How SNRIs and other antidepressants are tested on Step 1
Vignettes match a patient to the best antidepressant (neuropathic pain, insomnia, weight loss, smoking cessation, sexual side effects) or present a toxicity such as TCA overdose or a tyramine crisis.
Antidepressants have similar efficacy, so Step 1 asks you to pick by side effects: bupropion avoids sexual dysfunction and weight gain, mirtazapine helps insomnia and poor appetite, duloxetine treats coexisting neuropathic pain.
SNRI mechanism and uses
Blocking norepinephrine reuptake strengthens descending pain-inhibitory pathways from the brainstem to the dorsal horn.
| SNRI | Notable feature |
|---|---|
| Venlafaxine | Dose-dependent ↑ blood pressure; severe discontinuation symptoms |
| Desvenlafaxine | Active metabolite of venlafaxine |
| Duloxetine | Diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain; avoid in liver disease and heavy alcohol use |
| Milnacipran | Fibromyalgia |
Like SSRIs, SNRIs can cause serotonin syndrome, SIADH, and bleeding.
The other antidepressant classes
Older and atypical antidepressants have distinctive mechanisms and toxicities.
| Drug | Mechanism | Uses | Key adverse effects |
|---|---|---|---|
| TCAs (amitriptyline, nortriptyline, imipramine, clomipramine) | Block 5-HT and NE reuptake; also muscarinic, α1, H1, Na⁺ channels | Neuropathic pain, migraine prophylaxis, enuresis (imipramine), OCD (clomipramine) | Anticholinergic, orthostasis, sedation; lethal in overdose (3 Cs: convulsions, coma, cardiotoxicity) |
| MAOIs (phenelzine, tranylcypromine, selegiline) | Inhibit MAO-A and MAO-B | Atypical or refractory depression; Parkinson (selegiline) | Tyramine hypertensive crisis; serotonin syndrome |
| Bupropion | Inhibits NE and DA reuptake | Depression, smoking cessation, ADHD | Seizures (avoid in bulimia, anorexia, seizure disorders); no sexual dysfunction or weight gain |
| Mirtazapine | α2 antagonist (↑ NE, 5-HT release); 5-HT2/5-HT3 and H1 antagonist | Depression with insomnia and poor appetite | Sedation, weight gain, ↑ cholesterol |
| Trazodone | 5-HT2 antagonist, weak SERT inhibitor | Insomnia (low dose) | Sedation, orthostasis, priapism |
Nortriptyline and desipramine (secondary amines) have fewer anticholinergic effects than amitriptyline and imipramine.
Toxic emergencies
Two antidepressant emergencies are classic.
Clinical application
Pick the antidepressant that fits the whole patient.
A 58-year-old with type 2 diabetes has major depression and burning pain in both feet that worsens at night. Which antidepressant addresses both problems, and what must be checked first?
- Bilateral burning foot pain in diabetes suggests painful diabetic peripheral neuropathy.
- Duloxetine is approved for both depression and diabetic neuropathic pain.
- Duloxetine is hepatotoxic and avoided in liver disease and heavy alcohol use.
- Blood pressure can rise with noradrenergic drugs.
Answer. Duloxetine. Check liver function and alcohol use, and monitor blood pressure. Amitriptyline also treats neuropathic pain but carries anticholinergic and overdose risks.
