Imipramine
Formerly Tofranil, Tofranil-PM
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major depressive disorder | Adults | Monotherapy | FDA Approved |
| Nocturnal enuresis | Children ≥6 years | Temporary adjunctive therapy | FDA Approved |
Imipramine holds a unique place in psychopharmacology as the first tricyclic antidepressant marketed (1957), and it remains the prototypical agent of its class. It is FDA-approved for two distinct indications: depression in adults (where endogenous depression has historically shown the best response) and nocturnal enuresis in children aged 6 years and older as temporary adjunctive therapy after organic causes have been excluded. The mechanism by which imipramine reduces bedwetting is thought to be separate from its antidepressant effect, likely involving anticholinergic bladder relaxation, reduced delta-wave sleep time, and possibly increased vasopressin release. Despite its historical significance, imipramine is now rarely used as a first-line antidepressant due to its side-effect burden and overdose lethality.
Panic disorder — Evidence quality: High. Imipramine was the first drug shown to be effective for panic disorder in Donald Klein’s landmark 1964 study. Supported by multiple RCTs; recommended in APA panic disorder guideline.
Neuropathic pain — Evidence quality: Moderate. Effective for diabetic neuropathy and other neuropathic pain syndromes, though amitriptyline is generally preferred for pain indications due to more extensive evidence.
ADHD (children and adults) — Evidence quality: Low-Moderate. Third-line option when stimulants and atomoxetine are contraindicated or ineffective; used more commonly in the past.
Urinary incontinence (stress/urge) in adults — Evidence quality: Low. Anticholinergic and alpha-adrenergic effects may help; largely supplanted by newer agents.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Depression — outpatient initiation | 75 mg/day (bedtime or divided) | 50–150 mg/day | 200 mg/day | Increase by 25–50 mg every 3–7 days as tolerated 1–3 weeks needed before therapeutic effects are evident |
| Depression — hospitalised / treatment-resistant | 100 mg/day | 100–200 mg/day | 300 mg/day | If no response after 2 weeks at 200 mg, may increase to 250–300 mg TDM recommended: target 175–300 ng/mL (imipramine + desipramine) |
| Panic disorder (off-label) | 10–25 mg at bedtime | 75–200 mg/day | 300 mg/day | Panic patients often sensitive to initial side effects; start very low Effect may take 4–8 weeks; used when SSRIs fail or are not tolerated |
| Neuropathic pain (off-label) | 10–25 mg at bedtime | 25–75 mg/day | 150 mg/day | Titrate every 3–7 days by 10–25 mg Lower doses effective for pain than for depression |
Paediatric & Special Population Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Nocturnal enuresis — children 6–11 years | 25 mg at bedtime | 50 mg at bedtime | 2.5 mg/kg/day | Give 1 hour before bedtime; for early-night wetters, split dose (25 mg mid-afternoon + 25 mg bedtime) Temporary use; consider drug-free period after adequate trial |
| Nocturnal enuresis — adolescents 12–17 years | 25 mg at bedtime | 75 mg at bedtime | 2.5 mg/kg/day | ECG monitoring recommended; effectiveness may decrease over time Taper gradually; do not stop abruptly |
| Elderly patients (≥65 years) | 30–40 mg/day (tablets) or 25–50 mg/day (capsules) | Individualised | 100 mg/day | Increased sensitivity to anticholinergic and cardiovascular effects Beers Criteria: avoid due to strong anticholinergic effects |
| CYP2D6 poor metabolisers | Reduce by 50% | Guided by TDM | Guided by TDM | 5–10% of Caucasians are poor metabolisers; markedly reduced 2-hydroxylation CPIC recommends alternative TCA or dose reduction with TDM |
Combined imipramine plus desipramine trough concentrations of 175–300 ng/mL are associated with optimal antidepressant response per AGNP consensus guidelines. Levels above 300 ng/mL are associated with increased side effects, particularly cardiac toxicity. In the paediatric enuresis population, doses exceeding 2.5 mg/kg/day should not be used, as ECG changes of unknown significance have been reported at higher doses. TDM is recommended for all children receiving imipramine, when daily dose exceeds 150 mg in adults, in poor responders, and when CYP2D6 inhibitors are co-prescribed.
Pharmacology
Mechanism of Action
Imipramine is the prototypical tertiary amine tricyclic antidepressant and the first TCA introduced into clinical practice. It potently inhibits the reuptake of both serotonin and norepinephrine at presynaptic terminals, with somewhat greater serotonergic than noradrenergic selectivity at the parent compound level. Imipramine undergoes hepatic N-demethylation to its principal active metabolite, desipramine, which is a highly selective norepinephrine reuptake inhibitor. The combined action of parent drug and metabolite produces balanced monoaminergic enhancement. Imipramine also blocks muscarinic acetylcholine receptors (producing anticholinergic effects), histamine H1 receptors (sedation, weight gain), alpha-1 adrenergic receptors (orthostatic hypotension), and dopamine D2 receptors. Sodium channel blockade at supratherapeutic concentrations underlies its cardiac toxicity in overdose. The mechanism by which imipramine reduces enuresis is considered distinct from antidepressant action and likely involves anticholinergic effects on detrusor muscle tone, reduced time in delta-wave sleep, and possibly increased vasopressin secretion.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly and completely absorbed; bioavailability 22–77% (mean ~43%) due to extensive first-pass metabolism; Tmax 1–2 h | Highly variable bioavailability drives the wide interindividual variation in plasma levels; food does not affect absorption |
| Distribution | Vd ~10–21 L/kg; protein binding ~86–96%; widely distributed to brain, heart, liver | Extensive tissue distribution; crosses placenta; distributed into breast milk at concentrations similar to maternal plasma; not removed by dialysis |
| Metabolism | Hepatic: N-demethylation to desipramine (active) via CYP1A2, CYP3A4, CYP2C19; 2-hydroxylation via CYP2D6 (polymorphic) | CYP2D6 polymorphism critically affects 2-hydroxylation; poor metabolisers (5–10% of Caucasians) have severely reduced clearance and higher plasma levels; desipramine metabolite has longer half-life and contributes to therapeutic and toxic effects |
| Elimination | t½ 11–25 h (imipramine), 12–28 h (desipramine); ~40% excreted in urine within 24 h, ~70% within 72 h as metabolites; <5% unchanged; small biliary/faecal component | Steady state in approximately 5–7 days for parent drug, longer for desipramine; highly lethal in overdose due to cardiac sodium channel blockade and extensive tissue distribution |
Side Effects
Imipramine shares the class-wide side-effect profile of tertiary amine TCAs, with prominent anticholinergic, sedative, and cardiovascular effects. The incidence figures below are drawn from clinical trial data, observational studies, and the FDA PI, noting that many frequencies are reported without precise percentages in the original label. Paediatric patients may experience different or more pronounced effects than adults.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dry mouth | ≥20% | Anticholinergic; persists throughout treatment; dental caries risk |
| Drowsiness / sedation | 15–25% | H1 blockade; less sedating than amitriptyline but more than desipramine; bedtime dosing helps |
| Constipation | 15–20% | Anticholinergic-mediated; can progress to ileus in severe cases |
| Orthostatic hypotension | 10–20% | Alpha-1 blockade; prominent with imipramine; significant fall risk; worse at initiation |
| Dizziness | 10–15% | Related to orthostasis and CNS effects; advise caution with position changes |
| Weight gain | 10–15% | H1 antagonism and appetite stimulation; typically 1–3 kg |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Blurred vision | 5–10% | Anticholinergic effect on accommodation; screen for glaucoma risk |
| Tachycardia | 5–10% | Anticholinergic-mediated sinus tachycardia; dose-related; persistent |
| Urinary retention / hesitancy | 5–8% | Anticholinergic; more problematic in men with prostatic hypertrophy |
| Nausea / GI distress | 5–8% | Usually transient; take with food if persistent |
| Tremor | 3–6% | Fine postural tremor; dose-related; may signal supratherapeutic levels |
| Sexual dysfunction | 3–5% | Erectile dysfunction, decreased libido, delayed orgasm |
| Diaphoresis | 2–5% | Noradrenergic-mediated; can persist |
| Insomnia / agitation (children) | 3–8% | Children may experience nervousness, sleep disturbance, or adverse personality changes |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation / behaviour | Uncommon | First 1–2 months or dose change | FDA Boxed Warning; close monitoring in those <25 years |
| Cardiac arrhythmia / QRS & QT prolongation | Rare at therapeutic doses; common in overdose | Any time; lethal in overdose | Baseline ECG; in children exceed 2.5 mg/kg/day and ECG changes may occur; sodium bicarbonate for QRS widening in overdose |
| Seizures | Rare (~0.1–0.4%) | Dose-dependent; common in overdose | Lowers seizure threshold; use with caution in epilepsy; benzodiazepines for acute management |
| Serotonin syndrome | Rare | Hours to days after adding serotonergic agent | Discontinue all serotonergic agents; cyproheptadine if severe |
| Paralytic ileus | Very rare | Any time; elderly at highest risk | Surgical emergency; discontinue imipramine |
| Hepatotoxicity (jaundice) | Very rare | Weeks to months | Monitor LFTs if symptoms arise; discontinue if jaundice |
| Bone marrow suppression (agranulocytosis, eosinophilia) | Very rare | Weeks to months | CBC if unexplained fever or infection; discontinue if confirmed |
| Mania / hypomania induction | Uncommon | First 2–8 weeks | Screen for bipolar disorder before starting; discontinue and manage |
| Sudden death in children (case reports) | Extremely rare | Any time during treatment | Baseline and periodic ECG in paediatric patients; do not exceed 2.5 mg/kg/day; use lowest effective dose for shortest duration |
There have been rare reports of sudden death in children receiving imipramine and other TCAs, particularly desipramine. The FDA PI states that a dose of 2.5 mg/kg/day should not be exceeded in children, as ECG changes of unknown significance have been reported at doses twice that amount. Baseline ECG before initiation and periodic monitoring during treatment are strongly recommended for all paediatric patients receiving imipramine for enuresis. The safety of long-term use for enuresis has not been established; consider drug-free periods to reassess need.
Drug Interactions
Imipramine is metabolised by multiple CYP enzymes, with CYP2D6-mediated 2-hydroxylation being the critical polymorphic pathway. Its pharmacological profile creates additional interaction risks through anticholinergic, adrenergic, serotonergic, and sodium-channel blocking mechanisms. The wide interindividual variability in bioavailability (22–77%) further amplifies the clinical significance of metabolic interactions.
Monitoring
-
ECG
Baseline; in children prior to starting; repeat if dose >150 mg/day or symptoms
Routine Assess QRS, QTc, PR interval. Particularly important in paediatric enuresis (ECG changes reported at >2.5 mg/kg/day). QRS >100 ms is a warning; >120 ms warrants cardiology input or discontinuation. -
Plasma Drug Level
At steady state when dose >150 mg/day; in paediatric patients; with dose changes
Routine Measure combined imipramine + desipramine trough. AGNP target: 175–300 ng/mL for depression. Levels >300 ng/mL increase toxicity risk substantially. In children, obtain levels to confirm safe range. -
Blood Pressure
Each visit during titration; then periodically
Routine Orthostatic vital signs (lying and standing). Imipramine has prominent orthostatic hypotension risk, especially in the elderly. -
Psychiatric Status
Weekly for first 4 weeks; then every 2–4 weeks
Routine Assess for worsening depression, suicidality, agitation, mania. FDA mandates close monitoring especially in patients <25 years and during dose adjustments. -
Weight & Metabolic
Baseline, then every 3–6 months
Routine Record weight and BMI. Monitor blood glucose; both elevation and lowering of blood sugar reported. -
Hepatic Function
If symptoms develop
Trigger-based Check LFTs if jaundice, dark urine, malaise, or right upper quadrant discomfort occurs. Hepatitis and jaundice are rare but documented. -
Enuresis Response
After 1–2 weeks; then periodically
Routine In paediatric enuresis, assess response after 1 week; if inadequate, may increase dose per guidelines. Consider drug-free trial after adequate response to determine if continued treatment is necessary. Effectiveness may decrease with continued use.
Contraindications & Cautions
Absolute Contraindications
- Concurrent or recent MAOI use — at least 14 days between MAOI discontinuation and imipramine, and vice versa. Includes linezolid and IV methylene blue.
- Acute recovery phase after myocardial infarction — elevated risk of arrhythmias and conduction disturbances.
- Known hypersensitivity to imipramine or other dibenzazepine compounds (cross-reactivity possible with desipramine, clomipramine, trimipramine).
Relative Contraindications (Specialist Input Recommended)
- Pre-existing cardiac conduction disease — requires cardiology consultation and ECG monitoring.
- Narrow-angle glaucoma — anticholinergic effects may precipitate angle closure.
- Severe hepatic impairment — extensively metabolised; anticipate reduced clearance.
- CYP2D6 poor metaboliser status without TDM access — markedly reduced clearance of active hydroxylated metabolites.
Use with Caution
- Elderly patients — Beers Criteria: avoid due to strong anticholinergic effects and orthostatic hypotension risk.
- Children receiving enuresis treatment — do not exceed 2.5 mg/kg/day; baseline ECG recommended; rare case reports of sudden death.
- History of seizure disorder — lowers seizure threshold.
- Bipolar disorder — may precipitate manic episode; screen before initiating.
- Urinary retention / prostatic hypertrophy — anticholinergic effects worsen obstruction.
- Hyperthyroidism — enhanced cardiovascular effects.
- Patients undergoing surgery — discontinue several days before elective surgery when possible.
Antidepressants increase the risk of suicidal thinking and behaviour in children, adolescents, and young adults (18–24 years) with major depressive disorder and other psychiatric disorders. Imipramine is not approved for use in paediatric patients other than for nocturnal enuresis (≥6 years). All patients started on therapy must be monitored closely for clinical worsening, suicidality, or unusual behavioural changes. Families and caregivers should be advised of the need for daily observation.
Patient Counselling
Purpose of Therapy
For depression, imipramine works by increasing the levels of brain chemicals that regulate mood. It may take 1 to 3 weeks before the full antidepressant benefit appears. For bedwetting, imipramine helps reduce the frequency of nighttime accidents through a different mechanism. It is important to continue taking the medication as directed even if improvement is not immediately noticeable.
How to Take
Imipramine can be taken with or without food. For depression, the dose is usually taken once daily at bedtime or in divided doses. For bedwetting, the dose should be taken 1 hour before bedtime. Tablets and capsules should be swallowed whole with water. Do not stop imipramine abruptly; your doctor will advise a gradual taper to prevent withdrawal symptoms.
Sources
- Leading Pharma LLC. Imipramine Hydrochloride Tablets USP — Full Prescribing Information. DailyMed; 2012. DailyMed Primary US prescribing reference for indications, dosing (depression and enuresis), contraindications, and boxed warning.
- FDA. Imipramine Hydrochloride Tablets USP 10 mg, 25 mg, 50 mg Prescribing Information. 2012. FDA Label (PDF) FDA-hosted label with detailed paediatric enuresis dosing, ECG warnings, and the 2.5 mg/kg/day ceiling.
- Klein DF. Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia. 1964;5:397–408. DOI Landmark study establishing imipramine’s efficacy in panic disorder, leading to the pharmacological dissection of anxiety subtypes.
- Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry. 1958;115(5):459–464. DOI First published report of imipramine’s antidepressant effects in humans, marking the birth of modern psychopharmacology.
- Mavissakalian M, Michelson L. Two-year follow-up of exposure and imipramine treatment of agoraphobia. Am J Psychiatry. 1986;143(9):1106–1112. DOI Follow-up study demonstrating sustained efficacy of imipramine combined with exposure therapy for agoraphobia/panic.
- Glazener CM, Evans JH, Peto RE. Tricyclic and related drugs for nocturnal enuresis in children. Cochrane Database Syst Rev. 2003;(3):CD002117. DOI Cochrane review confirming TCA efficacy for enuresis but noting high relapse rates after discontinuation and overdose risks.
- Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clin Pharmacol Ther. 2017;102(1):37–44. DOI CPIC guideline recommending dose adjustments for CYP2D6 polymorphisms affecting imipramine 2-hydroxylation.
- Hiemke C, Bergemann N, Clement HW, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51(1-02):9–62. DOI AGNP consensus guidelines recommending TDM for imipramine with target range of 175–300 ng/mL (imipramine + desipramine).
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Panic Disorder, Second Edition. Am J Psychiatry. 2009;166(2 Suppl):1–68. DOI APA guideline recommending imipramine as an effective option for panic disorder when SSRIs are inadequate.
- Fayez R, Gupta V. Imipramine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; Updated May 22, 2023. NCBI Clinical review covering mechanism, dosing, pharmacogenomics, adverse effects, and monitoring of imipramine.
- Abernethy DR, Greenblatt DJ, Shader RI. Absolute bioavailability of imipramine: influence of food. Psychopharmacology. 1984;83(2):104–106. DOI PK study establishing mean absolute bioavailability of ~43%, Vd ~21 L/kg, and confirming food does not affect absorption.
- Gram LF. Imipramine: a model substance in pharmacokinetic research. Acta Psychiatr Scand Suppl. 1988;345:81–84. PubMed Review describing the pharmacokinetic variability of imipramine, CYP2D6 polymorphism impact, and clinical implications for dosing.
- Sallee FR, Pollock BG. Clinical pharmacokinetics of imipramine and desipramine. Clin Pharmacokinet. 1990;18(5):346–364. DOI Comprehensive PK review covering absorption, distribution, metabolism, elimination, and age-related changes for imipramine and its active metabolite desipramine.