CLOMIPRAMINE HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Tricyclic antidepressant that inhibits serotonin and norepinephrine reuptake, with additional anticholinergic, antihistaminergic, and alpha-adrenergic blocking effects.
| Metabolism | Hepatic via CYP1A2, CYP2C19, CYP3A4, and CYP2D6; active metabolite desmethylclomipramine inhibits serotonin reuptake. |
| Excretion | Renal: ~60% (as conjugated metabolites and unchanged drug); Fecal: ~30% (biliary excretion); 2-3% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life of clomipramine is 19-37 hours (mean ~30 hours); active metabolite desmethylclomipramine has half-life of 54-77 hours. Steady-state achieved within 1-2 weeks. |
| Protein binding | 97-98% bound; primarily to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Vd: 9-16 L/kg (mean ~12 L/kg); extensive tissue distribution (higher in brain, lungs, liver). |
| Bioavailability | Oral: ~50% (first-pass hepatic metabolism reduces bioavailability; range 36-62%). |
| Onset of Action | Oral: 2-3 weeks for antidepressant effect (initial therapeutic response); IV: not clinically available. |
| Duration of Action | Duration of therapeutic effect persists for several days after discontinuation due to long half-life; tapers gradually over 1-2 weeks. |
| Molecular Weight | 314.9 |
Oral, initial 25 mg three times daily; increase gradually to 100-250 mg/day in divided doses; maximum 300 mg/day for severe conditions.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-59 mL/min: reduce dose by 25-50%; GFR <30 mL/min: avoid use or reduce by 50-75% with monitoring. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated or use with extreme caution at 25% of normal dose. |
| Pediatric use | Children 10-17 years: oral 25 mg/day initially, increase over 2 weeks to 3 mg/kg/day or 100 mg/day (whichever is less) in divided doses; maximum 200 mg/day. |
| Geriatric use | Initial 20-30 mg/day in divided doses; increase slowly to max 100 mg/day; monitor for orthostasis, sedation, anticholinergic effects, and QT prolongation. |
| 1st trimester | Risk of neural tube defects and cardiovascular malformations. Use only if benefit outweighs risk. |
| 2nd trimester | Risk of fetal growth restriction and preterm birth. Monitor closely. |
| 3rd trimester | Risk of neonatal withdrawal syndrome (irritability, hypertonia, seizures) and persistent pulmonary hypertension of the newborn (PPHN). Avoid near term. |
Clinical note
MAOIs can cause serotonin syndrome and hyperpyrexia Strong anticholinergic effects may occur with other drugs Increased risk of suicide in children and young adults.
| Placental transfer | Yes, crosses placenta. Fetal drug accumulation evident with maternal dosing. |
| Breastfeeding | Enters breast milk in significant amounts. Infant exposure levels may be high; risks include sedation, poor feeding, and apnea. Generally not recommended; consider alternative antidepressants with lower infant exposure. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies. Clomipramine is not approved for use in pediatric patients except for OCD in children aged 10 and older.
| Common Effects | Dry mouth |
| Serious Effects |
Hypersensitivity to clomipramine or other tricyclic antidepressantsRecent myocardial infarctionConcomitant use with MAOIs (risk of serotonin syndrome)Severe hepatic impairmentNarrow-angle glaucomaUrinary retentionHistory of seizures (low threshold)
| Precautions | Seizure potential: dose-dependent, increased at daily doses >250 mg, Activation of mania/hypomania, Cardiovascular effects: QTc prolongation, orthostatic hypotension, arrhythmias, Anticholinergic effects: urinary retention, constipation, blurred vision, Serotonin syndrome when combined with serotonergic drugs, Withdrawal symptoms with abrupt discontinuation |
Loading safety data…
| Lactation Rating | L5 |
| Teratogenic Risk | First trimester: Limited data suggest a small increased risk of cardiovascular malformations (e.g., VSD). Second and third trimesters: Risk of neonatal withdrawal symptoms (irritability, tachypnea, poor feeding) and possible serotonin syndrome if used near term. Overall, not considered a major teratogen but use only if benefit outweighs risk. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, and ECG for QTc prolongation; hepatic and renal function tests; serum drug levels if toxicity suspected. Fetal/neonatal: Ultrasound for cardiac anomalies if first-trimester exposure; monitor neonate for withdrawal symptoms (tremors, respiratory distress, irritability) and serotonin syndrome (hypertonia, hyperreflexia) for at least 48 hours after delivery. |
| Fertility Effects | Clomipramine can elevate prolactin levels, potentially causing galactorrhea, menstrual irregularities, and reduced fertility in women. In men, may cause ejaculatory dysfunction or decreased libido. These effects are reversible upon drug discontinuation. No direct evidence of permanent impairment. |
| Food/Dietary |
| Avoid grapefruit and grapefruit juice as they may increase clomipramine levels via CYP450 inhibition. Limit alcohol due to additive CNS depression. High-tyramine foods (aged cheese, cured meats) may rarely precipitate hypertensive crisis if taking MAOIs concurrently (contraindicated). No other specific dietary restrictions. |
| Clinical Pearls | Clomipramine is a tricyclic antidepressant (TCA) with potent serotonin reuptake inhibition, making it first-line for OCD. Start low (25 mg/day) and titrate slowly to minimize anticholinergic and orthostatic effects. Monitor for QTc prolongation; contraindicated in recent MI. Abrupt discontinuation can cause withdrawal symptoms. May lower seizure threshold, especially at doses >250 mg/day. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly due to withdrawal risk. · May cause drowsiness, dizziness, dry mouth, constipation, or blurred vision. · Avoid driving until you know how this medication affects you. · Report any suicidal thoughts, worsening depression, or unusual behavior immediately. · Avoid alcohol and grapefruit juice while taking this medication. · Males may experience sexual side effects (e.g., ejaculatory delay); discuss if bothersome. · Use caution when rising from sitting or lying position to prevent falls. |