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Lamotrigine might potentiate valproic acid-induced hyperammonemic encephalopathy
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1747–1748
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report)
Lamotrigine might potentiate valproic acid-induced hyperammonemic encephalopathy 1. Introduction The combined use of lamotrigine (LTG) and valproic acid (VPA) is increasingly being used for a wide range of neuropsychiatric disorders including seizure control and bipolar disorder (Grof, 2003). Though beneficial, it is also associated with increased risk for the occurrence of adverse effects (Hahn et al., 2004). The reported adverse effects are largely lamotrigine-related, partly because VPA can cause a two to three fold increase in plasma concentration of LTG (Anderson et al., 1996). Previous reviews on valproic acidinduced hyperammonemic encephalopathy (VHE) indicated that polypharmacy is an important risk factor for VHE (Carr and Shrewsbury, 2007; McCall and Bourgeois, 2004; Dealberto, 2007). However, there has been a paucity of concern in the literature regarding the potential effect of co-administrating LTG on VHE (Dealberto, 2007; Kimmel et al., 2005). Therefore, we present a patient who developed VHE exclusively during concomitant treatment with VPA and LTG in the psychiatric setting. 2. Case report A 72-year-old female patient had suffered from multiple recurrent manic episodes with psychotic features since the age of 57 when she was first diagnosed as having bipolar I disorder. Under the combination treatment of valproic acid and clozapine, she had maintained a stable condition in the recent 2 years without laboratory evidence of hyperammonemia or signs of VHE. However, she was again hospitalized for a full-blown manic episode with psychosis following two months of poor drug compliance to sodium valproate 900 mg/day and clozapine 125 mg/day. After 3 weeks of admission, the manic symptoms attenuated under valproate 900 mg/day (blood level 105.8 μg/mL) and clozapine 150 mg/day. Her liver enzymes, ammonia level, and electroencephalogram (EEG) showed normal results at that time. She was well-oriented and had only subtle cognitive impairment. The score on Mini-Mental State Examination was 24. However, her mood switched to severe depression with psychomotor retardation rapidly after 1 week following the resolution of manic symptoms. LTG was then added for 12.5 mg/day initially, with an increment rate of 12.5 mg every 3 days up to final dose of 75 mg/day in 2 weeks. She did not report any side effects of LTG and the depression improved significantly. But general weakness, hand tremor, lethargy and asterixis developed after 3 weeks of valproate–lamotrigine combination therapy. EEG revealed typical triphasic waves. The ammonia level elevated to 101 μg/dL (reference range: 15–51 μg/dL) while VPA level was 85.9 μg/mL and liver enzymes in normal range. Concerning possible 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.06.006
VHE, valproate was discontinued immediately. Her symptoms of VHE resolved in the subsequent 1 week, with ammonia level 38 μg/ dL and normal EEG finding. Throughout the course, clozapine dose has been kept at 150 mg/day. Unfortunately, her manic symptoms relapsed 2 weeks later. LTG was then discontinued and sodium valproate 700 mg/day was reintroduced at a level of 94.7 μg/mL. Her manic symptoms improved 1 week later without recurrence of hyperammonemia or VHE hereafter. 3. Discussion Our case developed the typical symptoms of hyperammonemic encephalopathy (Carr and Shrewsbury, 2007; McCall and Bourgeois, 2004) only when she was receiving both LTG and VPA, but not when receiving LTG or VPA alone. Therefore, this combination regimen could account for the development of her hyperammonemia, rather than the non-altering use of clozapine. The major metabolic pathways of VPA are glucuronidation, via UDP-glucuronyltransferase (UGT), and β-oxidation (Anderson et al., 1996). Given that UGT is also responsible for the metabolism of LTG, the competitive interaction for UGT between VPA and LTG might make VPA tend to be metabolized through β-oxidation (Anderson et al., 1996). The resulted VPA metabolite, such as 4-en-VPA, indirectly inhibits fatty acid oxidation and ultimately interrupts urea cycle, leading to ammonia accumulation as well as the occurrence of VHE (McCall and Bourgeois, 2004). The emergence of VHE is indeed an unpredictable adverse effect, irrespective of the dosage or length of VPA treatment (McCall and Bourgeois, 2004; Dealberto, 2007). To date, the only case report in literature stating VHE induced potentially by VPA and LTG is reported by Kimmel and colleagues (2005), describing a VPA-treated patient that experienced VHE after adding LTG and lorazepam. Regarding this case, some authors suggested lorazepam rather than LTG, when combining with VPA, was the main cause to trigger VHE (Carr and Shrewsbury, 2007), but others emphasized that the potential effect of LTG on VHE cannot be ignored (Dealberto, 2007). However, our patient did not administer benzodiazepines during the treatment course. And the fact that she had not experienced hyperammonemic events under VPA treatment for 2 years also argues against the possibility that she had urea cycle disorders, which may precipitate VHE. Hence, concomitant LTG is postulated to explain the triggering of VHE in our case. Adding back VPA afterwards without re-emergence of VHE further supports this point. The titration rate of LTG in our case was faster than recommended (Hahn et al., 2004). However, the recommended titration
1748
Letter to the Editor (Case report)
rate is to avoid possible lamotrigine-related adverse reaction rather than the risk for enhancing VHE (Hahn et al., 2004). Besides, VHE could still occur despite the patient being under slow titration of LTG over 4 months (Kimmel et al., 2005). The potential effect of rapid LTG titration on VHE during concurrent dosing of VPA and LTG cannot be completely excluded in our case, which needs further investigation in the future. In sum, this case report clearly suggests that the risk for VHE may be increased by concomitant treatment of LTG and VPA. If mental status changes or new neurological symptoms appear in patients under this regimen, the ammonia level and EEG should be checked with care. References Anderson GD, Yau MK, Gidal BE, Harris SJ, Levy RH, Lai AA, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996;60:145–56. Carr RB, Shrewsbury K. Hyperammonemia due to valproic acid in the psychiatric setting. Am J Psychiatry 2007;164:1020–7. Dealberto MJ. Valproate-induced hyperammonaemic encephalopathy: review of 14 cases in the psychiatric setting. Int Clin Psychopharmacol 2007;22:330–7. Grof P. Selecting effective long-term treatment for bipolar patients: monotherapy and combinations. J Clin Psychiatry 2003;64:53–61. Hahn CG, Gyulai L, Baldassano CF, Lenox RH. The current understanding of lamotrigine as a mood stabilizer. J Clin Psychiatry 2004;65:791–804.
Kimmel RJ, Irwin SA, Meyer JM. Valproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric setting. Int Clin Psychopharmacol 2005;20:57–8. Mccall M, Bourgeois JA. Valproic acid-induced hyperammonemia: a case report. J Clin Psychopharmacol 2004;24:521–6.
Chun Chieh Fan Ming Chyi Huang Hsing Cheng Liu⁎ Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan ⁎Corresponding author. Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, #309, Sung-Te Road, 110, Taipei, Taiwan. Tel.: +886 2 2726 3141x1219; fax: +886 2 2726 7246. E-mail address: [email protected] (H.C. Liu). Ming Chyi Huang Hsing Cheng Liu Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan 8 April 2008
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report)
Lamotrigine might potentiate valproic acid-induced hyperammonemic encephalopathy 1. Introduction The combined use of lamotrigine (LTG) and valproic acid (VPA) is increasingly being used for a wide range of neuropsychiatric disorders including seizure control and bipolar disorder (Grof, 2003). Though beneficial, it is also associated with increased risk for the occurrence of adverse effects (Hahn et al., 2004). The reported adverse effects are largely lamotrigine-related, partly because VPA can cause a two to three fold increase in plasma concentration of LTG (Anderson et al., 1996). Previous reviews on valproic acidinduced hyperammonemic encephalopathy (VHE) indicated that polypharmacy is an important risk factor for VHE (Carr and Shrewsbury, 2007; McCall and Bourgeois, 2004; Dealberto, 2007). However, there has been a paucity of concern in the literature regarding the potential effect of co-administrating LTG on VHE (Dealberto, 2007; Kimmel et al., 2005). Therefore, we present a patient who developed VHE exclusively during concomitant treatment with VPA and LTG in the psychiatric setting. 2. Case report A 72-year-old female patient had suffered from multiple recurrent manic episodes with psychotic features since the age of 57 when she was first diagnosed as having bipolar I disorder. Under the combination treatment of valproic acid and clozapine, she had maintained a stable condition in the recent 2 years without laboratory evidence of hyperammonemia or signs of VHE. However, she was again hospitalized for a full-blown manic episode with psychosis following two months of poor drug compliance to sodium valproate 900 mg/day and clozapine 125 mg/day. After 3 weeks of admission, the manic symptoms attenuated under valproate 900 mg/day (blood level 105.8 μg/mL) and clozapine 150 mg/day. Her liver enzymes, ammonia level, and electroencephalogram (EEG) showed normal results at that time. She was well-oriented and had only subtle cognitive impairment. The score on Mini-Mental State Examination was 24. However, her mood switched to severe depression with psychomotor retardation rapidly after 1 week following the resolution of manic symptoms. LTG was then added for 12.5 mg/day initially, with an increment rate of 12.5 mg every 3 days up to final dose of 75 mg/day in 2 weeks. She did not report any side effects of LTG and the depression improved significantly. But general weakness, hand tremor, lethargy and asterixis developed after 3 weeks of valproate–lamotrigine combination therapy. EEG revealed typical triphasic waves. The ammonia level elevated to 101 μg/dL (reference range: 15–51 μg/dL) while VPA level was 85.9 μg/mL and liver enzymes in normal range. Concerning possible 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.06.006
VHE, valproate was discontinued immediately. Her symptoms of VHE resolved in the subsequent 1 week, with ammonia level 38 μg/ dL and normal EEG finding. Throughout the course, clozapine dose has been kept at 150 mg/day. Unfortunately, her manic symptoms relapsed 2 weeks later. LTG was then discontinued and sodium valproate 700 mg/day was reintroduced at a level of 94.7 μg/mL. Her manic symptoms improved 1 week later without recurrence of hyperammonemia or VHE hereafter. 3. Discussion Our case developed the typical symptoms of hyperammonemic encephalopathy (Carr and Shrewsbury, 2007; McCall and Bourgeois, 2004) only when she was receiving both LTG and VPA, but not when receiving LTG or VPA alone. Therefore, this combination regimen could account for the development of her hyperammonemia, rather than the non-altering use of clozapine. The major metabolic pathways of VPA are glucuronidation, via UDP-glucuronyltransferase (UGT), and β-oxidation (Anderson et al., 1996). Given that UGT is also responsible for the metabolism of LTG, the competitive interaction for UGT between VPA and LTG might make VPA tend to be metabolized through β-oxidation (Anderson et al., 1996). The resulted VPA metabolite, such as 4-en-VPA, indirectly inhibits fatty acid oxidation and ultimately interrupts urea cycle, leading to ammonia accumulation as well as the occurrence of VHE (McCall and Bourgeois, 2004). The emergence of VHE is indeed an unpredictable adverse effect, irrespective of the dosage or length of VPA treatment (McCall and Bourgeois, 2004; Dealberto, 2007). To date, the only case report in literature stating VHE induced potentially by VPA and LTG is reported by Kimmel and colleagues (2005), describing a VPA-treated patient that experienced VHE after adding LTG and lorazepam. Regarding this case, some authors suggested lorazepam rather than LTG, when combining with VPA, was the main cause to trigger VHE (Carr and Shrewsbury, 2007), but others emphasized that the potential effect of LTG on VHE cannot be ignored (Dealberto, 2007). However, our patient did not administer benzodiazepines during the treatment course. And the fact that she had not experienced hyperammonemic events under VPA treatment for 2 years also argues against the possibility that she had urea cycle disorders, which may precipitate VHE. Hence, concomitant LTG is postulated to explain the triggering of VHE in our case. Adding back VPA afterwards without re-emergence of VHE further supports this point. The titration rate of LTG in our case was faster than recommended (Hahn et al., 2004). However, the recommended titration
1748
Letter to the Editor (Case report)
rate is to avoid possible lamotrigine-related adverse reaction rather than the risk for enhancing VHE (Hahn et al., 2004). Besides, VHE could still occur despite the patient being under slow titration of LTG over 4 months (Kimmel et al., 2005). The potential effect of rapid LTG titration on VHE during concurrent dosing of VPA and LTG cannot be completely excluded in our case, which needs further investigation in the future. In sum, this case report clearly suggests that the risk for VHE may be increased by concomitant treatment of LTG and VPA. If mental status changes or new neurological symptoms appear in patients under this regimen, the ammonia level and EEG should be checked with care. References Anderson GD, Yau MK, Gidal BE, Harris SJ, Levy RH, Lai AA, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996;60:145–56. Carr RB, Shrewsbury K. Hyperammonemia due to valproic acid in the psychiatric setting. Am J Psychiatry 2007;164:1020–7. Dealberto MJ. Valproate-induced hyperammonaemic encephalopathy: review of 14 cases in the psychiatric setting. Int Clin Psychopharmacol 2007;22:330–7. Grof P. Selecting effective long-term treatment for bipolar patients: monotherapy and combinations. J Clin Psychiatry 2003;64:53–61. Hahn CG, Gyulai L, Baldassano CF, Lenox RH. The current understanding of lamotrigine as a mood stabilizer. J Clin Psychiatry 2004;65:791–804.
Kimmel RJ, Irwin SA, Meyer JM. Valproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric setting. Int Clin Psychopharmacol 2005;20:57–8. Mccall M, Bourgeois JA. Valproic acid-induced hyperammonemia: a case report. J Clin Psychopharmacol 2004;24:521–6.
Chun Chieh Fan Ming Chyi Huang Hsing Cheng Liu⁎ Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan ⁎Corresponding author. Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, #309, Sung-Te Road, 110, Taipei, Taiwan. Tel.: +886 2 2726 3141x1219; fax: +886 2 2726 7246. E-mail address: [email protected] (H.C. Liu). Ming Chyi Huang Hsing Cheng Liu Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan 8 April 2008