Antidepressant Mechanisms

## The Monoamine Hypothesis and Beyond

The classical monoamine hypothesis proposes that depression results from deficient serotonin, norepinephrine, or both. While monoamine-based drugs remain first-line, the 2-4 week delay in therapeutic effect and treatment-resistant cases have driven interest in downstream mechanisms: neuroplasticity, BDNF signaling, neuroinflammation, and glutamatergic transmission.

## Drug Classes and Mechanisms

### SSRIs (Selective Serotonin Reuptake Inhibitors)

Fluoxetine, sertraline, escitalopram selectively block SERT. Acute SERT blockade increases synaptic 5-HT, but the therapeutic delay correlates with desensitization of 5-HT1A autoreceptors and downstream BDNF upregulation. Generally well tolerated; common side effects include sexual dysfunction and GI disturbance.

### SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Venlafaxine and duloxetine block both SERT and NET. Dual action may provide additional efficacy in severe depression and comorbid pain conditions (diabetic neuropathy, fibromyalgia).

### TCAs (Tricyclic Antidepressants)

Amitriptyline, nortriptyline block SERT and NET but also antagonize H1, muscarinic, and alpha-1 receptors, causing sedation, dry mouth, and orthostatic hypotension. Dangerous in overdose due to cardiac sodium channel blockade (QRS prolongation).

### MAOIs (Monoamine Oxidase Inhibitors)

Phenelzine, tranylcypromine irreversibly inhibit MAO-A and MAO-B, increasing all monoamines. Effective but require dietary tyramine restriction to prevent hypertensive crisis. Selegiline transdermal patch selectively inhibits MAO-B at low doses, reducing dietary risk.

### Atypical Antidepressants

- **Bupropion** -- NDRI (norepinephrine-dopamine reuptake inhibitor); no sexual dysfunction; also for smoking cessation
- **Mirtazapine** -- alpha-2 antagonist and 5-HT2/5-HT3 blocker; sedating, appetite-stimulating
- **Trazodone** -- SARI (serotonin antagonist and reuptake inhibitor); primarily used for insomnia at low doses

### Novel Rapid-Acting Agents

- **Esketamine** (Spravato) -- NMDA antagonist nasal spray for treatment-resistant depression; onset in hours
- **Psilocybin** -- 5-HT2A agonist under investigation; promotes neuroplasticity in a single or few sessions
- **Brexanolone** -- GABA-A modulating neurosteroid for postpartum depression

## Key Takeaways

- SSRIs remain first-line due to efficacy and tolerability; therapeutic lag is 2-4 weeks
- TCAs and MAOIs are effective but limited by safety concerns
- Ketamine/esketamine represent a paradigm shift with rapid-onset glutamatergic mechanisms
- Future directions include neuroplasticity enhancers and psychedelic-assisted therapy