The only FDA approved use for clomipramine is for the treatment of obsessive-compulsive disorder (OCD) in ages 10 and older. Clomipramine was the first FDA approved medication for OCD in 1989. For the treatment of OCD, clomipramine was found to be more effective than sertraline, fluoxetine, and fluvoxamine in a meta-analysis. Clomipramine was found to improve Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) by 37% in children and adolescents.
Clomipramine is used off-label for the treatment of patients with depression, anxiety, treatment-resistant depression, cataplexy syndrome, insomnia, neuropathic pain, chronic pain, body dysmorphic disorder, panic disorder, premature ejaculation, pediatric nocturnal enuresis, and trichotillomania.
Clomipramine is a tertiary amine belonging to the class of medications known as tricyclic antidepressants (TCA). It is a dibenzazepine TCA. Clomipramine is a serotonin reuptake inhibitor (S-RI) with a stronger affinity for the serotonin transporter (SERT), compared to other TCAs and S-RIs. The resulting action of clomipramine increases serotonergic and noradrenergic transmission.
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 has more noradrenergic activity than serotonergic. Experts often use fluvoxamine, a CYP450 1A2 inhibitor, with clomipramine in treatment-resistant OCD. By adding the CYP450 1A2 inhibitor, the conversion from clomipramine to desmethyl clomipramine is blocked, resulting in increased serotonergic activity.
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. Clomipramine is available in capsule form, as a hydrochloride salt, with dosages of 25 mg, 50 mg, and 75 mg. The initial dose for adults and children is 25 mg per day. The dose is titrated in increments of 25 mg per day every 4 to 7 days to a target dose between 100 mg to 250 mg per day. For children and adolescents, the typical daily dose is 1 to 3 mg per kg. The maximum daily dose, for both children and adults, is 250 mg per day. Clomipramine may be given in single or split doses, with the largest dose given at bedtime, due to the risk of sedation. Due to gastrointestinal side effects, patients may take it with meals; although absorption is not affected by food. Patients with trouble swallowing can open the capsules and mix the contents with soft foods such as applesauce or pudding (swallow the mixture without chewing).
The onset of action of clomipramine is usually between 6 to 12 weeks for OCD; it may treat anxiety or insomnia immediately. If OCD remission is achieved with clomipramine, treatment should continue indefinitely. 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. A later study noted that 40 to 60% of individuals given a trial of SRIs respond to treatment.
For non-responders or those with side effects, clomipramine may require discontinuation; to taper clomipramine, reduce the dose by 50% every 3 days until reaching the lowest dose of 25 mg per day and then discontinue. Abrupt discontinuation of clomipramine can result in patients experiencing withdrawal symptoms of dizziness, irritability, headache, vivid dreams, and flu-like symptoms.
Clomipramine is often augmented with buspirone, lithium, atypical antipsychotics, or fluvoxamine for OCD.
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.
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.
Adverse effects of clomipramine have been found in fetuses, as the medication crosses the placenta. Lethargy, congenital heart defects, and withdrawal have occurred in infants born to mothers taking clomipramine during pregnancy. Clomipramine may also be present in breast milk; therefore it is recommended to bottle feed or discontinue the medication if the risk outweighs the benefits. If the benefits outweigh the risk, clomipramine therapy may continue during pregnancy and breastfeeding.
Clomipramine is contraindicated in patients taking monoamine oxidase inhibitors (MAOI), or CYP450 2D6 inhibitors. Clomipramine therapy may not initiate until at least 14 days after discontinuation of the MAO. Other S-RIs or MAOIs may be added or started two weeks after discontinuation of clomipramine. CYP450 2D6 inhibitors may result in increased drug levels of clomipramine. Initiating clomipramine is contraindicated while being treated with linezolid or IV methylene blue, nor can it be started during the acute phase after myocardial infarction. Other contraindications to clomipramine include patients with any degree of heart block, prolonged QTc interval, arrhythmia, acute heart failure, mania, liver disease, narrow-angle glaucoma, urinary retention, or allergy to clomipramine.
Due to the risk of QTc prolongation and arrhythmia, electrocardiogram (EKG) testing is recommended at baseline and once therapeutic effect reached. Due to the risk of metabolic adverse effects, weight, body mass index (BMI), fasting plasma glucose, and fasting lipids are recommended at baseline and during treatment. In patients with risk of electrolyte imbalances, basic metabolic panel (BMP) in addition to magnesium, should be obtained at baseline and during treatment. In 7% of the population, a phenotypic variant of CYP450 2D6 is present; therefore dose reduction or phenotypic testing may be pursued. 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 with clomipramine is often associated with doses over 300 mg per day. 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 toxicity are arrhythmias, seizures, and hypotension. Coma and death may also occur in severe overdoses. The antidote for TCAs is IV sodium bicarbonate (NaHCO3), along with supportive care of vital signs.
Clomipramine in combination with S-RI, MAOI, or other serotonergic medications may result in serotonin syndrome, with a triad of altered mental status, myoclonus, and autonomic hyperactivity. The antidote in serotonin syndrome is cyproheptadine, along with supportive care of vital signs.
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 EKG at baseline and routinely during treatment. Providers including the pharmacist and nurses with specialty training in psychiatric health should also monitor for 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, discontinued, or the patient referred to a psychiatrist or mental health nurse. The treatment outcomes for clomipramine in OCD are superior to S-RIs, but adverse effects limit medication tolerability.
|||Psychopharmacological treatment of Obsessive-Compulsive Disorder (OCD)., Casale AD,Sorice S,Padovano A,Simmaco M,Ferracuti S,Lamis DA,Rapinesi C,Sani G,Girardi P,Kotzalidis GD,Pompili M,, Current neuropharmacology, 2018 Aug 13 [PubMed PMID: 30101713]|
|||Hollander E,Kaplan A,Allen A,Cartwright C, Pharmacotherapy for obsessive-compulsive disorder. The Psychiatric clinics of North America. 2000 Sep; [PubMed PMID: 10986733]|
|||Eddy KT,Dutra L,Bradley R,Westen D, A multidimensional meta-analysis of psychotherapy and pharmacotherapy for obsessive-compulsive disorder. Clinical psychology review. 2004 Dec; [PubMed PMID: 15533282]|
|||Greist JH,Jefferson JW,Kobak KA,Katzelnick DJ,Serlin RC, Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Archives of general psychiatry. 1995 Jan; [PubMed PMID: 7811162]|
|||Meyer JH,Wilson AA,Ginovart N,Goulding V,Hussey D,Hood K,Houle S, Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. The American journal of psychiatry. 2001 Nov; [PubMed PMID: 11691690]|
|||Montgomery SA,Baldwin DS,Blier P,Fineberg NA,Kasper S,Lader M,Lam RW,Lépine JP,Möller HJ,Nutt DJ,Rouillon F,Schatzberg AF,Thase ME, Which antidepressants have demonstrated superior efficacy? A review of the evidence. International clinical psychopharmacology. 2007 Nov; [PubMed PMID: 17917550]|
|||Hollander E,Allen A,Kwon J,Aronowitz B,Schmeidler J,Wong C,Simeon D, Clomipramine vs desipramine crossover trial in body dysmorphic disorder: selective efficacy of a serotonin reuptake inhibitor in imagined ugliness. Archives of general psychiatry. 1999 Nov; [PubMed PMID: 10565503]|
|||Palmer NR,Stuckey BG, Premature ejaculation: a clinical update. The Medical journal of Australia. 2008 Jun 2; [PubMed PMID: 18513177]|
|||Caldwell PH,Sureshkumar P,Wong WC, Tricyclic and related drugs for nocturnal enuresis in children. The Cochrane database of systematic reviews. 2016 Jan 20; [PubMed PMID: 26789925]|
|||Rothbart R,Amos T,Siegfried N,Ipser JC,Fineberg N,Chamberlain SR,Stein DJ, Pharmacotherapy for trichotillomania. The Cochrane database of systematic reviews. 2013 Nov 8; [PubMed PMID: 24214100]|
|||Franklin ME,Zagrabbe K,Benavides KL, Trichotillomania and its treatment: a review and recommendations. Expert review of neurotherapeutics. 2011 Aug; [PubMed PMID: 21797657]|
|||Kellner M, Drug treatment of obsessive-compulsive disorder. Dialogues in clinical neuroscience. 2010; [PubMed PMID: 20623923]|
|||Suhara T,Takano A,Sudo Y,Ichimiya T,Inoue M,Yasuno F,Ikoma Y,Okubo Y, High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Archives of general psychiatry. 2003 Apr; [PubMed PMID: 12695316]|
|||Pallanti S,Hollander E,Bienstock C,Koran L,Leckman J,Marazziti D,Pato M,Stein D,Zohar J, Treatment non-response in OCD: methodological issues and operational definitions. The international journal of neuropsychopharmacology. 2002 Jun; [PubMed PMID: 12135542]|
|||Warneke LB, The use of intravenous chlorimipramine in the treatment of obsessive compulsive disorder. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 1984 Mar; [PubMed PMID: 6722705]|
|||Warneke L, Intravenous chlorimipramine therapy in obsessive-compulsive disorder. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 1989 Dec; [PubMed PMID: 2611753]|
|||Bloch MH,Green C,Kichuk SA,Dombrowski PA,Wasylink S,Billingslea E,Landeros-Weisenberger A,Kelmendi B,Goodman WK,Leckman JF,Coric V,Pittenger C, Long-term outcome in adults with obsessive-compulsive disorder. Depression and anxiety. 2013 Aug; [PubMed PMID: 23532944]|
|||Dold M,Aigner M,Lanzenberger R,Kasper S, Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. The international journal of neuropsychopharmacology. 2013 Apr; [PubMed PMID: 22932229]|
|||Källén B,Otterblad Olausson P, Antidepressant drugs during pregnancy and infant congenital heart defect. Reproductive toxicology (Elmsford, N.Y.). 2006 Apr; [PubMed PMID: 16406480]|
|||Bloem BR,Lammers GJ,Roofthooft DW,De Beaufort AJ,Brouwer OF, Clomipramine withdrawal in newborns. Archives of disease in childhood. Fetal and neonatal edition. 1999 Jul; [PubMed PMID: 10744432]|
|||Clomipramine 2006; [PubMed PMID: 30000234]|
|||Bertilsson L,Dahl ML,Dalén P,Al-Shurbaji A, Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. British journal of clinical pharmacology. 2002 Feb; [PubMed PMID: 11851634]|