hypothesis of depression proposes that a deficiency in serotonin, norepinephrine, and dopamine underlies the pathophysiology of Major Depressive Disorder?

Explanation

## The Monoamine Hypothesis of Depression **Key Point:** The **monoamine hypothesis** (also called the catecholamine hypothesis or biogenic amine hypothesis) posits that depression results from a deficiency of monoamine neurotransmitters — specifically **serotonin (5-HT), norepinephrine (NE), and dopamine (DA)** — in the brain. ### Historical Context This hypothesis emerged in the 1960s after observations that: - Reserpine (depletes monoamines) causes depression - Early antidepressants (TCAs, MAOIs) increase monoamine availability - SSRIs and SNRIs (which elevate serotonin and norepinephrine) are effective ### The Three Monoamines Implicated | Neurotransmitter | Key Roles in Depression | Brain Regions | | --- | --- | --- | | **Serotonin (5-HT)** | Mood regulation, sleep, appetite, impulse control | Raphe nuclei → prefrontal cortex, limbic system | | **Norepinephrine (NE)** | Attention, arousal, motivation, energy | Locus coeruleus → cortex, limbic system | | **Dopamine (DA)** | Motivation, reward, pleasure (anhedonia) | VTA/SNc → nucleus accumbens, prefrontal cortex | **High-Yield:** The monoamine hypothesis directly explains why: - **SSRIs** work (↑ serotonin) - **SNRIs** work (↑ serotonin + norepinephrine) - **Bupropion** works (↑ dopamine + norepinephrine) - **TCAs** work (↑ all three monoamines) ### Clinical Pearl While the monoamine hypothesis remains the foundation of antidepressant pharmacotherapy, modern neuroscience recognizes it is incomplete — neuroinflammation, HPA axis dysregulation, neuroplasticity changes, and glutamate dysfunction also contribute to depression. **Mnemonic:** **SND** = Serotonin, Norepinephrine, Dopamine (the three monoamines in depression). [cite:Harrison 21e Ch 470]