Introduction
Imipramine is a tricyclic antidepressant (TCA) that was first synthesized in the 1950s and remains an important therapeutic agent in clinical practice. As the prototype TCA, it has served as a foundation for understanding the pharmacology of this drug class. While newer antidepressants have emerged, imipramine continues to be used for various psychiatric and non-psychiatric conditions due to its well-established efficacy profile.
Mechanism of Action
Imipramine exerts its therapeutic effects primarily through inhibition of norepinephrine and serotonin reuptake in the central nervous system. The drug blocks the presynaptic norepinephrine transporter (NET) and serotonin transporter (SERT), increasing the availability of these neurotransmitters in the synaptic cleft. Additionally, imipramine demonstrates significant anticholinergic activity through muscarinic receptor blockade, antihistaminic effects via H1 receptor antagonism, and alpha-1 adrenergic receptor blockade. These multiple receptor interactions contribute to both its therapeutic benefits and side effect profile.
Indications
FDA-approved indications:- Major depressive disorder
- Nocturnal enuresis in children ≥6 years
- Panic disorder
- Generalized anxiety disorder
- Neuropathic pain
- Migraine prophylaxis
- Attention-deficit/hyperactivity disorder (ADHD)
Dosage and Administration
Depression in adults:- Initial dose: 25-50 mg orally at bedtime
- Titration: Increase by 25-50 mg every 3-7 days
- Maintenance dose: 75-150 mg daily (maximum 300 mg/day in divided doses)
- Initial dose: 10-25 mg at bedtime
- Maximum dose: 100 mg daily
- Initial dose: 25 mg orally 1 hour before bedtime
- May increase to 50 mg in children 7-12 years or 75 mg in children ≥12 years
- May be administered in divided doses or as a single bedtime dose
- Should be taken with food to minimize gastrointestinal upset
- Abrupt discontinuation should be avoided; taper gradually
Pharmacokinetics
Absorption: Well absorbed from gastrointestinal tract with extensive first-pass metabolism; bioavailability approximately 40-60% Distribution: Widely distributed throughout body tissues; volume of distribution 10-20 L/kg; protein binding 85-95% Metabolism: Extensive hepatic metabolism via cytochrome P450 system (primarily CYP2C19, CYP2D6, CYP3A4) to active metabolite desipramine Elimination: Half-life 8-16 hours; excreted primarily in urine (70-80%) as metabolitesContraindications
- Hypersensitivity to imipramine or other TCAs
- Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation
- Recent myocardial infarction
- Acute recovery phase following myocardial infarction
- Narrow-angle glaucoma
- Severe liver impairment
- Urinary retention
Warnings and Precautions
Black Box Warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders Additional warnings:- Cardiovascular effects: May cause orthostatic hypotension, tachycardia, and prolonged QT interval
- Seizure threshold lowering: Use with caution in patients with seizure disorders
- Bone marrow suppression: Monitor for agranulocytosis, thrombocytopenia
- Hepatotoxicity: Monitor liver function tests
- Hyponatremia/SIADH: More common in elderly patients
- Angle-closure glaucoma: Screen patients with risk factors
- Mania/hypomania: May precipitate in bipolar patients
Drug Interactions
Major interactions:- MAOIs: Risk of serotonin syndrome and hypertensive crisis
- Other serotonergic drugs: Increased risk of serotonin syndrome
- CYP2D6 inhibitors (fluoxetine, paroxetine): Increased imipramine levels
- Anticholinergic agents: Additive anticholinergic effects
- Antihypertensives: May reduce antihypertensive efficacy
- CNS depressants: Additive sedation
- Sympathomimetics: Increased pressor effects
- Warfarin: May increase anticoagulant effect
Adverse Effects
Common (≥10%):- Dry mouth
- Constipation
- Blurred vision
- Drowsiness/sedation
- Orthostatic hypotension
- Weight gain
- Cardiac arrhythmias
- Seizures
- Agranulocytosis
- Neuroleptic malignant syndrome
- Serotonin syndrome
- Hepatitis
- Suicidal ideation
Monitoring Parameters
Baseline:- Complete blood count
- Liver function tests
- Renal function
- Electrocardiogram (especially in patients >40 years)
- Blood pressure and heart rate
- Mental status examination
- Therapeutic drug monitoring (therapeutic range 150-300 ng/mL)
- Regular assessment of mood symptoms
- Blood pressure and heart rate at each visit
- Weight monitoring
- Periodic liver function tests
- Assessment for emerging suicidal ideation
Patient Education
- Take medication exactly as prescribed; do not stop abruptly
- Therapeutic effects may take 2-4 weeks to become apparent
- Avoid alcohol consumption during treatment
- Use caution when driving or operating machinery until effects are known
- Rise slowly from sitting or lying position to prevent dizziness
- Maintain good oral hygiene to manage dry mouth
- Report any thoughts of self-harm or worsening depression immediately
- Inform all healthcare providers about imipramine use
- Use effective contraception; discuss pregnancy plans with provider
- Avoid excessive sun exposure; use sunscreen protection
References
1. FDA Prescribing Information: Tofranil (imipramine hydrochloride) 2. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. Cambridge University Press; 2013. 3. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill Education; 2017. 5. Haddad PM, Dursun SM, Deakin B. Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. Oxford University Press; 2004. 6. Joint Formulary Committee. British National Formulary. 84th ed. BMJ Group and Pharmaceutical Press; 2022. 7. UpToDate: Imipramine drug information. Wolters Kluwer Clinical Drug Information.