Serotonin-Norepinephrine Reuptake Inhibitors, Mirtazapine, and Bupropion

Module 3 — Chapter 17: Antidepressant Drugs

The Four Serotonin-Norepinephrine Reuptake Inhibitors
Agent Key Feature Approved Indications Cautions
Venlafaxine Dose-dependent dual action: low dose = serotonin; high dose = serotonin + norepinephrine Major depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder High discontinuation syndrome risk (short half-life); blood pressure monitoring required at higher doses
Desvenlafaxine Active metabolite of venlafaxine; fixed dose; minimal cytochrome P450 interactions Major depressive disorder only Dose reduction in renal impairment; discontinuation syndrome risk
Duloxetine Broadest indications including pain; moderate cytochrome P450 2D6 inhibitor Major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, musculoskeletal pain Avoid in liver disease (hepatotoxicity risk); contraindicated in narrow-angle glaucoma
Levomilnacipran Most norepinephrine-selective agent; urinary hesitancy most prominent Major depressive disorder only Dose reduction in renal impairment; blood pressure monitoring
Mirtazapine and Bupropion — Distinctive Mechanisms
Noradrenergic and Specific Serotonergic Antidepressant
Mirtazapine
  • Mechanism: alpha-2 antagonist → disinhibits norepinephrine and serotonin release
  • Serotonin-3 blockade: antiemetic — no nausea
  • Serotonin-2C blockade: appetite stimulation, weight gain
  • Histamine H1 blockade: sedation (more at 15 mg than 30 mg)
  • No serotonin transporter activity: no sexual dysfunction
  • No cytochrome P450 inhibition: clean interaction profile
  • Best for: insomnia, poor appetite, intolerance to nausea
Norepinephrine-Dopamine Reuptake Inhibitor
Bupropion
  • Mechanism: blocks dopamine and norepinephrine transporters; no serotonin effect
  • No sexual dysfunction; no weight gain (some weight loss)
  • Smoking cessation: approved as Zyban — raises dopamine tone, reduces craving
  • Cytochrome P450 2D6 inhibitor — monitor tricyclic antidepressant levels
  • Dose-dependent seizure risk
  • Contraindicated in: seizure disorder, bulimia/anorexia with purging, monoamine oxidase inhibitor use, alcohol/benzodiazepine withdrawal
Venlafaxine Dose-Dependence Rule

At 75 mg per day or below, venlafaxine behaves like a selective serotonin reuptake inhibitor (serotonin transporter inhibition only). At 150 mg per day and above, norepinephrine transporter inhibition emerges and dual action is achieved. Failure to respond at low dose does not mean the drug has failed — escalation to full dual-mechanism dosing is required before concluding treatment failure.