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clomipramine

Adjunctive therapy

Brand: Anafranil

Published 2025-09-28 · Last reviewed 2025-10-05 · 4 references

Content sourced from FDA labeling (DailyMed) and peer-reviewed literature.

Print sheet Review evidence

At a glance

Class: Adjunctive therapy·Typical dose: Typical initiation is 25 mg at bedtime; increase by 25 mg every 3–4 days as tolerated.·Half-life: Single-dose mean 32 h; Steady-state mean 37 h·TDM range: 150–300 ng/mL·LAI available: No

Class: Adjunctive therapy
Typical dose: Typical initiation is 25 mg at bedtime; increase by 25 mg every 3–4 days as tolerated.
Half-life: Single-dose mean 32 h; Steady-state mean 37 h
TDM range: 150–300 ng/mL
LAI available: No

Quick answers

What is clomipramine?: 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.
What is Anafranil?: Anafranil is a brand name for clomipramine.
What is Anafranil (clomipramine) used for?: Label indications include: Obsessive-compulsive disorder; depression when other treatments fail.
What drug class is Anafranil (clomipramine)?: Tricyclic Antidepressant.
What is the mechanism of action of Anafranil (clomipramine)?: Tricyclic antidepressant; potent serotonin reuptake inhibition.
What strengths does Anafranil (clomipramine) come in?: Capsules: 25 mg, 50 mg, 75 mg (Anafranil; typically divided 2–3 times daily).

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.

U.S. approvals

Obsessive-compulsive disorder (1990) — Adults and adolescents

Formulations & strengths

Capsules: 25 mg, 50 mg, 75 mg (Anafranil; typically divided 2–3 times daily).
Generic capsules/tablets: 25 mg, 50 mg, 75 mg; largest portion usually given at bedtime to limit daytime sedation.
No long-acting, liquid, or parenteral formulations are marketed in the United States.

Generic availability

Generic clomipramine is supplied by multiple manufacturers (e.g., Teva, Mylan/Viatris, Sun).
Brand Anafranil remains available; liquid preparations require compounding.

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.

View labelExact

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 & 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 & 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

FDA boxed warnings

Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults—monitor closely during initiation and dose changes.

Common side effects (≥10%)

Sedation: Up to 40%; bedtime dosing and gradual titration lessen daytime somnolence.
Anticholinergic effects: Dry mouth, constipation, blurred vision, and urinary hesitancy are frequent and dose-related.
Orthostasis and tachycardia: Alpha-1 blockade causes dizziness or palpitations, particularly during titration.
Weight gain: Average 1–2 kg over 12 weeks; diet and activity strategies may help.
Sexual dysfunction: Delayed orgasm or anorgasmia in 30–40% of patients.
Tremor and diaphoresis: Mild fine tremor and sweating occur in 10–20%.

Other notable effects

Dose-related QTc prolongation and QRS widening—obtain baseline and follow-up ECGs, especially when doses exceed 150 mg/day or with other QTc-prolonging agents.
Seizure risk rises sharply above 250 mg/day or with plasma concentrations >500 ng/mL; avoid rapid titration and concurrent threshold-lowering drugs.
Severe constipation or ileus—start bowel regimen early and monitor bowel function.
Hyponatremia/SIADH, particularly in older adults or with diuretic use.
Mania or hypomania can emerge in patients with underlying bipolar disorder.
High morbidity in overdose due to ventricular arrhythmias, hypotension, and CNS depression—counsel on safe storage.

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

Related hubs:SMI toolkit·Support resources