Usage
Clomipramine is primarily prescribed for obsessive-compulsive disorder (OCD). It helps reduce obsessions (persistent/unwanted thoughts) and compulsions (repetitive tasks). It’s also used to treat depression, panic disorder, and chronic pain conditions.
Its pharmacological classifications include tricyclic antidepressant and serotonin reuptake inhibitor (SRI).
Clomipramine’s mechanism of action involves increasing the availability of serotonin and norepinephrine in the brain by inhibiting their reuptake. This neurotransmitter modulation influences mood regulation and obsessive-compulsive behaviors.
Alternate Names
Clomipramine is also known as Anafranil (brand name). There are generic versions available internationally.
How It Works
Pharmacodynamics: Clomipramine primarily blocks the reuptake of serotonin and, to a lesser extent, norepinephrine at presynaptic nerve terminals, thereby increasing their concentration in the synaptic cleft. This enhances serotonergic and noradrenergic neurotransmission. It also exhibits anticholinergic, antihistaminic, and alpha-adrenergic blocking properties, which contribute to its side effects.
Pharmacokinetics:
- Absorption: Clomipramine is well-absorbed orally.
- Metabolism: It’s extensively metabolized in the liver, primarily by CYP2D6, to its active metabolite desmethylclomipramine (DMC).
- Elimination: Primarily eliminated through renal and hepatic routes. The half-life is variable, ranging from 21 to 31 hours for clomipramine and 32 to 89 hours for DMC, impacting the time to reach steady-state plasma levels (2–3 weeks).
Mode of Action: Clomipramine binds to the serotonin transporter (SERT) and norepinephrine transporter (NET), inhibiting the reuptake of these neurotransmitters. Its stronger affinity for SERT makes it more potent in enhancing serotonergic activity, crucial in treating OCD.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Primarily SERT and NET inhibition. Anticholinergic activity through muscarinic receptor blockade. CYP2D6 is the primary enzyme involved in its metabolism; therefore, drug interactions involving CYP2D6 inducers or inhibitors are important to consider.
Elimination Pathways: Primarily hepatic (CYP2D6 mediated) and renal excretion.
Dosage
Standard Dosage
Adults:
Initial: 25 mg orally once daily, preferably at bedtime.
Gradual increase: Increase by 25 mg increments every 3-4 days as tolerated, divided with meals to reduce gastrointestinal upset, up to 100 mg/day within two weeks.
Maintenance: 100–150 mg/day, up to a maximum of 250 mg/day. Higher doses may be necessary for OCD and panic disorder.
Children (10 years and older):
Initial: 25 mg orally once daily, preferably at bedtime.
Gradual increase: Increase by 25 mg increments every 3-4 days as tolerated, divided with meals, up to a maximum of 3 mg/kg/day or 100 mg/day (whichever is less) within two weeks.
Maintenance: May increase further to 200 mg/day or 3 mg/kg/day (whichever is less).
Special Cases:
- Elderly Patients: Initiate with a lower dose (10 mg/day) and titrate cautiously, typically not exceeding 30–75 mg/day.
- Patients with Renal Impairment: Dosage adjustments may be necessary based on creatinine clearance.
- Patients with Hepatic Dysfunction: Use with caution and initiate at lower doses.
- Patients with Comorbid Conditions: Dosage modifications may be required.
Clinical Use Cases
Clomipramine’s standard dosing applies to its primary indications (OCD, depression, panic disorder). Specific dosage adjustments for clinical use cases like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not routinely recommended or established.
Dosage Adjustments
Individualize dosage based on patient response, tolerability, and comorbid conditions. Renal/hepatic impairment warrants careful titration and lower initial doses. Drug interactions (especially with CYP2D6 inhibitors) may necessitate dose reductions.
Side Effects
Common Side Effects:
Dry mouth, constipation, blurred vision, drowsiness, dizziness, nausea, weight gain, tremor, sweating, sexual dysfunction.
Rare but Serious Side Effects:
Seizures, serotonin syndrome, cardiac arrhythmias, mania/hypomania, orthostatic hypotension, urinary retention.
Long-Term Effects:
Tardive dyskinesia (rare), sexual dysfunction, weight gain.
Adverse Drug Reactions (ADR):
Serotonin syndrome (agitation, confusion, fever, sweating, tremor), Neuroleptic malignant syndrome (rare), cardiac conduction abnormalities (QTc prolongation).
Contraindications
Hypersensitivity to clomipramine or tricyclic antidepressants. Recent myocardial infarction. Heart block or arrhythmias. Monoamine oxidase inhibitor (MAOI) use within 14 days. Angle-closure glaucoma. Urinary retention.
Drug Interactions
MAOIs (serotonin syndrome risk), serotonergic drugs (e.g., SSRIs, SNRIs), CYP2D6 inhibitors (fluoxetine, paroxetine), anticholinergics, CNS depressants (alcohol, benzodiazepines), antihypertensives.
Pregnancy and Breastfeeding
Pregnancy Safety Category: C.
Fetal risks: Potential for neonatal withdrawal syndrome if used near term. Monitor infants for adverse effects (poor feeding, irritability, respiratory distress).
Breastfeeding: Clomipramine and its metabolites are present in breast milk. Weigh the risks and benefits. Monitor infants for sedation, poor feeding, and developmental effects.
Drug Profile Summary
- Mechanism of Action: Inhibits serotonin and norepinephrine reuptake, enhancing their effects.
- Side Effects: Dry mouth, constipation, drowsiness, dizziness, sexual dysfunction; rarely, seizures, serotonin syndrome, cardiac effects.
- Contraindications: Hypersensitivity, recent MI, MAOI use, heart block.
- Drug Interactions: MAOIs, serotonergic drugs, CYP2D6 inhibitors.
- Pregnancy & Breastfeeding: Use with caution, monitor infant.
- Dosage: Adults: up to 250 mg/day; Children: up to 3 mg/kg/day or 200 mg/day (whichever is less).
- Monitoring Parameters: ECG, liver function tests, mental status, weight.
Popular Combinations
Combining clomipramine with other antidepressants or augmentation with antipsychotics is generally not recommended due to increased side effects and potential drug interactions.
Precautions
Pre-existing cardiovascular disease, hepatic or renal impairment, history of seizures, bipolar disorder, glaucoma, urinary retention. Monitor for suicidal ideation, especially in young adults. Avoid abrupt discontinuation. Advise against alcohol and other CNS depressants.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Clomipramine?
A: Adults: Start with 25mg daily, gradually increasing to 100-150mg/day, max 250mg/day. Children (10+): Start with 25mg daily, gradually increasing to a max of 3mg/kg/day or 200mg/day (whichever is less). Elderly: Start with 10mg/day, cautiously increase to a max of 30-75mg/day.
Q2: What are the common side effects of clomipramine?
A: Dry mouth, constipation, blurred vision, drowsiness, dizziness, nausea, tremor, sweating, sexual dysfunction, weight gain.
Q3: What are the serious side effects of clomipramine?
A: Seizures, serotonin syndrome, mania/hypomania, cardiac arrhythmias, orthostatic hypotension, urinary retention.
Q4: What are the contraindications for clomipramine?
A: Hypersensitivity to clomipramine, recent MI, concomitant or recent MAOI use, heart block/arrhythmias, severe hepatic disease, angle-closure glaucoma, urinary retention.
Q5: What are the key drug interactions with clomipramine?
A: MAOIs, SSRIs, SNRIs, alcohol, benzodiazepines, anticholinergics, CYP2D6 inhibitors, antihypertensives.
Q6: Can clomipramine be used during pregnancy and breastfeeding?
A: Use with caution. Potential risks to the fetus and neonate exist. Weigh the benefits against risks. Monitor infants for adverse effects.
Q7: How long does it take for clomipramine to reach steady-state plasma levels?
A: 2–3 weeks due to the long half-life of both clomipramine and its active metabolite.
Q8: How should clomipramine be discontinued?
A: Gradually taper the dose to avoid withdrawal symptoms. Abrupt discontinuation can lead to nausea, headache, and malaise.
Q9: What are the signs of serotonin syndrome?
A: Agitation, confusion, fever, sweating, tremor, muscle rigidity.
Q10: How does clomipramine’s action differ from other tricyclic antidepressants?
A: It has a higher selectivity for serotonin reuptake inhibition, making it more effective for OCD compared to other TCAs that have a more balanced effect on serotonin and norepinephrine.
