Neurobiology of Depression and Antidepressant Mechanisms

Module 1 — Chapter 17: Antidepressant Drugs

The Monoamine Hypothesis
Monoamine 1
Serotonin
  • Dorsal raphe → limbic system and prefrontal cortex
  • Regulates mood, anxiety, sleep, appetite
  • Deficiency: low mood, anhedonia, anxiety
  • Target of selective serotonin reuptake inhibitors
Monoamine 2
Norepinephrine
  • Locus coeruleus → cortex and limbic system
  • Regulates arousal, attention, stress response
  • Deficiency: fatigue, poor concentration, psychomotor slowing
  • Target of serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants
Monoamine 3
Dopamine
  • Mesolimbic and mesocortical pathways
  • Regulates motivation and reward
  • Deficiency: anhedonia
  • Target of bupropion
Antidepressant Drug Classes and Targets
Drug Class Primary Mechanism Key Agents
Selective serotonin reuptake inhibitors Block serotonin reuptake transporter Fluoxetine, sertraline, paroxetine, escitalopram, citalopram, fluvoxamine
Serotonin-norepinephrine reuptake inhibitors Block serotonin and norepinephrine reuptake transporters Venlafaxine, duloxetine, desvenlafaxine, levomilnacipran
Tricyclic antidepressants Block serotonin and norepinephrine transporters plus muscarinic, histamine, alpha-1 receptors Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine
Monoamine oxidase inhibitors Block monoamine oxidase A and B enzymes Phenelzine, tranylcypromine, isocarboxazid, selegiline patch
Atypical antidepressants Dopamine and norepinephrine reuptake blockade (bupropion); alpha-2 antagonism (mirtazapine) Bupropion, mirtazapine, trazodone, vilazodone, vortioxetine
Glutamate receptor antagonists Block N-methyl-D-aspartate receptor Esketamine (intranasal)
The Two-to-Four-Week Therapeutic Lag
Day 1
Reuptake transporter blocked; synaptic serotonin rises
→
Early weeks
Autoreceptors detect serotonin rise; reduce neuronal firing (negative feedback)
→
Weeks 2–4
Autoreceptors desensitize and downregulate; feedback brake removed
→
Clinical onset
Full serotonergic output restored; mood improvement begins
Clinical Rule

An adequate antidepressant trial = four to six weeks at therapeutic dose. The lag is caused by receptor adaptation, not slow drug absorption. Dose escalation in the first two weeks does not shorten the lag. Do not switch before four to six weeks unless intolerable adverse effects require it.

High-Yield Indications Beyond Depression
Indication group 1
Anxiety and Trauma Disorders
  • Generalized anxiety disorder: selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors first-line
  • Panic disorder: selective serotonin reuptake inhibitors first-line
  • Post-traumatic stress disorder: sertraline and paroxetine approved
  • Social anxiety disorder: selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors first-line
  • Obsessive-compulsive disorder: selective serotonin reuptake inhibitors at higher doses; clomipramine for refractory cases
Indication group 2
Pain and Other Conditions
  • Diabetic peripheral neuropathy: duloxetine approved
  • Fibromyalgia: duloxetine approved
  • Neuropathic pain and migraine prophylaxis: amitriptyline and nortriptyline
  • Smoking cessation: bupropion (Zyban)
  • Enuresis: imipramine
  • Premenstrual dysphoric disorder: selective serotonin reuptake inhibitors