Pharmacology  ·  CNS

Serotonin-Norepinephrine Reuptake Inhibitors, Mirtazapine, and Bupropion

Module 3 — Chapter 17: Antidepressant Drugs

• The SNRI table highlights a mechanistic subtlety that is easy to miss: venlafaxine behaves like an SSRI at low doses and only engages norepinephrine reuptake inhibition at doses of 150 mg/day and above — so a patient who fails low-dose venlafaxine has not failed dual-mechanism therapy and deserves dose escalation before the drug is abandoned.
• Duloxetine's breadth of FDA-approved indications sets it apart from other SNRIs — it is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain — but this comes with the caution that it should be avoided in significant liver disease due to hepatotoxicity risk.
• Mirtazapine's mechanism is fundamentally different from all other antidepressants in this chapter: it disinhibits both norepinephrine and serotonin release by blocking presynaptic alpha-2 autoreceptors, rather than blocking reuptake; the receptor profile that results — 5-HT3 blockade preventing nausea, H1 blockade causing sedation — makes it the agent of choice when insomnia and poor appetite are dominant features.
• Bupropion's dopaminergic and noradrenergic mechanism produces a profile that is the clinical opposite of SSRIs in two respects: no sexual dysfunction and no weight gain, often modest weight loss — making it a useful alternative in patients where these SSRI adverse effects are intolerable; the seizure risk at high doses and the absolute contraindication in eating disorders with purging are the critical safety constraints.
• The mirtazapine sedation paradox is worth flagging: H1 blockade is more pronounced at 15 mg than at 30 mg because at higher doses the noradrenergic stimulation partially offsets the sedating histamine blockade — counterintuitively, patients struggling with excessive sedation may benefit from a dose increase rather than a decrease.