Imipramine

Indications

• FDA-approved for the relief of symptoms of depression in adults, with endogenous depression responding better than reactive presentations.
• FDA-approved as temporary adjunctive therapy for nocturnal enuresis in children 6 years and older after organic causes are excluded.
• Off-label but strongly evidence-based for panic disorder, where it was the comparator in the foundational trials of the 1980s and 1990s.
• Off-label for generalized anxiety disorder, with randomized trial support showing benefit comparable to benzodiazepines after several weeks.
• Off-label for chronic neuropathic pain and for adjunctive treatment of attention-deficit hyperactivity disorder when stimulants fail.
• Tofranil-PM capsules are for adult use only and are specifically not indicated for children of any age.

Mechanism of action

• Blocks both serotonin and norepinephrine reuptake transporters; demethylation to desipramine shifts the balance toward noradrenergic activity.
• Antimuscarinic activity at the bladder detrusor plus altered sleep architecture explains the antienuretic effect independent of mood change.
• Histamine H1 blockade contributes sedation and weight gain, while alpha-1 blockade produces orthostatic hypotension and reflex tachycardia.
• Chronic dosing downregulates beta-adrenergic and serotonin 5-HT2 receptors, a change whose timing parallels the 2 to 4 week clinical response.
• Sodium channel blockade at high concentrations widens the QRS complex and lowers the seizure threshold, driving overdose morbidity.

Pharmacokinetics

• Rapidly absorbed orally with substantial first-pass metabolism; peak concentrations occur about 1 to 2 hours after an immediate-release dose.
• Half-life is roughly 11 to 25 hours for the parent drug and longer for desipramine, its pharmacologically active demethylated metabolite.
• Demethylation is mediated by CYP1A2, CYP2C19, and CYP3A4, while both imipramine and desipramine are hydroxylated by CYP2D6.
• CYP2D6 poor metabolizers accumulate drug and require a 50 percent dose reduction per CPIC guidance, with plasma level confirmation.
• Extensively protein bound with a large volume of distribution and predominantly renal excretion of inactive glucuronidated metabolites.

Dosing

• For depression start 25-75 mg/day PO in divided doses or at bedtime, increasing by 25 mg every few days toward 75-200 mg/day.
• Outpatient maximum is 200 mg/day; hospitalized patients under close supervision may receive up to 300 mg/day if clearly needed.
• For enuresis in children 6 years and older, give 25 mg PO one hour before bedtime; if needed raise to 50 mg under 12 years or 75 mg above 12 years.
• Pediatric enuresis dosing must not exceed 2.5 mg/kg/day, and the drug should be tapered rather than stopped abruptly after a course.
• Available as 10, 25, and 50 mg hydrochloride tablets plus 75, 100, 125, and 150 mg pamoate capsules for once-daily adult dosing.
• Taper gradually when discontinuing; abrupt cessation produces cholinergic rebound with nausea, headache, insomnia, and vivid dreams.

Adverse effects

• Anticholinergic effects predominate, with dry mouth, constipation, blurred vision, and urinary retention limiting dose escalation.
• Orthostatic hypotension is more pronounced than with secondary amines and is a leading cause of falls and treatment discontinuation.
• Sedation, weight gain, and sexual dysfunction are common and account for much of the long-term nonadherence with this agent.
• Dose-dependent PR, QRS, and QT prolongation occurs; overdose produces wide-complex tachycardia, seizures, and refractory hypotension.
• Seizure risk rises with dose and with concurrent proconvulsants; mania may be precipitated in patients with undiagnosed bipolar disorder.
• Rare but serious reactions include agranulocytosis, eosinophilia, cholestatic jaundice, and syndrome of inappropriate antidiuretic hormone.

Monitoring

• Combined imipramine plus desipramine plasma concentration above 200-250 ng/mL is the usual therapeutic threshold for antidepressant effect.
• Levels above roughly 300 ng/mL correlate with cardiac conduction delay and toxicity, so check a level before exceeding 200 mg/day.
• Obtain a baseline ECG in adults over 50 years, in any cardiac disease, and in all children treated for enuresis before dose escalation.
• Track orthostatic vital signs, weight, and anticholinergic symptoms at each visit during titration and periodically during maintenance.
• Monitor closely for emergent suicidality, agitation, or mood switch during the first weeks and after every dose adjustment.

Interactions

• Contraindicated with monoamine oxidase inhibitors and for 14 days after stopping one because of hypertensive crisis and serotonin syndrome.
• Strong CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine sharply raise levels and require dose reduction.
• CYP1A2 and CYP3A4 inducers including carbamazepine, rifampin, and tobacco smoke lower concentrations and can cause apparent nonresponse.
• Additive QT prolongation with methadone, ondansetron, and antiarrhythmics; additive anticholinergic burden with antihistamines and antispasmodics.
• Antagonizes the antihypertensive effect of clonidine and guanfacine, and potentiates sedation from alcohol, opioids, and benzodiazepines.

Special populations

• Pregnancy data show no consistent teratogenic signal, though third-trimester exposure has been linked to transient neonatal withdrawal.
• Excreted into breast milk in small amounts; nortriptyline is generally chosen preferentially when a tricyclic is needed during lactation.
• Approved from age 6 years for enuresis only; antidepressant efficacy in pediatric depression has never been demonstrated in controlled trials.
• The Beers Criteria list imipramine as potentially inappropriate at age 65 and older because of anticholinergic and orthostatic burden.
• Use lower doses in hepatic impairment; no formal renal adjustment exists, but metabolites accumulate in advanced kidney disease.

Clinical pearls

• Order the combined imipramine plus desipramine level, never the parent drug alone.
• Still the benchmark tricyclic for panic disorder, but start low since early jitteriness is common.
• The only TCA labeled for enuresis, capped at 2.5 mg/kg/day in children.