Antidepressant Mechanisms
How different classes of antidepressants work, from monoamine reuptake inhibition to glutamatergic and neuroplasticity-based 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