venlafaxine

MECHANISM: Venlafaxine inhibits presynaptic reuptake of serotonin (SERT) and norepinephrine (NET), and weakly of dopamine at very high doses. It is dose-dependent. At low doses (≤75 mg) it acts mostly as an SSRI. At moderate to high doses (≥150-225 mg) NE reuptake inhibition becomes clinically significant. It has minimal affinity for muscarinic, histaminic (H1), and alpha-1 adrenergic receptors, so it has fewer anticholinergic, sedative, and orthostatic effects than TCAs.

PHARMACOKINETICS: Metabolized by hepatic CYP2D6 to the active metabolite O-desmethylvenlafaxine (desvenlafaxine, Pristiq). Venlafaxine has a short half-life (~5 h; active metabolite ~11 h), and renal excretion is the main elimination route. Dose adjustment is needed in renal and hepatic impairment. The extended-release (XR) form is the common formulation.

INDICATIONS: - Major depressive disorder - Generalized anxiety disorder (GAD) - Social anxiety disorder - Panic disorder - Off-label: diabetic peripheral neuropathy and other neuropathic pain, fibromyalgia (duloxetine and milnacipran are the SNRIs more commonly tied to this), vasomotor symptoms of menopause, migraine prophylaxis, PTSD, and OCD.

ADVERSE EFFECTS: - Dose-dependent hypertension (NE effect). This is the classic distinguishing feature from SSRIs, so monitor BP. - Nausea, headache, insomnia, dizziness, sweating, dry mouth. - Sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation). - Increased suicidality in children, adolescents, and young adults (boxed warning for all antidepressants). - Serotonin syndrome, especially when combined with MAOIs, linezolid, triptans, tramadol, meperidine, St. John's wort, or other serotonergic drugs. Features are hyperthermia, autonomic instability, hyperreflexia, clonus, tremor, agitation, and diarrhea. Treat by stopping the drug, giving benzodiazepines, and giving cyproheptadine (5-HT2A antagonist) if needed. - Hyponatremia/SIADH (more in elderly patients). - Increased bleeding risk (platelet serotonin depletion), especially with NSAIDs, aspirin, or anticoagulants. - Mydriasis, which can precipitate acute angle-closure glaucoma. - Can induce mania or hypomania in unrecognized bipolar disorder. - Overdose is more dangerous than with SSRIs: seizures, QRS/QT prolongation, and tachycardia.

DISCONTINUATION SYNDROME: Because of its short half-life, abrupt cessation causes dizziness, "brain zaps" (electric-shock sensations), nausea, irritability, flu-like symptoms, insomnia, and anxiety. Prevent it by tapering slowly. Paroxetine and venlafaxine are the classic examples.

CONTRAINDICATIONS/INTERACTIONS: Concurrent or recent (within 14 days) MAOI use is contraindicated because of the serotonin syndrome risk. Use caution in uncontrolled hypertension. CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, bupropion, quinidine) raise venlafaxine levels.

PREGNANCY/LACTATION: Late-pregnancy exposure is linked to neonatal adaptation syndrome and possibly persistent pulmonary hypertension of the newborn (PPHN), a risk also described with SSRIs.

HIGH-YIELD COMPARISONS: - SNRIs: venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran. - Venlafaxine vs. SSRIs: it adds NE activity, so it carries a hypertension risk but may help with neuropathic pain and some treatment-resistant depression. - Venlafaxine vs. TCAs: it has similar dual reuptake inhibition, but without the anticholinergic, antihistaminic, or alpha-blocking effects, and it is much safer in overdose. - Duloxetine: the SNRI with the strongest evidence for diabetic neuropathy, fibromyalgia, and chronic musculoskeletal pain. Venlafaxine is the SNRI most associated with hypertension.

BOARD PEARL: A patient with depression and comorbid neuropathic pain or GAD, started on an SNRI, who later develops elevated blood pressure points to venlafaxine's dose-dependent noradrenergic effect. A patient on an SNRI who develops hyperthermia, clonus, and agitation after adding tramadol, a triptan, or linezolid has serotonin syndrome.