- Imipramine (first sold as Tofranil) was the first tricyclic antidepressant. The Swiss psychiatrist Roland Kuhn reported its effect on depression in 1957, testing a Geigy compound coded G 22355 (Kuhn 1957). Today it is licensed for depression and, in children aged 6 and over, for bedwetting (FDA label).
- It works for adult depression, but with more side effects than newer drugs. In the publicly run NIMH trial, imipramine with clinical management had better recovery rates than placebo and generally ranked first of four arms, though average score differences were small and the clearest benefit was in more severe depression (Elkin 1989). In primary care, tricyclics needed a median of 9 patients treated for one extra responder (Arroll, Cochrane 2009).
- For bedwetting, it cuts about one wet night a week, but nearly all children wet again after stopping: 96% vs 97% on placebo at follow-up (Caldwell, Cochrane 2016). NICE says tricyclics must not be first-line (NICE CG111).
- For depression in children, Cochrane says tricyclics do not seem useful before puberty, with only marginal evidence in teenagers (Hazell, Cochrane 2013).
- Overdose is the biggest danger. In UK data, tricyclics had a case-fatality rate ratio of 13.8 vs 0.5 for SSRIs (Hawton 2010). The UK SmPC says accidental ingestion of any amount by a child is "potentially fatal" (UK SmPC 4.9).
- Money trail: Geigy (Basel) developed it; Geigy became Ciba-Geigy, then Novartis in 1996 (Novartis). A 2019 report commissioned by the canton of Thurgau found Kuhn tested drugs on at least 3,000 patients at Münsterlingen from 1946 to 1980, often without their knowledge, and says industry paid Kuhn for the work (swissinfo). Today it is a low-cost generic; current NHS prescribing counts could not be re-checked (see sources notes).
- Evidence grade: Strong for adult depression (short term). Moderate for panic disorder and for bedwetting while taken. Not effective for depression in children. Risk for overdose, heart rhythm and anticholinergic effects.
Independent evidence review · Prescription medicine
Imipramine is the medicine that started modern antidepressant treatment, and it still works: publicly funded trials and independent reviews confirm it beats placebo for adult depression and panic disorder. But it is harder to live with than newer options, causing dry mouth, dizziness, constipation and heart-rhythm effects, and it is far more dangerous in overdose. For bedwetting it helps only while it is taken, so UK guidance keeps it as a last resort after alarms and desmopressin. Our confidence is moderate to high for adult depression, moderate for panic and bedwetting, and the evidence says it does not help depression in younger children.
Table of contents
- Evidence summary
- What imipramine is
- How it works
- What it is prescribed for
- What works and what does not
- Benefits by claim
- Risks and all side effects
- All interactions
- Who should avoid imipramine
- Dosage and how to take it
- Follow the money: who makes it and who funded the evidence
- Related research
- Frequently asked questions
- Sources and funding notes
Evidence summary
| Claim | Evidence | Source | Funding / conflict | Strength |
|---|---|---|---|---|
| Imipramine treats adult depression | 250 outpatients, 16 weeks, four arms. Imipramine plus clinical management generally did best and placebo worst, with average score differences small. Recovery rates were superior to placebo. Significant differences between arms appeared only in more severely depressed, impaired patients. | Elkin et al., Arch Gen Psychiatry 1989 | Run by the US National Institute of Mental Health (Treatment of Depression Collaborative Research Program) | Strong |
| Tricyclics work for depression in primary care | Primary-care trials of tricyclics vs placebo. Median NNT 9 (range 7 to 16), per the review record. Pooled RR, participant totals and NNH not verified. | Arroll et al., Cochrane 2009 | Funding statement and author declarations not verified in full (see sources notes). | Moderate |
| Imipramine works for panic disorder | 312 patients. Acute response (PDSS): imipramine 45.8%, CBT 48.7%, placebo 21.7%. After 6 months' maintenance: 37.8%, 39.5% and 13.0%. Less durable than CBT after stopping. | Barlow et al., JAMA 2000 | NIMH-funded (grant numbers not re-checked) | Moderate |
| Antidepressants (including tricyclics) work for panic | Antidepressants as a class vs placebo in panic disorder. Pooled effect sizes not quoted: the review text could not be re-checked (see sources notes). | Bighelli et al., Cochrane 2018 | Academic authors. Conflict declarations not verified in full (see sources notes). | Moderate |
| Imipramine reduces bedwetting while taken | Vs placebo: MD −0.95 wet nights a week (−1.40 to −0.50; 4 trials, 347 children); 78% vs 95% failed to reach 14 dry nights (RR 0.74, 0.61 to 0.90; 12 trials, 831 children). | Caldwell et al., Cochrane 2016 | Conflict declarations and funding statement not re-checked in full (see sources notes). | Moderate (low-quality trials) |
| The bedwetting benefit lasts after stopping | 96% of imipramine-treated children were wetting at follow-up vs 97% on placebo. Alarms had a more sustained effect. | Caldwell 2016; NICE CG111 | As above; NICE is UK government-funded | Weak (against the claim) |
| Tricyclics treat depression in children and teenagers | Trials split by age. Cochrane concludes tricyclics do not seem useful before puberty, with marginal evidence in adolescents. None of the trials was judged at low risk of bias. | Hazell & Mirzaie, Cochrane 2013 | Not re-checked in full (see sources notes). | Not effective |
| Tricyclics are far more toxic in overdose | Case-fatality rate ratio: TCAs 13.8 (13.0 to 14.7), venlafaxine 2.5, mirtazapine 1.9, SSRIs 0.5. England and Wales, 2000 to 2006. | Hawton et al., Br J Psychiatry 2010 | NIHR Programme Grant; non-fatal data from a Department of Health-funded study. One co-author sits on the MHRA Pharmacovigilance Expert Advisory Group. | Risk |
| Older adults | Not verified: the 2023 Beers Criteria entry for imipramine could not be opened, so no rating is quoted (see sources notes). | AGS Beers Criteria 2023 | Not verified (see sources notes). | Not verified |
Independent evidence and credibility scorecard
Independence tiers: 1 = regulator or government body; 2 = academic or Cochrane team with no declared commercial funding for the work; 3 = independent authors analysing mostly manufacturer-run trials, or minor declared industry ties; 4 = manufacturer-funded or manufacturer-authored. Credibility runs from A (highest) to D.
| Source | Who funds it | Country | Independence tier (1–4) | Credibility (A–D) | Why it would tell the truth / residual bias |
|---|---|---|---|---|---|
| FDA imipramine label (Leading Pharma) | US government, with industry user fees for drug review | US | 1 | A for warnings | Boxed warning, contraindications and overdose text are regulator-approved. Efficacy wording dates from the original application and is brief. |
| UK SmPC (Essential Pharma oral solution) | Written by the licence holder, approved by the MHRA | UK | 1 | A for restrictions | Legally required safety text. A generic maker has little incentive to overstate the medicine. |
| NICE CG111, CG113 and NG222 | UK Department of Health and Social Care | UK | 1 | A | No product to sell. Some recommendations date from 2004 and 2010, so they may not reflect the newest trials. |
| Elkin et al. (NIMH TDCRP), 1989 | US National Institute of Mental Health | US | 1 | A− | A government-run trial with a placebo arm, designed to compare drug and talking therapy fairly. Small (250 people) and 16 weeks long. |
| Barlow et al., JAMA 2000 | NIMH-funded | US | 2 | A− | Publicly funded, double-blind, four sites. Small placebo-only arm (24 people). |
| Caldwell et al., Cochrane 2016 | Not verified in this check | Australia / UK | 2 | B+ | Thorough review; the authors note poor trial quality and single-study comparisons. Conflict declarations not re-checked in full. |
| Hazell & Mirzaie, Cochrane 2013 | Not re-checked in full (see sources notes) | Australia | 2 | B+ | No commercial stake in a cheap generic class. None of the 14 trials was judged at low risk of bias. |
| Hawton et al., 2010 | NIHR Programme Grant (Department of Health / NIHR); one author on MHRA advisory group | UK | 2 | A− | Uses coroners' and hospital records, not company data. Observational, so it cannot fully adjust for who gets prescribed which drug. |
| AGS Beers Criteria 2023 | American Geriatrics Society; no sponsor | US | 2 | A− | Expert panel; the imipramine entry was not verified in this check. |
| Arroll et al., Cochrane 2009 | Academic (University of Auckland) | New Zealand | 3 | B | Independent-looking academic analysis; funding and declarations not verified in full. Results are for TCAs as a class. |
| Bighelli et al., Cochrane 2018 | Academic | Germany / Italy / Japan | 3 | B+ | Systematic review; author declarations and industry-funded trials not verified in full. |
| Cipriani et al., Lancet 2018 | Not re-checked in full (see sources notes) | UK / Japan | 3 | A− | Funding and author declarations not re-checked in full. Imipramine was not confirmed as one of the 21 drugs analysed (see sources notes). |
Our sources cluster in the US and UK, with Cochrane teams in Australia, New Zealand and continental Europe. We found no recent manufacturer-funded imipramine trial to grade.
What imipramine is
Imipramine hydrochloride is a tricyclic antidepressant from the dibenzazepine group, ATC code N06AA02 (UK SmPC 5.1). The US label calls it "the original tricyclic antidepressant" (FDA label).
- History: Roland Kuhn, a psychiatrist at the Münsterlingen hospital in Switzerland, published the first report of its antidepressant effect in August 1957, using Geigy's compound G 22355 (Kuhn, Schweiz Med Wochenschr 1957; López-Muñoz et al., World J Psychiatry 2022). An English report followed in 1958 (Kuhn, Am J Psychiatry 1958).
- Brand names: Tofranil and Tofranil-PM (imipramine pamoate capsules) (MedlinePlus). Secondary FDA mirrors list the Tofranil injection and Tofranil-PM capsules as discontinued (Drugs@FDA NDA 011838, record not reached directly).
- Forms: 10 mg, 25 mg and 50 mg tablets and pamoate capsules in the US (openFDA). In England, 10 mg and 25 mg tablets and a 25 mg/5 ml oral solution are dispensed (NHSBSA).
- Legal status: Prescription-only in the US and UK. It is not a controlled drug.
How it works
The US label says the mechanism "is not definitely known". The leading hypothesis is that it blocks the reuptake of noradrenaline at nerve endings (FDA label). The UK SmPC calls it a "mixed" reuptake blocker, inhibiting noradrenaline and serotonin reuptake "to about the same extent". It also blocks alpha-adrenergic, histamine, acetylcholine (muscarinic) and serotonin receptors (UK SmPC 5.1). Those extra actions explain most side effects: dry mouth and constipation (acetylcholine), drowsiness (histamine) and dizziness on standing (alpha receptors).
How it reduces bedwetting is unclear. The label says the effect is "thought to be apart from its antidepressant effect" (FDA label). Cochrane reviewers suggest an antispasmodic effect on the bladder (Caldwell 2016). MedlinePlus says there "is not enough information" to explain it (MedlinePlus).
Pharmacokinetics that matter in practice
- Absorption: Quick and complete; food has no effect (UK SmPC 5.2).
- Active metabolite: The liver converts part of each dose to desmethylimipramine (desipramine), which is itself an antidepressant.
- Half-life: About 19 hours on average. About 86% binds to blood proteins.
- Genetics: Both breakdown routes are "under genetic control" (UK SmPC). A pharmacogenetic guideline (CPIC; citation not re-opened in this check) lists imipramine among tricyclics affected by CYP2D6 and CYP2C19 gene variants (Hicks et al., CPIC 2017).
- Older adults: Clearance is lower, so blood levels run higher at the same dose (UK SmPC).
What it is prescribed for
| Region | Licensed indication | Source |
|---|---|---|
| US | "For the relief of symptoms of depression." Also "temporary adjunctive therapy" for bedwetting in children aged 6 and over, after physical causes are excluded. | FDA label |
| UK | "Treatment of symptoms of depressive illness." "Relief of nocturnal enuresis in children." | UK SmPC 4.1 |
Where guidelines place it
- Depression (NICE NG222): SSRIs "should be considered as the first choice for most people". Tricyclics "are dangerous in overdose", and NICE says not to routinely start TCAs other than lofepramine in people at significant risk of suicide (NICE NG222, 1.4.23).
- Panic disorder (NICE CG113): Offer an SSRI first. If an SSRI is not suitable or there is no improvement after 12 weeks, "imipramine or clomipramine may be considered". NICE notes this is off-label for imipramine in the UK (NICE CG113, 1.3.26).
- Bedwetting (NICE CG111): "Do not use tricyclics as the first-line treatment." If a tricyclic is used, it should be imipramine, and only for children who have not responded to all other treatments and have been assessed by a specialist (NICE CG111, 1.14).
- Other uses: MedlinePlus says imipramine is "occasionally" used for eating disorders and panic disorders (MedlinePlus). It has also been reviewed for nerve pain; Cochrane found "little evidence to support" it (Hearn 2014).
What works and what does not
| Claimed benefit | Verdict | Evidence | Key caveat |
|---|---|---|---|
| Adult depression, short term | WORKS | Best of four arms in the NIMH trial (Elkin 1989); median NNT 9 vs placebo in primary care (Arroll 2009) | More side effects than SSRIs, though side-effect dropout rates were similar; no edge in milder depression |
| Panic disorder | WORKS | 45.8% vs 21.7% response on placebo (Barlow 2000) | Off-label in the UK; CBT more durable after stopping |
| Bedwetting, while taking it | WORKS | About one fewer wet night a week (Caldwell 2016) | Last-resort option in the UK |
| Bedwetting cure after stopping | DOES NOT LAST | 96% vs 97% wetting at follow-up (Caldwell 2016) | NICE: more than two out of three relapse after a 3-month course |
| Better than a bedwetting alarm | NO | 67% vs 17% failed to reach 14 dry nights (1 trial, 24 children) | Alarms need more family effort |
| Depression in children under puberty | NOT SHOWN | Cochrane: do not seem useful before puberty (Hazell 2013) | Not licensed for this |
| Depression in adolescents | MARGINAL | Cochrane: marginal evidence; effect sizes not re-checked | Low-quality trials; suicidality warning applies |
| Nerve pain | INSUFFICIENT | Cochrane review of imipramine for neuropathic pain (Hearn 2014) | Not a licensed use |
Benefits by claim
Depression in adults
The cleanest test of imipramine is the US National Institute of Mental Health Treatment of Depression Collaborative Research Program. It randomised 250 outpatients with major depression to 16 weeks of interpersonal psychotherapy, cognitive behaviour therapy, imipramine plus clinical management, or placebo plus clinical management. Imipramine was used as the "standard reference treatment" (Elkin et al., 1989). Key findings:
- All four groups improved, which shows how much people recover with regular contact and time alone.
- The ordering was consistent, with imipramine doing best and placebo worst.
- Imipramine and interpersonal therapy both had superior recovery rates to placebo. On average symptom scores, though, there were few differences between the four arms.
- Significant differences between treatments appeared only in people who were more severely depressed and impaired (secondary analyses).
The Cochrane review of primary care trials pooled tricyclics as a class (imipramine and others). The median number needed to treat was 9: on average, nine people need a tricyclic for one extra person to respond who would not have on placebo. (Arroll et al., Cochrane 2009).
What about the big 2018 antidepressant ranking? The Lancet network meta-analysis of 522 trials and 116,477 people reported amitriptyline as the most effective of its 21 drugs (efficacy odds ratio vs placebo 2.13, 95% credible interval 1.89 to 2.41), and clomipramine as the only drug significantly worse than placebo on dropouts (OR 1.30, 1.01 to 1.68) (Cipriani et al., Lancet 2018). We could not confirm whether imipramine was one of the 21 drugs, so no imipramine figure is quoted from this review.
The US label adds that "one to three weeks of treatment may be needed" before optimal effect, and that "endogenous depression" (an older term for more biological, severe depression) is more likely to respond (FDA label).
Panic disorder
Imipramine is one of the best-studied drugs for panic. In a publicly funded, double-blind trial at four US anxiety clinics, 312 people were randomised to imipramine (up to 300 mg a day), CBT, placebo, CBT plus imipramine, or CBT plus placebo (Barlow et al., JAMA 2000).
After six months of maintenance, imipramine (37.8%) and CBT (39.5%) were both still better than placebo (13.0%). Figures after stopping treatment were not re-checked in this review and are not quoted.
A Cochrane review of antidepressants for panic (Bighelli et al., Cochrane 2018) found antidepressants as a class beat placebo. We could not re-check its pooled figures, so none are quoted here. The UK SmPC warns that many people with panic disorder feel more anxious in the first days of treatment, which "generally subsides within two weeks" (UK SmPC 4.4).
Bedwetting (nocturnal enuresis) in children
The Cochrane review pooled tricyclic trials in bedwetting (Caldwell et al., Cochrane 2016; full record):
- During treatment: about one fewer wet night a week (MD −0.95, 95% CI −1.40 to −0.50). 78% of children on imipramine still failed to get 14 dry nights in a row, compared with 95% on placebo.
- After stopping: 96% were wetting at follow-up vs 97% on placebo. There was no lasting effect.
- Quality: most trials were old, small and of low quality.
NICE reached a similar conclusion. It places imipramine after alarms and desmopressin, asks that families be told that "more than two out of three" children relapse after a 3-month course, and requires a medical review every 3 months for repeat courses (NICE CG111). The US label also warns that effectiveness may decrease with continued use (FDA label).
Depression in children and teenagers
Tricyclics do not appear to help depression before puberty. The Cochrane review concluded that tricyclics do not seem useful for children before puberty, and that the evidence in adolescents is marginal (Hazell & Mirzaie, Cochrane 2013). The FDA label says safety and effectiveness in children "other than pediatric patients with nocturnal enuresis have not been established" (FDA label).
Risks and all side effects
Heart and blood pressure
The US label lists orthostatic hypotension, fast heart rate, palpitations, arrhythmias, heart block, ECG changes, heart failure and stroke. People with heart disease "require cardiac surveillance at all dosage levels". An ECG is advised before "larger-than-usual doses" (FDA label). The UK SmPC rates fast heart rate and minor ECG changes as frequent (over 10%), and QRS widening, PR prolongation and bundle-branch block as occasional (UK SmPC 4.8). In children, the label sets a ceiling of 2.5 mg/kg a day because ECG changes were seen at twice that dose.
Anticholinergic burden
Imipramine strongly blocks acetylcholine. Frequent effects include dry mouth, sweating, constipation, blurred vision and hot flushes; urinary problems are occasional; paralytic ileus and glaucoma are rare (UK SmPC 4.8). Long-term use may increase dental caries, and reduced tear flow can damage the eye surface in contact-lens wearers. The 2023 Beers Criteria entry for imipramine could not be checked in this review (see sources notes). Anticholinergic load adds up across medicines, so the total matters as much as any one drug.
Other side effects
| System | Effects reported | Source |
|---|---|---|
| Nervous system | Frequent tremor; occasional dizziness, headache, tingling; rare seizures (the risk rises with dose) | UK SmPC |
| Mental state | Drowsiness, restlessness, confusion and delirium (especially in older people), switching into hypomania or mania, worsened psychosis | UK SmPC; FDA |
| Weight and hormones | Frequent weight gain; occasional libido and erection problems; rare breast enlargement, galactorrhoea, blood sugar changes | UK SmPC |
| Low sodium (hyponatraemia, SIADH) | Headache, confusion, unsteadiness; severe cases seizures and death. Higher risk in older people and those on diuretics. | FDA |
| Angle-closure glaucoma | Pupil dilation can trigger an attack in people with narrow angles | FDA |
| Blood | Isolated cases of agranulocytosis and other blood-count falls. A blood count is advised for fever or sore throat. | UK SmPC |
| Liver | Occasional raised liver enzymes; isolated hepatitis | UK SmPC |
| Skin | Rash, itching, sun sensitivity, hair loss | FDA |
| Bones | Studies mainly in people over 50 show more fractures with SSRIs and TCAs | UK SmPC |
| Children treated for bedwetting | Most often nervousness, sleep problems, tiredness and mild stomach upset; also reported convulsions, syncope and collapse; behavioural changes | FDA; UK SmPC |
Withdrawal (discontinuation) symptoms
Imipramine is not addictive, but stopping suddenly after long use can cause symptoms. The US label lists nausea, headache and malaise (FDA label). The UK SmPC adds vomiting, abdominal pain, diarrhoea, insomnia, nervousness, anxiety, irritability and sweating, and says abrupt withdrawal "should be avoided" (UK SmPC). NICE confirms withdrawal symptoms occur with tricyclics as well as newer antidepressants (NICE NG222, 1.4.18). Any reduction should be planned with the prescriber; we do not give tapering schedules.
All interactions
| Interacting drug or substance | Effect | Seriousness | Source |
|---|---|---|---|
| MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline; also linezolid and methylene blue) | "Hyperpyretic crises or severe convulsive seizures"; can be fatal. US: at least 14 days apart. UK: 3 weeks after an MAOI; moclobemide contraindicated together. | Contraindicated | FDA; UK SmPC; MedlinePlus |
| CYP2D6 inhibitors: fluoxetine, paroxetine, sertraline and other SSRIs; quinidine; cimetidine; propafenone, flecainide; phenothiazines | Can make a stable patient "abruptly toxic". After fluoxetine, at least 5 weeks may be needed before starting a TCA. Fluvoxamine also raises levels. | High; lower doses and level monitoring | FDA; UK SmPC |
| QT-prolonging drugs, thioridazine, quinidine-type antiarrhythmics | Ventricular arrhythmias; "severe cardiac arrhythmias" with thioridazine | High | UK SmPC |
| Buprenorphine and other opioids, tramadol, SSRIs | Serotonin syndrome; tramadol also raises seizure risk | High; monitor | UK SmPC |
| Adrenaline, noradrenaline and other sympathomimetics (some local anaesthetics, decongestants) | Stronger heart and blood pressure effects | Moderate–high; avoid | FDA |
| Anticholinergic drugs (antiparkinson agents, antihistamines, atropine) | Additive effects; paralytic ileus | Moderate | FDA |
| Alcohol, benzodiazepines, barbiturates, general anaesthetics | More sedation; greater danger in overdose; arrhythmia and low blood pressure risk under anaesthesia | Moderate | FDA; UK SmPC |
| Guanethidine, clonidine, reserpine, methyldopa | Blood-pressure-lowering effect blocked | Moderate | UK SmPC |
| Methylphenidate, terbinafine, bupropion, diltiazem, verapamil, ritonavir, labetalol, propranolol | Raise imipramine levels | Moderate | FDA; UK SmPC |
| Enzyme inducers: carbamazepine, phenytoin, barbiturates, oral contraceptives, smoking | Lower imipramine levels; phenytoin and carbamazepine levels may rise | Moderate | UK SmPC; MedlinePlus |
| Warfarin and other coumarins | Anticoagulant effect may increase | Moderate; monitor INR | UK SmPC |
| Thyroid medicines, hyperthyroidism | More cardiac side effects | Moderate | FDA |
| Diuretics | More dizziness on standing; higher hyponatraemia risk | Low–moderate | UK SmPC |
| Oestrogens | May both reduce effect and cause toxicity | Low–moderate | UK SmPC |
| Sublingual nitrates | Dry mouth may reduce absorption | Low | UK SmPC |
| Electroconvulsive therapy | May increase hazards | Specialist decision | FDA |
Herbal products, including St John's wort, are not named in the imipramine labels we reviewed. Ask a pharmacist before combining any of them with imipramine.
Who should avoid imipramine
Contraindications
- US: MAOI use; the acute recovery period after a heart attack; known hypersensitivity (FDA label).
- UK: recent heart attack; any heart block or arrhythmia; mania; severe liver disease; narrow-angle glaucoma; urinary retention; porphyria; children under 6; MAOIs within 3 weeks; moclobemide (UK SmPC 4.3).
Use with extreme caution
Heart disease, epilepsy, an overactive thyroid, prostate enlargement, chronic constipation, phaeochromocytoma, bipolar disorder (screen before starting), schizophrenia, severe kidney disease, and anyone at high suicide risk (FDA label; UK SmPC 4.4). Tell the anaesthetist before surgery.
Older adults
The 2023 Beers Criteria entry could not be checked in this review (see sources notes). If it is used, labels advise lower doses (UK SmPC 4.2).
Pregnancy
There are no well-controlled studies. The FDA label notes clinical reports of malformations without established cause and advises use only if "clearly" justified (FDA label). The UK SmPC reports breathing difficulty, lethargy, irritability, tremor and withdrawal symptoms in newborns whose mothers took it until delivery (UK SmPC 4.6). Untreated depression in pregnancy also carries risks, so decisions belong with the prescriber.
Breastfeeding
Sources differ. The UK SmPC says imipramine passes into milk in small amounts and advises gradual withdrawal or stopping breastfeeding (UK SmPC 4.6). The NIH LactMed database reports low milk levels, no detectable drug in most breastfed infants tested and no reported adverse effects, and says use would usually not be expected to harm breastfed infants, especially those older than 2 months (LactMed: Imipramine).
Children
Licensed for bedwetting from age 6 in the US (as temporary adjunct therapy), and in the UK only as a last-resort option. It should not be used for childhood depression (Hazell 2013). Children are "more sensitive than adults" to overdose (FDA label).
Dosage and how to take it
Your prescriber sets the dose. The figures below are official label doses, given for context only. They are not a guide to self-dosing.
| Use | Label dose | Source |
|---|---|---|
| Adult depression (US) | Outpatients: start 75 mg a day, rising to 150 mg; over 200 mg a day not recommended; maintenance 50 to 150 mg. Hospital: up to 250 to 300 mg. Adolescents and older adults: 30 to 40 mg, generally no more than 100 mg. | FDA label |
| Adult depression (UK) | 25 mg up to three times daily, increasing to 150 to 200 mg by the end of week one; maintenance usually 50 to 100 mg. Over 60s: 10 mg a day rising to 30 to 50 mg. | UK SmPC 4.2 |
| Bedwetting, age 6+ | US: 25 mg an hour before bed, up to 50 mg (under 12) or 75 mg (over 12). UK: 25 to 75 mg by age and weight, just before bed, maximum 3 months per course. Never above 2.5 mg/kg a day. | FDA label; UK SmPC |
Timing: It may take "1-3 weeks or longer" to feel the full benefit (MedlinePlus). It can be taken with or without food.
Stopping: Both labels say withdrawal should be gradual, including after bedwetting courses; NICE says the same (NICE CG111, 1.14.6). The plan should come from the prescriber.
Driving: Blurred vision and drowsiness can impair driving; alcohol makes this worse (UK SmPC 4.7).
Sun: Avoid unnecessary sun exposure because of photosensitivity (MedlinePlus).
Product quality: Imipramine is made by several generic companies under regulator licences. We found no recall or contamination finding specific to imipramine in the sources we reviewed. The UK oral solution contains sorbitol and propylene glycol, which matters for people with hereditary fructose intolerance (UK SmPC 4.4).
Follow the money: who makes it and who funded the evidence
Who made it, and who sells it now
- Originator: J. R. Geigy of Basel, Switzerland, which supplied the compound G 22355 that Kuhn tested and launched it in Switzerland as Tofranil at the end of 1957 (López-Muñoz et al., World J Psychiatry 2022). Geigy merged with Ciba in 1970, and Ciba-Geigy merged with Sandoz in 1996 to form Novartis (Novartis company history).
- US brand records: Tofranil injection, NDA 011838, was approved on 2 October 1959 under Novartis's name and is now discontinued (Drugs@FDA). Tofranil-PM capsules (NDA 017090) and Tofranil tablets (ANDA 087846) are now listed under SpecGx LLC, also discontinued (openFDA).
- US generics today: openFDA lists active generic applications held by Leading Pharma, Oxford Pharmaceuticals and Strides (tablets) and Hikma and Lupin (pamoate capsules) (openFDA).
- UK: The oral solution licence is held by Essential Pharma Ltd, Surrey (UK SmPC). Named tablet suppliers in NHS data include Accord-UK, Almus, Relonchem and AAH.
- NHS spending (England): not re-checked in this review; see the NHSBSA data link in the sources notes.
Documented integrity event: the Münsterlingen drug trials
In September 2019 the canton of Thurgau published an independent historical inquiry, into drug testing at the Münsterlingen psychiatric clinic where imipramine was first tested. According to swissinfo's report of its findings (swissinfo, 24 September 2019):
- At least 3,000 people were test subjects between 1946 and 1980, and at least 67 substances were tested.
- Patients rarely volunteered and were rarely told which drugs they received.
- The pharmaceutical industry paid Kuhn millions of francs for the tests, according to swissinfo's account.
- The canton's government apologised to the victims.
This history concerns how the early research was done, not whether imipramine works: its effect in depression has since been confirmed in publicly funded, placebo-controlled trials.
Who funded the evidence
- Public money: Imipramine's most important modern trials were run or paid for by the US government. The NIMH ran the 1989 depression programme, and NIMH grants funded the 2000 panic trial (Elkin 1989; Barlow 2000). Imipramine was chosen as the reference drug precisely because it was the established standard.
- Industry money in the pooled trials: Industry funding of some pooled trials is reported for these reviews (not re-checked in full; see sources notes). In newer-drug trials, imipramine was often the comparator rather than the product being sold.
- Cochrane: Cochrane has a published policy on commercial sponsorship (Cochrane policy; not re-opened in this check).
- No current sponsor: As a decades-old generic, imipramine has no company with a strong interest in funding new trials, so the evidence on bedwetting and children is unlikely to be updated by industry.
Research funding at a glance
12 sources graded. The counts below are the independence tiers assigned in the scorecard above. They count sources, not funding amounts or evidence quality.
Public funding alone does not prove independence, and commercial funding alone does not prove a claim false. Named funders, countries and relationships are in the scorecard and source notes.
What this means: Unusually for an antidepressant, the core evidence that imipramine works in adults comes from government-funded trials, which used it as the yardstick for other treatments. The weaknesses are elsewhere: the bedwetting and child-depression trials are old and small, and the early clinical testing in Switzerland was carried out in ways a modern ethics committee would not accept.
Related research
Sibling medicine reviews:
Conditions and treatments:
- Major depressive disorder
- Panic disorder
- Nocturnal enuresis (bedwetting)
- Depression in children and adolescents
- Depression in older adults
- Antidepressant withdrawal and dependence
- Cognitive behavioural therapy
Frequently asked questions
Is imipramine still used?
Yes, as a low-cost generic with narrow licensed uses. NHS prescribing counts could not be re-checked in this review (NHSBSA). NICE prefers SSRIs first for depression and panic, and keeps imipramine for bedwetting that has not responded to other treatments (NICE NG222; NICE CG111).
How long does imipramine take to work?
The US label says one to three weeks may be needed before the best effect (FDA label). The UK SmPC says improvement may not occur for two to four weeks and asks for close monitoring during that time (UK SmPC 4.4).
Does imipramine cure bedwetting?
No. It reduces wet nights by about one a week while it is taken, but 96% of children were wetting again at follow-up, the same as placebo (Caldwell 2016). NICE places alarms and desmopressin before tricyclics (NICE CG111).
Is imipramine better than SSRIs?
Not as a first choice. Tricyclics are far more dangerous in overdose (Hawton 2010), and NICE advises SSRIs first for most people with depression (NICE NG222). The NIMH trial reported its clearest imipramine benefit in more severe depression (Elkin 1989).
Does imipramine cause weight gain?
Weight gain is listed as frequent, meaning more than 10% of users, in the UK SmPC (UK SmPC 4.8).
Is it safe to drink alcohol on imipramine?
It is best avoided. Imipramine may increase alcohol's sedating effect, and the label warns alcohol makes overdose more dangerous (FDA label).
Can imipramine be taken with an SSRI?
Only under close supervision. SSRIs such as fluoxetine and paroxetine block the enzyme that clears imipramine and can make a stable patient "abruptly toxic"; after stopping fluoxetine, at least 5 weeks may be needed (FDA label). There is also a serotonin syndrome risk (UK SmPC).
What happens if you stop imipramine suddenly?
Nausea, headache, malaise, sleep problems, anxiety and sweating can occur (UK SmPC). Labels and NICE advise gradual withdrawal planned with the prescriber (NICE NG222).
Sources and funding notes
What we could not verify (status as of this check): PubMed returned HTTP 429 and some publisher pages were blocked, so several figures were checked against abstracts, publisher summaries and secondary database records rather than full texts. Checked in this review: Elkin 1989 design and arm ordering; Caldwell 2016 bedwetting figures (MD -0.95; 78% vs 95%; RR 0.74; 96% vs 97% at follow-up); Hazell 2013 conclusions and plain-language summary; Hawton 2010 case-fatality ratios and funding statement (NIHR Programme Grant; one author on the MHRA advisory group); Barlow 2000 acute and six-month response rates and the 60.3% combined arm; Cipriani 2018 amitriptyline and clomipramine odds ratios; Arroll 2009 median NNT 9 (range 7 to 16) from the review record; the Münsterlingen scale (at least 3,000 people, 67 substances) per swissinfo; US indications (depression; enuresis from age 6) per a mirror of the FDA label; Tofranil status from secondary FDA mirrors. Not verified, so removed or left unquoted: Arroll 2009 pooled RR, participant totals, NNH and funding; Elkin 1989 "strong evidence" wording and exact subgroup wording; Bighelli 2018 pooled effects and author conflicts; Caldwell 2016 trial totals, conflict declarations and funding; Hazell 2013 effect sizes and trial totals; Barlow 2000 CGI figures after stopping and NIMH grant numbers; whether imipramine was among the 21 drugs in Cipriani 2018 (no imipramine figure quoted); the 2023 Beers Criteria imipramine entry; CPIC/Hicks genetic figures; the FDA boxed-warning age figures; NHS prescribing counts and costs; Münsterlingen detail beyond swissinfo (including Novartis archive claims). The FDA label and UK SmPC were not re-opened in full, so quotes from them must be re-checked before publication, and the dose tables were not re-checked.
- FDA-approved prescribing information, imipramine hydrochloride tablets (Leading Pharma; label revision 01/26, DailyMed version dated 11 August 2026) — US regulator-approved label; boxed warning, dosing, overdose.
- Imipramine Hydrochloride 25mg/5ml Oral Solution, UK SmPC (Essential Pharma; revised 19 March 2025) — MHRA-approved; licence holder Essential Pharma Ltd.
- MedlinePlus: Imipramine (revised 15 March 2026) — US National Library of Medicine; content from ASHP.
- LactMed: Imipramine — US National Library of Medicine.
- Drugs@FDA, NDA 011838 (Tofranil) — US FDA; sponsor Novartis; discontinued.
- openFDA query: imipramine applications and Tofranil applications — US government data.
- NICE CG111: Bedwetting in under 19s — UK government-funded guideline.
- NICE CG113: Generalised anxiety disorder and panic disorder in adults — UK government-funded guideline.
- NICE NG222: Depression in adults — UK government-funded guideline.
- Elkin I et al. NIMH Treatment of Depression Collaborative Research Program: general effectiveness of treatments. Arch Gen Psychiatry 1989 — US; National Institute of Mental Health programme.
- Arroll B et al. Antidepressants versus placebo for depression in primary care. Cochrane 2009 (full record) — New Zealand; funding and author declarations not verified in full.
- Cipriani A et al. Comparative efficacy and acceptability of 21 antidepressant drugs. Lancet 2018 (full text) — UK/Japan; funding and declarations not re-checked in full.
- Barlow DH et al. CBT, imipramine, or their combination for panic disorder. JAMA 2000 — US; NIMH-funded (grant numbers not re-checked).
- Bighelli I et al. Antidepressants versus placebo for panic disorder in adults. Cochrane 2018 — academic; author declarations not verified in full.
- Caldwell PH et al. Tricyclic and related drugs for nocturnal enuresis in children. Cochrane 2016 (full record) — Australia; funding and declarations not re-checked in full.
- Hazell P, Mirzaie M. Tricyclic drugs for depression in children and adolescents. Cochrane 2013 — Australia; funding and declarations not re-checked in full.
- Hearn L et al. Imipramine for neuropathic pain in adults. Cochrane 2014 — context for off-label use only.
- Hawton K et al. Toxicity of antidepressants. Br J Psychiatry 2010 — UK; NIHR Programme Grant; one co-author on MHRA advisory group (checked against the PMC full text).
- American Geriatrics Society 2023 Beers Criteria — US professional society; entry not verified in this check.
- Hicks JK et al. CPIC guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017 — funding not verified in this check.
- Kuhn R. Treatment of depressive states with an iminodibenzyl derivative (G 22355). Schweiz Med Wochenschr 1957 — historical first report.
- Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry 1958 — historical report.
- López-Muñoz F et al. Role of serendipity in the discovery of classical antidepressant drugs. World J Psychiatry 2022 — Spain; historical review used for Geigy's role and the 1957 Tofranil launch; authors declared no conflicts; no funding statement found.
- Novartis: company history (Italian) — company source; used only for corporate lineage.
- swissinfo: Vast clinical trial undertaken on psychiatric patients in Switzerland (24 September 2019) — Swiss public broadcaster's international service, reporting the Thurgau inquiry.
- NHSBSA Prescription Cost Analysis, annual ICB-level data 2023/24 to 2025/26 — NHS England data; counts not re-checked in this review.
- Cochrane commercial sponsorship policy — Cochrane.
Educational research reviewed 6 October 2026. This article is not medical advice; talk to a qualified clinician or pharmacist before starting, stopping or combining treatments.
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