What is the normal dosage of venlafaxine (Selective Serotonin and Norepinephrine Reuptake Inhibitor), at what dose does it act as a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI), and how should it be titrated?

Venlafaxine Dosing, SNRI Activity, and Titration

Normal Dosage Range

Start venlafaxine at 75 mg/day (divided into 2-3 doses with food for immediate-release, or 37.5 mg once or twice daily for extended-release), with a therapeutic target of 150-225 mg/day for most patients with depression. 1, 2

• The FDA-approved starting dose for immediate-release venlafaxine is 75 mg/day in divided doses 1
• Extended-release formulations begin at 37.5 mg once or twice daily 2
• The therapeutic range for most indications (depression, neuropathic pain, anxiety disorders) is 150-225 mg/day 3, 2
• Maximum approved dose is 375 mg/day, though routine outpatient depression typically uses up to 225 mg/day 1, 2
• More severely depressed inpatients may require higher doses, with a mean effective dose around 350 mg/day 1

At What Dose Does Venlafaxine Act as a True SNRI?

Venlafaxine functions as a selective serotonin reuptake inhibitor at doses below 150 mg/day, but begins meaningful norepinephrine reuptake inhibition only at 225 mg/day or higher. 4, 5

• At 75 mg/day, venlafaxine acts as a selective serotonin reuptake inhibitor only, with approximately 55-60% serotonin transporter (SERT) inhibition but no significant norepinephrine transporter (NET) inhibition 5, 4
• Dual SNRI activity (both serotonin and norepinephrine inhibition) begins at 225 mg/day, where clinically significant NET inhibition is first demonstrated 4, 5
• This dose-dependent mechanism occurs because venlafaxine has a 30-fold difference in binding affinity between serotonin and norepinephrine transporters, requiring higher doses to engage NET 6
• At 225-375 mg/day, venlafaxine achieves over 90% SERT inhibition plus significant NET blockade 4, 5

How to Titrate and How Fast

Increase venlafaxine by 75 mg every 4-7 days as tolerated, taking 2-4 weeks to reach the efficacious range of 150-225 mg/day. 1, 2, 3

Standard Titration Schedule:

• Week 1: Start at 37.5-75 mg/day 2, 1
• Week 2: Increase to 150 mg/day (the lower end of therapeutic range) 2, 1
• Week 3-4: Titrate to target dose of 150-225 mg/day based on tolerability 3, 2
• Increments: Use 75 mg increases at intervals of no less than 4 days per FDA labeling, though clinical guidelines suggest 4-7 days 1, 2

Extended-Release Specific Titration:

• Week 1: 37.5 mg once or twice daily 2
• Week 2: 75 mg daily 2
• Week 3: 150 mg daily 2
• Week 4+: 225 mg daily if needed 2

Critical Monitoring During Titration:

• Monitor blood pressure at doses exceeding 150 mg/day, as dose-dependent hypertension becomes a risk 2, 6
• Blood pressure elevation is infrequent below 225 mg/day but increases at higher doses due to norepinephrine reuptake inhibition 6
• Allow 4-6 weeks total (including titration time) to assess adequate therapeutic response 3

Important Caveats and Pitfalls

Nausea Management:

• Nausea is the most common side effect and the leading cause of discontinuation 6
• It occurs in a dose-dependent manner, making gradual titration over 2-4 weeks essential to reduce this adverse effect 3
• Taking venlafaxine with food helps minimize gastrointestinal side effects 1

Cardiovascular Precautions:

• Prescribe with caution in patients with pre-existing cardiac disease due to reports of cardiac conduction abnormalities 3
• Dose-dependent blood pressure increases occur, particularly above 225 mg/day 6, 2

Discontinuation Syndrome:

• Never abruptly discontinue venlafaxine due to severe withdrawal syndrome risk, even after missing a single dose 7
• Taper over 10-14 days minimum when discontinuing 3
• For patients on chronic therapy, slower tapers of 10% reductions per week or even per month may be necessary (approximately 22.5 mg weekly decrements from 225 mg) 2, 7
• Some patients require tapers extending over several months to avoid withdrawal distress 2

Special Populations:

• Hepatic impairment: Reduce total daily dose by 50% in mild-to-moderate hepatic impairment 1
• Renal impairment: Reduce dose by 25% in mild-to-moderate renal impairment (GFR 10-70 mL/min); reduce by 50% in hemodialysis patients 1
• Elderly patients: No routine dose adjustment needed based on age alone, but exercise caution when increasing doses 1

Dose-Response Relationship:

• Data suggest a clear dose-response relationship in the 75-225 mg/day range for outpatients 1
• There is no evidence of increased efficacy beyond 225 mg/day in moderately depressed outpatients 1
• However, more severely depressed patients (particularly inpatients) may benefit from doses up to 375 mg/day 1