Desipramine

Indications

• FDA-approved for the relief of symptoms of depression in adults, particularly endogenous depression with prominent psychomotor retardation.
• Off-label for painful diabetic neuropathy and postherpetic neuralgia, where it matches amitriptyline with less anticholinergic burden.
• Off-label for attention-deficit hyperactivity disorder in adults and adolescents when stimulants are ineffective or contraindicated.
• Off-label for binge-eating and bulimia nervosa, though selective serotonin reuptake inhibitors remain the preferred first-line agents.
• A reasonable tricyclic choice for patients who need noradrenergic activation without the sedation of amitriptyline or doxepin.
• Not established as safe or effective in pediatric patients, and reports of sudden death in children argue strongly against routine use.

Mechanism of action

• The active demethylated metabolite of imipramine, acting almost purely as a norepinephrine reuptake inhibitor with minimal serotonergic effect.
• Muscarinic affinity is the lowest of the tricyclics, so dry mouth, constipation, and cognitive clouding are comparatively mild.
• Weak histamine H1 blockade means little sedation or weight gain, which makes morning dosing feasible and sometimes preferable.
• Alpha-1 adrenergic antagonism is modest, giving less orthostatic hypotension than tertiary amines but more than nortriptyline.
• Enhanced noradrenergic tone in descending spinal pathways underlies analgesia, while sodium channel blockade drives overdose cardiotoxicity.

Pharmacokinetics

• Well absorbed orally with peak plasma concentrations at roughly 4 to 6 hours; food does not meaningfully alter absorption.
• Elimination half-life averages about 22 hours with a range of 12 to 27 hours, supporting once-daily dosing at steady state.
• Hydroxylated principally by CYP2D6 to 2-hydroxydesipramine, which retains some activity and accumulates when renal clearance falls.
• CYP2D6 poor metabolizers show markedly elevated concentrations, and CPIC recommends a 50 percent dose reduction with level monitoring.
• Highly protein bound with a large volume of distribution; hemodialysis is ineffective and overdose care is supportive and cardiac-directed.

Dosing

• Start 25-50 mg/day PO in adults, often as a single morning or bedtime dose, and increase by 25 mg every 2 to 3 days as tolerated.
• Usual effective range is 100-200 mg/day; if no response after 2 weeks at that dose, obtain a plasma level before escalating further.
• Maximum is 300 mg/day in hospitalized patients under supervision; outpatients should generally not exceed 200 mg/day.
• In older or adolescent patients start at 10-25 mg/day and keep the total below 150 mg/day unless levels justify more.
• Supplied as 10, 25, 50, 75, 100, and 150 mg tablets; no formal renal adjustment exists but hepatic impairment requires lower doses.
• Taper over several weeks when stopping, because abrupt withdrawal causes nausea, headache, malaise, insomnia, and restlessness.

Adverse effects

• Anticholinergic effects occur but are the mildest of the class; dry mouth and constipation are still reported by many patients.
• Activation, insomnia, jitteriness, and tachycardia reflect noradrenergic tone and may require morning dosing or slower titration.
• Orthostatic hypotension, dizziness, and falls are less frequent than with tertiary amines but remain relevant in older adults.
• Dose-dependent conduction delay prolongs PR, QRS, and QT intervals; overdose causes wide-complex arrhythmia, seizures, and shock.
• Sudden unexplained death has been reported in children receiving desipramine, which is why pediatric use is strongly discouraged.
• Weight gain and sexual dysfunction occur, and rare agranulocytosis, hepatitis, or hyponatremia have been described in the label.

Monitoring

• Therapeutic plasma concentrations are generally cited as 115-300 ng/mL, with toxicity risk rising sharply above 300 ng/mL.
• Draw a trough level 10 to 14 hours after the dose and at least 5 days after any change so that steady state has been reached.
• Obtain a baseline ECG in patients over 50 years and in anyone with cardiac disease, then repeat after reaching the target dose.
• Monitor pulse and orthostatic blood pressure at each visit, since the noradrenergic profile can raise heart rate meaningfully.
• Watch closely for emergent suicidality, agitation, and manic switch during the first weeks and after each dose increase.

Interactions

• Contraindicated with monoamine oxidase inhibitors and within 14 days of stopping one because of hypertensive crisis and serotonin syndrome.
• Strong CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine can multiply levels several-fold and require dose reduction.
• Enzyme inducers including carbamazepine, phenytoin, rifampin, and cigarette smoking reduce concentrations and may cause treatment failure.
• Additive QT prolongation with methadone, ondansetron, and class IA or III antiarrhythmics; sympathomimetics may cause additive tachycardia.
• Antagonizes clonidine and guanfacine antihypertensive effects, and sedatives or alcohol add to central nervous system depression.

Special populations

• Pregnancy safety is not established; limited data show no clear teratogenic pattern, but neonatal adaptation problems can follow late exposure.
• Small amounts appear in breast milk and infant plasma levels are usually undetectable, though nortriptyline has more lactation data.
• Pediatric use is not recommended given absent efficacy data in child depression and reports of sudden cardiac death in this age group.
• Beers Criteria flag all tricyclics in adults 65 and older; if desipramine is used, start at 10-25 mg and monitor levels and ECG.
• Reduce the dose in hepatic impairment, and titrate cautiously in chronic kidney disease because hydroxy metabolites accumulate.

Clinical pearls

• Most activating tricyclic; dose in the morning when insomnia or daytime sedation is the problem.
• Least anticholinergic of the class, but overdose is still as cardiotoxic as any other TCA.
• Reports of sudden death in children make pediatric use hard to justify.