Medication approval journey
duloxetine (Cymbalta)
Approved for Major depressive disorder in adults
Before changing anything
Stopping abruptly causes withdrawal effects that can be severe
SNRIs — venlafaxine especially — are associated with some of the most difficult withdrawal of any antidepressant, partly because of their short half-life. Do not skip doses or stop abruptly. Any change should be a slow, prescriber-supervised taper.
How long the trials actually ran
The longest trial behind the duloxetine approval ran 9 weeks.
The gap between how long the trials ran and how long people actually take these medications is the single most important thing on this page. It is not evidence that longer use is unsafe or ineffective. It is evidence that longer use was not what got tested.
The boxed warning
The strongest warning the FDA puts on a label, reproduced word for word — not our summary of it.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1) ] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1) ] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants ( 5.1 ) Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.1 )
FDA label effective August 20, 2026 — read the full label on DailyMed
How many Americans take duloxetine
Survey-based federal estimates, published with a lag of about two years. They count prescriptions filled, not outcomes.
- 17,860,263
- prescriptions in the United States (2024)
- 4,071,231
- people filling them (2024)
Prescriptions are up 19% since 2014. Whatever you decide about duloxetine, you are deciding alongside about 4,071,231 other people this year.
Source: ClinCalc DrugStats (Medical Expenditure Panel Survey (MEPS), Agency for Healthcare Research and Quality), CC BY-SA 4.0, release 2026.08.
What people report to the FDA about duloxetine
Read this before the numbers.
Anyone can file an adverse event report — patients, doctors, manufacturers — and nobody verifies that the drug caused what was reported. There is no denominator: tens of millions of prescriptions generate reports at an unknowable rate, and reporting rises with news coverage, not necessarily with harm. Counts below are report volumes, not rates, and cannot be compared between drugs. The FDA itself says not to use this data to make medical decisions — we show it because you deserve to see what is in the public record, with its limits stated plainly.
- 186,798
- reports mentioning duloxetine, all time
- 115,020
- filed as serious (a report-level flag covering every drug and outcome in the report)
Most-reported reactions
- Nausea17,925
- Fatigue15,979
- Drug ineffective14,131
- Headache13,688
- Dizziness13,379
- Pain12,377
- Diarrhoea10,017
- Off label use9,952
- Insomnia9,797
- Anxiety9,678
“Drug ineffective” ranking this high is worth noticing: a report of not being helped counts as an adverse event too, and people file them in large numbers.
Source: FDA Adverse Event Reporting System (FAERS), via openFDA, data through 2026-07-30.
Known interactions, from the label
The FDA label’s interactions section, verbatim. A pharmacist checking your actual medication list beats any published list — including this one.
Read the label’s interactions section
7 DRUG INTERACTIONS Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potent inhibitors of CYP1A2 should be avoided ( 7.1 ) Potent inhibitors of CYP2D6 may increase Duloxetine delayed-release capsules concentrations ( 7.2 ) Duloxetine delayed-release capsules is a moderate inhibitor of CYP2D6 ( 7.9 )
7.1 Inhibitors of CYP1A2 When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C max was increased about 2.5-fold, and duloxetine t 1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.12) ].
7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions (5.12) ].
7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and C max.
7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with Duloxetine delayed-release capsules 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC τ,ss , C max,ss or t max,ss ) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when Duloxetine delayed-release capsules are initiated or discontinued [see Warnings and Precautions (5.5) ].
7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.
7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.
7.7 Drugs that Affect Gastric Acidity Duloxetine delayed-release capsules have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine delayed-release capsules in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co- administration of Duloxetine delayed-release capsules with aluminum- and magnesium-containing antacids (51 mEq) or Duloxetine delayed-release capsules with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions (5.14) ].
7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).
7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions (5.12) ].
7.10 Drugs Metabolized by CYP2C9 Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions (7.4) ].
7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.
7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.
7.13 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.9 , 2.10) , Contraindications (4) , and Warnings and Precautions (5.4) ].
7.14 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with Duloxetine delayed-release capsules increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Duloxetine delayed-release capsules and/or concomitant serotonergic drugs [see Warnings and Precautions (5.4) ].
7.15 Alcohol When Duloxetine delayed-release capsules and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloxetine delayed-release capsules did not increase the impairment of mental and motor skills caused by alcohol. In the Duloxetine delayed-release capsules clinical trials database, three Duloxetine delayed-release capsules-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions (5.2 , 5.12) ].
7.16 CNS Drugs [See Warnings and Precautions (5.12) ].
7.17 Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of Duloxetine delayed-release capsules to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions (7.4) ].
FDA label for duloxetine, effective August 20, 2026 — DailyMed.
Who pays for duloxetine
Two claims datasets and one survey, covering different populations with different instruments — they cannot be reconciled by arithmetic, and where their sum crowds the all-payer estimate, that is a finding about the estimates rather than a percentage.
- Medicare Part D
- Read the under-65 group correctly before the numbers: Medicare before 65 means the disabled and dual-eligible population — among the sickest, highest-need people in the program — and reading their utilization as typical adult use would be a category error. The beneficiary total sums brand-level rows, so treat it as an upper bound on distinct people. 2,663,949 beneficiaries filled 13,119,838 claims in 2024 — 2,084,537 aged 65 and over, and 579,412 under 65.
- Medicaid
- At least 4,452,576 prescriptions in 2024 — a floor, because 157 of 848 national data rows are suppressed for privacy and contribute zero. Medicaid covers more children than any insurer in the country and publishes no age split — how much of this number is pediatric use is not knowable from public data.
- All payers (survey estimate)
- The MEPS-based estimate above puts the whole country at 17,860,263 prescriptions and 4,071,231 people in 2024. Subtracting the public programs from it would produce a number for everyone else — and we do not print that number, because subtracting a survey from claims counts manufactures precision that does not exist.
- The population nobody counts
- The commercially insured working-age adult — statistically, the likeliest person to be reading this page — is the one population with no public per-drug count anywhere. Private claims data exists and is sold, but nothing a patient can check is published. For children the record is thinner still: no public source counts pediatric use of duloxetine specifically; the closest the public record comes is condition-level treatment rates for children, which we have traced for one condition in how childhood ADHD got counted.
Sources: Medicare Part D Prescribers — by Geography and Drug, data.cms.gov, National rows, data year 2024 (published with ~17-month lag). Medicaid State Drug Utilization Data 2024, data.medicaid.gov, national aggregate rows. Retrieved 2026-09-01.
The approval, step by step
Step 1
What the approval was actually based on
Which studies did the FDA rely on, how long did they run, and who was in them?
The efficacy of CYMBALTA as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD: In Studies MDD-1 and MDD-2, patients were randomized to CYMBALTA 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks In Study MDD-3, patients were randomized to CYMBALTA 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks
FDA-approved labelling, 14 CLINICAL STUDIES 14.2 Major Depressive Disorder in Adults — read the label on DailyMed
Our reading
Four trials of eight to nine weeks, with individual arms in the range of 86 to 139 people. The trials are small, short and numerous, which is the standard shape of an antidepressant registration package. What is unusual about duloxetine is the number of separate indications stacked onto the same molecule afterwards — anxiety, diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain — each with its own trials that are not these trials. If you were prescribed it for pain, the depression evidence is not your evidence.
Step 2
The approval
When was it approved, under what application, and by whose review?
- Approved
- August 3, 2004
- Application
- NDA021427
- Review
- STANDARD
- Original sponsor
- Eli Lilly and Company
- Holds it now
- Eli Lilly and Company
- Label submissions since
- 38
Source: openFDA Drugs@FDA, original application ORIG-1
Step 3
What was added after it was on the market
Which warnings arrived only after millions of people were already taking it?
PRAC recommendations on signals adopted at the 13-16 May 2019 PRAC meeting, section 1.3: SNRIs and SSRIs - persistent…
15 years after approval
On 16 May 2019 the EU drug regulator's safety committee ordered every manufacturer of citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, desvenlafaxine, and milnacipran to add this warning within two months: "There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI." The patient leaflet wording is "In some cases, these symptoms have continued after stopping treatment." This is a regulator acting on case reports and pharmacovigilance data, not a prevalence study — how often it happens is still unknown, and that uncertainty cuts both ways.
Worth asking
European regulators require a label warning that sexual side effects can persist after stopping an SSRI or SNRI — how would you and I tell that apart from the depression itself if it happened to me?
The antidepressant suicidality warning has an age ceiling most people never hear about
Antidepressants carry a boxed warning about suicidal thoughts and behaviour in children, adolescents and young adults. It came from pooling 24 short-term placebo-controlled trials of nine antidepressants in more than 4,400 young patients: suicidality was reported in about 4% on drug against 2% on placebo. There were no completed suicides in those trials.
The part that usually gets lost is the age boundary, which is in the label itself. The studies did not show an increased risk above age 24, and in patients 65 and older the risk went in the other direction — it was reduced. The warning is real and it is specific, not a blanket statement about everyone who takes one.
Worth asking
Given my age, which side of that line am I on, what specifically should I or the people around me watch for in the first two months, and who do I call if it happens.
Step 4
What independent research has found since
What has been learned by people who were not selling it?
Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major…
14 years after approval
In 522 trials covering 116,477 adults with major depression, duloxetine — like all 21 antidepressants studied — beat placebo for response (drug odds ratios ranged 1.37 to 2.13), but in head-to-head comparisons duloxetine was among the seven drugs with the highest dropout rates (odds ratios 1.30 to 2.32).
Worth asking
Worth asking your prescriber how duloxetine's tolerability compares with antidepressants that had lower dropout rates in this analysis (such as escitalopram or sertraline) if side effects are making it hard to stay on.
Antidepressants for pain management in adults with chronic pain: a network meta-analysis
19 years after approval
Across 176 trials with 28,664 adults with chronic pain, standard-dose duloxetine (60 mg) was the highest-ranked antidepressant, roughly doubling the odds of substantial (50% or greater) pain relief versus placebo (odds ratio 1.91, 95% CI 1.69 to 2.17, moderate-certainty evidence), and higher doses were no better than 60 mg for most outcomes.
Worth asking
Worth asking your prescriber whether 60 mg is sufficient if a dose increase is being considered for pain, since higher duloxetine doses showed no added benefit in this analysis.
Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical…
13 years after approval
In 4 placebo-controlled trials (1,913 women) of duloxetine for stress urinary incontinence — a European approval, not a US one — 1 in 8 rated themselves much or very much better (NNT 8, 95% CI 6 to 13), but 1 in 7 stopped treatment because of adverse events (NNH 7, 95% CI 6 to 8) and 1 in 7 experienced activation-type events the authors linked to potential suicidality risk (NNH 7, 95% CI 6 to 9).
Worth asking
Worth asking your prescriber to walk through early warning signs of agitation or activation when starting duloxetine, since this analysis found such events were about as common as the benefit.
Withdrawal from these medications can take months, and NICE says so
18 years after approval
NICE guideline NG215 covers safe prescribing and managed withdrawal for five groups of medication: opioids, benzodiazepines, gabapentinoids, Z-drugs and antidepressants. It is the closest thing there is to an official answer on how coming off actually goes.
It states that withdrawal can be difficult and may take several months or more, that symptoms vary widely in type and severity, that they affect both physical and mental health, and that they can be delayed in onset and can persist. Two recommendations are worth quoting to a prescriber. Do not stop a medicine abruptly except in exceptional medical circumstances. And taper using a slow, stepwise reduction proportionate to the current dose, so the decrements get smaller as the dose gets lower — not a fixed cut each time.
That last detail is the one most commonly missed. Gabapentinoids are the exception in the guideline and are reduced by a fixed amount at each step.
Worth asking
Can we write the taper down, what size are the steps near the end, and how long do I hold at each step before the next reduction.
In 2019 the Royal College of Psychiatrists changed its position on withdrawal
15 years after approval
For years people reporting long, severe antidepressant withdrawal were told it lasted a week or two. In May 2019 the Royal College of Psychiatrists published a position statement conceding the point: while withdrawal symptoms are often mild and self-limiting, there is substantial variation, and for some patients symptoms last much longer and are more severe.
It went further and asked for changes — that guidelines and patient information recognise the potential for severe and long-lasting withdrawal, that pharmacologically-informed tapering guidance be developed, that discontinuation be tapered at a rate the patient can tolerate over potentially several months, and that clinicians actively work to tell withdrawal apart from relapse.
One thing it explicitly does not say, and it is worth being accurate about: the College states that from a clinical perspective antidepressant use is not associated with dependence in the addiction sense. Withdrawal and dependence are not the same claim.
Worth asking
If I feel bad three weeks after a dose reduction, how will we decide whether that is withdrawal or my depression returning, and what do we do differently in each case.
Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia
10 years after approval
In 18 trials with 6,407 participants, duloxetine 60 mg daily achieved 50% or greater pain reduction more often than placebo in diabetic peripheral neuropathy (risk ratio 1.73, 95% CI 1.44 to 2.08; NNT 5) and fibromyalgia (risk ratio 1.57, 95% CI 1.20 to 2.06; NNT 8), while about 1 in 6 people stopped because of side effects; 20 mg daily did not work.
Worth asking
Worth asking your prescriber whether your dose is at the 60 mg level shown to help nerve pain and fibromyalgia, since the 20 mg dose was not effective in these trials.
Duloxetine versus other anti-depressive agents for depression
8 years after approval
Across 16 randomised trials with 5,735 participants, duloxetine was no more effective for depression than other antidepressants (for example, odds ratio 1.31, 95% CI 0.87 to 1.97 versus escitalopram), and more people stopped taking it than stopped escitalopram (odds ratio 1.62, 95% CI 1.01 to 2.62) or venlafaxine (odds ratio 1.56, 95% CI 1.14 to 2.15).
Worth asking
Worth asking your prescriber what duloxetine offers in your specific situation over alternatives that were easier to stay on in these trials, such as escitalopram.
Duloxetine versus other anti-depressive agents for depression — Cipriani A, et al. (2012)
Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis.
5 years after approval
When sexual function is actually asked about with a questionnaire rather than waited for as a spontaneous complaint, treatment-emergent sexual dysfunction ranged from 25.8% to 80.3% of patients across antidepressants, all significantly above placebo. In descending order of impact the drugs were sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine. Agomelatine, amineptine, bupropion, moclobemide, mirtazapine, and nefazodone showed no significant difference from placebo.
Worth asking
Where does the antidepressant I'm on sit on the sexual side-effect ranking, and is there a drug with a lower rate that would still treat my condition?
Step 5
What still is not known
Which questions you might reasonably have has nobody answered yet?
- Nine weeks at the longest. Duloxetine is commonly taken for years.
- Which indication were you prescribed it for, and did you read the trials for that indication or for depression?
- Discontinuation symptoms are common and the label acknowledges them. Is there a taper plan?
The legal and safety record
Settled and adjudicated matters only, from primary sources — including the litigation that was decided for the manufacturer, and the cases this drug is verifiably not part of.
Deciding about duloxetine?
- 12 questions to ask before starting a psychiatric medication — each with the study behind it
- Already on it? The 10-question annual review — including the honest case for staying
- How long every drug here was tested before approval — one chart, all medications
Open duloxetine (Cymbalta) in Resolv
The app has the full approval journey, the resources behind it, and people working through the same questions.
