Anti dipressent classification
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I have comprehensive content now. Let me compile a thorough classification of antidepressants.
Antidepressant Classification
Antidepressants are broadly divided by mechanism of action. The older "first-generation" drugs are TCAs and MAOIs. Newer agents (SSRIs, SNRIs, and atypicals) dominate current prescribing due to better tolerability and safety profiles.
1. Selective Serotonin Reuptake Inhibitors (SSRIs)
Mechanism: Block the serotonin transporter (SERT), prolonging serotonin's dwell time in the synapse. They have minimal effect on norepinephrine or dopamine transporters, which accounts for their favorable side-effect profile compared to TCAs.
Drugs:
| Drug | Notes |
|---|---|
| Fluoxetine | Longest half-life (~5 days); approved for bulimia nervosa & premenstrual dysphoric disorder (PMDD) |
| Sertraline | Favorable pharmacokinetics; approved for PTSD, panic disorder, OCD |
| Paroxetine | Short half-life, anticholinergic effects; not preferred in elderly |
| Citalopram | Linear kinetics; QTc prolongation at doses >40 mg/day (max 20 mg in elderly) |
| Escitalopram | S-enantiomer of citalopram; best tolerated SSRI in elderly |
| Fluvoxamine | Primarily used for OCD |
Indications beyond depression: Generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, OCD, PTSD, PMDD.
Side effects: GI upset (nausea, diarrhea), sexual dysfunction, insomnia/agitation, serotonin syndrome (in overdose/combination), SIADH.
Black-box warning: Increased risk of suicidal ideation in children and adolescents.
2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Mechanism: Inhibit both SERT and the norepinephrine transporter (NET), enhancing both serotonergic and noradrenergic neurotransmission.
Drugs:
| Drug | Approved Uses |
|---|---|
| Venlafaxine | MDD, GAD, panic disorder, social anxiety, PTSD |
| Desvenlafaxine | Active metabolite of venlafaxine |
| Duloxetine | MDD, GAD, diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain |
| Milnacipran | Fibromyalgia (USA), MDD (Europe) |
| Levomilnacipran | MDD |
Side effects: Similar to SSRIs plus hypertension (due to NE effects), urinary hesitancy, increased sweating. SNRIs (and TCAs) carry a higher risk than SSRIs of precipitating mania in bipolar patients.
3. Tricyclic Antidepressants (TCAs)
Mechanism: Block SERT and NET (like SNRIs) but also antagonize muscarinic, histamine H1, and alpha-1 adrenergic receptors - responsible for their broad side-effect burden.
Subdivided by amine type:
Tertiary amines (more anticholinergic, sedating):
- Amitriptyline, Imipramine, Clomipramine (also first-line for OCD), Doxepin, Trimipramine
Secondary amines (less anticholinergic, better tolerated):
- Nortriptyline (active metabolite of amitriptyline), Desipramine (active metabolite of imipramine), Protriptyline
Side effects: Anticholinergic (dry mouth, constipation, urinary retention, blurred vision, cognitive impairment), sedation (H1 blockade), orthostatic hypotension (alpha-1 blockade), weight gain, cardiotoxicity (QRS widening, arrhythmias - most dangerous in overdose).
Special uses: Neuropathic pain, migraine prophylaxis (amitriptyline), enuresis (imipramine), OCD (clomipramine).
4. Monoamine Oxidase Inhibitors (MAOIs)
Mechanism: Inhibit monoamine oxidase (MAO-A and/or MAO-B), the enzyme that catabolizes serotonin, norepinephrine, and dopamine - increasing the availability of these neurotransmitters in storage vesicles.
Types:
| Type | Drugs | Notes |
|---|---|---|
| Non-selective, irreversible | Phenelzine, Tranylcypromine, Isocarboxazid | Older; most drug/food interactions |
| Selective MAO-A, reversible (RIMA) | Moclobemide | Fewer interactions; used widely outside USA |
| Selective MAO-B, irreversible | Selegiline | Low dose for Parkinson's; patch form (EMSAM) approved for MDD |
Major hazard - Hypertensive crisis: Caused by consuming tyramine-rich foods (aged cheeses, cured meats, red wine) while on irreversible MAOIs. Tyramine normally metabolized by intestinal/hepatic MAO-A; when blocked, it enters systemic circulation and causes catecholamine surge.
Serotonin syndrome risk when combined with SSRIs/SNRIs/meperidine/tramadol (washout period required: 14 days after stopping MAOI, or 5 weeks after stopping fluoxetine before starting MAOI).
5. Atypical Antidepressants
These do not fit neatly into the above classes:
Bupropion (NDRI - Norepinephrine-Dopamine Reuptake Inhibitor)
- Blocks NET and DAT (dopamine transporter); no serotonergic activity
- No sexual side effects; activating (useful in fatigue/hypersomnia)
- Also FDA-approved for smoking cessation and ADHD (off-label)
- Contraindicated in eating disorders (bulimia/anorexia) and seizure disorders - lowers seizure threshold
Mirtazapine (NaSSA - Noradrenergic and Specific Serotonergic Antidepressant)
- Blocks presynaptic alpha-2 receptors (increases NE and 5HT release) and postsynaptic 5-HT2 and 5-HT3 receptors
- Strong H1 antagonism causes sedation and appetite stimulation/weight gain
- Useful when insomnia or poor appetite is prominent
Trazodone / Nefazodone (Serotonin Antagonist and Reuptake Inhibitors - SARIs)
- Block 5-HT2A receptors and weakly inhibit SERT
- Trazodone is heavily sedating; most often used at low dose for insomnia
- Nefazodone: hepatotoxicity risk limits use
Vortioxetine (Multimodal Serotonergic Agent)
- Inhibits SERT + directly acts as agonist/partial agonist/antagonist at multiple 5-HT receptor subtypes (5-HT1A, 5-HT3, 5-HT7)
- Procognitive effects; lower sexual dysfunction vs. SSRIs
Vilazodone (Serotonin Partial Agonist/Reuptake Inhibitor - SPARI)
- Inhibits SERT + partial agonist at 5-HT1A receptors
- Fewer sexual side effects than SSRIs
6. Novel/Emerging Antidepressants
| Drug | Mechanism | Indication |
|---|---|---|
| Esketamine (Spravato) | NMDA receptor antagonist (glutamatergic) | Treatment-resistant depression, nasal spray (intranasal), FDA-approved |
| Ketamine (IV) | NMDA antagonist | Rapid-acting; off-label for TRD |
| Brexanolone | GABA-A receptor positive allosteric modulator (neuroactive steroid) | Postpartum depression |
| Zuranolone | Oral GABA-A modulator | Postpartum depression & MDD |
| Psilocybin | 5-HT2A/2C agonist | FDA "Breakthrough Therapy" designation for TRD |
Summary Table
| Class | Mechanism | Key Examples |
|---|---|---|
| SSRI | SERT inhibition | Fluoxetine, Sertraline, Escitalopram |
| SNRI | SERT + NET inhibition | Venlafaxine, Duloxetine |
| TCA | SERT + NET + receptor blockade | Amitriptyline, Nortriptyline, Clomipramine |
| MAOI | MAO inhibition | Phenelzine, Tranylcypromine, Moclobemide |
| NDRI | NET + DAT inhibition | Bupropion |
| NaSSA | Alpha-2 blockade + 5HT2/3 antagonism | Mirtazapine |
| SARI | 5HT2A antagonism + weak SERT | Trazodone |
| Multimodal | SERT + multiple 5HT receptor actions | Vortioxetine |
| NMDA antagonist | Glutamatergic | Ketamine, Esketamine |
| GABA modulator | GABA-A positive allosteric modulator | Brexanolone, Zuranolone |
Sources:
- Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 18
- Kaplan & Sadock's Comprehensive Textbook of Psychiatry
- Harrison's Principles of Internal Medicine, 22nd Edition
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