Generic Name

Venlafaxine

Mechanism

• Dual reuptake inhibition: Blocks the serotonin transporter (SERT) and, at therapeutic plasma concentrations, the norepinephrine transporter (NET).
• Free‑radical inhibition: In high‑dose therapy (≥225 mg daily) a weak serotonin‑releasing effect may enhance serotonergic tone.
• Pharmacodynamic switch: Below 150 mg/day mainly serotonergic; above 150 mg shifts toward balanced serotonergic–noradrenergic activity.

Pharmacokinetics

• Absorption: Oral bioavailability ~38 % (first‑pass hepatic metabolism).
• Onset: Effects may begin 1–2 weeks; peak plasma concentration ~1 h post‑dose.
• Distribution: Highly protein‑bound (~50 %).
• Metabolism: Primarily hepatic via CYP2D6 to the active metabolite desvenlafaxine (≈40 % of total active exposure).
• Elimination: Half‑life 5–7 h (free drug); desvenlafaxine half‑life ~11 h.
• Renal excretion: 42 % as unchanged drug; dose adjustment for severe renal impairment.

Indications

• Major depressive disorder (MDD) in adults and adolescents (≥12 yrs).
• Generalized anxiety disorder (GAD).
• Social anxiety disorder (off‑label).
• Panic disorder, post‑traumatic stress disorder (off‑label).

Contraindications

• Contraindications:
• Hypersensitivity to venlafaxine or other SNRIs.
• Concomitant MAO inhibitor use (≥14 days gap).
• Warnings:
• Hypertension: Dose‑related pressor effect; monitor BP especially in the first week.
• Serotonin syndrome: Risk ↑ when combined with serotonergic agents (e.g., SSRI, tramadol).
• Pregnancy category C; limited data but avoid in later pregnancy if possible.
• Suicidal ideation: Monitor psychiatric status during initiation and dose changes.

Dosing

• Formulations: Immediate‑release (IR) and extended‑release (XR).
• Administration: With or without food; XR should be taken on an empty stomach to avoid missed absorption.
• Tapering: Reduce by 30–50 % every 1–2 weeks; avoid abrupt withdrawal.

Adverse Effects

• Common
• Nausea, dry mouth, dizziness, insomnia, increased sweating, constipation.
• Δ blood pressure (↑ systolic/diastolic 5–10 mm Hg).
• Serious
• Serotonin syndrome (hyperthermia, clonus, tremor).
• Hypertensive crisis (systolic > 200 mm Hg).
• Suicidal thoughts/behavior.
• QTc prolongation (rare).

Monitoring

• Blood pressure & pulse: Weekly for the first month; then monthly if stable.
• Weight & appetite: Every visit.
• Renal & hepatic function: Prior to initiation; repeat if dose ↑ >150 mg/day or in patients with CKD/GGT elevation.
• Serotonergic drug interaction risk: Review medication list at each follow‑up.
• Pregnancy: Counsel on fetal safety; avoid in late pregnancy unless benefit outweighs risk.

Clinical Pearls

• Start low, titrate slow: Begin with 37.5 mg (IR) or 37.5 mg XR; 5 mg QD increments every 3 days to avoid dizziness and BP spikes.
• Watch BP spikes: If the patient has baseline hypertension, consider a lower initial dose (e.g., 37.5 mg) and monitor the first week closely.
• CYP2D6 poor metabolizers: May experience higher plasma desvenlafaxine levels → monitor for increased side‑effects and consider dose reduction.
• Drug‑drug interactions: Strong CYP2D6 inhibitors (e.g., fluoxetine) can elevate venlafaxine levels; adjust dose accordingly.
• Serotonin syndrome vigilance: Educate patients to report agitation, hyperreflexia, or confusion, especially if adding other serotonergic agents.
• Withdrawal prevention: Plan a gradual taper over at least 2 weeks; abrupt discontinuation may precipitate rebound anxiety or depressive symptoms.
• Pregnancy counseling: Discuss limited data; if continuing, limit dose to the lowest effective level and discuss alternative options.

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• Venlafaxine remains a cornerstone for mood and anxiety disorders when carefully titrated and monitored, offering a balanced serotonergic‑noradrenergic profile with manageable safety when contraindications and drug interactions are meticulously overseen.