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Letters to the Editor   |    
Olanzapine-Induced Hyperglycemia in Anorexia Nervosa
DAISUKE YASUHARA; TOSHIHIRO NAKAHARA; TOSHIRO HARADA; AKIO INUI
Am J Psychiatry 2007;164:528-529.

To The Editor: Recent studies on anorexia nervosa have suggested that the atypical antipsychotic agent olanzapine has favorable effects on agitation, repetitive thinking about becoming obese, and subsequent weight gain (1, 2). Although hyperglycemia is a serious adverse effect of olanzapine (3), the incidence varies from less than 1% to 10%, and to the best of our knowledge, there have been no previous reports of this effect in patients with anorexia nervosa. We present a case report of a patient with anorexia nervosa with olanzapine-induced hyperglycemia.

A 27-year-old Japanese woman with a 2-year history of anorexia nervosa (restricting type) and no personal or family history of diabetes mellitus or other metabolic or mental disorders was admitted to our hospital with agitation, general fatigue, and fear of obesity. Laboratory results revealed aspartate aminotransferase of 39 IU/l and alanine aminotransferase of 61 IU/l; results of other laboratory examinations (e.g., antiglutamic acid decarboxylase antibodies) were normal. During the first week of hospitalization (body mass index: 14.1 kg/m2, mean value of daily energy intake: 1,043 kcal/day), we performed a corrected (1.75g-glucose/kg) oral glucose tolerance test, which showed impaired glucose tolerance (4.3 mmol/l at baseline, peak value of 9.2 mmol/l at 60 minutes, 8.6 mmol/l at 120 minutes) by World Health Organization criteria (4), with delayed insulin secretion (34.6 pmol/l at baseline, peak value of 198 pmol/l at 120 minutes).

Thereafter, we prescribed olanzapine 5 mg/day to reduce agitation and fear of obesity; we also started a multidisciplinary treatment program (4). The patient’s agitation improved, and we performed another oral glucose tolerance test during the third week (body mass index: 14.2 kg/m2, energy intake: 1,157 kcal/day). Results showed diabetes mellitus (4.2 mmol/l at baseline, peak value of 12.2 mmol/l at 120 minutes) with exaggerated insulin secretion (30.8 pmol/L at baseline, peak value of 1,210 pmol/L at 60 minutes). However, symptoms of diabetes (e.g., excessive thirst or urination) were absent. The patient’s fear of obesity gradually decreased, and olanzapine therapy at 5 mg/day was carefully continued with monitoring of diabetic symptoms, weekly fasting blood glucose levels, and monthly oral glucose tolerance test examinations (3). The lack of symptoms of diabetes and weekly fasting blood glucose levels (range 4.2 to 4.8 mmol/l) remained stable over 10 weeks. Although the patient showed impaired glucose tolerance during the seventh week (body mass index: 15.2 kg/m2, energy intake: 1,600 kcal/day), the oral glucose tolerance test results returned to normal at the time of her discharge (body mass index: 18.3 kg/m2, energy intake: 1,800 kcal/day).

The underlying mechanism of olanzapine-induced hyperglycemia remains unclear (3, 5, 6). Theories regarding this mechanism include the induction of insulin resistance via 5-HT1A antagonism or impaired insulin-signaling cascade, increased food intake via H1 antagonism, impaired pancreatic beta cell function, induction of glucogenesis via a decrease in glycogen synthase (5), increase in glycogen phosphorylase, and upregulation of cocaine and amphetamine regulated transcripts (6). Exacerbating glucose tolerance with exaggerated insulin secretion was evident on the second oral glucose tolerance test despite no marked differences in fasting plasma glucose levels, body mass index, and energy intake compared with the first oral glucose tolerance test. These findings suggest that glucose intolerance might have been induced by olanzapine via insulin resistance (3, 5, 6). Moreover, hyperglycemia improved after weight restoration despite continuous use of olanzapine, which indicates that undernutrition itself might be a risk factor for olanzapine-induced hyperglycemia, particularly in patients with anorexia nervosa. Clinicians treating acute patients with anorexia nervosa should carefully monitor glucose metabolism, especially in patients being treated with olanzapine.

1.Mondraty N, Birmingham CL, Touyz S, Sundakov V, Chapman L, Beumont P: Randomized controlled trial of olanzapine in the treatment of cognitions in anorexia nervosa. Australas Psychiatry 2005; 13:72–75
 
2.Barbarich NC, McConaha CW, Gaskill J, La Via M, Frank GK, Achenbach S, Plotnicov KH, Kaye WH: An open trial of olanzapine in anorexia nervosa. J Clin Psychiatry 2004; 65:1480–1482
 
3.American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity: Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. J Clin Psychiatry 2004; 65:267–272
 
4.Yasuhara D, Naruo T, Nagai N, Muranaga T, Nakahara T, Tanaka M, Kojima S, Sagiyama K, Masuda A, Inui A: Glucose tolerance predicts short-term refeeding outcome in females with anorexia nervosa. Psychosom Med 2005; 67:669–676
 
5.Engl J, Laimer M, Niederwanger A, Kranebitter M, Starzinger M, Pedrini MT, Fleischhacker WW, Patsch JR, Ebenbichler CF: Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2006; 11:524–525
 
6.Fatemi SH, Reutiman TJ, Folsom TD, Bell C, Nos L, Fried P, Pearce DA, Singh S, Siderovski DP, Willard FS, Fukuda M: Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique. Neuropsychopharmacology 2006; 31:1888–1899
 
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References

+Supported by a research grant from the Japanese Ministry of Health, Labor, and Welfare. The authors report no competing interests.

Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

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References

1.Mondraty N, Birmingham CL, Touyz S, Sundakov V, Chapman L, Beumont P: Randomized controlled trial of olanzapine in the treatment of cognitions in anorexia nervosa. Australas Psychiatry 2005; 13:72–75
 
2.Barbarich NC, McConaha CW, Gaskill J, La Via M, Frank GK, Achenbach S, Plotnicov KH, Kaye WH: An open trial of olanzapine in anorexia nervosa. J Clin Psychiatry 2004; 65:1480–1482
 
3.American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity: Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. J Clin Psychiatry 2004; 65:267–272
 
4.Yasuhara D, Naruo T, Nagai N, Muranaga T, Nakahara T, Tanaka M, Kojima S, Sagiyama K, Masuda A, Inui A: Glucose tolerance predicts short-term refeeding outcome in females with anorexia nervosa. Psychosom Med 2005; 67:669–676
 
5.Engl J, Laimer M, Niederwanger A, Kranebitter M, Starzinger M, Pedrini MT, Fleischhacker WW, Patsch JR, Ebenbichler CF: Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2006; 11:524–525
 
6.Fatemi SH, Reutiman TJ, Folsom TD, Bell C, Nos L, Fried P, Pearce DA, Singh S, Siderovski DP, Willard FS, Fukuda M: Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique. Neuropsychopharmacology 2006; 31:1888–1899
 
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Olanzapine-induced hyperglycemia in anorexia nervosa. Am J Psychiatry 2007;164(3):528-9.