East Asian Arch Psychiatry 2011;21:10-6

ORIGINAL ARTICLE

思觉失调患者服用奥氮平对腹部脂肪和其他代谢参数影响的6 至10周随访研究：与对比组对照之成像研究

Dr Anup Mathew Joseph, MD, Department of Psychiatry, Kasturba Medical College and Hospital, Manipal University, Manipal, India.
A/Prof Ganesan Venkatasubramanian, MD, The Metabolic Clinic in Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.
Prof Podila Satya Venkata Narasimha Sharma, DPM, MD, Department of Psychiatry, Kasturba Medical College and Hospital, Manipal University, Manipal, India.

Address for correspondence: Dr Anup Mathew Joseph, Department of Psychiatry, Kasturba Medical College and Hospital, Manipal, Karnataka state, India 576104.
Tel: (0091) 9886216512; Fax: (0091) 8202571930; Email: docamj81@yahoo.com

Submitted: 11 June 2010; Accepted: 3 August 2010

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Introduction

Evidence suggests that patients taking certain atypical antipsychotics such as olanzapine have various metabolic abnormalities like hyperglycaemia, insulin resistance, and type II diabetes mellitus, which may be a consequence of increased abdominal obesity.^1-3 An earlier study of body composition and insulin sensitivity in Asian Indians found that only visceral or intra-abdominal fat (IAF) was correlated with insulin resistance.⁴

Urban and migrant Asian Indians have an unexpectedly high percentage of body fat relative to body mass index (BMI) and muscle mass, which is associated with a proportionate increase in visceral fat.⁴ Asian Indians have also been identified as an ethnic group with a high prevalence of type 2 diabetes mellitus and high familial aggregation of type 2 diabetes mellitus.⁵ Recently, a study⁶ examining patients with schizophrenia from south India reported significantly higher mean plasma insulin levels and mean insulin resistance scores than healthy subjects, even during antipsychotic-naïve periods. Hence, considering their predisposition to developing various components of the metabolic syndrome, it is possible that olanzapine may have a particularly deleterious impact on the metabolic profile of Asian Indians with psychosis.

Methods

This study was conducted in Kasturba Hospital, a tertiary- care multi-specialty hospital which has excellent laboratory and radiological imaging facilities in India. Approval for the study was obtained from the Kasturba Hospital Ethics Committee. The patients consisted of persons who had been diagnosed by a consultant psychiatrist to have a psychotic disorder (F20-F29) as per criteria of the 10th edition of the International Classification of Diseases (ICD-10) and started on olanzapine treatment.

Only patients who were not taking any oral antipsychotics for at least the past 6 weeks or any depot antipsychotics for at least 6 months were included. Moreover, it was a requirement that they should not have tried any second-generation (atypical) antipsychotic agent for their present illness exacerbation. The control group consisted of healthy relatives of the patients, who were not on any medication known to cause weight gain. Written informed consent was obtained from patients and controls. All the subjects were aged 18 to 65 years.

Subjects with any medical condition known to affect the brain or the various parameters under study, and those detected to have a metabolic syndrome, hypertension or fasting blood sugars in the diabetic range at baseline, were excluded. Subjects fulfilling ICD-10 criteria for current substance dependence syndrome (except tobacco use) were also excluded. Of the 36 patients and 16 controls approached, 34 patients and 15 controls agreed for participation, though 2 patients and 1 control withdrew from the study at the outset. Four patients taking olanzapine were suspended from the study, as their treatment was discontinued or augmented with other antipsychotic / anticonvulsant drugs. Five patients and 2 controls defaulted follow-up assessment during the ensuing 6 to 10 weeks. One control subject was excluded as his fasting sugars were in the diabetic range. Thus, the effective sample size in the completed study consisted of 23 patients and 11 controls. One of the controls was evaluated based on biochemical parameters alone as he did not consent for abdominal scanning. In another control subject, biochemical parameters were unavailable. The mean dose of olanzapine was calculated for each patient at the end of the assessment. Anthropometric measurements included: weight (kg), height (m), waist circumference (cm), hip circumference (cm), waist-to-hip ratios (WHRs), and BMI (kg/m²). Biochemical measurements included: fasting plasma glucose (FPG), fasting lipid profile, glycosylated haemoglobin (GlyHb), and computed tomographic (CT) scans for abdominal fat parameters, and these were performed at baseline and during the 6 to 10 weeks’ follow-up. For biochemical measurements, venous blood samples were drawn from the antecubital vein after a 12-hour overnight fasting. The waist was measured at the point midway between the iliac crests and the costal margins, and the hip was measured at the most rotund portion across the buttocks. Compliance was assessed verbally from the patient as well as via reports by family members. Total weekly leisure activity in patients was ascertained during the interview using the Godin Leisure-time Exercise Questionnaire.⁷

All of the subjects were scanned on a GE CT Prospeed FX Advantage Computed Tomography Scanner (GE Healthcare, US). Computed tomography–based assessment of visceral fat areas has been shown to be an accurate technique.^8,9 All scans were performed in the supine position. Visceral fat areas from a single scan taken at the level of the umbilicus (approximately the level of L4 and L5) correlate strongly with total visceral fat volume.^8-10 While repeating assessments, for the purpose of uniformity, a single 3-mm axial section was taken at the level of the pedicles of the fourth lumbar vertebra. The fourth vertebral body was identified from an antero-posterior scout. The various abdominal fat parameters were manually calculated using ImageJ software that yielded the area of fat in square pixels.¹¹ This was multiplied by a conversion factor (0.6729), calculated from the specifications of the CT scanner to obtain the area involved in square millimetres. The images were coded by one of the investigators and subsequently analysed by another investigator blinded to the particulars of the images. To assess the inter-rater reliability, all the images were analysed by another trained rater. Both the raters were blinded to subject details during the image analyses. The inter-rater reliability assessed by the intra-class correlation coefficient was found to be good (> 0.9) for the area measures of subcutaneous fat (SCF), IAF, and total fat.

Data Analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences software, Windows version 10.0. Comparison of baseline values of the 2 study groups was performed using the independent sample t test. Changes in the various parameters from baseline to follow-up assessment were calculated, and an independent sample t test was used to compare the changes encountered in the 2 study groups. Correlation analysis using Pearson test was performed to study the relationship between mean dose of olanzapine and the various parameters under study. Similarly, the correlation between IAF and the biochemical parameters were also studied.

Results

Table 1 shows a comparison of mean age and follow-up duration in patients and controls. There was a statistically significant difference between mean age, being 34 years in patients and 47 years in controls (p < 0.01).

Comparison of Physical and Biochemical Parameters at Baseline

Comparison of the baseline measures of abdominal fat parameters showed that patients had significantly higher mean SCF area (13,233 mm² vs. 5865 mm²; p < 0.01) and IAF area (4945 mm² vs. 1920 mm²; p = 0.03) when compared with the controls. No statistically significant differences were observed in any of the other parameters between the 2 groups at baseline (Table 2).

Comparison of Change from Baseline to Follow-up in Physical and Biochemical Parameters

Significant increases in all weight and fat parameters were noticed after 6 to 10 weeks of treatment with olanzapine, but no significant changes were observed in any other biochemical parameters (Table 3).

Figures 1 and 2 compared the changes in SCF and IAF of patients and controls from baseline to follow-up, respectively. Analysis revealed that the mean daily dose of olanzapine showed a significant correlation with the change in IAF (Pearson’s correlation = 0.52; p < 0.05).

Paired t test of the total leisure activity score (TLAS) and daily calorie intake were also performed for the patients; there was a mean (± standard deviation) increase in intake of 295 kcal (p < 0.001), from 1427 ± 500 kcal at baseline to 1722 ± 573 kcal at follow-up. The TLAS increased by a mean of 1 unit (p > 0.05), i.e. 21 ± 16 units at baseline to 22 ± 13 units at follow-up.

Discussion

The present study provides preliminary data on the effects of olanzapine on various abdominal fat and biochemical parameters in an Indian population. In this respect, it is probably unique. Being a naturalistic study, the sample reflects real-world patients whose susceptibility to metabolic problems may differ from those typically seen in randomised controlled studies.

The patient group in this study had significantly higher amounts of both IAF and SCF compared with the controls at baseline. A cross-sectional study by Thakore et al¹², comparing the various fat compartments using CT scanning and anthropometry in drug-naïve and drug-free subjects with schizophrenia who were matched for age and sex, found that the patients and controls differed significantly only for measures of IAF. Using a similar methodology, Ryan et al¹³ found that at baseline, patients with schizophrenia had significantly more IAF than the age- and sex-matched controls, as measured by CT and anthropometry. Not surprisingly, the mean age of the patients in our study was significantly less than that of controls, as in some instances their parents served as controls. This difference though is unlikely to have had any major effect, given the short duration of this study. A more likely contributory factor for the apparent discrepancy may be that a large proportion of our patients (74%) had previously received antipsychotics. Correspondingly, slightly more than 50% of the patients in the study by Thakore et al¹² had received antipsychotics. The results of the present study also differ from the baseline measures of fat reported in the magnetic resonance imaging – based study by Zhang et al¹⁴ comparing patients of Han ethnicity diagnosed with schizophrenia with age- and sex-matched normal controls. They found no significant difference in weight or fat deposition between controls and the patients, though they did note slight elevations in the fat indicators in patients as opposed to controls.

Comparison between Baseline and Follow-up Measures of Variables

Significant increases were noted in the follow-up measures of all the abdominal fat parameters studied. This was contrary to the finding of Ryan et al¹³ who studied the effects of risperidone and olanzapine on IAF in drug-naïve patients over a longer period of 6 months. All the participating subjects of that study were Caucasians. The study by Zhang et al¹⁴ on Chinese patients, however, demonstrated that antipsychotic use did result in accumulation of IAF and SCF over a 10-week period. The patients in the latter study were on risperidone or chlorpromazine. Olanzapine has been shown to have much higher potential to induce weight gain as well as other components of the metabolic syndrome^15-17; our results also support that observation.

The findings of significant increase in weight (3.1 kg), waist circumference (3.6 cm), hip circumference (1.1 cm), and BMI (1.2 kg/m²) are in keeping with the wealth of data on olanzapine-induced weight gain.^16,18 Interestingly, we failed to detect a significant change in WHR, which was probably because of the associated marked increase in the SCF compartment.

Graham et al¹⁹ studied the effects of olanzapine on body composition and found a significant increase in body fat as measured by dual-energy X-ray absorptiometry over 7 to 12 weeks. An 8-week prospective controlled open study,²⁰ which compared body weight, fat mass, and indices of insulin resistance / sensitivity in olanzapine-treated patients with an ICD-10 diagnosis of schizophrenia and a group of 10 mentally and physically healthy volunteers, concluded that most of the weight gained by the patients was fat. Given the increase in all compartments of abdominal fat in the patients in the present study, it may be reasonable to expect that most of the weight gained was due to fat.

The mean gain of 3.1 kg over 6 to 10 weeks for patients in this study was similar to that reported in Allison et al’s comprehensive research synthesis,¹⁶ which estimated olanzapine-induced weight gain as exceeding 4 kg over 10 weeks. With respect to weight gain and BMI increase, the results of this study are more robust than those of another study in the Indian population by Guha et al.²¹ The changes in these parameters continued to be significant when compared with controls. Of the 23 patients, 22 had gained weight and 1 maintained the same weight when measured at follow-up. This increase was despite the fact that in the patient group the TLAS had improved from baseline. The significant increase in the daily calorie intake among patients could be partly responsible for the weight gain.

It might be argued that the observed increase in body fat parameters as well as weight and BMI could just be a function of change in the nutritional input, as a result of symptomatic improvement. However, the significantly higher levels of baseline IAF and SCF among patients suggest otherwise.

Unlike most other studies that evaluated changes in FPG with use of olanzapine, we found no significant change in any of the metabolic parameters as compared to controls. Graham et al¹⁹ also did not find any statistically significant increase in the levels of FPG, though significant increases in fasting insulin and C-peptide levels were noted. It is possible that the short duration of follow-up may have been responsible for the discrepant findings.

No significant changes were noted during follow- up in any of the fasting lipid parameters. Nevertheless, several studies reported that olanzapine may cause dyslipidaemia.^15,22-24 A retrospective review of patient records found that the mean time to peak triglyceride levels was 10 months,²⁵ our study patients might therefore still be at risk of dyslipidaemia. Besides, most of them had received antipsychotics in the past and therefore, some elevation in the serum lipid levels could have occurred prior to the initiation of this study. In turn, this might have mitigated any further change in various lipid level indicators.

The change in weight parameters in our study was similar to those of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study.²⁶ In the latter study, an average weight gain of 0.9 kg per month was noted in the olanzapine group, and 30% of the patients gained more than 7% of their baseline weight. There too, no significant changes in the biochemical parameters such as FPG, serum cholesterol and GlyHb were observed. However, a statistically significant change from baseline triglyceride levels (41 mg/dL) was noted in the patients on olanzapine.

Correlational Analysis

Notably, there were no significant correlations between changes in IAF and any of the biochemical parameters studied. On the other hand, Zhang et al¹⁴ found a strong correlation between the change in SCF and fasting insulin concentrations at baseline and after 10 weeks of treatment. This difference in results could be due to differing sample characteristics, as the latter study only targeted first-episode patients never previously exposed to antipsychotics.

The mean dose of olanzapine correlated significantly with the change in IAF, which was in contrast to Kinon et al’s²⁷ findings in which the dose was not a significant predictor of greater long-term weight gain, based on a retrospective analysis of 573 patients. Allison and Casey²⁸ found good correlation between dose of olanzapine and weight gain at 10 weeks, based on a meta-analysis of antipsychotic-induced weight gain studies. It is possible that duration of exposure may affect weight gain differentially in different populations. The distribution of fat, especially visceral obesity, has been proposed to be a more important determinant of insulin resistance, diabetes, and cardiovascular disease than generalised obesity.^29,30 This apart, Banerji et al⁴ have shown that Asian Indians have an unexpectedly high percentage of body fat relative to BMI and muscle mass. Moreover, this is associated with a proportionate increase in visceral fat. High body fat and low muscle mass may explain the high prevalence of hyperinsulinaemia and the greater risk for developing type 2 diabetes. Earlier studies have demonstrated the propensity of olanzapine to increase measures of insulin resistance.^19,31

Given the observed increase in visceral fat (p < 0.05), it may be that several of the patients in our study could have developed insulin resistance and by extension were at increased risk of developing the metabolic syndrome. Taken together, these findings indicate an increased risk of various metabolic side-effects of olanzapine (particularly an increase in abdominal fat) in the Indian population. This may mean that extra precautions should be exercised when using olanzapine in this population.

Limitations

This study entailed a relatively small control group compared with the patients. The patients and controls were not matched for age, physical activity or calorie intake, which might have had a bearing on the parameters studied. In addition, the duration of follow-up was relatively short; changes in blood sugar and cholesterol levels may take several months to develop.

The confounding effects of tobacco use in any form were not controlled for. Smoking is a factor affecting weight gain. However, such effects were unlikely to have made a significant contribution to the observed changes over a duration of 6 to 10 weeks.

Most of the patients had already tried on antipsychotics in the past. This might have led to confounding, although care was taken to only recruit patients who were off oral antipsychotics for at least 6-week depot treatment in the last 6 months.

This study did not look for any specific genetic predisposition to adverse effects caused by olanzapine. Moreover, the change in clinical status was not measured and hence correlations between change in weight indicators and change in clinical status could not be performed.

Despite the above limitations, evidence from this study does support the observation of significant weight gain and increase in IAF with olanzapine treatment. In vulnerable populations such as in Asia, this may have a special significance for the development of insulin resistance, metabolic syndrome, and diabetes mellitus.

Acknowledgements

We would like to thank the Head of the Department of Radiodiagnosis, Kasturba Medical College, Manipal for providing us with technical expertise in the performance of CT scans. We would also like to thank Dr Vijay Danivas, Junior Resident, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore for lending his help in measuring the various fat parameters for assessing inter-rater reliability.

Declaration

A thesis research grant was provided by Kasturba Medical College, Manipal and supplementary grants were given by the Department of Psychiatry, Kasturba Medical College, Manipal to perform this work. One of the authors, Dr G Venkatasubramanian, was partially supported by the Innovative Young Biotechnologist Award by the Department of Biotechnology, Government of India. The authors declare that there is no conflict of interest in performing this study.

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