OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Clomipramine	303-49-1	C19- H23-Cl-N2

ANNOTATED BIBLIOGRAPHY

References updated: 15 October 2017

• Zimmerman HJ. Tricyclic antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 495-8.

  (Expert review of hepatotoxicity published in 1999; hepatic injury caused by tricyclic antidepressants is less frequent and less consistent than with monamine oxidase inhibitors).
• Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62.

  (Review of tricylic antidepressant hepatotoxicity mentions that clomipramine has been implicated as a cause of hepatotoxicity with a latency of 1 week to 4 years and both hepatocellular and mixed patterns of injury).
• O'Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 397-416.

  (Textbook of pharmacology and therapeutics).
• Klerman GL, Cole JO. Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol Rev 1965; 17: 101-41. [PubMed: 14294030]

  (Extensive review of structure, pharmacology, clinical effects, mechanisms of action, drug interactions, and side effects of imipramine and related tricyclic antidepressants; jaundice is said to occur in 0.5 to 1% of treated patients and usually resolves rapidly with stopping).
• Clarke AE, Maritz VM, Denborough MA. Phenothiazines and jaundice. Aust N Z J Med 1972; 2: 376-82. [PubMed: 4144624]

  (Chlorpromazine and amitriptyline cause precipitation of proteins when added to human bile in vitro and hepatotoxicity of these agents may relate to this characteristic).
• Fiori MG. Tricyclic antidepressants: a review of their toxicology. Curr Dev Psychopharmacol 1977; 4: 71-110. [PubMed: 340145]

  (Review of cardiac, hepatic, neurological, fetal and psychotoxicity of tricyclic antidepressants; most cases of hepatotoxicity have been attributed to hypersensitivity, but tricyclics are taken up and extensively metabolized by hepatocytes and thus may produce a toxic or immunogenic intermediate).
• Døssing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol 1982; 17: 205-11. [PubMed: 6982502]

  (Among 572 cases of drug induced liver disease seen between 1968-78 in Denmark, psychotropic agents accounted for 93 cases, 54 of which were due to chlorpromazine; tricyclics were not specifically mentioned).
• Larrey D, Rueff B, Pessayre D, Algard M, Geneve J, Benhamou JP. Cross hepatotoxicity between tricyclic antidepressants. Gut 1986; 87-90. [PMC free article: PMC1433318] [PubMed: 3721296]

  (39 year old woman developed abdominal pain 2 weeks after starting amineptine [a tricyclic antidepressant], with fever and eosinophilia [bilirubin 1.2 mg/dL, ALT 1360 U/L, Alk P 1.5 times ULN] resolving rapidly on stopping, but recurring 7 days after starting clomipramine [ALT 1050 U/L, Alk P 1.5 times ULN], again resolving rapidly upon stopping).
• Geneve J, Larrey D, Pessayre D, Benhamou JP. Structure tricyclique des medicaments et hepatotoxicite. Gastroenterol Clin Biol 1987; 11: 242-9. [PubMed: 2884161]

  (Review of structural similarity and hepatotoxicity of tricyclic antidepressants focusing on amineptine, imipramine and amitriptyline).
• Pirmohamed MKL, Kittringham NR, Parkl BK. Idiosyncratic reactions to antidepressants: a review of the possible mechanism and predisposing factors. Pharm Ther 1992; 53: 105-25. [PubMed: 1641399]

  (Review of idiosyncratic reactions to antidepressants; possible mechanism of injury being production of a chemically reactive metabolite that is either directly toxic or induces a hypersensitivity reaction).
• Alderman CP, Atchison MM, McNeece JI. Concurrent agranulocytosis and hepatitis secondary to clomipramine therapy. Br J Psychiatry 1993; 162: 688-9. [PubMed: 8149124]

  (67 year old man developed elevations in ALT [510 U/L], but normal bilirubin and Alk P one month after starting clomipramine, with transient neutropenia lasting 14 days before recovery).
• Berson A, Fréneaux E, Larrey D, Lepage V, Douay C, Mallet C. Possible role of HLA in hepatotoxicity. An exploratory study. J Hepatol 1994; 20: 336-42. [PubMed: 8014443]

  (Human leukocyte antigen [HLA] haplotypes were determined in 71 patients with drug induced liver disease, 12 due to tricyclics, including 7 amineptine, 3 amitriptyline and 2 clomipramine; 6 [50%] were A11 positive including 2 of the 3 amitriptyline cases, but only 12% in controls).
• Remy AL, Larrey D, Pageaux GP, Desprez D, Ramos J, Michel H. Cross hepatotoxicity between tricyclic antidpressants and phenothiazines. Eur J Gastroenterol 1995; 7: 373-6. [PubMed: 7600146]

  (65 year old woman developed fatigue and serum enzyme elevations [ALT ~1300 U/L; Alk P ~380 U/L] 1 month after starting trimipramine; 3 years later, she developed nausea and ALT elevations 10 days after starting desipramine [ALT ~250 U/L], and 2 years later developed abdominal pain and fever and enzyme elevations [ALT ~1100 U/L, Alk P ~510 U/L] 8 days after starting cyamemazine; each time with rapid recovery and no jaundice).
• Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96. [PubMed: 10553730]

  (Systematic review of 81 articles on weight change with antipsychotics; using change after 10 weeks to compare: clozapine +5.7, olanzapine +4.2, chlorpromazine +4.2, risperidone +1.7, loxapine +0.6, haloperidol +0.5, ziprasidone +0.3, molindone -0.1, and pimozide -2.7 kilograms).
• Grohmann R, Rüther E, Engel RR, Hippius H. Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRIs. Pharmacopsychiatry 1999; 32: 21-8. [PubMed: 10071179]

  (Analysis of reporting of adverse events among inpatients in 29 German hospitals between 1993 to 1997; 896 severe adverse events among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).
• Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco MA, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135-7. [PubMed: 11874214]

  (Analysis of cases of hepatotoxicity from antidepressants in Spanish Pharmacovigilance System from 1989-1999, identified 99 cases; among SSRIs, 26 were due to fluoxetine, 14 paroxetine, 6 fluvoxamine, 5 sertraline, 3 venlafaxine and 2 citalopram; among tricyclics, 16 clomipramine 7 amitriptyline, 6 imipramine; among miscellaneous, 3 nefazodone and 1 trazodone; but all similar in rate ~1-3 per 100,000 patient-years of exposure except for nefazodone=29/100,000).
• Lucena M, Carvajal A, Andrade R, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003; 2: 249-62. [PubMed: 12904104]

  (Review of hepatotoxicity of antidepressants: antidepressant use has increased markedly between 1992 and 2002, accounting for 5% of cases of hepatotoxicity; tricyclics less likely to cause injury than MAO inhibitors; predominantly cholestatic patterns with onset in first 2-3 weeks; occasional reports of prolonged cholestasis).
• Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004; 37 Suppl 1: S39-45. [PubMed: 15052513]

  (53,042 patients treated with antidepressants in 35 psychiatric hospitals in Germany from 1993-2000 were monitored for adverse drug reactions; increased liver enzymes reported in 16% on tricyclics, 5.5% on SSRIs and 12% of monamine oxidase inhibitors).
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]

  (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 3 were due to amitriptyline with a relative risk of 14.2: estimated frequency of 6 per 100,000 person-year exposures).
• DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007; 41: 1201-11. [PubMed: 17609231]

  (Review of drug induced liver injury and summary analysis of reports of injury from MAO inhibitors, SSRIs, tricyclics and atypical agents).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, only 1 case was attributed to amitriptyline, no other tricyclic antidepressant mentioned).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury but none were linked to tricyclic antidepressants).
• Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N; Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. [PMC free article: PMC3634369] [PubMed: 21788760]

  (Among 30 children with suspected drug induced liver injury, half [n=15] were due to antimicrobials [minocycline 4, INH 3, azithromycin 3] and the rest largely due to anticonvulsants and CNS agents; one case was attributed to amitriptyline, but no other tricyclic antidepressant was listed).
• Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. [PubMed: 23914755]

  (Systematic review of the literature on hepatotoxicity of antidepressants discusses novel antidepressants and SSRIs, but not the tricyclics).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to a tricyclic antidepressant).
• Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171: 404-15. [PubMed: 24362450]

  (Review of hepatotoxicity of antidepressants, mentions 2 case reports of liver injury due to clomipramine with latency of about 1 month, hepatocellular pattern of injury and recovery in both: DeSanty [2007] and Larrey [1986]).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 20 cases [2%] were attributed to antidepressants, but none were due to clompiramine).
• Friedrich ME, Akimova E, Huf W, Konstantinidis A, Papageorgiou K, Winkler D, Toto S, et al. Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol 2016; 19. pii: pyv126. [PMC free article: PMC4851269] [PubMed: 26721950]

  (Among 184,234 psychiatric inpatients from 80 German, Austrian or Swiss hospitals, 149 cases [0.08%] of drug induced liver injury were reported, of which 13 occurred in 5,657 patients taking clomipramine [0.23%], which was higher than rates with other tricyclics, but most represented serum enzyme elevations without jaundice).
• Ferrajolo C, Scavone C, Donati M, Bortolami O, Stoppa G, Motola D, Vannacci A, et al.; DILI-IT Study Group. Antidepressant-induced acute liver injury: a case-control study in an Italian inpatient population. Drug Saf 2018; 41: 95-102. PubMed Citation. [PubMed: 28770534]

  (Among 179 cases of hospitalizations for unexplained acute liver injury enrolled in an prospective study between 2010 and 2014, 17 had been exposed to antidepressants including 1 who received clomipramine [bilirubin 4.5 mg/dL, ALT 389 U/L, Alk P not given]; outcomes not provided).