desipramine

General Information

Desipramine (brand Norpramin; generics) is a secondary-amine tricyclic antidepressant (TCA) indicated for depression. Compared with tertiary-amine TCAs, it is often described as having relatively greater norepinephrine activity and somewhat less sedation, but the TCA class still carries clinically important anticholinergic and cardiac liabilities (label/clinical).

In serious mental illness, TCAs are most often used when first-line antidepressants (SSRIs/SNRIs) have been ineffective or poorly tolerated, or when a prior documented response supports revisiting the class despite monitoring burden (clinical).

The narrow therapeutic index matters: overdose can be rapidly lethal, and regimen decisions often weigh symptom severity, monitoring capacity, and safe-storage planning (clinical).

Therapeutic drug monitoring (TDM) is commonly used for TCAs. AGNP guideline therapeutic reference range for desipramine is 100–300 ng/mL (Hiemke 2018).

The compare view, desipramine evidence feed, and desipramine print page support counseling, cross-taper planning, and documenting monitoring decisions.

Desipramine is less commonly chosen than SSRIs/SNRIs because of overdose lethality and monitoring demands. When it is used, the highest-yield follow-up topics are tolerability (anticholinergic effects and orthostatic symptoms), cardiac risk (ECG planning), and adequate exposure supported by TDM in partial response.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Like other TCAs, desipramine inhibits monoamine transporters. It is a secondary-amine TCA and is generally characterized by stronger norepinephrine transporter (NET) inhibition than serotonin transporter (SERT) inhibition (mechanism/class).

It also antagonizes histamine H1, muscarinic, and α1-adrenergic receptors to varying degrees, explaining sedation, constipation/urinary retention, and Orthostatic hypotension (class effects).

Sodium-channel blockade contributes to QRS widening and ventricular arrhythmia risk in overdose and in susceptible patients (class warning).

• Predominantly NET inhibition (secondary-amine TCA profile).
• H1/M1/α1 antagonism (sedation, anticholinergic effects, orthostasis).

Metabolism and Pharmacokinetics

• Absorbed orally and metabolized hepatically; CYP2D6 variability and drug interactions contribute to wide interpatient exposure differences (label/clinical).
• Label notes that ~70% of a dose is excreted in urine after hepatic metabolism; renal function and age influence tolerability (label).
• AGNP guideline elimination half-life range is 15–18 hours; steady state is typically reached within several days, but timing of TDM depends on clinical context and dose changes (Hiemke 2018/clinical).
• Because TCAs are highly protein bound and distribute widely, acute toxicity does not reliably correlate with early serum levels; clinical monitoring is prioritized in suspected overdose (clinical).

Dosing and Administration

• Label dosing is individualized. Adult outpatient titration commonly starts low (often 25–50 mg/day) and increases gradually toward 100–200 mg/day as tolerated; the labeled maximum is 300 mg/day (label).
• Older adults and medically frail patients often start at lower doses with slower titration and earlier follow-up because anticholinergic effects, orthostasis, and conduction changes can emerge quickly (clinical).
• Some regimens use bedtime dosing to reduce daytime adverse effects, while others split dosing to improve tolerability; this is individualized to sedation and blood-pressure effects (clinical).
• TDM: the AGNP therapeutic reference range is 100–300 ng/mL. Levels are often obtained after steady state or when nonresponse, toxicity, or interacting medications create uncertainty (Hiemke 2018/clinical).
• When discontinuing after longer courses, gradual tapering is commonly used to reduce cholinergic rebound (GI upset, insomnia, anxiety) and to distinguish withdrawal from relapse (clinical).

Monitoring & Labs

• Baseline and follow-up ECG planning in patients with cardiac history, older age, electrolyte disturbance risk, or multiple QT-active drugs (clinical).
• TDM after steady state or after major interaction changes when response is partial or toxicity is suspected (Hiemke 2018/clinical).
• Anticholinergic burden (bowel and bladder symptoms, cognition), falls risk, and orthostatic vitals during titration (clinical).
• Suicidality and mood switching surveillance early in treatment and after dose changes, especially in young adults and bipolar-spectrum illness (label/clinical).

Monitoring for TCAs is structured around safety (ECG + anticholinergic burden + overdose risk) while ensuring adequate exposure when response is incomplete (TDM).

Adverse Effects

Interactions

• MAOIs are contraindicated; washout periods are used to reduce risk of serotonin syndrome and hypertensive reactions (label).
• Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can raise TCA exposure; dose adjustment and/or TDM are common mitigation strategies (clinical).
• Other anticholinergic medications (some antipsychotics, antihistamines) can compound constipation, urinary retention, and delirium risk (clinical).
• Additive hypotension and sedation can occur with benzodiazepines, alcohol, opioids, and other sedating agents (clinical).
• QT- and conduction-active drugs increase cumulative arrhythmia risk; medication reconciliation typically includes OTC cold/sleep products (clinical).

Other Useful Information

• Desipramine is generally positioned after SSRI/SNRI trials in major depressive disorder guidelines because TCAs require more monitoring and have higher overdose risk (APA/CANMAT/clinical).
• When depressive symptoms occur in bipolar disorder, antidepressants are commonly paired with a mood stabilizer and monitored for mania/hypomania; see the bipolar disorder hub for longitudinal care pathways.
• If daytime sedation is a major barrier, clinicians often compare desipramine and nortriptyline (both secondary-amine TCAs) while weighing anticholinergic and cardiac risks (clinical).
• If constipation, urinary retention, or cognitive effects become limiting, a medication review for additive anticholinergic burden is often higher yield than adding multiple “side-effect” medications (clinical).

References

1. NORPRAMIN (desipramine) prescribing information — DailyMed (2025)
2. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018)
3. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
4. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)