Molindone is a conventional antipsychotic used in the therapy of schizophrenia. Molindone therapy is commonly associated with minor serum aminotransferase elevations but has rarely been linked to cases of clinically apparent acute liver injury.
Molindone (moe lin' done) is a dihydroindolone antipsychotic medication that is not structurally related to the phenothiazines and which appears to act by blocking dopamine type 2 (D2) receptors. Molindone has other central and peripheral effects including anticholinergic and alpha adrenergic blockade. Molindone was approved for use in the therapy of psychotic disorders in the United States in 1974. Since then, however, molindone has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Molidone was withdrawn from use in the United States in 2013, but was previously available as tablets of 5, 10, 25 and 50 mg generically and under the brand name Moban. Recommended doses of molindone were 50 to 75 mg daily initially, increasing based upon efficacy and tolerance to as high as 225 mg daily. Common side effects included drowsiness, dizziness, headache, blurred vision, dry mouth, and tremor.
Liver test abnormalities have been reported to occur in a small proportion of patients on long term therapy with molindone, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to molindone, but are rare. The onset of injury is within 4 to 8 weeks, and the pattern of serum enzyme elevations is typically hepatocellular. Jaundice is uncommon and most cases are self-limited and mild. Immunoallergic features and autoantibody formation are not typical.
Mechanism of Injury
The mechanism by which molindone causes serum aminotransferase elevations is not known, but is likely due to production of a toxic intermediate by its metabolism. Molindone is extensively metabolized by the liver via sulfoxidation and oxidation, partially via the P450 system.
Outcome and Management
The serum aminotransferase elevations that occur on molindone therapy are usually self-limited and do not require dose modification or discontinuation of therapy. No instances of acute liver failure or vanishing bile duct syndrome due to molindone have been reported. Patients with molindone induced liver injury probably do not have cross sensitivity to atypical antipsychotics.
REPRESENTATIVE TRADE NAMES
Molindone – Moban®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 February 2014
Zimmerman HJ. Neuroleptic drugs. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 483-91. (Expert review of hepatotoxicity of neuroleptic drugs including molindone published in 1999; mentions that molindone can cause serum aminotransferase elevations and has been linked to rare cases of clinically apparent cases of liver injury).
Larrey D, Ripault MP. Molindone. Hepatotoxicity of psychotropic drugs and drugs of abuse.
In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam:
Elsevier, 2013, pp. 455. (Review of hepatotoxicity of psychiatric agents mentions mentions a single case of clinically apparent liver injury due to molindone).
Meyer JM. Pharmacotherapy of psychosis and mania. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 417-55. (Textbook of pharmacology and therapeutics).
Kellner R, Rada RT, Egelman A, Macaluso B. Long-term study of molindone hydrochloride in chronic schizophrenics. Curr Ther Res Clin Exp 1976; 20: 686-94. PubMed Citation (Open label study of molindone for 6 months in 23 patients; 2 had minimal ALT elevations; no details given).
Bhatia SC, Banta LE, Ehrlich DW. Molindone and hepatotoxicity. Drug Intell Clin Pharm 1985; 19: 744-6. PubMed Citation (17 year old male developed fever and fatigue 4 weeks after starting molindone [bilirubin 0.3 mg/dL, ALT 694 U/L, Alk P 100 U/L], resolving within 3 weeks of stopping; rechallenge for 4 days led to ALT elevations [134 U/L]; patient later tolerated thioridazine; authors mention 11 previous instances of hepatotoxicity, all of which were asymptomatic and self-limited).
Claghorn JL. Review of clinical and laboratory experiences with molindone hydrochloride. J Clin Psychiatry 1985; 46(8 Pt 2): 30-3. PubMed Citation (Review of pharmacokinetics, mechanism of action and efficacy of molindone; no mention of hepatic side effects).
Munyon WH, Salo R, Briones DF. Cytotoxic effects of neuroleptic drugs. Psychopharmacology(Berl) 1987; 91: 182-8. PubMed Citation (In vitro testing for cytotoxicity suggested that the phenothiazines are the most, haloperidol intermediate and loxapine and molindone the least toxic).
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 Citation (Systematic review of 81 articles on weight change with antipsychotics, using change after 10 weeks to compare agents: 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).
Bagnall A, Fenton M, Kleijnen J, Lewis R. Molindone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2007;(1): CD002083. PubMed Citation (Cochrane review of efficacy and safety; no mention of hepatotoxicity or serum ALT elevations).
Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, Ambler D, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders(TEOSS) study. Am J Psychiatry 2008; 165: 1420-31. PubMed Citation (Prospective trial of molindone [1st generation] vs olanzapine or risperidone [2nd generation] for schizophrenia in 119 youths found similar rates of efficacy [34-50%], but more weight gain [mean 6.1 kg] and ALT elevations with olanzapine).
Torrent C, Amann B, Sanchez-Moreno J, Colom F, Feinares M, Comes M, Rosa AR, et al. Weight gain in bipolar disorder: pharmacological treatment as a contributing factor. Acta Psychiatr Scand 2008; 118: 4-18. PubMed Citation (Review of frequency of weight gain in patients treated for bipolar disorders, most weight gain occurred with clozapine and olanzapine, but some weight gain also with quetiapine, risperidone, lithium, valproate and gabapentin; little or none with molindone, loxapine, carbamazepine and lamotrigine).
Findling RL, Johnson JL, McClellan J, Frazier JA, Vitiello B, Hamer RM, Lieberman JA, et al. Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study. J Am Acad Child Adolesc Psychiatry 2010; 49: 583-94; PubMed Citation (119 youths with early onset schizophrenia were treated with olanzapine, risperidone or molindone for 8 weeks and 54 were treated in a maintenance study; those on molindone showed the highest numerical increases in ALT [increase of 3-5 U/L], but there were no drug discontinuations for liver disease).
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