International Journal of Psychiatry in Clinical Practice, 2005; 9(1): 65 /67
CASE REPORT
Jaundice and hepatic enzyme induction during lamotrigine therapy in a bipolar II patient
SALIH SELEK1, HALUK A. SAVAS1, ESEN SAVAS2, HASAN HERKEN1, HAMDI TUTKUN1 & H. SERDAR GERGERLIOGLU3 Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
1
Psychiatry Department, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey and 2Department of Internal Medicine, State Hospital, Av. Cengiz Gokcek, Gaziantep, Turkey, 3Psychology Department, Gaziantep University, Gaziantep, Turkey
Abstract Lamotrigine is a novel mood stabiliser as well as an anti-epileptic drug that has already been used for the prevention of convulsions. Despite several known side effects, hepatic dysfunction related to the drug has not been widely reported. A few cases have been observed in neurological, especially paediatric patients, but not in psychiatric patients. We report a case of cholestatis which occurred 6 weeks after starting lamotrigine therapy and which resolved after discontinuation, during the acute phase of disease. To the best of our knowledge, this is the first case of lamotrigine associated with cholestasis reported in patients with bipolar disorder.
Key Words: Lamotrigine, cholestasis, bipolar II disorder
Introduction Lamotrigine is a new mood stabiliser, as well as antiepileptic drug, that has already been used for the prevention of convulsions. It has been recently approved by the United States Food and Drug Administration (FDA) [1,2,12]. Also well tolerated, the most common side effects associated with lamotrigine in the randomised phase of studies were: nausea, insomnia, somnolence, back pain, fatigue, rhinitis, non-serious rash, abdominal pain, dry mouth, constipation, vomiting, exacerbation of cough, pharyngitis [1]. Adverse events which occurred in ]/5% and were numerically more common in patients during the dose escalation phase of these trials, when patients may have been receiving concomitant psychotropic medications compared to the monotherapy phase, were: headache, rash, dizziness, diarrhoea, dream abnormality, and pruritus. It has also been associated with the rare, potentially lifethreatening Stevens/Johnson syndrome. Although hepatic dysfunction or injury due to drug administration has not been widely reported, and hepatic enzyme induction has been denied, several cases of hepatic dysfunction have been already reported, including porphyria and hepatic failure, which
responded to discontinuation [3 /7]. The hepatic side effects were assumed to be hypersensitivity, especially T-cell-related reactions in some cases [8,9]. All previous situations were observed in neurological diseases, and until now no cases related to psychiatric diseases have been reported [4]. In addition to the previous cases, we report a case of cholestatis which occurred 6 weeks after starting lamotrigine therapy and which resolved after discontinuation, during the acute phase of disease. To the best of our knowledge, this is the first case of lamotrigine associated with cholestasis reported for bipolar disorders. Case report A 19-year-old female, with no known history of liver disease, was followed as a bipolar II disorder patient in the Mood Disorders Unit of Gaziantep University Medical School. No other psychiatric illness was present according to DSM-IV criteria. A mood stabilising agent, lithium, was started initially. Since lithium 1500 mg daily with a 1.0 mmol/l serum level was not enough to cope with depressive/ hypomanic mood swings during 3 months followup, lamotrigine was then added to the management.
Correspondence: Haluk A. Savas, M.D., Department of Psychiatry, Faculty of Medicine, Gaziantep University, 27100 Gaziantep, Turkey. Tel: /90-3423606060. Fax: /90-342-3365505, ext. 76361. E-mail: [email protected]
(Received 6 June 2004; accepted 4 November 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014774
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
66
S. Selek et al.
Compliance was an additional problem during therapy, and the patient stopped taking lamotrigine due to health covery problems. Lamotrigine was restarted with an initial dose of 50 mg/day, escalated 50 mg/day weekly to a 200-mg daily dose. The psychiatric symptoms significantly resolved after 6 weeks, but the patient complained of jaundice and pruritus at the control visit, associated with an elevation of alkaline phosphatase and g-glutamyltransferase (GGT) up to 515 and 216 U/l, respectively. Total bilirubin was 4.69 mg/dl with a direct bilirubin dominance; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were, respectively, elevated 2- and 3-fold. There were no risk factors of viral liver disease and she denied any alcohol intake. On examination she was icteric; fever, skin rash, abdominal tenderness or palpable liver, spleen or abdominal mass were all absent. Serological studies for hepatitis A, B, C, were all negative, except for anti-Hepatitis A immunoglobulin G, indicating a previous infection not related to the current clinical condition. Total plasma bilirubin was significantly high (4.69 mg/dl) and direct bilirubin was raised (3.90 mg/dl) indicating cholestasis. In addition to the high urine urobilinogen (68 mmol/l), ultrasonography (US) was negative for biliary tract obstruction, gallbladder stones or pancreatic lesions. Thus, intrahepatic cholestasis was considered in this case. There was no biochemical/ genetic evidence of haemochromatosis or Wilson disease. Because of the temporal relationship between drug administration and cholestasis, a diagnosis of lamotrigine-associated cholestasis was considered. Lamotrigine was then discontinued. Seven days after discontinuation, jaundice was not clinically apparent and bilirubin, AST, ALT, ALP and GGT levels progressively decreased during fortnightly follow-ups. A full recovery from jaundice was achieved within 2 months. Discussion Lamotrigine is a new antiepileptic drug that inhibits the release of excitatory amino acids, primarily glutamate, and to a lesser extent, aspartate. Glucuronic acid metabolism in the liver is the main metabolic pathway of lamotrigine [10]. The most commonly reported side effects are dizziness, headache, diplopia, ataxia, and skin rash. The potential mechanisms by which lamotrigine may induce hepatotoxicity are not known. Allergic mechanisms are probably important, at least in some patients reported previously. A direct toxic effect of one of the lamotrigine metabolites may explain the occurrence of his toxicity in patients on polytherapy. In spite of the few reported cases in neurological, especially paediatric patients, such a clinical situation in adult psychiatric patients has not yet been reported. Because lamotrigine has been newly introduced for
psychiatric treatment, satisfactory information on its side effects is scarcely available. Though the patient received additional medication such as lithium, the jaundice emerging on starting lamotrigine and resolving completely after discontinuation, suggested a relationship between the acute disease state and lamotrigine. The temporal relationship between the initiation of the lamotrigine therapy and the reversal of the liver abnormalities with lamotrigine discontinuation argues against a cause other than lamotrigine; however, because of the complexity of the previously reported cases, the causality remains a general assumption. In the report by Arnon et al., a child was treated rather quickly with lamotrigine and had been previously comedicated with valproic acid, resembling our titration regimen; however, no data of drug interactions between lamotrigine and other applied medications (in our patient lithium) have yet been reported [5]. In addition, dominantly elevated plasma direct bilirubin, high urine urobilinogen levels and no ultrasonography findings indicated an intrahepatic cholestasis, which was a feature already mentioned but not emphasised adequately in previous cases [4,5]. Thus, the possibility of hepatic compromise should be considered in a patient taking lamotrigine if jaundice becomes evident. Emphasising that it has already been widely used in academic clinical settings for mood disorders, recent research promises an arousal of interest in the drug’s all over effects [13]. Nevertheless, its side effects still appear to be controversial. In conclusion, further evidence has to be acquired to define a clear cause-and-effect relationship. Conclusion Psychiatric experience with lamotrigine is still somewhat limited. Although recent research has underlined the safety of the drug, we report a case of jaundice that began with lamotrigine administration and resolved completely after discontinuation. To the best of our knowledge, this is the first case of cholestatic jaundice observed in psychiatric patients [11]. Based on this experience, because of our case, we recommend monitoring hepatic function during lamotrigine therapy. As a result, it is imperative that
Key points . As reccomended previously, regular liver function test screenings before and during lamotrigine administration is suggested . In contrast with previous cases, the present case had expressive cholestatic jaundice . This is the first case of jaundice associated with lamotrigine in psychiatric patients
Lamotrigine and jaundice further research be made to understand lamotrigine and its effects in bipolar patients
[6]
Statement of interest The author has no conflict of interest with any commercial or other associations in connection with the submitted article.
[7] [8]
[9]
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
References [1] Post RM, Denicoff KD, Leverich GS, et al. Presentations of depression in bipolar illness. Clinical Neurosci Res 2002;2:142 /57. [2] Bowden CL, Calabrese JR, Sachs G, et al. A placebocontrolled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003;60:392 / 400. [3] Gaida-Hommernick B, Rieck K, Runge U. Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report. Epilepsia 2001;42:793 /5 [Comment in Epilepsia 2002;43:455.]. [4] Fayad M, Choueiri R, Mikati M. Potential hepatotoxicity of lamotrigine. Pediatr Neurol 2000;22:49 /52. [5] Arnon R, DeVivo D, Defelice AR, Kazlow PG, Arnon R, DeVivo D, Defelice AR, Kazlow PG. Acute hepatic failure
[10]
[11]
[12]
[13]
67
in a child treated with lamotrigine. Pediatr Neurol 1998; 18:251 /2. Haider A, Tuchek JM. Seizure control: how to use the new antiepileptic drugs in older patients. Geriatrics 1996;51:42 / 5. Meldrum BS. Lamotrigine / A novel approach. Seizure 1994;3(Suppl A):41 /5. Galindo PA, Borja J, Gomez E, Mur P, Gudin M, Garcia R, et al. Anticonvulsant drug hypersensitivity. J Invest Allergol Clin Immunol 2002;12:299 /304. Leeder JS. Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 1998;39(Suppl 7):S8 /16. Magdalou J, Herber R, Bidault R, Siest G. In vitro N glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharmacol Exp Ther 1992;260:1166 /73. Bowden CL, Asnis GM, Ginsberg LD, Bentley B, Leadbetter R, White R. Safety and tolerability of lamotrigine for bipolar disorder. Drug Saf 2004;27:173 /84. Gareri P, Falconi U, De Fazio P, De Sarro G. Conventional and new antidepressant drugs in the elderly. Prog Neurobiol 2000;61:353 /96. Marangell LB, Martinez JM, Ketter TA, Bowden CL, Goldberg JF, Calabrese JR, et al. Lamotrigine treatment of bipolar disorder: data from the first 500 patients in STEPBD. Bipolar Disord 2004;6:139 /43.
CASE REPORT
Jaundice and hepatic enzyme induction during lamotrigine therapy in a bipolar II patient
SALIH SELEK1, HALUK A. SAVAS1, ESEN SAVAS2, HASAN HERKEN1, HAMDI TUTKUN1 & H. SERDAR GERGERLIOGLU3 Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
1
Psychiatry Department, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey and 2Department of Internal Medicine, State Hospital, Av. Cengiz Gokcek, Gaziantep, Turkey, 3Psychology Department, Gaziantep University, Gaziantep, Turkey
Abstract Lamotrigine is a novel mood stabiliser as well as an anti-epileptic drug that has already been used for the prevention of convulsions. Despite several known side effects, hepatic dysfunction related to the drug has not been widely reported. A few cases have been observed in neurological, especially paediatric patients, but not in psychiatric patients. We report a case of cholestatis which occurred 6 weeks after starting lamotrigine therapy and which resolved after discontinuation, during the acute phase of disease. To the best of our knowledge, this is the first case of lamotrigine associated with cholestasis reported in patients with bipolar disorder.
Key Words: Lamotrigine, cholestasis, bipolar II disorder
Introduction Lamotrigine is a new mood stabiliser, as well as antiepileptic drug, that has already been used for the prevention of convulsions. It has been recently approved by the United States Food and Drug Administration (FDA) [1,2,12]. Also well tolerated, the most common side effects associated with lamotrigine in the randomised phase of studies were: nausea, insomnia, somnolence, back pain, fatigue, rhinitis, non-serious rash, abdominal pain, dry mouth, constipation, vomiting, exacerbation of cough, pharyngitis [1]. Adverse events which occurred in ]/5% and were numerically more common in patients during the dose escalation phase of these trials, when patients may have been receiving concomitant psychotropic medications compared to the monotherapy phase, were: headache, rash, dizziness, diarrhoea, dream abnormality, and pruritus. It has also been associated with the rare, potentially lifethreatening Stevens/Johnson syndrome. Although hepatic dysfunction or injury due to drug administration has not been widely reported, and hepatic enzyme induction has been denied, several cases of hepatic dysfunction have been already reported, including porphyria and hepatic failure, which
responded to discontinuation [3 /7]. The hepatic side effects were assumed to be hypersensitivity, especially T-cell-related reactions in some cases [8,9]. All previous situations were observed in neurological diseases, and until now no cases related to psychiatric diseases have been reported [4]. In addition to the previous cases, we report a case of cholestatis which occurred 6 weeks after starting lamotrigine therapy and which resolved after discontinuation, during the acute phase of disease. To the best of our knowledge, this is the first case of lamotrigine associated with cholestasis reported for bipolar disorders. Case report A 19-year-old female, with no known history of liver disease, was followed as a bipolar II disorder patient in the Mood Disorders Unit of Gaziantep University Medical School. No other psychiatric illness was present according to DSM-IV criteria. A mood stabilising agent, lithium, was started initially. Since lithium 1500 mg daily with a 1.0 mmol/l serum level was not enough to cope with depressive/ hypomanic mood swings during 3 months followup, lamotrigine was then added to the management.
Correspondence: Haluk A. Savas, M.D., Department of Psychiatry, Faculty of Medicine, Gaziantep University, 27100 Gaziantep, Turkey. Tel: /90-3423606060. Fax: /90-342-3365505, ext. 76361. E-mail: [email protected]
(Received 6 June 2004; accepted 4 November 2004) ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510014774
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
66
S. Selek et al.
Compliance was an additional problem during therapy, and the patient stopped taking lamotrigine due to health covery problems. Lamotrigine was restarted with an initial dose of 50 mg/day, escalated 50 mg/day weekly to a 200-mg daily dose. The psychiatric symptoms significantly resolved after 6 weeks, but the patient complained of jaundice and pruritus at the control visit, associated with an elevation of alkaline phosphatase and g-glutamyltransferase (GGT) up to 515 and 216 U/l, respectively. Total bilirubin was 4.69 mg/dl with a direct bilirubin dominance; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were, respectively, elevated 2- and 3-fold. There were no risk factors of viral liver disease and she denied any alcohol intake. On examination she was icteric; fever, skin rash, abdominal tenderness or palpable liver, spleen or abdominal mass were all absent. Serological studies for hepatitis A, B, C, were all negative, except for anti-Hepatitis A immunoglobulin G, indicating a previous infection not related to the current clinical condition. Total plasma bilirubin was significantly high (4.69 mg/dl) and direct bilirubin was raised (3.90 mg/dl) indicating cholestasis. In addition to the high urine urobilinogen (68 mmol/l), ultrasonography (US) was negative for biliary tract obstruction, gallbladder stones or pancreatic lesions. Thus, intrahepatic cholestasis was considered in this case. There was no biochemical/ genetic evidence of haemochromatosis or Wilson disease. Because of the temporal relationship between drug administration and cholestasis, a diagnosis of lamotrigine-associated cholestasis was considered. Lamotrigine was then discontinued. Seven days after discontinuation, jaundice was not clinically apparent and bilirubin, AST, ALT, ALP and GGT levels progressively decreased during fortnightly follow-ups. A full recovery from jaundice was achieved within 2 months. Discussion Lamotrigine is a new antiepileptic drug that inhibits the release of excitatory amino acids, primarily glutamate, and to a lesser extent, aspartate. Glucuronic acid metabolism in the liver is the main metabolic pathway of lamotrigine [10]. The most commonly reported side effects are dizziness, headache, diplopia, ataxia, and skin rash. The potential mechanisms by which lamotrigine may induce hepatotoxicity are not known. Allergic mechanisms are probably important, at least in some patients reported previously. A direct toxic effect of one of the lamotrigine metabolites may explain the occurrence of his toxicity in patients on polytherapy. In spite of the few reported cases in neurological, especially paediatric patients, such a clinical situation in adult psychiatric patients has not yet been reported. Because lamotrigine has been newly introduced for
psychiatric treatment, satisfactory information on its side effects is scarcely available. Though the patient received additional medication such as lithium, the jaundice emerging on starting lamotrigine and resolving completely after discontinuation, suggested a relationship between the acute disease state and lamotrigine. The temporal relationship between the initiation of the lamotrigine therapy and the reversal of the liver abnormalities with lamotrigine discontinuation argues against a cause other than lamotrigine; however, because of the complexity of the previously reported cases, the causality remains a general assumption. In the report by Arnon et al., a child was treated rather quickly with lamotrigine and had been previously comedicated with valproic acid, resembling our titration regimen; however, no data of drug interactions between lamotrigine and other applied medications (in our patient lithium) have yet been reported [5]. In addition, dominantly elevated plasma direct bilirubin, high urine urobilinogen levels and no ultrasonography findings indicated an intrahepatic cholestasis, which was a feature already mentioned but not emphasised adequately in previous cases [4,5]. Thus, the possibility of hepatic compromise should be considered in a patient taking lamotrigine if jaundice becomes evident. Emphasising that it has already been widely used in academic clinical settings for mood disorders, recent research promises an arousal of interest in the drug’s all over effects [13]. Nevertheless, its side effects still appear to be controversial. In conclusion, further evidence has to be acquired to define a clear cause-and-effect relationship. Conclusion Psychiatric experience with lamotrigine is still somewhat limited. Although recent research has underlined the safety of the drug, we report a case of jaundice that began with lamotrigine administration and resolved completely after discontinuation. To the best of our knowledge, this is the first case of cholestatic jaundice observed in psychiatric patients [11]. Based on this experience, because of our case, we recommend monitoring hepatic function during lamotrigine therapy. As a result, it is imperative that
Key points . As reccomended previously, regular liver function test screenings before and during lamotrigine administration is suggested . In contrast with previous cases, the present case had expressive cholestatic jaundice . This is the first case of jaundice associated with lamotrigine in psychiatric patients
Lamotrigine and jaundice further research be made to understand lamotrigine and its effects in bipolar patients
[6]
Statement of interest The author has no conflict of interest with any commercial or other associations in connection with the submitted article.
[7] [8]
[9]
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Melbourne on 10/26/14 For personal use only.
References [1] Post RM, Denicoff KD, Leverich GS, et al. Presentations of depression in bipolar illness. Clinical Neurosci Res 2002;2:142 /57. [2] Bowden CL, Calabrese JR, Sachs G, et al. A placebocontrolled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003;60:392 / 400. [3] Gaida-Hommernick B, Rieck K, Runge U. Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report. Epilepsia 2001;42:793 /5 [Comment in Epilepsia 2002;43:455.]. [4] Fayad M, Choueiri R, Mikati M. Potential hepatotoxicity of lamotrigine. Pediatr Neurol 2000;22:49 /52. [5] Arnon R, DeVivo D, Defelice AR, Kazlow PG, Arnon R, DeVivo D, Defelice AR, Kazlow PG. Acute hepatic failure
[10]
[11]
[12]
[13]
67
in a child treated with lamotrigine. Pediatr Neurol 1998; 18:251 /2. Haider A, Tuchek JM. Seizure control: how to use the new antiepileptic drugs in older patients. Geriatrics 1996;51:42 / 5. Meldrum BS. Lamotrigine / A novel approach. Seizure 1994;3(Suppl A):41 /5. Galindo PA, Borja J, Gomez E, Mur P, Gudin M, Garcia R, et al. Anticonvulsant drug hypersensitivity. J Invest Allergol Clin Immunol 2002;12:299 /304. Leeder JS. Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 1998;39(Suppl 7):S8 /16. Magdalou J, Herber R, Bidault R, Siest G. In vitro N glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharmacol Exp Ther 1992;260:1166 /73. Bowden CL, Asnis GM, Ginsberg LD, Bentley B, Leadbetter R, White R. Safety and tolerability of lamotrigine for bipolar disorder. Drug Saf 2004;27:173 /84. Gareri P, Falconi U, De Fazio P, De Sarro G. Conventional and new antidepressant drugs in the elderly. Prog Neurobiol 2000;61:353 /96. Marangell LB, Martinez JM, Ketter TA, Bowden CL, Goldberg JF, Calabrese JR, et al. Lamotrigine treatment of bipolar disorder: data from the first 500 patients in STEPBD. Bipolar Disord 2004;6:139 /43.
