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SSRI AND MIRTAZAPINE IN PTSD
LETTERS TO THE EDITOR
March of 1999, at age 9 years 5 months. Lithium was replaced by carbamazepine and D. was given a 6-week trial of carbamazepine and valproate. The unsatisfactory therapeutic outcome resulted in a subsequent hospitalization in September of 1999. Atypical neuroleptics had been used intermittently to treat psychotic symptoms throughout the course of his illness. During D.’s hospitalization in September 1999, the Kaufman Brief Intelligence Test (K-BIT) was administered to assess his cognitive functioning. His vocabulary standard score of 71 placed him in the borderline range of verbal intelligence and overall K-BIT IQ composite score of 70 ranked him in the borderline range. Carbamazepine was stopped and TPM, 1 mg/kg per day, was started. D. tolerated weekly increments of approximately 2 mg/kg to a target dose of 75 mg b.i.d. over a period of 3 weeks along with low doses of valproate and risperidone. He went into remission for the first time in 2 years. Three months later, recurrent hypomania prompted a dose titration up to 100 mg b.i.d. Four weeks later, his schoolteacher reported the emergence of academic difficulties including spelling, sound reversals, inability to complete simple addition problems, and difficulty acquiring and retaining new information. These cognitive deficits represented a significant decline from his previous level of functioning, from fourth-grade special education to second-gradelevel special education. A decrease in the TPM dose from 100 mg to 75 mg b.i.d. resulted in a reemergence of hypomanic symptoms and only minimal cognitive improvement. TPM was tapered and subsequently discontinued while D. was in the hospital. The WISC was administered, and D. was noted to have word-finding difficulties. His verbal standard score ranked him in the very low range of intelligence (Full Scale IQ = 58; Verbal IQ = 66; Performance IQ = 57). Although the WISC and KBIT are two different measures of intellectual capacity, this overall discrepancy between the initial IQ = 70 on the K-BIT and the IQ = 58 on the WISC was considered a clinically significant drop. Two months after TPM was discontinued (while D. was in remission and taking nimodipine and gabapentin), the Clinical Evaluation of Language Fundamentals-3rd edition (CELF-3) was administered. He received a standard score of 55 on receptive and expressive language, 3 SD below the mean. As this test had not been obtained prior to TPM treatment, we cannot draw a definitive conclusion regarding the role of exposure to TPM (or the concurrent medications) in his substandard language testing (i.e., semantics and grammatical errors). Nevertheless, the discrepancy between the vocabulary standard score of 71 on the K-BIT and the standard score of 55 on the CELF-3 was also suggestive of a clinical drop in this area. At present (approximately 10 months after discontinuation of TPM), D. is reported to be achieving at a third grade level (special education) in spelling and arithmetic, a moderate improvement from his previous drop.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 3 , M A RC H 2 0 0 1
In summary, this case suggests that considerable caution should be used when prescribing TPM for children and that our understanding of the potential risks of this medication in youngsters is unclear. Baseline and follow-up assessment of language and mathematics functioning may be indicated for children treated with TPM until controlled studies of its safety and efficacy are available. Pablo Davanzo, M.D. Erin Cantwell, B.S. Jillian Kleiner, M.D. Christine Baltaxe, Ph.D. Belinda Najera, M.A. Gia Crecelius, M.D. James McCracken, M.D. Division of Child and Adolescent Psychiatry Department of Psychiatry UCLA School of Medicine, Los Angeles Calabrese JR, Fatemi SH, Woyshville MJ (1996), Antidepressant effects of lamotrigine in rapid cycling bipolar disorder (letter). Am J Psychiatry 153:1236 Farnham SJ, Risse GL, Gustafson M, Gates JR, Penovich PE (1999), Effect of topiramate on cognitive test performance (abstract). Epilepsia 40:52 Martin R, Kuzniecky R, Ho S et al. (1999), Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 52:321–327 Thompson PJ, Baxendale SA, Duncan JS, Ley JW, Sander LJ (1999), Changes in intellect and verbal processing in association with topiramate treatment (abstract). Epilepsia 40:50 White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH (1997), Topiramate enhances GABA mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 28:167–179
SSRI AND MIRTAZAPINE IN PTSD To the Editor: The psychopharmacological treatment of pediatric posttraumatic stress disorder (PTSD) is in its infancy as there are limited numbers of controlled drug trials. Treatment is complicated by the complex neurobiology of PTSD and the relatively high frequency of comorbid psychiatric conditions. Selective serotonin reuptake inhibitors (SSRIs) have shown promise in adults with PTSD and are being widely used to treat depression, obsessive-compulsive disorder, and anxiety in children and adolescents (Donnelly et al., 1999; Labellarte et al., 1999). A small pilot study of mirtazapine in six adult patients with chronic, severe PTSD showed improvement in 50% of patients (Connor et al., 1999). The following is a case of pediatric PTSD with comorbid anxiety disorder not otherwise specified that initially responded well to an SSRI. After a subsequent regression, the patient benefited from combination therapy with mirtazapine. The patient is an 8-year-old girl with a complicated medical history including autoimmune disease and congenital heart 263
LETTERS TO THE EDITOR
defects. One year before presentation, she told her mother that her father had been “peeing” in her mouth. For several months, the mother had noted regressive and acting-out behaviors following the child’s visits with her father. At times the child would refuse to eat for several days after returning home from these visits. After psychiatric consultation, the diagnosis of PTSD was made and therapy with fluvoxamine was initiated. This medication greatly reduced the patient’s compulsive ritualistic behaviors, which included excessive washing and reorganizing her room. The patient was reportedly doing well until 1 month before admission, when she was evaluated by a pediatric gastroenterologist for chronic gastrointestinal complaints. A rectal examination was performed at that visit with the child’s consent and cooperation. After the examination the child became immediately anxious; she remained in a dissociative state for several days and had no recollection of the event. Over the next few weeks she increasingly sought reassurance from her mother for a fear that she would choke on food and die. The patient refused to sleep at times because of this fear. Immediately prior to admission the patient had refused to eat for 2 to 3 days; she experienced an approximate 4-lb weight loss, which resulted in a weight below the 2nd percentile for age. Previously her height and weight had been stable at the 5th percentile. The patient was admitted for inpatient treatment involving individual, group, activity, family, milieu, and behavior modification therapies. Fluvoxamine was continued at the same dose. The patient’s oral intake remained poor; she was eating 25% of her meals or less. She continued to seek reassurance for several hours after meals and at bedtime for fears that she would choke on food and die. On day 3 of hospitalization, mirtazapine 7.5 mg p.o. at bedtime was started. For the next 2 days she continued to have multiple somatic complaints and was noted by staff to retain food in her mouth at times. Her calorie counts improved to an adequate level within the next 2 days despite the continued complaints of a painful sensation in her throat after eating. On day 7 of hospitalization, daytime sedation was noted and the morning dose of fluvoxamine was decreased. The child’s need for reassurance decreased and her mood improved
264
with continued pharmacological and multimodal therapy. She was discharged on day 12. At a 4-week follow-up, the patient continued to have some anxiety around mealtime but had regained 5 lb. Her appetite and ability to initiate sleep continue to improve. The indications of the combined noradrenergic and serotonergic drug mirtazapine are broadening (Falkai, 1999). There are no open or controlled studies of mirtazapine augmentation in children, but this case did show a good response in the context of intensive inpatient treatment following a partial response to an SSRI. This report suggests the usefulness of studies of mirtazapine in children with PTSD. Candace Good, M.D. Christopher Petersen, M.D. Division of Child and Adolescent Psychiatry Penn State College of Medicine Milton S. Hershey Medical Center Hershey, PA Connor KM, Davidson JRT, Weisler RH, Ahearn E (1999), A pilot study of mirtazapine in post-traumatic stress disorder. Int Clin Psychopharmacol 14:29–31 Donnelly CL, Amaya-Jackson L, March JS (1999), Psychopharmacology of pediatric posttraumatic stress disorder. J Child Adolesc Psychopharmacol 9:203–220 Falkai P (1999), Mirtazapine: other indications. J Clin Psychiatry 60(suppl 17):36–40 Labellarte MJ, Ginsburg GS, Walkup JT, Riddle MA (1999), The treatment of anxiety disorders in children and adolescents. Biol Psychiatry 46:1567–1578
The Letters column is a corner of the Journal that encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the Journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed double-spaced, and submitted in duplicate, accompanied by an electronic copy on diskette. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to Mina K. Dulcan, M.D., Editor, Journal of the AACAP Editorial Office, Children’s Memorial Hospital, 2300 Children’s Plaza #156, Chicago, IL 60614-3394.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 3 , M A RC H 2 0 0 1
March of 1999, at age 9 years 5 months. Lithium was replaced by carbamazepine and D. was given a 6-week trial of carbamazepine and valproate. The unsatisfactory therapeutic outcome resulted in a subsequent hospitalization in September of 1999. Atypical neuroleptics had been used intermittently to treat psychotic symptoms throughout the course of his illness. During D.’s hospitalization in September 1999, the Kaufman Brief Intelligence Test (K-BIT) was administered to assess his cognitive functioning. His vocabulary standard score of 71 placed him in the borderline range of verbal intelligence and overall K-BIT IQ composite score of 70 ranked him in the borderline range. Carbamazepine was stopped and TPM, 1 mg/kg per day, was started. D. tolerated weekly increments of approximately 2 mg/kg to a target dose of 75 mg b.i.d. over a period of 3 weeks along with low doses of valproate and risperidone. He went into remission for the first time in 2 years. Three months later, recurrent hypomania prompted a dose titration up to 100 mg b.i.d. Four weeks later, his schoolteacher reported the emergence of academic difficulties including spelling, sound reversals, inability to complete simple addition problems, and difficulty acquiring and retaining new information. These cognitive deficits represented a significant decline from his previous level of functioning, from fourth-grade special education to second-gradelevel special education. A decrease in the TPM dose from 100 mg to 75 mg b.i.d. resulted in a reemergence of hypomanic symptoms and only minimal cognitive improvement. TPM was tapered and subsequently discontinued while D. was in the hospital. The WISC was administered, and D. was noted to have word-finding difficulties. His verbal standard score ranked him in the very low range of intelligence (Full Scale IQ = 58; Verbal IQ = 66; Performance IQ = 57). Although the WISC and KBIT are two different measures of intellectual capacity, this overall discrepancy between the initial IQ = 70 on the K-BIT and the IQ = 58 on the WISC was considered a clinically significant drop. Two months after TPM was discontinued (while D. was in remission and taking nimodipine and gabapentin), the Clinical Evaluation of Language Fundamentals-3rd edition (CELF-3) was administered. He received a standard score of 55 on receptive and expressive language, 3 SD below the mean. As this test had not been obtained prior to TPM treatment, we cannot draw a definitive conclusion regarding the role of exposure to TPM (or the concurrent medications) in his substandard language testing (i.e., semantics and grammatical errors). Nevertheless, the discrepancy between the vocabulary standard score of 71 on the K-BIT and the standard score of 55 on the CELF-3 was also suggestive of a clinical drop in this area. At present (approximately 10 months after discontinuation of TPM), D. is reported to be achieving at a third grade level (special education) in spelling and arithmetic, a moderate improvement from his previous drop.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 3 , M A RC H 2 0 0 1
In summary, this case suggests that considerable caution should be used when prescribing TPM for children and that our understanding of the potential risks of this medication in youngsters is unclear. Baseline and follow-up assessment of language and mathematics functioning may be indicated for children treated with TPM until controlled studies of its safety and efficacy are available. Pablo Davanzo, M.D. Erin Cantwell, B.S. Jillian Kleiner, M.D. Christine Baltaxe, Ph.D. Belinda Najera, M.A. Gia Crecelius, M.D. James McCracken, M.D. Division of Child and Adolescent Psychiatry Department of Psychiatry UCLA School of Medicine, Los Angeles Calabrese JR, Fatemi SH, Woyshville MJ (1996), Antidepressant effects of lamotrigine in rapid cycling bipolar disorder (letter). Am J Psychiatry 153:1236 Farnham SJ, Risse GL, Gustafson M, Gates JR, Penovich PE (1999), Effect of topiramate on cognitive test performance (abstract). Epilepsia 40:52 Martin R, Kuzniecky R, Ho S et al. (1999), Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 52:321–327 Thompson PJ, Baxendale SA, Duncan JS, Ley JW, Sander LJ (1999), Changes in intellect and verbal processing in association with topiramate treatment (abstract). Epilepsia 40:50 White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH (1997), Topiramate enhances GABA mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 28:167–179
SSRI AND MIRTAZAPINE IN PTSD To the Editor: The psychopharmacological treatment of pediatric posttraumatic stress disorder (PTSD) is in its infancy as there are limited numbers of controlled drug trials. Treatment is complicated by the complex neurobiology of PTSD and the relatively high frequency of comorbid psychiatric conditions. Selective serotonin reuptake inhibitors (SSRIs) have shown promise in adults with PTSD and are being widely used to treat depression, obsessive-compulsive disorder, and anxiety in children and adolescents (Donnelly et al., 1999; Labellarte et al., 1999). A small pilot study of mirtazapine in six adult patients with chronic, severe PTSD showed improvement in 50% of patients (Connor et al., 1999). The following is a case of pediatric PTSD with comorbid anxiety disorder not otherwise specified that initially responded well to an SSRI. After a subsequent regression, the patient benefited from combination therapy with mirtazapine. The patient is an 8-year-old girl with a complicated medical history including autoimmune disease and congenital heart 263
LETTERS TO THE EDITOR
defects. One year before presentation, she told her mother that her father had been “peeing” in her mouth. For several months, the mother had noted regressive and acting-out behaviors following the child’s visits with her father. At times the child would refuse to eat for several days after returning home from these visits. After psychiatric consultation, the diagnosis of PTSD was made and therapy with fluvoxamine was initiated. This medication greatly reduced the patient’s compulsive ritualistic behaviors, which included excessive washing and reorganizing her room. The patient was reportedly doing well until 1 month before admission, when she was evaluated by a pediatric gastroenterologist for chronic gastrointestinal complaints. A rectal examination was performed at that visit with the child’s consent and cooperation. After the examination the child became immediately anxious; she remained in a dissociative state for several days and had no recollection of the event. Over the next few weeks she increasingly sought reassurance from her mother for a fear that she would choke on food and die. The patient refused to sleep at times because of this fear. Immediately prior to admission the patient had refused to eat for 2 to 3 days; she experienced an approximate 4-lb weight loss, which resulted in a weight below the 2nd percentile for age. Previously her height and weight had been stable at the 5th percentile. The patient was admitted for inpatient treatment involving individual, group, activity, family, milieu, and behavior modification therapies. Fluvoxamine was continued at the same dose. The patient’s oral intake remained poor; she was eating 25% of her meals or less. She continued to seek reassurance for several hours after meals and at bedtime for fears that she would choke on food and die. On day 3 of hospitalization, mirtazapine 7.5 mg p.o. at bedtime was started. For the next 2 days she continued to have multiple somatic complaints and was noted by staff to retain food in her mouth at times. Her calorie counts improved to an adequate level within the next 2 days despite the continued complaints of a painful sensation in her throat after eating. On day 7 of hospitalization, daytime sedation was noted and the morning dose of fluvoxamine was decreased. The child’s need for reassurance decreased and her mood improved
264
with continued pharmacological and multimodal therapy. She was discharged on day 12. At a 4-week follow-up, the patient continued to have some anxiety around mealtime but had regained 5 lb. Her appetite and ability to initiate sleep continue to improve. The indications of the combined noradrenergic and serotonergic drug mirtazapine are broadening (Falkai, 1999). There are no open or controlled studies of mirtazapine augmentation in children, but this case did show a good response in the context of intensive inpatient treatment following a partial response to an SSRI. This report suggests the usefulness of studies of mirtazapine in children with PTSD. Candace Good, M.D. Christopher Petersen, M.D. Division of Child and Adolescent Psychiatry Penn State College of Medicine Milton S. Hershey Medical Center Hershey, PA Connor KM, Davidson JRT, Weisler RH, Ahearn E (1999), A pilot study of mirtazapine in post-traumatic stress disorder. Int Clin Psychopharmacol 14:29–31 Donnelly CL, Amaya-Jackson L, March JS (1999), Psychopharmacology of pediatric posttraumatic stress disorder. J Child Adolesc Psychopharmacol 9:203–220 Falkai P (1999), Mirtazapine: other indications. J Clin Psychiatry 60(suppl 17):36–40 Labellarte MJ, Ginsburg GS, Walkup JT, Riddle MA (1999), The treatment of anxiety disorders in children and adolescents. Biol Psychiatry 46:1567–1578
The Letters column is a corner of the Journal that encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the Journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed double-spaced, and submitted in duplicate, accompanied by an electronic copy on diskette. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to Mina K. Dulcan, M.D., Editor, Journal of the AACAP Editorial Office, Children’s Memorial Hospital, 2300 Children’s Plaza #156, Chicago, IL 60614-3394.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 3 , M A RC H 2 0 0 1