clomipramine

General Information

Clomipramine (brand Anafranil) is a serotonin-preferring tricyclic antidepressant (TCA) approved in 1990 for obsessive-compulsive disorder (OCD); it remains a key option when maximized SSRI therapy is ineffective or poorly tolerated.

Desmethylclomipramine, the active metabolite, adds norepinephrine reuptake inhibition and broadens efficacy in treatment-resistant depression but increases anticholinergic and cardiovascular burden, making therapeutic drug monitoring critical.

The clomipramine compare view, clomipramine evidence feed, and clomipramine print page can support counseling and shared decision-making; the bipolar disorder hub summarizes antidepressant switch and mania-risk considerations.

Despite strong efficacy in OCD and select treatment-resistant depression cases, clomipramine use is constrained by anticholinergic burden, seizure risk at higher plasma concentrations, and the need for ECG and therapeutic drug monitoring. Many clinicians reserve it for specialty care or after SSRI/SNRI trials.

Mechanism of Action

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

Clomipramine potently blocks the serotonin transporter (SERT), producing robust serotonergic augmentation central to OCD efficacy.

Its active metabolite desmethylclomipramine preferentially inhibits norepinephrine reuptake, enhancing dual-action antidepressant effects while increasing autonomic side effects.

• High-affinity serotonin reuptake inhibition (SERT).
• Moderate norepinephrine reuptake inhibition (NET) via desmethylclomipramine.
• Antagonism at muscarinic acetylcholine, histamine H1, and α1-adrenergic receptors contributes to anticholinergic, sedative, and orthostatic effects.
• Weak sodium-channel blockade increases arrhythmogenic potential in overdose.

Metabolism and Pharmacokinetics

• Oral bioavailability roughly 50%; peak clomipramine concentrations occur 2–6 hours post dose.
• Extensive hepatic metabolism via CYP2D6 and CYP3A4 produces desmethylclomipramine, which has a longer half-life (~54 hours) than the parent compound (~32–37 hours).
• Approximately 60% of metabolites are renally eliminated; <5% of clomipramine is excreted unchanged.
• Steady-state concentrations are reached in about two weeks; therapeutic drug monitoring (goal 150–300 ng/mL combined) is recommended when doses exceed 150 mg/day or toxicity is suspected.
• CYP2D6 phenotype strongly influences exposure—poor metabolizers accumulate higher levels and may require lower doses.

Dosing and Administration

• Typical initiation is 25 mg at bedtime; increase by 25 mg every 3–4 days as tolerated.
• Typical OCD target 100–250 mg/day divided two or three times; outpatient maximum 250 mg/day (300 mg/day inpatient).
• The largest portion is often given at bedtime to reduce daytime sedation and orthostasis.
• Obtain combined clomipramine/desmethylclomipramine trough after 3–4 weeks on a stable dose; adjust to maintain 150–300 ng/mL.
• Use slower titration and lower targets in older adults or those sensitive to anticholinergic effects.

Adverse Effects

Interactions

• Contraindicated with MAOIs or within 14 days of discontinuation (serotonin syndrome, hypertensive crisis).
• Strong CYP2D6 or CYP3A4 inhibitors (fluoxetine, fluvoxamine, paroxetine, ritonavir, ketoconazole) raise levels—reduce dose and monitor concentrations closely.
• CYP inducers (carbamazepine, rifampin, phenytoin, St. John’s wort, cigarette smoking) lower levels—dose adjustments may be required.
• Additive serotonergic agents (SSRIs, SNRIs, triptans, linezolid) increase serotonin syndrome risk—monitor for clonus, hyperreflexia, and autonomic instability.
• Additive QTc prolongation with class Ia/III antiarrhythmics, macrolides, certain antipsychotics, and other TCAs.
• Combined anticholinergic burden with antihistamines, bladder antimuscarinics, or low-potency antipsychotics heightens constipation and cognitive adverse effects.

Other Useful Information

• Baseline ECG and electrolytes are typically obtained before titration, with repeats after major dose increases or if symptoms emerge.
• Therapeutic drug monitoring (goal 150–300 ng/mL combined) helps balance efficacy with seizure and arrhythmia risk; draw trough after 3–4 weeks on a stable dose.
• Bowel regimens are often needed; hydration and fiber intake can help prevent ileus and constipation.
• Because overdose is highly lethal, limited quantities are often dispensed in patients at acute suicide risk, with counseling on secure storage.
• Bipolar disorder screening is important before initiation, and emergent hypomania or mania is monitored during treatment.

References

1. Anafranil (clomipramine) prescribing information — DailyMed (2024)
2. APA Clinical Practice Guideline FOR THE Treatment OF Patients With Obsessive Compulsive Disorder — American Psychiatric Association (2020)
3. Evidence Based Pharmacotherapy FOR Obsessive Compulsive Disorder — International Clinical Psychopharmacology (2020)
4. Sertraline versus clomipramine in pediatric OCD — American Journal of Psychiatry (1998)
5. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology — Pharmacopsychiatry (2018)