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OXCARBAZEPINE IN BIPOLAR DISORDER
LETTERS TO THE EDITOR
4:00 P.M. Polysomnography showed that nighttime sleep was severely shortened. Epileptiform activity as a cause for awakening was excluded by sleep electroencephalogram. Results of routine blood tests were normal. Multiple plasma melatonin measurements for 24 hours showed a normal melatonin profile with a melatonin peak during nighttime and almost undetectable levels during the day. In a first step, melatonin (6 mg) was administered at 8:00 P.M. and led to prolonged nighttime sleep (plus 2 hours). To avoid daytime sleep the patient was treated with methylphenidate (2.5 mg) at 1:00 P.M. Under this regimen the sleep-wake cycle synchronized to a regular 24-hour schedule with a total nighttime sleep duration of 10 hours. Successful treatment greatly reduced the burden to the patient’s family. The administration of melatonin led to improvement of nighttime sleep, although the melatonin profile previously had been normal in our patient. It has been reported that exogenous melatonin significantly advances sleep onset, delays sleep offset, and thus increases night sleep duration and reduces daytime napping (Jan and O’Donnell, 1996; Zhdanova et al., 1997). As blind subjects lack information about the circadian light-dark shift, they appear to require higher levels of melatonin to maintain a regular circadian rhythm (Zhdanova et al., 1997). In our patient, melatonin alone was able to prolong nighttime sleep for approximately 2 hours, but the situation was still unsatisfying because of awakenings between 2:00 and 5:00 A.M. Therefore, to additionally avoid daytime sleeping, we administered methylphenidate as a stimulant medication in the early afternoon. Although methylphenidate is a wellknown medication in the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children and young adults and has been used for more than 50 years, it has never been described for the treatment of sleep disorders in blind retarded children. In our patient, the stimulating effect of methylphenidate induced enhancement of daytime vigilance, thus avoiding sleep in the afternoon. Another effect of methylphenidate that might play a role in our case is the ability to alter the domains of nonacademic adaptive functioning such as daily living, communication, and socialization skills, although the patient did not meet diagnostic criteria for ADHD. In our patient, the combination of melatonin and methylphenidate proved to be successful in the treatment of this sleep disorder and led to enormous improvement in the social life of the patient’s family. Therefore, this treatment may be an option for similar cases. Heinz Zotter, M.D. Reinhold Kerbl, M.D. Michael Millner, M.D. Ronald Kurz, M.D. Department of Pediatrics University of Graz, Austria
Jan JE, O’Donnell ME (1996), Use of melatonin in the treatment of pediatric sleep disorders. J Pineal Res 21:193–199 Kirkwood CK (1999), Management of insomnia. J Am Pharm Assoc (Wash) 39:688–696 Palm L, Blennow G, Wetterberg L (1997), Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 39:319–325 Zhdanova IV, Lynch HJ, Wurtman RJ (1997), Melatonin: a sleep-promoting hormone. Sleep 20:899–907
OXCARBAZEPINE IN BIPOLAR DISORDER To the Editor: Oxcarbazepine, a 10-keto analog of carbamazepine, is an anticonvulsant medication indicated in children aged 4 to 16 years for use as an adjunctive therapy for partial seizures. This drug has been extensively researched internationally in the treatment of epilepsy. The clinical similarities with carbamazepine, along with an improved safety profile, are important considerations for treatment of children with bipolar disorder, given the risk for comorbidity and multiple medication trials. I present here a child with unstable bipolar disorder who demonstrated significant symptom remission with the addition of oxcarbazepine. A., a 6-year-old African-American girl, presented with a diagnosis of bipolar I disorder. There had been four involuntary psychiatric hospitalizations over the previous year secondary to episodic “out-of-control” behaviors. Outbursts included property destruction, such as breaking windows and knocking doors off hinges, and extreme aggression evidenced by attacking police officers, guidance counselors, her older brother, and her mother, including while in moving vehicles and with a knife. Previously used medications included lithium carbonate, lamotrigine, valproate, gabapentin, clonidine, guanfacine, risperidone, olanzapine, quetiapine, fluoxetine, and methylphenidate. Although possibly demonstrating initial benefit, lamotrigine was discontinued following rash development. Methylphenidate caused symptom exacerbation. At presentation, A. had been on a regimen of lithium carbonate 150 mg three times daily (0.7 mEq/L blood level) and guanfacine 0.5 mg twice daily for 3 months. At a higher dose guanfacine caused sedation without benefit, and no benefits were described with this combination. A. had been hospitalized 1 week earlier, but ongoing irritability and episodic outbursts were still occurring. Family psychotherapy over several months was not helpful, and the teacher continued to describe behavior alternating between being a “model student” and a “holy terror.” Oxcarbazepine, possibly having mood-stabilizing qualities and clearly having a reduced risk for leukopenia, rashes, interactions, and autoinduction compared with carbamazepine (Dunn et al., 1998; Emrich, 1990; Greil et al., 1985; Müller and Stoll, 1984; Velikonja and Heinrich, 1984), was started at 150 mg twice daily in combination with lithium carbonate and guanfacine.
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 9 , S E P T E M B E R 2 0 0 1
993
LETTERS TO THE EDITOR
Within 6 weeks A. experienced full mood stabilization. There was no property destruction, social skills improved to an age-appropriate level, defiant behavior was vastly reduced, and all schoolwork was being completed. No aggression or outbursts were observed, with ongoing maintenance also described at 3 months. Psychotherapy had been reduced to monthly from weekly, and the teacher and mother described A. as “a perfect angel” and “fabulous,” respectively. Given A.’s stability and the question of whether guanfacine and lithium carbonate were playing roles in her progress, the decision to gradually taper these medications was made. At 3 months the lithium carbonate dosage had been reduced to 150 mg twice daily (serum level not yet drawn) while the guanfacine dosage was maintained. Full symptom remission was maintained for 7 months on oxcarbazepine without side effects or blood levels indicating the presence of hyponatremia (most recent laboratory work seen was from 3 months), the most significant shared possible side effect with carbamazepine (Emrich, 1990; Müller and Stoll, 1984). The treatment plan was to continue to gradually taper the lithium carbonate and, if A. was still symptom-free, the guanfacine in an effort to provide full bipolar I symptom coverage through oxcarbazepine monotherapy. However, transient recurrent mild symptoms (i.e., defiance about school and destructiveness) were noted during a vacation week from school and again 1 month later, after a viral infection. Consequently, at the time of authorship, the lithium carbonate and guanfacine dosages were still at the previous dosages of 150 mg twice daily and 0.5 mg twice daily, respectively, with the plan for continued dose reduction upon adequate symptom remission. It is unclear why oxcarbazepine demonstrated greater efficacy than other agents. However, because of the treatment resistance in childhood bipolar disorder, new options are necessary and oxcarbazepine may be one of them. Further investigation is required. Marshall Teitelbaum, M.D. Palm Beach Gardens, FL Dunn RT, Frye MS, Frye S et al. (1998), The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol 21:215–235 Emrich HM (1990), Studies with oxcarbazepine (Trileptal) in acute mania. Int Clin Psychopharmacol 5(suppl 1):83–88 Greil W, Kruger R, RoBnagle G, Schertel M, Walther A (1985), Prophylactic treatment of affective disorders with carbamazepine and oxcarbazepine: an open clinical trial. In: Psychiatry: The State of the Art, Vol 3: Pharmacopsychiatry, Pichot P et al., eds (Proceedings of the VIIth World Congress of Psychiatry; July 11–16, 1983, Vienna, Austria). New York: Plenum, pp 491–494 Müller AA, Stoll KD (1984), Carbamazepine and oxcarbazepine in the treatment of manic syndromes: studies in Germany. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Müller AA, eds (International Congress Series No. 626). Amsterdam: Excerpta Medica, pp 139–147 Velikonja M, Heinrich K (1984), Effect of oxcarbazepine (CG 47.680) on affective and schizoaffective symptoms: a preliminary report. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Müller AA, eds (International Congress Series No. 626). Amsterdam: Excerpta Medica, pp 208–210
994
SUICIDE ATTEMPT WITH CYPROHEPTADINE To the Editor: Cyproheptadine poisoning has been rarely reported in the U.S. literature, but it has been widely reported in Germany (von Mühlendahl and Krienke, 1978). To our knowledge, cyproheptadine poisoning has not been reported in Japan. We report a case of toxic ingestion of cyproheptadine in a suicide attempt in an adolescent. A 15-year-old female was brought to our emergency department on August 29, 2000, because of an altered mental state. Her mother stated that 2 hours previously the patient had become unable to walk and speak and that her face had become flushed. On arrival at the emergency department, the patient was agitated and confused, and she spoke only a few words incoherently. She could not answer any questions. The patient had a history of steroid-dependent, frequently relapsing, minimal-change nephrotic syndrome since she was 10 years old and atopic dermatitis since she was 8 years old. She had been treated with prednisone for nephrotic syndrome and cyproheptadine for atopic dermatitis for 4 months after the cessation of prednisone. On arrival at the emergency department, the patient’s vital signs were as follows: pulse rate, 160 beats/minute; respiratory rate, 40/minute; blood pressure, 132/80 mm Hg; and temperature, 37.0⬚C. She had severe atopic dermatitis, especially on the arms and legs. Laboratory studies including complete blood cell count, ammonia, blood glucose, creatine kinase, renal and hepatic function tests, and electrolytes were within normal limits. Urinalysis revealed no abnormalities. A computed tomography scan of her head showed no evidence of intracranial hemorrhage or mass effect. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed clear, colorless fluid with white blood cell count of 2/μL, glucose level of 71 mg/dL, and protein less than 1.0 g/dL. Six hours after the patient was admitted, her mother reported that she had found 93 empty packages of cyproheptadine (total 279 mg, 6.6 mg/kg) hidden under the patient’s desk. We diagnosed cyproheptadine poisoning at this time, and activated charcoal and magnesium sulfate were administered via a tube. Phenobarbital and diazepam were given for agitation and confusion. The patient awoke at 9:30 the following morning and explained that she had taken the cyproheptadine to become sick to avoid going to school. The patient felt distress about other people looking at the atopic dermatitis on her legs on trains and at school. She denied any further suicidal intentions and was released on the 10th day of her hospital stay with psychiatric follow-up. In a recently reported case of a cyproheptadine fatality, the patient also drank alcohol; his heart-blood contained 0.46 mg/L of cyproheptadine and 0.09 g/dL of ethanol (Levine et al., 1998). The estimated acute fatal dose of cyproheptadine is 25 to
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 9 , S E P T E M B E R 2 0 0 1
4:00 P.M. Polysomnography showed that nighttime sleep was severely shortened. Epileptiform activity as a cause for awakening was excluded by sleep electroencephalogram. Results of routine blood tests were normal. Multiple plasma melatonin measurements for 24 hours showed a normal melatonin profile with a melatonin peak during nighttime and almost undetectable levels during the day. In a first step, melatonin (6 mg) was administered at 8:00 P.M. and led to prolonged nighttime sleep (plus 2 hours). To avoid daytime sleep the patient was treated with methylphenidate (2.5 mg) at 1:00 P.M. Under this regimen the sleep-wake cycle synchronized to a regular 24-hour schedule with a total nighttime sleep duration of 10 hours. Successful treatment greatly reduced the burden to the patient’s family. The administration of melatonin led to improvement of nighttime sleep, although the melatonin profile previously had been normal in our patient. It has been reported that exogenous melatonin significantly advances sleep onset, delays sleep offset, and thus increases night sleep duration and reduces daytime napping (Jan and O’Donnell, 1996; Zhdanova et al., 1997). As blind subjects lack information about the circadian light-dark shift, they appear to require higher levels of melatonin to maintain a regular circadian rhythm (Zhdanova et al., 1997). In our patient, melatonin alone was able to prolong nighttime sleep for approximately 2 hours, but the situation was still unsatisfying because of awakenings between 2:00 and 5:00 A.M. Therefore, to additionally avoid daytime sleeping, we administered methylphenidate as a stimulant medication in the early afternoon. Although methylphenidate is a wellknown medication in the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children and young adults and has been used for more than 50 years, it has never been described for the treatment of sleep disorders in blind retarded children. In our patient, the stimulating effect of methylphenidate induced enhancement of daytime vigilance, thus avoiding sleep in the afternoon. Another effect of methylphenidate that might play a role in our case is the ability to alter the domains of nonacademic adaptive functioning such as daily living, communication, and socialization skills, although the patient did not meet diagnostic criteria for ADHD. In our patient, the combination of melatonin and methylphenidate proved to be successful in the treatment of this sleep disorder and led to enormous improvement in the social life of the patient’s family. Therefore, this treatment may be an option for similar cases. Heinz Zotter, M.D. Reinhold Kerbl, M.D. Michael Millner, M.D. Ronald Kurz, M.D. Department of Pediatrics University of Graz, Austria
Jan JE, O’Donnell ME (1996), Use of melatonin in the treatment of pediatric sleep disorders. J Pineal Res 21:193–199 Kirkwood CK (1999), Management of insomnia. J Am Pharm Assoc (Wash) 39:688–696 Palm L, Blennow G, Wetterberg L (1997), Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 39:319–325 Zhdanova IV, Lynch HJ, Wurtman RJ (1997), Melatonin: a sleep-promoting hormone. Sleep 20:899–907
OXCARBAZEPINE IN BIPOLAR DISORDER To the Editor: Oxcarbazepine, a 10-keto analog of carbamazepine, is an anticonvulsant medication indicated in children aged 4 to 16 years for use as an adjunctive therapy for partial seizures. This drug has been extensively researched internationally in the treatment of epilepsy. The clinical similarities with carbamazepine, along with an improved safety profile, are important considerations for treatment of children with bipolar disorder, given the risk for comorbidity and multiple medication trials. I present here a child with unstable bipolar disorder who demonstrated significant symptom remission with the addition of oxcarbazepine. A., a 6-year-old African-American girl, presented with a diagnosis of bipolar I disorder. There had been four involuntary psychiatric hospitalizations over the previous year secondary to episodic “out-of-control” behaviors. Outbursts included property destruction, such as breaking windows and knocking doors off hinges, and extreme aggression evidenced by attacking police officers, guidance counselors, her older brother, and her mother, including while in moving vehicles and with a knife. Previously used medications included lithium carbonate, lamotrigine, valproate, gabapentin, clonidine, guanfacine, risperidone, olanzapine, quetiapine, fluoxetine, and methylphenidate. Although possibly demonstrating initial benefit, lamotrigine was discontinued following rash development. Methylphenidate caused symptom exacerbation. At presentation, A. had been on a regimen of lithium carbonate 150 mg three times daily (0.7 mEq/L blood level) and guanfacine 0.5 mg twice daily for 3 months. At a higher dose guanfacine caused sedation without benefit, and no benefits were described with this combination. A. had been hospitalized 1 week earlier, but ongoing irritability and episodic outbursts were still occurring. Family psychotherapy over several months was not helpful, and the teacher continued to describe behavior alternating between being a “model student” and a “holy terror.” Oxcarbazepine, possibly having mood-stabilizing qualities and clearly having a reduced risk for leukopenia, rashes, interactions, and autoinduction compared with carbamazepine (Dunn et al., 1998; Emrich, 1990; Greil et al., 1985; Müller and Stoll, 1984; Velikonja and Heinrich, 1984), was started at 150 mg twice daily in combination with lithium carbonate and guanfacine.
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 9 , S E P T E M B E R 2 0 0 1
993
LETTERS TO THE EDITOR
Within 6 weeks A. experienced full mood stabilization. There was no property destruction, social skills improved to an age-appropriate level, defiant behavior was vastly reduced, and all schoolwork was being completed. No aggression or outbursts were observed, with ongoing maintenance also described at 3 months. Psychotherapy had been reduced to monthly from weekly, and the teacher and mother described A. as “a perfect angel” and “fabulous,” respectively. Given A.’s stability and the question of whether guanfacine and lithium carbonate were playing roles in her progress, the decision to gradually taper these medications was made. At 3 months the lithium carbonate dosage had been reduced to 150 mg twice daily (serum level not yet drawn) while the guanfacine dosage was maintained. Full symptom remission was maintained for 7 months on oxcarbazepine without side effects or blood levels indicating the presence of hyponatremia (most recent laboratory work seen was from 3 months), the most significant shared possible side effect with carbamazepine (Emrich, 1990; Müller and Stoll, 1984). The treatment plan was to continue to gradually taper the lithium carbonate and, if A. was still symptom-free, the guanfacine in an effort to provide full bipolar I symptom coverage through oxcarbazepine monotherapy. However, transient recurrent mild symptoms (i.e., defiance about school and destructiveness) were noted during a vacation week from school and again 1 month later, after a viral infection. Consequently, at the time of authorship, the lithium carbonate and guanfacine dosages were still at the previous dosages of 150 mg twice daily and 0.5 mg twice daily, respectively, with the plan for continued dose reduction upon adequate symptom remission. It is unclear why oxcarbazepine demonstrated greater efficacy than other agents. However, because of the treatment resistance in childhood bipolar disorder, new options are necessary and oxcarbazepine may be one of them. Further investigation is required. Marshall Teitelbaum, M.D. Palm Beach Gardens, FL Dunn RT, Frye MS, Frye S et al. (1998), The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol 21:215–235 Emrich HM (1990), Studies with oxcarbazepine (Trileptal) in acute mania. Int Clin Psychopharmacol 5(suppl 1):83–88 Greil W, Kruger R, RoBnagle G, Schertel M, Walther A (1985), Prophylactic treatment of affective disorders with carbamazepine and oxcarbazepine: an open clinical trial. In: Psychiatry: The State of the Art, Vol 3: Pharmacopsychiatry, Pichot P et al., eds (Proceedings of the VIIth World Congress of Psychiatry; July 11–16, 1983, Vienna, Austria). New York: Plenum, pp 491–494 Müller AA, Stoll KD (1984), Carbamazepine and oxcarbazepine in the treatment of manic syndromes: studies in Germany. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Müller AA, eds (International Congress Series No. 626). Amsterdam: Excerpta Medica, pp 139–147 Velikonja M, Heinrich K (1984), Effect of oxcarbazepine (CG 47.680) on affective and schizoaffective symptoms: a preliminary report. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Müller AA, eds (International Congress Series No. 626). Amsterdam: Excerpta Medica, pp 208–210
994
SUICIDE ATTEMPT WITH CYPROHEPTADINE To the Editor: Cyproheptadine poisoning has been rarely reported in the U.S. literature, but it has been widely reported in Germany (von Mühlendahl and Krienke, 1978). To our knowledge, cyproheptadine poisoning has not been reported in Japan. We report a case of toxic ingestion of cyproheptadine in a suicide attempt in an adolescent. A 15-year-old female was brought to our emergency department on August 29, 2000, because of an altered mental state. Her mother stated that 2 hours previously the patient had become unable to walk and speak and that her face had become flushed. On arrival at the emergency department, the patient was agitated and confused, and she spoke only a few words incoherently. She could not answer any questions. The patient had a history of steroid-dependent, frequently relapsing, minimal-change nephrotic syndrome since she was 10 years old and atopic dermatitis since she was 8 years old. She had been treated with prednisone for nephrotic syndrome and cyproheptadine for atopic dermatitis for 4 months after the cessation of prednisone. On arrival at the emergency department, the patient’s vital signs were as follows: pulse rate, 160 beats/minute; respiratory rate, 40/minute; blood pressure, 132/80 mm Hg; and temperature, 37.0⬚C. She had severe atopic dermatitis, especially on the arms and legs. Laboratory studies including complete blood cell count, ammonia, blood glucose, creatine kinase, renal and hepatic function tests, and electrolytes were within normal limits. Urinalysis revealed no abnormalities. A computed tomography scan of her head showed no evidence of intracranial hemorrhage or mass effect. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed clear, colorless fluid with white blood cell count of 2/μL, glucose level of 71 mg/dL, and protein less than 1.0 g/dL. Six hours after the patient was admitted, her mother reported that she had found 93 empty packages of cyproheptadine (total 279 mg, 6.6 mg/kg) hidden under the patient’s desk. We diagnosed cyproheptadine poisoning at this time, and activated charcoal and magnesium sulfate were administered via a tube. Phenobarbital and diazepam were given for agitation and confusion. The patient awoke at 9:30 the following morning and explained that she had taken the cyproheptadine to become sick to avoid going to school. The patient felt distress about other people looking at the atopic dermatitis on her legs on trains and at school. She denied any further suicidal intentions and was released on the 10th day of her hospital stay with psychiatric follow-up. In a recently reported case of a cyproheptadine fatality, the patient also drank alcohol; his heart-blood contained 0.46 mg/L of cyproheptadine and 0.09 g/dL of ethanol (Levine et al., 1998). The estimated acute fatal dose of cyproheptadine is 25 to
J . A M . AC A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 9 , S E P T E M B E R 2 0 0 1