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Diabetic ketoacidosis associated with olanzapine in an adolescent patient
Diabetic ketoacidosis associated with olanzapine in an adolescent patient Karin A. Selva, MD, and Susan Marie Scott, MD Olanzapine (Zyprexa) is an atypical neuroleptic used in adult and pediatric patients for the management of schizophrenia. Common side effects include increased appetite and weight gain. An uncommon but severe adverse effect is the development of diabetic ketoacidosis, reported until now only in adults. We report a case of acute onset diabetic ketoacidosis presenting in a 16-year-old girl during olanzapine therapy. (J Pediatr 2001;138:936-8)
Schizophrenia has an estimated prevalence of 1% in the American population, equally distributed between the sexes.1 Olanzapine (Zyprexa) is an atypical neuroleptic agent used in 1.2 million adults and children for the management of schizophrenia.2 Atypical neuroleptics are currently recommended for adults because of their low incidence of extrapyramidal symptoms (Parkinsonism, akathesia, and dyskinesia).3 However, olanzapine is currently not approved by the Food and Drug Administration for use in younger or adolescent populations, and its safety in these groups is unknown. Historically, psychotropic drugs have been associated with alterations in the endocrine system, including changes in thyroid stimulating hormone or prolactin levels. The reported endocrine side effects of psychotropic
medications include abnormal glucose control in the form of diabetic ketoacidosis. This case report details this potentially serious side effect of olanzapine, previously reported only in the adult population.
CASE REPORT A 16-year-old Hispanic girl was given the diagnosis of DiGeorge syndrome at birth, but she required no calcium or phosphorous therapy. She had an 18-month history of both auditory and visual hallucinations and major depressive disorder. At the time of her presentation to an area psychiatrist, she had received olanzapine for an undetermined duration at a dose of 10 mg/d. She had had a 30-pound weight gain since the initiation of the drug,
From the Division of Pediatric Endocrinology, University of New Mexico Children’s Hospital, University of New Mexico School of Medicine, Albuquerque.
The adverse side effect of diabetic ketoacidosis with olanzapine (Zyprexa) treatment was reported by the corresponding author to the Eli Lilly pharmaceutical company. Submitted for publication May 10, 2000; revision received Nov 16, 2000; accepted Jan 4, 2001. Reprint requests: Susan M. Scott, MD, Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Ambulatory Care Center, 3rd Floor, 2211 Lomas Blvd NE, Albuquerque, NM 87131-5311. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/114016 doi:10.1067/mpd.2001.114016
936
and she was subsequently tapered off the drug. However, her hallucinations worsened, and olanzapine was restarted within a month, along with imipramine for depressive symptoms. During the next 6 months, she received olanzapine at a daily dose of 10 to 15 mg/d. Other medications were altered as a result of increases in psychotic behavior and suicidal ideation. She presented to an outlying area emergency department with the complications of lethargy, vomiting, and inability to walk. She had received olanzapine continuously for 6 months and was also taking risperidone and venlafaxime. In the emergency department, her serum glucose level was 669 mg/dL, her pH was 6.9, pCO2 8 mm Hg, PO2 125 mm Hg, and bicarbonate 2 mmol/L. Serum electrolytes, including blood urea nitrogen, creatinine, calcium, phosphorous, and magnesium, were normal, except for hypokalemia (potassium of 2.8 meq/L.) Urine revealed significant glucosuria and ketonuria and was otherwise normal. She was then transferred to the Pediatric Intensive Care Unit at the University of New Mexico Hospital for management of new onset diabetic ketoacidosis. The patient responded well to continuous insulin infusion. Olanzapine therapy was discontinued at the recommendation of the patient’s psychiatrist, who had noted the association of this drug with new onset diabetes in adults. The other psychotropic medications were continued at half dose. Acute tubular necrosis complicated her course, requiring continuation of the insulin infusion for 4 days, at a dose of 0.05 U/kg per hour. Admission hemoglobin A1C was 17.7% (normal range
SELVA AND SCOTT
THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 4.4% to 5.8%). The patient received subcutaneous insulin on hospital day 4, requiring minimal amounts of insulin for euglycemia. After 17 days, insulin therapy was discontinued. By hospital discharge, kidney function had returned to normal. The patient was discharged to a psychiatric unit while receiving risperidone and venlafaxime. There, capillary blood glucose was monitored twice daily. The patient’s anti-islet cell antibodies were negative. She had a strong maternal and paternal family history for type 2 diabetes mellitus. The patient did not have acanthosis nigricans, and there had been no symptoms of diabetes mellitus before her admission. After her hospitalization, she did not receive olanzapine; however, she remained overweight. When her blood sugars began to increase at 6 months from hospitalization and repeat hemoglobin A1C was 10.5%, she was then judged to have type 2 diabetes mellitus.
DISCUSSION Conventional neuroleptics such as haloperidol have been used to treat children with schizophrenia and other psychiatric entities such as psychotic mood disorder and pervasive developmental disorder. However, such medications have the disadvantage of serious side effects, the most important being extrapyramidal symptoms, with tardive dyskinesia being irreversible. In children and adolescents, these symptoms occur with lower drug doses and shorter therapy duration; they also have an increased frequency (8% to 51%) when compared with adults.3 The introduction of atypical neuroleptics for the management of childhood schizophrenia poses an alternative to conventional therapies; these new pharmacotherapies offer a lower risk of extrapyramidal symptoms because they spare the nigrostriatal dopamine system.3 Olanzapine is one of the most commonly used atypical neuroleptics
for the treatment of patients with pediatric schizophrenia, although not approved for children by the Food and Drug Administration. There are currently no published controlled clinical studies, with only case reports of safety and efficacy being reported in this population. The adverse effects of olanzapine have been reported as minimal, with side effects including increased appetite, weight gain, headache, increased agitation, and insomnia requiring additional medications. Diabetic ketoacidosis or diabetes mellitus associated with olanzapine therapy has been reported in the adult population, with a total of 11 cases with age ranges of 31 to 56 years.7-10 Presentation varied from acute diabetic ketoacidosis to symptoms of polyuria and polydipsia, with one half experiencing significant weight gain. Not all patients were tapered off of insulin after discontinuation of olanzapine therapy. In premarketing trials, Eli Lilly reports the incidence of diabetes mellitus in patients receiving olanzapine as 0.6%.10 A postmarketing series documents 139 cases of diabetes associated with olanzapine therapy, with 14 (10%) patients having no predisposing factors (Eli Lilly, data on file).9 Our patient had a strong family history of type 2 diabetes. It is unknown whether she had pre-existing glucose intolerance of diabetes mellitus. She did not have the physical manifestations of hyperinsulinism (acanthosis nigricans) or an increased body mass index. Her subsequent demonstration of re-expression glucose intolerance, evaluation of hemoglobin A1C, and persistent obesity at 6 months after hospitalization is consistent with the phenotype of type 2 diabetes mellitus. Because of the limited studies of olanzapine in the pediatric population, it is unclear what recommendations should be made to primary caregivers in monitoring for the expression of diabetes mellitus and prevention of diabetic ketoacidosis. Glucose intolerance caused by olanzapine therapy may appear after therapy is initiated. The
lack of weight gain in approximately 50% of those who have clinical expression of glucose intolerance and the reversal of diabetes mellitus after therapy is stopped in some patients suggest that the effect of olanzapine is not entirely related to the accelerated expression of type 2 diabetes mellitus. We suggest that documentation of family history for type 2 diabetes mellitus and a baseline fasting blood sugar to rule out undiagnosed type 2 diabetes mellitus would be reasonable before the therapy is initiated. The development of diabetic ketoacidosis as a serious complication from the use of olanzapine may be prevented by following changes in weight and monitoring for the development of glucose intolerance through fasting blood sugars, HgA1C values, or both. The authors acknowledge Dr Barry Irons, who referred this patient to our institution and provided initial insight into the reported complications of olanzapine therapy in adults, and Karen Dominguez and Dawn Lomako, clinical pharmacists, UNMH, who further investigated these complications and alerted the clinical staff involved with this patient’s care.
REFERENCES 1. Schulz SC, Findlin RL, Wise A, Friedman L, Kenny J. Child and adolescent schizophrenia. Psychiatr Clin North Am 1998;21:43–56. 2. Mandoki M. Olanzapine in the treatment of early onset schizophrenia in children and adolescents. Biol Psychiatry 1997;41:22s. 3. Toren P, Laor N, Weizman A. Use of atypical neuroleptics in child and adolescent psychiatry. J Clin Psychiatry 1998;59:644–56. 4. Potenza M, Holmes J, Kanes S, McDougle C. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open pilot study. J Clin Psychopharmacol 1999;1:37–44. 5. Horrigan JP, Barnhill LJ, Courvoise HE. Olanzapine in PDD [letter]. J Am Acad Child Adolesc Psychiatry 1997;36:1166–7. 6. Kumra S, Jacobsen L, Lenane M, Karp BI, Frazier JA, Smith AK, et al. Childhood onset schizophrenia: an 937
SELVA AND SCOTT
open label study of olanzapine in adolescents. J Am Acad Child Adolesc Psychiatry 1998;4:377-85. 7. Wirshing DA, Spellburg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998;44:778-83.
THE JOURNAL OF PEDIATRICS JUNE 2001 8. Gatta B, Rigalleu V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care 1999;6:435-6. 9. Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, et al. New onset diabetes mellitus and diabetic ketoacidosis associated with
olanzapine treatment. Psychosomatics 1999;5:438-43. 10. Lindenmayer JP, Patel R. Olanzapine induced ketoacidosis with diabetes mellitus [letter]. Am J Psychiatry 1999;9:1471.
50 Years Ago in The Journal of Pediatrics PERTUSSIS: CLINICAL COMPARISONS OF THE NEWER ANTIBIOTICS Booher CE, Farrell JB, West KJ. J Pediatr 1951;38:411-22 During the period from 1922 to 1948, pertussis was the leading cause of death from an infectious agent among children in the United States. By the early 1950s, pertussis vaccine had been introduced, and a number of reports on the in vitro antibiotic susceptibility of Bordetella pertussis started to appear in the literature. In their article in The Journal, Booher et al describe an outbreak of pertussis in Providence, Rhode Island (111 cases requiring hospitalization), which afforded them the opportunity of setting up a comparative study to examine the efficacy of the “newer antibiotics” for pertussis. The antibiotics they used to treat their patients (3 groups) were chloramphenicol and two tetracycline preparations, Aureomycin (chlortetracycline) and Terramycin (oxytetracycline). They compared these patients with an untreated group (historical control subjects) and also with a group of patients from a previous outbreak who were treated with streptomycin. They concluded that streptomycin had no effect but that the other 3 antibiotics were of equal clinical value in that they reduced the whooping stage of the disease but not the duration of coughing or length of hospitalization. So what has changed over the last 50 years? Certainly, in industrialized countries, outbreaks of pertussis are still being seen because of inadequate vaccination rates, often fueled by adverse publicity surrounding vaccines in general. A particular problem is the ongoing burden of disease in young, pre-vaccinated infants (<3 months). Older siblings and adults are the usual source of infection for these infants, attesting to a rethinking of pertussis vaccination policy, especially in the United Kingdom, where only the primary course is given. As far as treatment is concerned, B pertussis is susceptible to many antibiotics in vitro, which include ampicillin, cotrimoxazole, tetracyclines, and chloramphenicol. Unfortunately, in subsequent trials, none have been shown to be very effective therapeutically, and this includes erythromycin, which greatly diminishes nasopharyngeal carriage but does not alter the course of the disease unless it is administered during the catarrhal stage. Obviously, tetracycline preparations are now contraindicated in children less than 8 years of age, and chloramphenicol has only limited use in developed countries. The article by Booher et al ends with the following: “We believe that the specific drug for the complete and successful treatment of pertussis still lies in the future.” Unfortunately, 50 years later, we are still unable to alleviate the distressing symptoms of the young child in the paroxysmal stage of pertussis. Current trials of pertussis immunoglobulin may provide an answer. Vas M. Novelli, MD Infectious Diseases Unit Great Ormond Street Hospital for Children London, United Kingdom 9/37/115893 doi:10.1067/mpd.2001.115893
938
Schizophrenia has an estimated prevalence of 1% in the American population, equally distributed between the sexes.1 Olanzapine (Zyprexa) is an atypical neuroleptic agent used in 1.2 million adults and children for the management of schizophrenia.2 Atypical neuroleptics are currently recommended for adults because of their low incidence of extrapyramidal symptoms (Parkinsonism, akathesia, and dyskinesia).3 However, olanzapine is currently not approved by the Food and Drug Administration for use in younger or adolescent populations, and its safety in these groups is unknown. Historically, psychotropic drugs have been associated with alterations in the endocrine system, including changes in thyroid stimulating hormone or prolactin levels. The reported endocrine side effects of psychotropic
medications include abnormal glucose control in the form of diabetic ketoacidosis. This case report details this potentially serious side effect of olanzapine, previously reported only in the adult population.
CASE REPORT A 16-year-old Hispanic girl was given the diagnosis of DiGeorge syndrome at birth, but she required no calcium or phosphorous therapy. She had an 18-month history of both auditory and visual hallucinations and major depressive disorder. At the time of her presentation to an area psychiatrist, she had received olanzapine for an undetermined duration at a dose of 10 mg/d. She had had a 30-pound weight gain since the initiation of the drug,
From the Division of Pediatric Endocrinology, University of New Mexico Children’s Hospital, University of New Mexico School of Medicine, Albuquerque.
The adverse side effect of diabetic ketoacidosis with olanzapine (Zyprexa) treatment was reported by the corresponding author to the Eli Lilly pharmaceutical company. Submitted for publication May 10, 2000; revision received Nov 16, 2000; accepted Jan 4, 2001. Reprint requests: Susan M. Scott, MD, Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Ambulatory Care Center, 3rd Floor, 2211 Lomas Blvd NE, Albuquerque, NM 87131-5311. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/114016 doi:10.1067/mpd.2001.114016
936
and she was subsequently tapered off the drug. However, her hallucinations worsened, and olanzapine was restarted within a month, along with imipramine for depressive symptoms. During the next 6 months, she received olanzapine at a daily dose of 10 to 15 mg/d. Other medications were altered as a result of increases in psychotic behavior and suicidal ideation. She presented to an outlying area emergency department with the complications of lethargy, vomiting, and inability to walk. She had received olanzapine continuously for 6 months and was also taking risperidone and venlafaxime. In the emergency department, her serum glucose level was 669 mg/dL, her pH was 6.9, pCO2 8 mm Hg, PO2 125 mm Hg, and bicarbonate 2 mmol/L. Serum electrolytes, including blood urea nitrogen, creatinine, calcium, phosphorous, and magnesium, were normal, except for hypokalemia (potassium of 2.8 meq/L.) Urine revealed significant glucosuria and ketonuria and was otherwise normal. She was then transferred to the Pediatric Intensive Care Unit at the University of New Mexico Hospital for management of new onset diabetic ketoacidosis. The patient responded well to continuous insulin infusion. Olanzapine therapy was discontinued at the recommendation of the patient’s psychiatrist, who had noted the association of this drug with new onset diabetes in adults. The other psychotropic medications were continued at half dose. Acute tubular necrosis complicated her course, requiring continuation of the insulin infusion for 4 days, at a dose of 0.05 U/kg per hour. Admission hemoglobin A1C was 17.7% (normal range
SELVA AND SCOTT
THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 6 4.4% to 5.8%). The patient received subcutaneous insulin on hospital day 4, requiring minimal amounts of insulin for euglycemia. After 17 days, insulin therapy was discontinued. By hospital discharge, kidney function had returned to normal. The patient was discharged to a psychiatric unit while receiving risperidone and venlafaxime. There, capillary blood glucose was monitored twice daily. The patient’s anti-islet cell antibodies were negative. She had a strong maternal and paternal family history for type 2 diabetes mellitus. The patient did not have acanthosis nigricans, and there had been no symptoms of diabetes mellitus before her admission. After her hospitalization, she did not receive olanzapine; however, she remained overweight. When her blood sugars began to increase at 6 months from hospitalization and repeat hemoglobin A1C was 10.5%, she was then judged to have type 2 diabetes mellitus.
DISCUSSION Conventional neuroleptics such as haloperidol have been used to treat children with schizophrenia and other psychiatric entities such as psychotic mood disorder and pervasive developmental disorder. However, such medications have the disadvantage of serious side effects, the most important being extrapyramidal symptoms, with tardive dyskinesia being irreversible. In children and adolescents, these symptoms occur with lower drug doses and shorter therapy duration; they also have an increased frequency (8% to 51%) when compared with adults.3 The introduction of atypical neuroleptics for the management of childhood schizophrenia poses an alternative to conventional therapies; these new pharmacotherapies offer a lower risk of extrapyramidal symptoms because they spare the nigrostriatal dopamine system.3 Olanzapine is one of the most commonly used atypical neuroleptics
for the treatment of patients with pediatric schizophrenia, although not approved for children by the Food and Drug Administration. There are currently no published controlled clinical studies, with only case reports of safety and efficacy being reported in this population. The adverse effects of olanzapine have been reported as minimal, with side effects including increased appetite, weight gain, headache, increased agitation, and insomnia requiring additional medications. Diabetic ketoacidosis or diabetes mellitus associated with olanzapine therapy has been reported in the adult population, with a total of 11 cases with age ranges of 31 to 56 years.7-10 Presentation varied from acute diabetic ketoacidosis to symptoms of polyuria and polydipsia, with one half experiencing significant weight gain. Not all patients were tapered off of insulin after discontinuation of olanzapine therapy. In premarketing trials, Eli Lilly reports the incidence of diabetes mellitus in patients receiving olanzapine as 0.6%.10 A postmarketing series documents 139 cases of diabetes associated with olanzapine therapy, with 14 (10%) patients having no predisposing factors (Eli Lilly, data on file).9 Our patient had a strong family history of type 2 diabetes. It is unknown whether she had pre-existing glucose intolerance of diabetes mellitus. She did not have the physical manifestations of hyperinsulinism (acanthosis nigricans) or an increased body mass index. Her subsequent demonstration of re-expression glucose intolerance, evaluation of hemoglobin A1C, and persistent obesity at 6 months after hospitalization is consistent with the phenotype of type 2 diabetes mellitus. Because of the limited studies of olanzapine in the pediatric population, it is unclear what recommendations should be made to primary caregivers in monitoring for the expression of diabetes mellitus and prevention of diabetic ketoacidosis. Glucose intolerance caused by olanzapine therapy may appear after therapy is initiated. The
lack of weight gain in approximately 50% of those who have clinical expression of glucose intolerance and the reversal of diabetes mellitus after therapy is stopped in some patients suggest that the effect of olanzapine is not entirely related to the accelerated expression of type 2 diabetes mellitus. We suggest that documentation of family history for type 2 diabetes mellitus and a baseline fasting blood sugar to rule out undiagnosed type 2 diabetes mellitus would be reasonable before the therapy is initiated. The development of diabetic ketoacidosis as a serious complication from the use of olanzapine may be prevented by following changes in weight and monitoring for the development of glucose intolerance through fasting blood sugars, HgA1C values, or both. The authors acknowledge Dr Barry Irons, who referred this patient to our institution and provided initial insight into the reported complications of olanzapine therapy in adults, and Karen Dominguez and Dawn Lomako, clinical pharmacists, UNMH, who further investigated these complications and alerted the clinical staff involved with this patient’s care.
REFERENCES 1. Schulz SC, Findlin RL, Wise A, Friedman L, Kenny J. Child and adolescent schizophrenia. Psychiatr Clin North Am 1998;21:43–56. 2. Mandoki M. Olanzapine in the treatment of early onset schizophrenia in children and adolescents. Biol Psychiatry 1997;41:22s. 3. Toren P, Laor N, Weizman A. Use of atypical neuroleptics in child and adolescent psychiatry. J Clin Psychiatry 1998;59:644–56. 4. Potenza M, Holmes J, Kanes S, McDougle C. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open pilot study. J Clin Psychopharmacol 1999;1:37–44. 5. Horrigan JP, Barnhill LJ, Courvoise HE. Olanzapine in PDD [letter]. J Am Acad Child Adolesc Psychiatry 1997;36:1166–7. 6. Kumra S, Jacobsen L, Lenane M, Karp BI, Frazier JA, Smith AK, et al. Childhood onset schizophrenia: an 937
SELVA AND SCOTT
open label study of olanzapine in adolescents. J Am Acad Child Adolesc Psychiatry 1998;4:377-85. 7. Wirshing DA, Spellburg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998;44:778-83.
THE JOURNAL OF PEDIATRICS JUNE 2001 8. Gatta B, Rigalleu V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care 1999;6:435-6. 9. Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, et al. New onset diabetes mellitus and diabetic ketoacidosis associated with
olanzapine treatment. Psychosomatics 1999;5:438-43. 10. Lindenmayer JP, Patel R. Olanzapine induced ketoacidosis with diabetes mellitus [letter]. Am J Psychiatry 1999;9:1471.
50 Years Ago in The Journal of Pediatrics PERTUSSIS: CLINICAL COMPARISONS OF THE NEWER ANTIBIOTICS Booher CE, Farrell JB, West KJ. J Pediatr 1951;38:411-22 During the period from 1922 to 1948, pertussis was the leading cause of death from an infectious agent among children in the United States. By the early 1950s, pertussis vaccine had been introduced, and a number of reports on the in vitro antibiotic susceptibility of Bordetella pertussis started to appear in the literature. In their article in The Journal, Booher et al describe an outbreak of pertussis in Providence, Rhode Island (111 cases requiring hospitalization), which afforded them the opportunity of setting up a comparative study to examine the efficacy of the “newer antibiotics” for pertussis. The antibiotics they used to treat their patients (3 groups) were chloramphenicol and two tetracycline preparations, Aureomycin (chlortetracycline) and Terramycin (oxytetracycline). They compared these patients with an untreated group (historical control subjects) and also with a group of patients from a previous outbreak who were treated with streptomycin. They concluded that streptomycin had no effect but that the other 3 antibiotics were of equal clinical value in that they reduced the whooping stage of the disease but not the duration of coughing or length of hospitalization. So what has changed over the last 50 years? Certainly, in industrialized countries, outbreaks of pertussis are still being seen because of inadequate vaccination rates, often fueled by adverse publicity surrounding vaccines in general. A particular problem is the ongoing burden of disease in young, pre-vaccinated infants (<3 months). Older siblings and adults are the usual source of infection for these infants, attesting to a rethinking of pertussis vaccination policy, especially in the United Kingdom, where only the primary course is given. As far as treatment is concerned, B pertussis is susceptible to many antibiotics in vitro, which include ampicillin, cotrimoxazole, tetracyclines, and chloramphenicol. Unfortunately, in subsequent trials, none have been shown to be very effective therapeutically, and this includes erythromycin, which greatly diminishes nasopharyngeal carriage but does not alter the course of the disease unless it is administered during the catarrhal stage. Obviously, tetracycline preparations are now contraindicated in children less than 8 years of age, and chloramphenicol has only limited use in developed countries. The article by Booher et al ends with the following: “We believe that the specific drug for the complete and successful treatment of pertussis still lies in the future.” Unfortunately, 50 years later, we are still unable to alleviate the distressing symptoms of the young child in the paroxysmal stage of pertussis. Current trials of pertussis immunoglobulin may provide an answer. Vas M. Novelli, MD Infectious Diseases Unit Great Ormond Street Hospital for Children London, United Kingdom 9/37/115893 doi:10.1067/mpd.2001.115893
938