Decrease of Energy Expenditure Causes Weight Increase in Olanzapine Treatment - A Case Study

• Introduction
• Method
• Results
• Discussion
• References

The aim of this study was to evaluate the mechanisms underlying weight gain induced by the atypical antipsychotic, olanzapine. We performed euglycemic, hyperinsulinemic clamp combined with indirect calorimetry on a 48-year-old male with antisocial personality disorder, alcohol dependence and paranoid ideation before and after one month of olanzapine (10 - 15 mg/day) therapy. The patient gave his informed, written consent for this study. The results were a weight gain of 6 kg and a decrease in both basal (from 1673 to 1613 kcal/24 h) and 3-hour (from 22.8 to 20.2 cal/kg fat free mass/min) energy expenditure. Serum thyroid hormone and high-density lipoprotein cholesterol levels decreased, and the triglyceride and low-density lipoprotein cholesterol levels increased. Insulin sensitivity did not change. We conclude that decreased basal energy expenditure may contribute to weight gain in olanzapine treatment.

Introduction

Atypical neuroleptics, especially olanzapine and clozapine, increase body weight [1] [2] [3]. The mean weight gain after 10 weeks of treatment with these agents is more than 4 kg [2]. Olanzapine has also been linked to hypertriglyceridemia, hyperglycaemia, and even to diabetes [4] and diabetic ketoacidosis [5]. The mechanisms behind this weight gain and its metabolic concomitants are still unclear. They may involve increased energy intake or lowered energy expenditure. Although some study results have suggested increased appetite in patients treated with antipsychotics, no systematic studies have as yet been focussed on energy intake or expenditure in these patients [6].

We therefore studied basal energy expenditure and insulin sensitivity before and after olanzapine treatment.

Method

The patient was a 48-year old man with the diagnoses of antisocial personality disorder and alcohol dependence that began at adolescence. He was habitually violent under the influence of alcohol, and had committed two impulsive homicides at ages 37 and 47. He was therefore twice subjected to mental examination at Department of Psychiatry, University of Helsinki, by court order.

During the first forensic psychiatric in-patient examination at age 37, APD and alcohol dependence were diagnosed according to DSM-III-R. No paranoid symptoms were found. The oral 75 mg glucose tolerance test was normal. The insulin values during the test were normal (basal insulin level 10.6 mU/l, and a maximum value 55.2 mU/l one hour after intake of glucose), indicating that the patient was not resistant to insulin.

During the second two-month in-patient forensic psychiatric examination at age 47, the APD and alcohol dependence diagnoses were confirmed by SCID interview. The patient also showed paranoid symptoms, and olanzapine treatment was started. The paranoid symptoms diminished and impulsiveness and irritability vanished, but at the same time, body weight started to increase. The first euglycemic, hyperinsulinemic clamp combined with indirect calorimetry was carried out before olanzapine was started, and these measurements were repeated after one month on olanzapine (10 - 15 mg/day). The study was approved by the Ethical Committee of the Helsinki University Hospital, and the patient gave his written informed consent.

A three-hour euglycemic, hyperinsulinemic clamp combined with indirect calorimetry [7] was performed to estimate insulin sensitivity and substrate oxidation and energy expenditure in the recumbent position at 7.30 a.m. after a 12-hour overnight fast. Fat-free mass was measured by bioimpedance. The person was not taking any medication before the study.

After obtaining basal samples for glucose and insulin, a primed continuous infusion of short-acting human insulin (Actrapid Human, Novo Nordisk, Copenhagen, Denmark) was administered at a rate of 45 mU/m²/min (about 340 pmol/m²/min) for three hours. Plasma glucose concentration was determined at 5-minute intervals, and 20 % glucose was infused to maintain a constant plasma glucose concentration [8].

Indirect calorimetry was performed in the basal state and at 150 - 180 minutes [9] with a computerized open-circuit system (Deltatrac, Datex, Helsinki, Finland) to measure gas exchange rates (CO₂ production and O₂ consumption) [10]. The monitor has a precision of 2.6 % for oxygen and 1 % for carbon dioxide production [11].

Protein oxidation was calculated from urinary urea nitrogen excretion obtained before and after the insulin clamp and was corrected for urea clearance [12].

Results

During one month of olanzapine therapy, the weight of the subject increased from 70 kg to 76 kg, and BMI increased from 23.7 kg/m² to 25.7 kg/m². Changes in glucose disposal, energy expenditure and metabolism after olanzapine treatment are listed in Table [1]. A decrease in energy expenditure was evident, which was accompanied by a decrease in thyroid hormone levels and elevation of low-density lipoprotein (LDL) cholesterol and triglycerides and a decrease of high density lipoprotein (HDL) cholesterol.

Discussion

The olanzapine-induced weight gain of 6 kg in our patient was accompanied by a 60 kcal or 4 % decrease in daily basal energy expenditure. This cannot be explained by chance variation of the method applied. In a diabetes study, a 6 % drop in basal energy expenditure after 12 months of insulin treatment explained a 4 kg weight gain [13].

The patient himself felt that the increase of weight was because the medicine increased sleep and tiredness, even during daytime, so motor restlessness and movements decreased. Olanzapine is known to increase appetite by interaction with several receptor types in the brain [14], including leptin [15] [16]. All these factors obviously contributed to the weight gain.

It would be important to clarify whether decreased energy expenditure is associated with weight gain with some or all atypical neuroleptics in studies on schizophrenic patients with larger cohorts. Longitudinal studies are the only possible way of investigating drug-induced changes. There is also a need to clarify why not all patients treated gain weight.

References

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• 8 Franssila-Kallunki A, Schalin-Jäntti C, Groop L. Effect of gender on insulin resistance associated with aging.  Am J Physiol. 1992;  263 (Endocrinol Metab 26) E780-E785
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• 12 Tappy L, Owen O E, Boden G. Effects of hyperinsulinemia on urea pool size and substrate oxidation rates.  Diabetes. 1988;  17 1212-1216
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• 13 Franssila-Kallunki A, Groop L. Factors associated with basal metabolic rate in patients with type 2 (non-insulin dependent) diabetes mellitus.  Diabetologia. 1992;  35 962-966
  CrossrefPubMedSearch in Google Scholar
• 14 Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management.  Acta Psychiatr Scand. 1999;  100 3-16
  PubMedSearch in Google Scholar
• 15 Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, Pollmacher T. Body weight and leptin plasma levels during treatment with antipsychotic drugs.  Am J Psychiatry. 1999;  156 312-314
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• 16 Herran A, Garcia-Unzueta M T, Amado J A, de la Maza M T, Alvarez C, Vazquez-Barquero J L. Effects of long-term treatment with antipsychotics on serum leptin levels.  Br J Psychiatry. 2001;  179 59-62
  CrossrefPubMedSearch in Google Scholar

Matti VirkkunenMD, PhD 

Department of Psychiatry, University of Helsinki

Lapinlahti Hospital

PO Box 320

00029 Huch

Finland

Phone: +358 (9) 47 18 12 60

Email: matti.virkkunen@huch.fi

References

• 1 Conley R R, Meltzer H Y. Adverse events related to olanzapine.  J Clin Psychiatry. 2000;  61 (8) 26-29
  PubMedSearch in Google Scholar
• 2 Allison D B, Mentore J L, Heo M, Chandler L P, Cappelleri J C, Infante M C, Weiden P J. Antipsychotic-induced weight gain: a comprehensive research synthesis.  Am J Psychiatry. l999;  156 1686-1696
  PubMedSearch in Google Scholar
• 3 Taylor D M, McAskill R. Atypical antipsychotics and weight gain-a systematic review.  Acta Psychiatr Scand. 2000;  101 416-432
  PubMedSearch in Google Scholar
• 4 Wirshing D A, Spellberg B J, Erhart S M, Marder S R, Wirshing W C. Novel antipsychotics and new onset diabetes.  Biol Psychiatry. 1998;  44 778-783
  CrossrefPubMedSearch in Google Scholar
• 5 Lindenmayer J P, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus.  Am J Psychiatry. 1999;  156 1471
  PubMedSearch in Google Scholar
• 6 Devlin M J, Yanovski S Z. Obesity: What mental health professionals need to know.  Am J Psychiatry. 2000;  157 854-866
  CrossrefPubMedSearch in Google Scholar
• 7 DeFronzo R A. Glucose intolerance and aging: Evidence for tissue insensitivity to insulin.  Diabetes. l979;  28 1091-1111
  PubMedSearch in Google Scholar
• 8 Franssila-Kallunki A, Schalin-Jäntti C, Groop L. Effect of gender on insulin resistance associated with aging.  Am J Physiol. 1992;  263 (Endocrinol Metab 26) E780-E785
  PubMedSearch in Google Scholar
• 9 Ferrannini E. The theoretical basis for indirect calorimetry: a review.  Metabolism. 1988;  37 287-301
  CrossrefPubMedSearch in Google Scholar
• 10 Merilainen P T. Metabolic monitor.  Inst I Clin Comput. 1987;  4 167-177
  PubMedSearch in Google Scholar
• 11 Franssila-Kallunki A. Energy metabolism in insulin resistant states. Academic Dissertation, Helsinki University. Helsinki Yliopistopaino 1994
  Search in Google Scholar
• 12 Tappy L, Owen O E, Boden G. Effects of hyperinsulinemia on urea pool size and substrate oxidation rates.  Diabetes. 1988;  17 1212-1216
  PubMedSearch in Google Scholar
• 13 Franssila-Kallunki A, Groop L. Factors associated with basal metabolic rate in patients with type 2 (non-insulin dependent) diabetes mellitus.  Diabetologia. 1992;  35 962-966
  CrossrefPubMedSearch in Google Scholar
• 14 Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management.  Acta Psychiatr Scand. 1999;  100 3-16
  PubMedSearch in Google Scholar
• 15 Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, Pollmacher T. Body weight and leptin plasma levels during treatment with antipsychotic drugs.  Am J Psychiatry. 1999;  156 312-314
  PubMedSearch in Google Scholar
• 16 Herran A, Garcia-Unzueta M T, Amado J A, de la Maza M T, Alvarez C, Vazquez-Barquero J L. Effects of long-term treatment with antipsychotics on serum leptin levels.  Br J Psychiatry. 2001;  179 59-62
  CrossrefPubMedSearch in Google Scholar

Matti VirkkunenMD, PhD 

Department of Psychiatry, University of Helsinki

Lapinlahti Hospital

PO Box 320

00029 Huch

Finland

Phone: +358 (9) 47 18 12 60

Email: matti.virkkunen@huch.fi