Prozac (fluoxetine) vs Zoloft (sertraline)
Prozac and Zoloft, compared on what the public record actually supports: side effects by rate from each FDA label, what the largest trial comparison found, who takes each one, who pays, what the labels warn, and what the litigation record holds. Sources on every number.
the short answer
- is Prozac or Zoloft more effective? in the largest comparison of antidepressant trials (522 trials, 116,477 people, Lancet 2018), both beat placebo on response at about 8 weeks: fluoxetine odds ratio 1.52 (95% CrI 1.40 to 1.66), sertraline 1.67 (1.49 to 1.87). the authors called the differences between drugs mostly modest, with wide intervals.
- which has fewer side effects? the labels say their trials “cannot be directly compared”, because each drug was tested in different people under different rules. what each label prints: Prozac (fluoxetine): the label prints no discontinuation rate in the section we transcribed. Zoloft (sertraline): 12% stopped for an adverse reaction vs 4% on placebo (Zoloft label, Revised: 8/2023). the reactions both labels list, side by side, are in the table below. in the 2018 network, all-cause dropout against placebo was 0.88 for fluoxetine and 0.96 for sertraline.
- which should i take? not a question this page answers. the odds ratios are averages across thousands of strangers; your history, other medications and what you can live with are not in them. the questions for your prescriber below are built from what is on this page.
What this page will not do is rank them. For most same-class pairs, head-to-head efficacy differences are smaller than the rankings look — the largest network meta-analysis ever run (21 antidepressants, 522 trials) found every drug beat placebo and the gaps between drugs mostly modest and uncertain. Which one fits you turns on your history, your other medications, and side-effect trade-offs — a prescriber conversation. This page arms that conversation; here are the questions worth taking into it →
what the 522-trial comparison found for fluoxetine and sertraline
the 2018 Lancet network meta-analysis pooled 522 trials comprising 116 477 participants, the median duration of the acute treatment was 8 weeks (iqr 6–8), and compared 21 antidepressants against placebo and against each other on two outcomes: response (at least a 50% fall on the depression scale) and all-cause dropout, its stand-in for acceptability. odds ratios are against placebo. an odds ratio above 1 on response favours the drug; below 1 on dropout means fewer people stopped than on placebo.
| drug | response vs placebo, OR (95% CrI) | dropout vs placebo, OR (95% CrI) |
|---|---|---|
| Prozac (fluoxetine) | 1.52 (1.40 to 1.66) | 0.88 (0.80 to 0.96), fewer dropouts than placebo |
| Zoloft (sertraline) | 1.67 (1.49 to 1.87) | 0.96 (0.85 to 1.08) |
- fluoxetine: among the least efficacious in head-to-head trials; among the more tolerable (fewer dropouts) in head-to-head trials.
- sertraline: among the more tolerable (fewer dropouts) in head-to-head trials.
the other direction, in the authors' words. “the certainty of evidence was moderate to very low”; “The random-effects summary SMD for all antidepressants was 0·30 (95% CrI 0·26–0·34)”, a modest average effect; “positive results need to be taken with great caution, because the trials in this network meta-analysis were of short duration”. 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low. 409 (78%) of 522 studies were funded by pharmaceutical companies. the trials excluded people with psychotic, treatment-resistant or bipolar depression, and the paper says it cannot guide the next choice after a first drug fails. a difference between two odds ratios in the table above is not a difference between the drugs unless the direct comparison shows one.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; doi:10.1016/S0140-6736(17)32802-7. funding of the analysis: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science. The funder of this study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. read 2026-10-11 at PMC.
side effects by rate: what each label prints, not a head-to-head trial
the labels' own warning, first: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.” the two columns below come from different trials, in different people, under different inclusion rules. read each against its own placebo column, not against the other drug.
| reaction | PROZAC (N=2869) vs Placebo (N=1673) | ZOLOFT (N=3066) vs Placebo (N=2293) |
|---|---|---|
| nausea | 22% vs 9% | 26% vs 12% |
| dry mouth | 9% vs 6% | 14% vs 9% |
| diarrhea | 11% vs 7% | 20% vs 10% |
| constipation | 5% vs 4% | 6% vs 4% |
| insomnia | 19% vs 10% | 20% vs 13% |
| somnolence | 12% vs 5% | 11% vs 6% |
| dizziness | 9% vs 6% | 12% vs 8% |
| tremor | 9% vs 2% | 9% vs 2% |
| sweating | 7% vs 3% | 7% vs 3% |
| decreased appetite | 10% vs 3% | 7% vs 2% |
| vomiting | 3% vs 2% | 4% vs 1% |
| dyspepsia | 8% vs 4% | 8% vs 4% |
| libido decreased | 4% vs 1% | 6% vs 2% |
- Prozac (fluoxetine): the label prints no discontinuation rate in the section we transcribed.
- Zoloft (sertraline): 12% stopped for an adverse reaction vs 4% on placebo (Zoloft label, Revised: 8/2023).
what makes each table, in the labels' words
- Prozac (fluoxetine), SPL effective 2026-01-08 (the PI carries no printed 'Revised:' footer; only the attached Medication Guide is dated, revised August, 2023), 6 ADVERSE REACTIONS / 6.1 Clinical Trials Experience. inclusion rule: “...treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials.” trials: “Multiple doses of PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC in panic clinical trials. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials).” DailyMed
- Zoloft (sertraline), Revised: 8/2023, 6 ADVERSE REACTIONS / 6.1 Clinical Trials Experience. inclusion rule: “Adverse reactions that occurred greater than 2% in ZOLOFT-treated patients and at least 2% greater in ZOLOFT-treated patients than placebo-treated patients.” trials: “The data described below are from randomized, double-blind, placebo-controlled trials of ZOLOFT (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to ZOLOFT for 8 to12 weeks [sic — spacing as printed] represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males.” DailyMed
every row above was transcribed from the current FDA label on 2026-09-08; the full tables, including the reactions only one label lists, are on side-effect rates, drug vs placebo. the sexual side-effect rows carry each label's own underreporting caveat on the SSRI sexual side effects page.
fluoxetine (Prozac)
SSRI antidepressant
- FDA approval
- 1987 · full approval journey →
- Who takes it (US, 2024)
- 6,177,252 patients · 29,517,276 prescriptions (AHRQ MEPS)2014 → 2024: 23,867,189 → 29,517,276 prescriptions; the change is within the survey’s margin of errorCorrection (29 September 2026): An earlier version of this section took its numbers from ClinCalc DrugStats, a third-party site that republishes this survey; we now compute them from AHRQ’s public-use files ourselves. It said prescriptions were up 24% since 2014; that change is within the survey’s margin of error, so we no longer state a direction.
- Who pays (2024)
- Medicare: 7,496,788 claims · 1,487,371 beneficiariesMedicaid: ≥6,359,320 prescriptionsCommercial claims: not published in any public dataset — a real absence, not a zero.
- Boxed warning
- Yes — on the current FDA label. read it in context →
- Adverse-event reports (FAERS)
- Caveat first: FAERS counts unverified REPORTS, not patients or rates — no denominator, and attention inflates reporting. Never compare these counts head-to-head; a longer-marketed, more-prescribed drug accumulates more reports by exposure alone. how to read FAERS →131,850 all-time reports; most-reported terms: drug ineffective, nausea, fatigue
- Legal & safety record
- the full litigation & recall record →
sertraline (Zoloft)
SSRI antidepressant
- FDA approval
- 1991 · full approval journey →
- Who takes it (US, 2024)
- 10,233,569 patients · 44,634,056 prescriptions (AHRQ MEPS)2014 → 2024: 37,723,879 → 44,634,056 prescriptions; the change is within the survey’s margin of errorCorrection (29 September 2026): An earlier version of this section took its numbers from ClinCalc DrugStats, a third-party site that republishes this survey; we now compute them from AHRQ’s public-use files ourselves. It said prescriptions were up 18% since 2014; that change is within the survey’s margin of error, so we no longer state a direction.
- Who pays (2024)
- Medicare: 16,155,695 claims · 3,200,756 beneficiariesMedicaid: ≥9,178,192 prescriptionsCommercial claims: not published in any public dataset — a real absence, not a zero.
- Boxed warning
- Yes — on the current FDA label. read it in context →
- Adverse-event reports (FAERS)
- Caveat first: FAERS counts unverified REPORTS, not patients or rates — no denominator, and attention inflates reporting. Never compare these counts head-to-head; a longer-marketed, more-prescribed drug accumulates more reports by exposure alone. how to read FAERS →218,320 all-time reports; most-reported terms: nausea, drug ineffective, fatigue
- Legal & safety record
- the full litigation & recall record →
questions for your prescriber, built from this page
this page does not tell you to start, stop or switch anything. it arms the conversation where that decision belongs. take these in:
- which of Prozac and Zoloft did you have in mind first, and what in my history points that way?
- the trials put these two close together on average. what, for me specifically, breaks the tie: another medication i take, a side effect i can't live with, sleep, weight, sexual function?
- the label lists these reactions above placebo for the one you're suggesting. which of them should i expect in the first weeks, and which would make you want to hear from me the same day?
- how long were the approval trials, and what do we know past that point?
- how will we judge whether it is working, by when, and what is the plan if it isn't?
- if i ever want to come off it, how is that done, and over how long?
- is there a cheaper generic or a formulation that changes the dosing, and does my insurance prefer one of these two?
the longer checklist, for any antidepressant, is questions to ask before starting antidepressants. if you are already on one and it feels like it stopped working, that has its own page.
What the warnings mean, drug by drug
Each explainer reads one drug's current FDA label and the studies in our library, in both directions: the boxed warnings with the label's own numbers, the trials behind the approval and how long they ran, side effects by rate, and the research since.
Questions people search
Is Prozac or Zoloft better?
No honest page can answer that in one line. Head-to-head differences between comparable psychiatric medications are usually smaller than rankings suggest, and which fits you depends on your history, other medications, and side-effect trade-offs, a prescriber conversation. What can be compared is the public record (usage, payers, label warnings, approval history, litigation), which is what this page does, with sources.
Is Prozac the same as fluoxetine, and Zoloft the same as sertraline?
Prozac is a brand name for fluoxetine. Zoloft is a brand name for sertraline. fluoxetine is a SSRI antidepressant; sertraline is a SSRI antidepressant. This page uses the generic names because the federal datasets do.
Which has fewer side effects, Prozac or Zoloft?
The two FDA labels cannot be compared head to head, in their own words, because each drug's trials ran in different people under different rules. What each label prints: Prozac (fluoxetine): the label prints no discontinuation rate in the section we transcribed. Zoloft (sertraline): 12% stopped for an adverse reaction vs 4% on placebo (Zoloft label, Revised: 8/2023). The page shows the reactions both labels list, each against its own placebo column. In the 2018 Lancet network meta-analysis, all-cause dropout against placebo was 0.88 for fluoxetine and 0.96 for sertraline.
Is Prozac or Zoloft more effective for depression?
In the 2018 Lancet network meta-analysis of 522 trials and 116,477 adults with major depressive disorder, both beat placebo on response at about 8 weeks: fluoxetine odds ratio 1.52 (95% CrI 1.40 to 1.66), sertraline 1.67 (1.49 to 1.87). The authors described the differences between drugs as mostly modest, with wide intervals. The certainty of evidence was moderate to very low, 78% of the trials were industry funded, and the pooled effect of all antidepressants against placebo was a standardised mean difference of 0.30. None of that says which one fits you.
Which is prescribed more, Prozac or Zoloft?
The page shows federal survey estimates we compute from AHRQ’s Medical Expenditure Panel Survey public-use files for both fluoxetine and sertraline: patients and prescriptions in the latest reliable year, and the yearly series from 2014 where AHRQ’s reliability rule allows it, with a direction stated only when the change is larger than the survey’s margin of error. Prescription volume reflects habits, prices, and marketing as much as evidence, so it is context, not a verdict.
Where these numbers come from
- Patients and prescriptions: computed by us from AHRQ's public-use Medical Expenditure Panel Survey Prescribed Medicines files, 2014 (HC-168A) to 2024 (HC-254A), with AHRQ's reliability rule (a year with fewer than 60 respondents or a relative standard error over 50% is not shown) — counts of people filling prescriptions, not outcomes. A direction is stated only when the change is larger than the survey's margin of error. Until 29 September 2026 these came from ClinCalc DrugStats, a third-party site; see the correction under each drug where a figure changed.
- Medicare/Medicaid: CMS public datasets; commercial insurance publishes no per-drug series, so it renders as an absence, never a synthesized number.
- Label facts: the drugs' current FDA labels via DailyMed — quoted in context on each drug's approval-journey page.
- FAERS: openFDA — reports, never rates; the caveat travels above every count.
- Litigation: court records and regulator documents only, on the linked record pages; settled is never adjudicated.
Explore both drugs in depth: /m/fluoxetine · /m/sertraline · or the whole library →