Clomipramine

Mechanism of Action

Clomipramine is a tertiary amine and a dibenzazepine belonging to the tricyclic antidepressants (TCA) class. Clomipramine is a serotonin reuptake inhibitor (S-RI) with a stronger affinity for the serotonin transporter (SERT) than other TCAs and S-RIs.[2] The effect of clomipramine administration is increased serotonergic and noradrenergic neurotransmitter levels within the synapses and increased transmission.[2]

Pharmacokinetics

Absorption: After a single 50 mg oral dose of clomipramine, maximum plasma concentrations are achieved within 2 to 6 hours. Clomipramine may exhibit nonlinear pharmacokinetics at higher doses.

Metabolism: Metabolism of clomipramine is primarily through the liver via oxidation by CYP450 2D6. The half-life of clomipramine is 17 to 28 hours. Clomipramine is then metabolized to the steady-state active metabolite desmethyl clomipramine by CYP450 1A2. Desmethyl clomipramine demonstrates more significant noradrenergic activity than serotonergic.[13] Experts often use fluvoxamine, a CYP450 1A2 inhibitor, in combination with clomipramine for treatment-resistant OCD. Adding fluvoxamine blocks the conversion from clomipramine to desmethyl clomipramine, increasing serotonergic activity.[14]

Distribution: Clomipramine is distributed into cerebrospinal fluid, CNS, and breast milk, with a mean CSF/plasma ratio of 2.6. Clomipramine is approximately 97% protein-bound, primarily to albumin.

Excretion: After clomipramine administration, approximately 60% of the dose is recovered in urine and 32% in feces. The elimination of clomipramine and its metabolite, desmethyl-clomipramine, may be capacity-limited, leading to potential accumulation and increased risk of dose-dependent adverse effects, including seizures. The half-life of clomipramine ranges from 19 to 37 hours, and that of desmethyl-clomipramine ranges from 54 to 77 hours.

Administration

Available Dosage Forms and Strengths

Clomipramine is available in generic formulations. Clomipramine is routinely administered orally, per os (PO), although open trials have taken place with intravenous (IV) clomipramine in treatment-resistant OCD.[15][16][17] Clomipramine is available in capsule form as a hydrochloride salt, with dosages of 25 mg, 50 mg, and 75 mg. Patients with difficulty swallowing can open the capsules, mix the contents with soft foods such as applesauce or pudding, and swallow the mixture without chewing.

Adult Dosage

The recommended initial dose for adults and children is 25 mg per day, which may be titrated in increments of 25 mg per day every 4 to 7 days to a target dose between 100 and 250 mg per day, with a maximum dose of 100 mg per day the first 2 weeks. The maximum daily dose for adults is 250 mg daily. Clinicians may administer clomipramine in single or split doses, with the larger dose given at bedtime due to the risk of sedation. Prescribers often augment clomipramine therapy with buspirone, lithium, atypical antipsychotics, or fluvoxamine for OCD.[2] For off-label use, the dosing is between 25 and 100 mg at bedtime, with variations depending on the specific indication.

The onset of action of clomipramine is usually between 6 to 12 weeks for OCD; it may alleviate anxiety or insomnia immediately. If the patient achieves OCD remission with clomipramine, treatment should continue indefinitely.[18][15] There have only been a few long-term studies for clomipramine. Long-term OCD studies reveal a low remission rate, with one study noting 20% at 40 years.[18] A later study noted that 40% to 60% of patients given a trial of SRIs respond to treatment. For non-responders or those with side effects, clomipramine should be discontinued. To taper clomipramine, the dose is reduced by 50% every 3 days until reaching the lowest dose of 25 mg daily and then discontinued completely. Abrupt discontinuation of clomipramine can result in patients experiencing withdrawal symptoms of dizziness, irritability, headache, vivid dreams, and flu-like symptoms.

Specific Patient Populations

Hepatic impairment: Clomipramine has been linked to elevated levels of AST and ALT. Most instances of liver enzyme elevation did not correlate with other signs of liver injury or jaundice. However, rare cases of severe liver damage have been reported.[19] Caution is warranted in patients with pre-existing liver conditions, and regular monitoring of liver enzyme levels and dose adjustment is required.

Renal impairment: No dosage adjustment is specified for clomipramine. However, clomipramine should be prescribed cautiously in patients with severe renal impairment.

Pregnancy considerations: Adverse effects of clomipramine have been observed in fetuses, indicating the medication crosses the placenta.[20] Lethargy, congenital heart defects, and withdrawal have occurred in infants born to mothers taking clomipramine during pregnancy.[20][21]

Breastfeeding considerations: Clomipramine may also be present in breast milk; it is recommended to bottle feed or discontinue the medication if the risk outweighs the benefits.[22] If the benefits outweigh the risks, clomipramine therapy may continue during pregnancy and breastfeeding.

Pediatric patients: Clomipramine is effective for pediatric OCD, but its use in other psychiatric disorders lacks sufficient evidence.[23] Available data is insufficient to establish the safety and efficacy of clomipramine hydrochloride in pediatric patients younger than 10 years. The typical daily dose for children (aged 10 and older) and adolescents is 1 to 3 mg/kg, and the maximum daily dose for children is 250 mg.

Older patients: According to the 2023 American Geriatrics Society Beers Criteria, clomipramine and other tricyclic antidepressants should be avoided due to their high anticholinergic properties, sedative effects, and potential to cause orthostatic hypotension.[24]

Adverse Effects

The adverse effects of clomipramine include nausea, weight gain, increased appetite, sedation, dry mouth, constipation, urinary retention, blurred vision, headache, dizziness, fatigue, hypotension, anxiety, restlessness, sweating, blue-green urine, and sexual dysfunction.[2] Life-threatening adverse effects include arrhythmia, tachycardia, QTc prolongation, orthostasis, seizures, paralytic ileus, hyperthermia, hepatic failure, increased intraocular pressure, mania induction, and activation of suicidality.[2][25]

Drug-Drug Interactions

Hepatic enzyme inhibitors: Hepatic enzyme inhibitors like cimetidine and fluoxetine can increase plasma levels of clomipramine, increasing the risk of toxicity.

Hepatic enzyme inducers: Hepatic inducers such as barbiturates and phenytoin can reduce plasma levels of clomipramine, potentially decreasing its therapeutic efficacy.

Cytochrome P4502D6 inhibitors: Inhibitors of cytochrome P450 2D6, including quinidine and cimetidine, can increase plasma levels of clomipramine in “poor metabolizers,” leading to higher effects and potential toxicity.

Protein-bound drugs: Co-administration of clomipramine with highly protein-bound drugs such as warfarin or digoxin may increase their plasma levels, leading to a higher risk of adverse effects. Conversely, clomipramine levels may decrease if displaced by other protein-bound drugs, altering the efficacy.

Selective serotonin reuptake inhibitors: SSRIs like fluoxetine and sertraline can inhibit P450 2D6 and increase clomipramine levels; fluvoxamine also inhibits P450 1A2. Caution is advised when prescribing SSRIs and TCAs, and a washout period of at least 5 weeks is required before initiating TCA therapy in a patient currently receiving fluoxetine.[26]

Contraindications

Clomipramine is contraindicated for patients taking monoamine oxidase inhibitors (MAOIs) or CYP450 2D6 inhibitors. Clomipramine therapy may not be initiated until at least 14 days after MAOI therapy is completely discontinued. Other S-RIs or MAOIs may be added or started 2 weeks after discontinuing clomipramine. CYP450 2D6 inhibitors may cause increased levels of clomipramine. Initiating clomipramine is contraindicated for patients receiving linezolid or IV methylene blue, nor can it be started during the acute phase after myocardial infarction. Other contraindications to clomipramine include hypersensitivity reactions.[2][27][28]

Box Warnings

Suicidality and antidepressant drugs: The USFDA has issued a warning that antidepressants, including clomipramine, have been shown to increase the risk of suicidality compared to placebo in children, adolescents, and young adults, particularly in short-term studies of psychiatric conditions and major depressive disorders.[29] Clinicians must weigh this risk against the clinical benefits when considering clomipramine or any antidepressant for these patients. In contrast, short-term studies have not demonstrated any significant risk of suicidality associated with antidepressants in adults older than 24, and there is evidence of a reduced risk in adults aged 65 and older. Depression and other psychiatric disorders themselves are associated with an increased risk of suicide.[30]  Patients of all ages starting antidepressant therapy should be closely monitored for suicidality or unusual behavioral changes. Families and caregivers should be informed of the need for vigilant observation and communication with the prescriber. Clomipramine is approved for pediatric use only for patients with obsessive-compulsive disorder (OCD).

Warning and Precautions

Use clomipramine with extreme caution in heart block, prolonged QTc interval, arrhythmia, acute heart failure, mania, liver disease, narrow-angle glaucoma, urinary retention, or allergy to clomipramine.[2][31] A systematic review and meta-analysis estimated that antidepressant discontinuation symptoms occur in about 15% of patients.[32] A pharmacovigilance study indicates that antidepressants, including clomipramine, are associated with a significant risk of withdrawal syndrome, highlighting the need for careful management of discontinuation symptoms.[33]

Monitoring

Due to the risk of QTc prolongation and arrhythmia, electrocardiogram testing is recommended at baseline and after achieving the desired clinical effect.[2] Due to the risk of metabolic adverse effects, monitoring weight, body mass index (BMI), fasting plasma glucose, and fasting lipids are recommended before and during treatment. A basic metabolic panel (BMP) and magnesium level should be obtained before and during treatment in patients with a risk of electrolyte imbalances. In 7% of the population, a phenotypic variant of CYP450 2D6 is present; dose reduction or phenotypic testing may be considered.[34] These phenotypic variants can result in a 40-fold difference in clomipramine concentrations. In children and adolescents, the clinician should monitor for growth, activation of mania in bipolar disorder, and the emergence of suicidality.

Toxicity

Signs and Symptoms of Overdose

Clomipramine toxicity is often associated with doses over 300 mg per day.[2] Toxicity with clomipramine can occur in overdose or if a patient is taking MAOI, S-RI, or drugs that inhibit CYP450 2D6. The most common symptoms seen in patients experiencing clomipramine toxicity include arrhythmias, seizures, and hypotension. Severe overdoses may also result in coma and death.

Management of Overdose

The antidote for TCAs is IV sodium bicarbonate (NaHCO₃), along with supportive care of vital signs. When combined with an S-RI, MAOI, or other serotonergic medications, clomipramine may result in serotonin syndrome, which classically presents as a patient with the triad of altered mental status, myoclonus, and autonomic hyperactivity. The treatment for serotonin syndrome is cyproheptadine, along with appropriate supportive care.[35][36] Immediate management includes securing IV access, administering high-flow oxygen, attaching monitoring equipment, and performing endotracheal intubation. As clomipramine is a lipophilic TCA, lipid emulsion therapy can be used for patients who are hemodynamically unstable.[37] Lipid emulsion acts as a lipid sink, sequestering lipophilic clomipramine and reducing its harmful effects.[38]

Enhancing Healthcare Team Outcomes

Healthcare providers should monitor patients on clomipramine for metabolic effects and cardiac abnormalities by obtaining weight, BMI, fasting glucose, fasting lipid panel, BMP, magnesium, and electrocardiogram at baseline and routinely during treatment.[2] Providers, including all clinicians, specialists, pharmacists, and nurses with specialty training in psychiatric health, should also monitor for the risk of mania induction or suicidality as part of an interprofessional team approach to care. If patients on clomipramine experience adverse effects, the medication regimen should be titrated down or discontinued, or the patient should be referred to a psychiatrist or mental health nurse. A pharmacy consult is necessary to identify potential interactions, verify dosing, and make recommendations to the team as needed. In an overdose, emergency medicine physicians should rapidly stabilize the patient while coordinating with neurologists and psychiatrists. A poison control center/medical toxicologist should be consulted for complicated overdose. A randomized clinical trial showed that pharmacogenetics-informed treatment of TCAs resulted in faster attainment of therapeutic plasma concentrations and potentially fewer and less severe adverse effects.[39] The treatment outcomes associated with clomipramine for patients with OCD are superior to S-RIs. However, adverse effects limit medication tolerability; this is why an interprofessional team collaborating across disciplines can optimize the therapeutic benefits of clomipramine while minimizing adverse effects.[2]