Sertraline (Zoloft®) vs Fluoxetine (Prozac®)

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

Sertraline advantages over Fluoxetine

  • In relation to use of sertraline and flouxetine during breastfeeding - sertraline is a preferrable option. There were no reported short term side effects in infants and sertraline plasma level is undetectable1. Fluxetine, on the other hand, produces one of the highest pasma levels in infants among newer antidepressants and may cause side effects.
  • Fluoxetine has a higher risk of CYP-mediated drug interactions than sertraline. Sertraline has a relatively low potential to interfere with CYP isoenzymes and is therefore a good choice for persons taking multiple medications.
  • Sertraline mildly inhibits dopamine reuptake and this property may help with cognitive and emotional flattening.
  • Tolerability. Sertraline is considered to be better tolerated than fluoxetine 10.

Fluoxetine advantages over Sertraline

  • Sertraline has been studied less extensively than fluoxetine in the treatment of eating disorders.
  • Fluoxetine produces less gastrointestinal side effects, such as nausea and diarrhea, than does sertraline.
  • Fluoxetine is available in once weekly formulation. A weekly dosing regimen is suitable for persons who have difficulty remembering their daily doses.
  • Fluoxetine has a lower risk of weight gain.
  • Due to its very long half-life and relatively weak potency as a serotonin inhibitor, fluoxetine has less prominent discontinuation symptoms than sertraline
  • Prozac® is the only SSRI approved by the FDA for use in children 8 years of age and older.


Sertraline Fluoxetine
Brand names
• Zoloft® • Prozac®
• Serafem®
zoloft pills prozac pills
Drug class
Selective Serotonin Reuptake Inhibitor
Dose formulations
• Tablets
• Oral concentrate
• Capsules
• Tablets
• Capsules, delayed-release
• Solution, oral
Legal status
• Rx only
• Not a controlled drug
FDA-approved indications
• Depression
• Obsessive-compulsive disorder
• Panic attacks
• Premenstrual dysphoric disorder
• Post-traumatic stress disorder
• Social anxiety (social phobia)
• Bulimia nervosa
"Off-label" uses
• General anxiety disorder
• Binge Eating Disorder
• Seasonal affective disorder
• Postpartum depression
• Somatoform disorders 2
• Social anxiety
• Anorexia
Mechanism of action
• Selectively inhibit reabsorption (reuptake) of neurotransmitter serotonin in the brain.
• Sertraline has mild dopamine stimulating effects, and increases neurotransmission of dopamine. Of the SSRIs, sertraline is the most potent inhibitor of dopamine reuptake transporter.
• Fluoxetine weakly blocks the reuptake of norepinephrine. This property accounts for the stimulating effects of fluoxetine.
• 26 hours • 1-3 days (after a single dose)
• 4-6 days (long-term use)
• Half-life of active metabolite norfluoxetine is 96–364 hours
Oral bioavailability
• 20-36% • 60–80%
Metabolism, Elimination
• 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%.
• Main active metabolite of fluoxetine is norfluoxetine.
• Fluoxetine is metabolized in the liver by hepatic enzyme CYP2D6 to its active metabolite.
• Eliminated in urine (18%), small amounts in feces.
• Complete elimination of fluoxetine takes 4 to 6 weeks after its discontinuation
• Use of MAO inhibitors
• Hypersensitivity to sertraline
• Concomitant use with pimozide
• Hypersensitivity to fluoxetine
Side effects
• Weight gain
Fluoxetine is usually associated with weight loss during initial period of treatment. Long-term use of fluoxetine may lead to weight gain.
• Sertraline usually causes modest weight gain13. However, substantial increase in body weight is possible 14.
Sexual side effects
Fluoxetine produces more adverse effects on sexual function than sertraline15.
Both drugs may cause:
• impairment in sexual desire
• orgasm difficulties
• impairment in arousal
• problems to obtain or maintain an erection
• Withdrawal syndrome
Fluoxetine has fewer discontinuation-emergent events than sertraline 11.
• Fluoxetine is associated with a higher incidence of agitation, anxiety and insomnia than sertraline 10.


Sertraline vs Fluoxetine for Anxiety

Zoloft® has a wider range of licensed indications for anxiety disorders.

General anxiety disorder (GAD)

Both fluoxetine and sertraline are used in the treatment of generalized anxiety disorder despite the lack of strong evidence. SSRIs improve the psychic and somatic anxiety symptoms of generalized anxiety. Fluoxetine may be superior to sertraline in terms of response and remission5.

There is evidence that both SSRIs are safe and effective for the treatment of GAD in children and adolescents3, 4.

Social anxiety

Sertraline is FDA-approved for social phobia, while fluoxetine is used for this mental condition "off-label".

Sertraline reduces fear, avoidance, physiological arousal, blushing, and palpitations6.

Fluoxetine may alleviate symptoms of social anxiety such as social distress and behavioral avoidance7.

Sertraline vs Fluoxetine for Major depression

Sertraline and fluoxetine have comparable antidepressant efficacy in the treatment of Major depression. However, sertraline has advantages over fluoxetine in patients with severe depression or those with melancholia and low anxiety 8, 9.

Sertraline is better than fluoxetine for improving sleep and weight disturbance in severely depressed patients, and sleep problems, weight, cognitive impairment and mental retardation in melancholic patients 9.

Sertraline vs Fluoxetine for Premenstrual Dysphoric Disorder

Both SSRIs are indicated for the management of premenstrual dysphoric disorder (PMDD). These antidepressants reduce symptoms of anger, tension, irritability, fatigue, dysphoria, mood swings, depressed feelings, and improve psychosocial functioning and quality of life.

Zoloft® dosage for PMDD: 50 mg/day on daily basis throughout the menstrual cycle or only during the luteal phase of the cycle (daily dose is started 14 days prior to the onset of menstruation through the first full day of menses). Maximum sertraline dose should not exceed 150 mg per day.

Serafem® dosage for PMDD: 20 mg/day on daily basis throughout the menstrual cycle or only during the luteal phase of the cycle (daily dose is started 14 days prior to the onset of menstruation through the first full day of menses). The maximum fluoxetine dose should not exceed 80 mg per day.

Sertraline vs Fluoxetine for Obsessive-compulsive disorder

Both medications are very effective in the treatment of moderate to severe OCD. However, patients treated with sertraline have a greater likelihood of remission as well as an earlier improvement 12.

Further reading


  • 1. Berle JO, Spigset O. Antidepressant Use During Breastfeeding. Curr Womens Health Rev. 2011 Feb;7(1):28-34.
  • 2. Han C, Pae CU, Lee BH, Ko YH, Masand PS, Patkar AA, Jung IK. Fluoxetine versus sertraline in the treatment of patients with undifferentiated somatoform disorder: a randomized, open-label, 12-week, parallel-group trial. ProgNeuropsychopharmacolBiol P sychiatry. 2008 Feb 15;32(2):437-44
  • 3. Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003 Apr;42(4):415-23.
  • 4. Keeton CP, Kolos AC, Walkup JT. Pediatric generalized anxiety disorder: epidemiology, diagnosis, and management. Paediatr Drugs. 2009;11(3):171-83.
  • 5. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ. 2011 Mar 11;342:d1199.
  • 6. Connor KM, Davidson JR, Chung H, Yang R, Clary CM. Multidimensional effects of sertraline in social anxiety disorder. Depress Anxiety. 2006;23(1):6-10.
  • 7. Beidel DC, Turner SM, Sallee FR, Ammerman RT, Crosby LA, Pathak S. SET-C versus fluoxetine in the treatment of childhood social phobia. J Am Acad Child Adolesc Psychiatry. 2007 Dec;46(12):1622-32.
  • 8. Feiger AD, Flament MF, Boyer P, Gillespie JA. Sertraline versus fluoxetine in major depression: a combined analysis of five double-blind comparator studies. Int Clin Psychopharmacol. 2003 Jul;18(4):203-10. PubMed
  • 9. Flament MF, Lane RM, Zhu R, Ying Z. Predictors of an acute antidepressant response to fluoxetine and sertraline. Int Clin Psychopharmacol. 1999 Sep;14(5):259-75. PubMed
  • 10. Aguglia E, Casacchia M, Cassano GB, Faravelli C, Ferrari G, Giordano P, Pancheri P, Ravizza L, Trabucchi M, Bolino F, et al. Sertraline versus fluoxetine in major depression. Int Clin Psychopharmacol. 1993 Fall;8(3):197-202. PubMed
  • 11. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. SSRI discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998 Jul 15;44(2):77-87. PubMed
  • 12. Bergeron R, Ravindran AV, Chaput Y, Goldner E, Swinson R, van Ameringen MA, Austin C, Hadrava V. Sertraline and fluoxetine in obsessive-compulsive disorder: results of a double-blind, 6-month study. J Clin Psychopharmacol. 2002 Apr;22(2):148-54. PubMed
  • 13. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry. 2000 Nov;61(11):863-7. PubMed
  • 14. 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. PubMed
  • 15. Khazaie H, Rezaie L, Rezaei Payam N, Najafi F. Antidepressant-induced sexual dysfunction during treatment with fluoxetine, sertraline and trazodone. Gen Hosp Psychiatry. 2015 Jan-Feb;37(1):40-5

Published: January 27, 2018
Last reviewed: February 05, 2018


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