Desipramine Drug Interactions: What to Avoid and What to Tell Your Doctor

Desipramine has a complex interaction profile. According to published drug interaction databases, desipramine interacts with more than 700 medications. While most interactions are mild or manageable, several can be life-threatening. This guide focuses on the most clinically important ones — the interactions you and your doctor absolutely need to know about before starting or changing medications.

Most Dangerous Interaction: MAOIs (Monoamine Oxidase Inhibitors)

Combining desipramine with an MAOI is absolutely contraindicated. MAOIs include:

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Isocarboxazid (Marplan)

Selegiline (Eldepryl, Zelapar)

Linezolid (Zyvox) — an antibiotic with MAOI-like activity

Intravenous methylene blue — used in certain procedures

Taking desipramine with an MAOI can cause serotonin syndrome — a potentially fatal reaction involving agitation, high fever, seizures, unstable blood pressure, and death. A washout period of at least 14 days must elapse between stopping an MAOI and starting desipramine (and vice versa).

Fluoxetine (Prozac): A Special Case

Fluoxetine is a strong inhibitor of the liver enzyme CYP2D6, which is the primary enzyme responsible for metabolizing desipramine. When taken together (or in sequence), fluoxetine dramatically increases desipramine blood levels — sometimes by 4–8 times. This can lead to desipramine toxicity: QT prolongation, cardiac arrhythmias, and CNS effects.

Because fluoxetine has an extremely long half-life (and an active metabolite, norfluoxetine, with an even longer half-life), you must wait at least 5 weeks after stopping fluoxetine before starting desipramine.

Other CYP2D6 Inhibitors: Elevated Desipramine Levels

Any drug that inhibits CYP2D6 can increase desipramine blood levels and toxicity risk. Common CYP2D6 inhibitors to be aware of include:

Paroxetine (Paxil) — also an SSRI; strong CYP2D6 inhibitor

Quinidine — antiarrhythmic

Propafenone (Rythmol) — antiarrhythmic

Flecainide (Tambocor) — antiarrhythmic

Cimetidine (Tagamet) — OTC heartburn medication

If you start or stop any of these medications while on desipramine, your doctor may need to adjust your desipramine dose.

QT-Prolonging Drugs: Cardiac Risk

Desipramine itself can prolong the QT interval — a measurement on an ECG that reflects the heart's electrical cycle. Combining it with other QT-prolonging drugs increases the risk of a dangerous heart arrhythmia called torsade de pointes. QT-prolonging medications to avoid or use with extreme caution include:

Antiarrhythmic drugs (amiodarone, sotalol, quinidine, disopyramide)

Some antibiotics (azithromycin, clarithromycin, fluoroquinolones)

Antifungals (fluconazole, ketoconazole)

Antipsychotics (haloperidol, quetiapine, ziprasidone)

Toremifene (used for breast cancer)

Alcohol: A Particularly Dangerous Combination

Alcohol is a central nervous system depressant. Combined with desipramine, it significantly increases sedation, impairs coordination and judgment, and can be dangerous or even fatal. Alcohol also affects liver enzyme activity, which can alter desipramine blood levels unpredictably.

Do not drink alcohol while taking desipramine.

CNS Depressants: Additive Sedation

Desipramine's sedating effects are additive with other CNS depressants. Use with caution and only under medical supervision if you also take:

Benzodiazepines (lorazepam, diazepam, clonazepam, alprazolam)

Sleep aids (zolpidem/Ambien, eszopiclone/Lunesta)

Opioid pain medications

Antihistamines (diphenhydramine/Benadryl)

SSRIs and Other Serotonergic Drugs

Combining desipramine with SSRIs or other serotonin-affecting drugs increases the risk of serotonin syndrome. While less dangerous than the MAOI combination, combinations like desipramine + sertraline or desipramine + tramadol require careful monitoring. Always tell your doctor about all antidepressants or pain medications you take.

St. John's Wort: The Supplement Risk

St. John's Wort is an herbal supplement sometimes used for mild depression. It affects serotonin levels and can interact with desipramine, increasing the risk of serotonin syndrome. It also induces liver enzymes that can reduce desipramine blood levels, potentially reducing its effectiveness. Avoid St. John's Wort while taking desipramine.

Always Tell Your Doctor and Pharmacist Everything

This guide covers the major categories, but desipramine has interactions with hundreds of medications. Before starting any new prescription, OTC drug, supplement, or herbal product, tell your doctor and pharmacist you're taking desipramine. Also review our post on desipramine side effects to understand related safety topics.