Antidepressant Classes Compared: SSRIs, SNRIs, and TCAs

Three major antidepressant classes dominate clinical practice, each with distinct mechanisms, side effect profiles, and therapeutic niches.

Comparative Overview

Class	Mechanism	Representative Agents	Key Side Effects	Clinical Notes
SSRIs (Selective Serotonin Reuptake Inhibitors)	Block SERT → ↑ synaptic serotonin	Fluoxetine, sertraline, escitalopram, citalopram, paroxetine	GI upset, sexual dysfunction, insomnia, activation, withdrawal syndrome	First-line for depression and anxiety; favorable overdose safety
SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)	Block SERT + NET → ↑ serotonin & norepinephrine	Venlafaxine, duloxetine, desvenlafaxine, levomilnacipran	Nausea, hypertension, sweating, withdrawal (notably venlafaxine)	Useful for pain comorbidities; often second-line
TCAs (Tricyclic Antidepressants)	Block SERT + NET + α₁, H₁, M₁ antagonism	Sedation, anticholinergic effects, orthostasis, QT prolongation, lethal in overdose	Amitriptyline, nortriptyline, imipramine, desipramine	Reserved for refractory cases; effective for neuropathic pain

Other Classes & Selection Principles

Additional options include MAOIs (requiring dietary tyramine restriction) and atypical agents such as bupropion, mirtazapine, trazodone, and vortioxetine. Selection should be guided by symptom profile, comorbidities, side effect tolerance, drug interactions, and patient preference. Measurement-based care using tools like the PHQ-9 helps guide titration and assess response.