Venlafaxine (Effexor) vs Sertraline (Zoloft)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Venlafaxine advantages over Sertraline

  • Unlike paroxetine, venlafaxine does not significantly inhibit CYP enzymes.

Sertraline advantages over Venlafaxine

  • Unlike venlafaxine, which is associated with hypertension at high doses, sertraline does not cause elevation of blood pressure.
  • Sertraline is less toxic than venlafaxine in overdose.


Venlafaxine Sertraline
Brand names
• Effexor®
• Effexor XR®
• Zoloft®
effexor xr pills zoloft pills
Drug class
• Antidepressant, antianxiety agent
• Serotonin-norepinephrine reuptake inhibitor (SNRI) • Selective serotonin reuptake inhibitor (SSRI)
Dose formulations
• Tablets
• Tablets, extended release
• Capsule, extended release
• Tablets
• Oral concentrate
Legal status
• Rx only
• Not a controlled drug
FDA-approved indications
• Depressive disorder
• Social anxiety disorder
• Panic disorder
• Generalized anxiety • Post-traumatic stress disorder
• Obsessive-compulsive disorder
"Off-label" uses
• Hot flashes
• Somatization disorder
• Neuropathic pain
• Premenstrual dysphoric disorder
• Seasonal affective disorder
• Postpartum depression
Mechanism of action
• Venlafaxine inhibits the reuptake of serotonin and norepinephrine in the brain.
• The reuptake effects of venlafaxine are dose dependent. At low doses it blocks only serotonin neurotransmission. At higher doses venlafaxine blocks neurotransmission of both serotonin and noradrenaline.
• Sertraline selectively inhibits reabsorption of neurotransmitter serotonin in the brain.
• Sertraline mildly increases neurotransmission of dopamine.
• 5 hours
• 11 hours for active metabolite O-desmethylvenlafaxine
• 26 hours
Oral bioavailability
• 45% • 20-36%
Metabolism, Elimination
• Venlafaxine is metabolized in the liver via the CYP2D6 to its active metabolite, O-desmethylvenlafaxine.
• 87% of venlafaxine dose is excreted by the kidneys.
• Sertraline undergoes extensive hepatic metabolism by CYP enzymes. The drug is primarily metabolized by CYP3A4 to its active metabolite N-desmethylsertraline and several other metabolites.
• Excretion: urine 51-60%, feces 24-32%.
• Concurrent use with monoamine oxidase inhibitors or within 14 days of stopping an MAOI.
• Hypersensitivity to venlafaxine • Hypersensitivity to sertraline
• Concomitant use with pimozide
Side effects
• Venlafaxine is associated with the risk of blood pressure increase.
• Antidepressant-induced sexual dysfunction occurs more frequently with sertraline, than with venlafaxine 5.
Effects on body weight
Generally, venlafaxine is regarded as weight-neutral antidepressant7. Nevertheless both sertraline and venlafaxine may lead to significant weight gain.
• Discontinuation syndrome
Sertraline may be associated with a lower symptom burden during treatment discontinuation 6.
Pregnancy category

Venlafaxine vs Sertraline for Hot flashes

Hot flashes and night sweats are common vasomotor symptoms during the peri- and early post-menopausal period. Women have variable responses when treated with antidepressants for their hot flashes.

Venlafaxine is effective in reducing the frequency and severity of hot flashes8. Sertraline appears to be less effective and is considered as an acceptable alternative option.

Venlafaxine Extended-release dose: 75 mg per day.

Sertraline dose: 50 mg per day 9.

Venlafaxine vs Sertraline for Depression

Treatment with venlafaxine results in higher response and remission rates than treatment with sertraline in the major depressive disorder 1, 2.

Results of randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder 2. Venlafaxine XR Sertraline
Maximum study dosage
225 mg/day
150 mg/day
Final scores on the primary or secondary measures (Quality of Life Enjoyment and Satisfaction Questionnaire; 17-item Hamilton Rating Scale for Depression) No significant differences, both antidepressants led to significant improvement in depressive symptoms and quality-of-life measures
Responders percentage
Remitters percentage
Response rates in patients who achieved the maximum dose of drug and maintained it for 3 weeks
Remission rates in patients who achieved the maximum dose of drug and maintained it for 3 weeks

Results of randomized, double-blind comparison of venlafaxine and sertraline for major depressive disorder 1. Venlafaxine Sertraline
Mean HAM-D, MADRS, or CGI scores
No significant differences
HAM-D response rate at week 8
HAM-D score less than 10 at week 8
Remission rate (HAM-D score < 10) at week 8
Discontinuation rate
Most common adverse events nausea, headache, sweating nausea, headache, diarrhea


Bipolar depression

There is a significantly increased risk of switches into hypomania or mania with venlafaxine compared with sertraline treatment 3.

Effects on depression, cognition and daily living in Alzheimer patients

Sertraline may provide a superior effectiveness in relation to depressive, cognitive, and behavioral symptoms in Alzheimer patients than venlafaxine 4.

Further reading


  • 1. Mehtonen OP, Sogaard J, Roponen P, Behnke K. Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine 631 Study Group. J Clin Psychiatry. 2000 Feb;61(2):95-100 PubMed
  • 2. Shelton RC, Haman KL, Rapaport MH, Kiev A, Smith WT, Hirschfeld RM, Lydiard RB, Zajecka JM, Dunner DL. A randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder. J Clin Psychiatry. 2006 Nov;67(11):1674-81. PubMed
  • 3. Post RM, Altshuler LL, Leverich GS, Frye MA, Nolen WA, Kupka RW, Suppes T, McElroy S, Keck PE, Denicoff KD, Grunze H, Walden J, Kitchen CM, Mintz J. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006 Aug;189:124-31. PubMed
  • 4. Mokhber N, Abdollahian E, Soltanifar A, Samadi R, Saghebi A, Haghighi MB, Azarpazhooh A. Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. Pharmacopsychiatry. 2014 Jul;47(4-5):131-40. PubMed
  • 5. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry. 2000 Apr;61(4):276-81. PubMed
  • 6. Sir A, D'Souza RF, Uguz S, George T, Vahip S, Hopwood M, Martin AJ, Lam W, Burt T. Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. J Clin Psychiatry. 2005 Oct;66(10):1312-20. PubMed
  • 7. Uguz F, Sahingoz M, Gungor B, Aksoy F, Askin R.Weight gain and associated factors in patients using newer antidepressant drugs.Gen Hosp Psychiatry. 2015 Jan-Feb;37(1):46-8.
  • 8. Handley AP, Williams M.The efficacy and tolerability of SSRI/SNRIs in the treatment of vasomotor symptoms in menopausal women: a systematic review. J Am Assoc Nurse Pract. 2015 Jan;27(1):54-61.
  • 9. Kerwin JP, Gordon PR, Senf JH. The variable response of women with menopausal hot flashes when treated with sertraline. Menopause. 2007 Sep-Oct;14(5):841-5.

Published: February 14, 2018
Last updated: February 14, 2018


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