Mechanism of Action of Antidepressants

Underlying Theory: Biogenic Amine Hypothesis

Important caveat: This theory is overly simplistic. It does not explain the delayed therapeutic response - pharmacodynamic effects (reuptake blockade) are immediate, but clinical benefit takes 2-12 weeks. This suggests reuptake inhibition is only the initial effect and is not directly responsible for the antidepressant effect; long-term receptor adaptations likely play a bigger role.

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Highly selective for SERT vs. norepinephrine transporter (NET)
• Little blocking activity at muscarinic, α-adrenergic, or histamine H1 receptors (hence fewer side effects than TCAs)
• First-line agents for depression due to better safety profile and tolerability

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Venlafaxine inhibits NE reuptake only at higher doses; predominantly serotonergic at low doses
• Duloxetine has strong dual reuptake inhibition (++++ for both)
• The dual mechanism may confer efficacy for painful physical symptoms (e.g., diabetic neuropathy, fibromyalgia)

3. Tricyclic Antidepressants (TCAs)

• Muscarinic receptors - anticholinergic side effects (dry mouth, urinary retention, constipation, blurred vision)
• α1-adrenergic receptors - orthostatic hypotension
• H1 histamine receptors - sedation, weight gain
• Sodium channels (cardiac) - arrhythmias, QRS widening in overdose

4. Monoamine Oxidase Inhibitors (MAOIs)

• MAO-A metabolizes serotonin, NE, and dopamine
• MAO-B primarily metabolizes dopamine
• Most MAOIs (e.g., phenelzine) irreversibly inactivate MAO, forming stable enzyme complexes
• This leads to accumulation of NE, serotonin, and dopamine in the neuron and diffusion into the synapse
• Also inhibit MAO in the liver and gut, preventing first-pass metabolism of dietary tyramine (the "cheese effect")

Tyramine reaction: Normally, gut/liver MAO inactivates tyramine from aged cheeses, cured meats, and wine. When MAO is inhibited, absorbed tyramine triggers massive NE release from sympathetic terminals, causing hypertensive crisis (severe headache, hypertension, risk of stroke).

• Selegiline is selective for MAO-B at low doses (also used in Parkinson disease), but non-selective at high antidepressant doses

5. Atypical Antidepressants

Bupropion

• Weak dopamine and norepinephrine reuptake inhibitor (NDRI)
• No serotonergic activity - avoids sexual dysfunction (a key advantage)
• Also approved for smoking cessation
• Dose-dependent seizure risk; avoid in anorexia/bulimia

Mirtazapine

• Blocks presynaptic α2 autoreceptors - these normally inhibit NE/5-HT release; blockade disinhibits release, enhancing both norepinephrine and serotonin neurotransmission
• Also antagonizes 5-HT2 receptors (contributes to antidepressant effect and avoids sexual dysfunction)
• Potent H1 antihistamine - causes sedation and weight gain

Trazodone / Nefazodone

• Block 5-HT2 receptors and inhibit serotonin reuptake (serotonin antagonist-reuptake inhibitors, SARIs)

Vilazodone / Vortioxetine

• Serotonin partial agonist/reuptake inhibitors (SPARIs)
• Block SERT AND partially activate 5-HT1A receptors

Esketamine (S-ketamine)

• NMDA glutamate receptor antagonist (non-selective, non-competitive)
• Represents a completely different mechanism - targets glutamate, not monoamines
• Faster-acting than conventional antidepressants
• Used intranasally for treatment-resistant depression and MDD with suicidal ideation
• Administered in a monitored clinical setting (risk of dissociation, sedation, BP elevation)

Brexanolone

• A GABA-A receptor positive allosteric modulator (neuroactive steroid)
• Used specifically for postpartum depression

Summary Table