Fluoxetine (Prozac) versus ...

Fluoxetine (Prozac) appears to be the weakest of the SSRIs. Due to its very long half-life and relatively weak potency as a serotonin inhibitor fluoxetine has less prominent discontinuation symptoms than many other antidepressants.

Fluoxetine unique features led to that Prozac is the only SSRI approved by the FDA for use in children 8 years of age and older.

Fluoxetine (Prozac) vs. Citalopram (Celexa)

Major depressive disorder

Citalopram is as effective as fluoxetine in the treatment of major depression. In the study citalopram showed an earlier onset of recovery than fluoxetine 12.

Bulimia nervosa

In the study patients treated with fluoxetine achieved a greater reduction in introjected anger, whereas those treated with citalopram achieved a greater reduction in depression feelings. Citalopram may be useful in depressed patients with bulimia, whereas fluoxetine is more specific for those with introjected anger and bulimia 13.

Sexual side effects
Citalopram delays ejaculation more significantly than fluoxetine 27.

Fluoxetine (Prozac) vs. Paroxetine (Paxil)

Major depressive disorder

Paroxetine and fluoxetine have comparable efficacy in the treatment of depression. However, paroxetine has a significantly higher response rate than fluoxetine. Paroxetine appears to produce earlier antidepressant effect, improvement in agitation and anxiety symptoms 22, 23.

Side effects

Constipation, indigestion, tremor, sweating and abnormal ejaculation are more common with paroxetine, whereas nausea and nervousness are more frequent with fluoxetine. Weight loss is more common with fluoxetine 23.

Withdrawal symptoms

Discontinuation of paroxetine more often results in somatic and psychological symptoms than discontinuation of fluoxetine. Patients treated with fluoxetine appear to be protected by its longer half-life 1.

Fluoxetine (Prozac) vs. Sertraline (Zoloft)

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 17, 18.

Obsessive-compulsive disorder

Both medications are significantly 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 20.

Sertraline is considered to be better tolerated than fluoxetine 19.

Side effects:
Sertraline has advantages over fluoxetine on parameters such as sleep and weight disturbance in severely depressed patients, and sleep disturbance, weight, cognitive disturbance and retardation in melancholic patients 18.
Fluoxetine is associated with a higher incidence of agitation, anxiety and insomnia than sertraline 19.

Withdrawal syndrome:
Fluoxetine has fewer discontinuation-emergent events than sertraline 21.

Drug interactions:
Sertraline has significantly lower potential for drug interactions than fluoxetine.

Fluoxetine (Prozac) vs. Venlafaxine (Effexor)

Major depressive disorder

Venlafaxine appears to be superior to fluoxetine and produces higher rate of remission in the treatment for depression 24.

Venlafaxine therapy has superior remission rates in patients with severe anxiety and improves psychic anxiety better compared with fluoxetine. Superior efficacy of venlafaxine in depression may be attributed to early improvement in anxiety symptoms 25.

Results of comparative study of venlafaxine vs. fluoxetine in the treatment of depression and anxiety 12. Fluoxetine Venlafaxine
Dosage 20 mg per day for 12 weeks 75 mg per day for 12 weeks
Response rate at week 12
Sustained response (for at least 2 weeks) at the end of the study
Remission rate
Conclusion: Venlafaxine is significantly more effective than fluoxetine in improving depressive symptoms and concomitant anxiety.

Fluoxetine (Prozac) vs. Bupropion (Wellbutrin)


Onset of action -- no difference in speed of onset of action between bupropion and fluoxetine26.

Bupropion SR and fluoxetine are similarly effective and well tolerated in the treatment of depression. In clinical trials there were no statistically significant differences between both medications on any of the efficacy variables 15, 16.

Results of placebo-controlled comparison of bupropion sustained release and fluoxetine 15. Bupropion SR Fluoxetine
Dosage 150-400 mg per day 20 to 60 mg per day
Efficacy Similarly effective in the treatment of depressive symptoms.
Sexual side effects   Fluoxetine is more frequently associated with sexual dysfunction
Results of double-blind comparison of bupropion and fluoxetine for depression 16. Bupropion SR Fluoxetine
Dosage 225-450 mg per day 20-80 mg per day
50% or greater reduction in the HAM-D scores, number of patients, % 37 of 61 patients, 63% 35 of 62 patients, 58%
Much or very much improved number of patients, % 40 of 61 patients, 68% 35 of 62 patients, 58%
Prematurely discontinuation of treatment, number of patients 16 of 61 patients, 26% 18 of 62 patients, 29%

Premenstrual Dysphoric Disorder

Fluoxetine is significantly superior to bupropion in the treatment of premenstrual dysphoric disorder 14.

Results of placebo-controlled comparison of bupropion sustained release and fluoxetine 14. Bupropion Fluoxetine
Dosage 100 mg 3 times daily 20 mg daily
Efficacy Some improvement was noted. Fluoxetine was superior to bupropion. Patients satisfaction was far greater with fluoxetine.

Fluoxetine (Prozac) vs. Amitriptyline (Elavil)

Major depressive disorder
Both are effective in relieving the symptoms of depression 5. Recent memory can be improved significantly with the fluoxetine treatment 6.

Anxious depression
Fluoxetine and amitriptyline have comparable efficacy in the treatment of major depression with associated anxiety 3.

Fluoxetine and amitriptyline are similarly effective treatments for fibromyalgia, and they work better in combination than either medication alone 2.

Musculo-skeletal pain
In the study moderate or good pain relief was reported by 82% patients with amitriptyline, and by 77% patients with fluoxetine. Fluoxetine relieved low back pain and whiplash associated cervical pain as effectively as amitriptyline 4.

Migraine headache
Amitriptyline appears to be more effective than fluoxetine for migraine headache prophylaxis9.

Side effects
Adverse effects are more frequent and more severe with the amitriptyline 3. The most frequent side effects with fluoxetine are nausea, nervousness, sleep disturbances, and headaches; and dry mouth, dizziness, and drowsiness with amitriptyline 5, 6, 8. Weight gain is associated more with amitriptyline 7.

Fluoxetine (Prozac) vs. Mirtazapine (Remeron)

Major depressive disorder

Mirtazapine is significantly more effective than fluoxetine after 3 and 4 weeks of treatment in moderate to severe major depressive disorder 10, 11.

Side effects
Tolerability profiles are comparable except for changes in body weight. Mirtazapine is associated with significantly more pronounced body weight gain compared to the fluoxetine. In the study mirtazapine was associated with a mean weight gain of 0.8 +/- 2.7 kg, whereas fluoxetine was associated with a mean decrease in weight of 0.4 +/- 2.1 kg 10, 11.


Further reading
  • 1. Judge R, Parry MG, Quail D, Jacobson JG. Comparison of brief interruption of fluoxetine and paroxetine. Int Clin Psychopharmacol. 2002 Sep;17(5):217-25. PubMed
  • 2. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. Fluoxetine and amitriptyline in fibromyalgia. Arthritis Rheum. 1996 Nov;39(11):1852-9. PubMed
  • 3. Versiani M, Ontiveros A, Mazzotti G, Ospina J, Da'vila J, Mata S, Pacheco A, Plewes J, Tamura R, Palacios M. Fluoxetine versus amitriptyline in major depression with associated anxiety. Int Clin Psychopharmacol. 1999 Nov;14(6):321-7. PubMed
  • 4. Schreiber S, Vinokur S, Shavelzon V, Pick CG, Zahavi E, Shir Y. Fluoxetine versus amitriptyline in musculo-skeletal pain. Isr J Psychiatry Relat Sci. 2001;38(2):88-94. PubMed
  • 5. Feighner JP. A comparative trial of fluoxetine and amitriptyline in patients with major depressive disorder. J Clin Psychiatry. 1985 Sep;46(9):369-72. PubMed
  • 6. Keegan D, Bowen RC, Blackshaw S, Saleh S, Dayal N, Remillard F, Shrikhande S, Cebrian Perez S, Boulton A. A comparison of fluoxetine and amitriptyline in major depression. Int Clin Psychopharmacol. 1991 Summer;6(2):117-24. PubMed
  • 7. Altamura AC, De Novellis F, Guercetti G, Invernizzi G, Percudani M, Montgomery SA. Fluoxetine compared with amitriptyline in elderly depression. Int J Clin Pharmacol Res. 1989;9(6):391-6. PubMed
  • 8. Young JP, Coleman A, Lader MH. A controlled comparison of fluoxetine and amitriptyline in depressed out-patients. Br J Psychiatry. 1987 Sep;151:337-40. PubMed
  • 9. Amelin AV, Skoromets AA, Korenko LA, Tumelevich BCh, Gonchar MA. A comparative efficiency of amitriptyline, fluoxetine and maprotiline in prevention of migraine in attack-free period. Zh Nevrol Psikhiatr Im S S Korsakova. 2000;100(8):20-3. PubMed
  • 10. Versiani M, Moreno R, Ramakers-van Moorsel CJ, Schutte AJ. Comparison of mirtazapine and fluoxetine in severely depressed patients. CNS. 2005;19(2):137-46. PubMed
  • 11. Wheatley DP, van Moffaert M, Timmerman L, Kremer CM. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry. 1998 Jun;59(6):306-12. PubMed
  • 12. Patris M, Bouchard JM, Bougerol T, Charbonnier JF, Chevalier JF, Clerc G, Cyran C, Van Amerongen P, Lemming O, Hopfner Petersen HE. Citalopram versus fluoxetine: a double-blind, controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. Int Clin Psychopharmacol. 1996 Jun;11(2):129-36. PubMed
  • 13. Leombruni P, Amianto F, Delsedime N, Gramaglia C, Abbate-Daga G, Fassino S. Citalopram versus fluoxetine in bulimia nervosa: a single-blind randomized controlled trial. Adv Ther. 2006 May-Jun;23(3):481-94. PubMed
  • 14. Pearlstein TB, Stone AB, Lund SA, Scheft H, Zlotnick C, Brown WA. Comparison of fluoxetine, bupropion, and placebo in premenstrual dysphoric disorder. J Clin Psychopharmacol. 1997 Aug;17(4):261-6. PubMed
  • 15. Coleman CC, King BR, Bolden-Watson C, Book MJ, Segraves RT, Richard N, Ascher J, Batey S, Jamerson B, Metz A. A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine. Clin Ther. 2001 Jul;23(7):1040-58. PubMed
  • 16. Feighner JP, Gardner EA, Johnston JA, Batey SR, Khayrallah MA, Ascher JA, Lineberry CG. Double-blind comparison of bupropion and fluoxetine in depressed outpatients. J Clin Psychiatry. 1991 Aug;52(8):329-35. PubMed
  • 17. 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
  • 18. 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
  • 19. 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
  • 20. 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
  • 21. 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
  • 22. Geretsegger C, Bo"hmer F, Ludwig M. Paroxetine in the elderly depressed patient: randomized comparison with fluoxetine of efficacy, cognitive and behavioural effects. Int Clin Psychopharmacol. 1994 Spring;9(1):25-9. PubMed
  • 23. Chouinard G, Saxena B, Be'langer MC, Ravindran A, Bakish D, Beauclair L, Morris P, Vasavan Nair NP, Manchanda R, Reesal R, Remick R, O'Neill MC. A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder. J Affect Disord. 1999 Jul;54(1-2):39-48. PubMed
  • 24. Silverstone PH, Ravindran A. Venlafaxine extended release compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. J Clin Psychiatry. 1999 Jan;60(1):22-8. PubMed
  • 25. Rudolph RL, Feiger AD. A double-blind, randomized, placebo-controlled trial of venlafaxine extended release and fluoxetine for the treatment of depression. J Affect Disord. 1999 Dec;56(2-3):171-81. PubMed
  • 26. George MS, Lydiard RB. Speed of onset of action of the newer antidepressants--fluoxetine and bupropion. Int Clin Psychopharmacol. 1991 Winter;6(4):209-17.
  • 27. Madeo B, Bettica P, Milleri S, Balestrieri A, Granata AR, Carani C, Rochira V. The effects of citalopram and fluoxetine on sexual behavior in healthy men. J Sex Med. 2008 Oct;5(10):2431-41 PubMed
  • 28. De Nayer A, Geerts S, Ruelens L, Schittecatte M, De Bleeker E, Van Eeckhoutte I, Evrard JL, Linkowski P, Fossion P, Leyman S, Mignon A. Venlafaxine compared with fluoxetine in outpatients with depression and concomitant anxiety. Int J Neuropsychopharmacol. 2002 Jun;5(2):115-20. PubMed

Published: March 31, 2008
Last updated: May 20, 2017


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