SHORT COMMUNICATION Increased visceral fat distribution ... - Nature

International Journal of Obesity (2002) 26, 137–141 ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00 www.nature.com/ijo

SHORT COMMUNICATION Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia JH Thakore1*, JN Mann2, I Vlahos3, A Martin3 and R Reznek3 1

Neuroscience Centre, St Vincent’s Hospital, Dublin, Ireland; 2St Clement’s Hospital, London, UK; and 3Academic Department of Radiology, St Bartholomew’s Hospital, London, UK OBJECTIVE: To investigate visceral fat distribution in patients with schizophrenia. DESIGN: Cross sectional study using CT scanning in patients with drug-naive and drug-free schizophrenia. SUBJECTS: Fifteen (13 men and two women) subjects with schizophrenia (mean age 33.7 y; mean body mass index (BMI) ¼ 26.7 kg=m2), and 15 age- and sex-matched controls (mean age 30.5 y; mean BMI ¼ 22.8 kg=2). MEASUREMENTS: Various fatness and fat distribution parameters (by CT scanning and anthropometry) and 16:00 h plasma cortisol. RESULTS: In comparison to controls, patients with schizophrenia had central obesity and had significantly higher levels of plasma cortisol. Furthermore, previous neuroleptic exposure did not appear to influence these findings as both drug-naive and drug-free patients had equally high levels of visceral fat deposition. CONCLUSION: Central obesity is a well recognized risk factor in developing certain general medical conditions. This study shows that patients with schizophrenia have increased intra-abdominal fat which may provide one explanation for why they die prematurely. International Journal of Obesity (2002) 26, 137 – 141. DOI: 10.1038=sj=ijo=0801840 Keywords: schizophrenia; cortisol; imaging

Introduction Reduced life expectancy is a well recognized feature of psychiatric illness.1 – 3 With respect to schizophrenia, the precise reasons underlying this excessive mortality are as yet unknown.4,5 However, it is clear that suicide cannot fully account for these findings.6,7 A meta-analysis of the relevant literature by Harris and Barraclough found that ‘unnatural’ causes of death such as suicide and accidents were far more likely to occur than expected in patients with schizophrena.8 However, the standardized mortality ratios for ‘natural causes’, such as cardiovascular illness, was also significantly increased, a finding which was supported by Allbeck9 and Ruschena et al.3 A number of reasons may explain the excessive death rate due to ‘natural causes’ observed in schizophrenia; these

*Correspondence: JH Thakore, Neuroscience Centre, St Vincent’s Hospital, Richmond Rd, Fairview, Dublin 3, Ireland. E-mail: [email protected] Received 17 April 2001; revised 6 June 2001; accepted 2 July 2001

include psychosocial deprivation, an unhealthy lifestyle and psychotropic medication.10 – 12 Yet, the general medical illnesses which tend to occur in those suffering from schizophrenia form a cluster which is termed the metabolic syndrome.13 Hypertension, type 2 diabetes mellitus and dyslipidaemias are the primary constituents of this syndrome and are associated with increased intra-abdominal fat deposition.14,15 Abdominal fat distribution consists of two discrete depots, subcutaneous and visceral (intra-abdominal) and numerous variables can account for the pattern of body fat deposition observed in the general population.16,17 Of note is the fact that cortisol has a marked effect on regional fat distribution, in that patients with Cushing’s syndrome who have marked hypercortisolaemia, have increased visceral fat distribution as measured by computerized axial tomography (CT) scanning.18,19 Indeed, reduction of plasma cortisol in this subgroup of patients leads to a decrease in intra-abdominal fat stores20 and also a normalization of certain features of the metabolic syndrome. These findings highlight the importance of this adrenocorticoid in determining regional adiposity and associated general medical disorders.21

Visceral fat distribution in schizophrenia JH Thakore et al

138 Abdominal fat distribution can be measured by indirect (waist-to-hip ratio (WHR), body mass index (BMI)) and by direct means (computerized axial tomography, magnetic resonance imaging).15 However, a single 3 mm CT scan slice through the level of the fourth lumbar vertebra still remains the best validated direct measure of visceral fat deposition as is reflected by a number of published studies which have used this technique to determine central obesity in patients suffering from certain general medical conditions18,19 and psychiatric disorders.22,23 To date, there has been no published study in the literature directly examining regional abdominal adiposity in patients with schizophrenia. Therefore, it was our intention in this study to measure abdominal fat distribution using CT scanning in patients with schizophrenia and compare them to normal controls. As the adrenocortical milieu is an important determinant of regional adiposity24 we also elected to measure plasma levels of cortisol in both groups of subjects.

Methods (experimental) Fifteen subjects (mean age ¼ 33.7 y, s.d. 12.7 y; 13 males and two females) who fulfilled DSM IV25 criteria for schizophrenia were recruited. The study had Ethics Committee approval and all subjects who agreed to participate gave fully informed written consent. Seven of the patients were drug naive and eight were drug free of oral neuroleptics for at least 6 weeks or drug free for 6 months of intra-muscular preparations, prior to testing. In particular, none of the patients had been on any form of an atypical neuroleptic prior to entering the study. Twelve were inpatients and the rest were outpatients. None of the patients had co-morbid DSM IV25 diagnoses and all of the patients were physically healthy. The mean Brief Psychiatric Rating Scale26 score was 22.6 (s.d. ¼ 8.4). The Abnormal Involuntary Movement Scale27 was used to ensure that patients with tardive dyskinesia did not enter the study and the mean score was 3.1 (s.d. ¼ 0.1). The normal control group, consisting of 15 subjects (13 males and two females; mean age ¼ 30.5 y; s.d. ¼ 1.9), were physically healthy and had no personal or family history of psychiatric illness. All normal controls were recruited from within the hospital, university and the general community. None of the subjects was taking any form of prescribed or over-the-counter medication. Patients and normal controls were matched in terms of age, exercise, diet, smoking habits and alcohol intake. All subjects had their weight (kg), height (m), waist and hip measurements taken and waist-to-hip ratios (WHRs) and body mass indices (BMI; weight in kg=height in m2) were calculated. In terms of the WHR, ‘waist’ was taken as the point midway between the iliac crests and the costal margins whilst ‘hip’ was considered to be across the most rotund portion across the buttocks. International Journal of Obesity

All of the subjects were scanned on an IGE High Speed Advantage, Computed Tomography Scanner. For a full description of the techniques used please refer to Kvist et al,28 and Sjostrom.29 All scans were performed in the supine position. The fourth vertebral body was identified from a lateral scout. A single 3 mm axial section was performed at the level of the pedicles of the fourth lumbar vertebra (200 mA, 120 kV). The total number of pixels of fat density ( 7 50 to 7 150 Hounsfield units) was then obtained for each cross-section. Multiplication of the pixel size and the number of pixels gave the area containing fat in each scan. This was achieved using analysis software (General Electric, Milwaukee, WI, USA). The area of fat was then calculated by subtracting the intra-abdominal fat from the total area of fat in each scan. At 16:00 h, approximately 8 ml of blood was drawn into lithium — heparin treated tubes for plasma cortisol estimation, immediately centrifuged and put on ice. A 16:00 h sample was chosen as this is a time when plasma cortisol levels are likely to be low. All subjects had breakfast although they fasted thereafter. Analysis was carried out in batches and was blind to the subjects’ status. Cortisol was measured using a sensitive in-house radioimmunoassay.30 The assay has negligible cross-reactions with all the endogenously, produced steroids. It has approximately 8.0% cross-reactivity with prednisone. The working range was 50 – 2000 nmol=l. The intra- and interassay coefficients of variation across the entire working range of the assay were less than 8.0%. Student’s t-tests (two-tailed) and Pearson’s product — moment correlational analyses were used when appropriate. All results are expressed as mean standard deviation (s.d.) and the data was analysed by means of Statgraphics.31

Results Patients with schizophrenia were observed to have higher BMIs (26.7 1.1 vs 22.8 0.5 kg=m2, respectively) and higher WHRs (0.99 0.03 vs 0.86 0.01, respectively) than did control subjects (d.f. ¼ 13, P < 0.003; d.f. ¼ 13, P < 0.005, respectively). Furthermore, there was no significant difference in terms of age between the two groups (33.7 3.2 y vs 30.1 0.7 y, respectively; d.f. ¼ 13, P < 0.28). However, baseline plasma cortisol levels were significantly higher in patients with schizophrenia than in control subjects (253.9 40.5 vs 134.3 12.8 nmol=l, respectively; d.f. ¼ 13, P < 0.008). Total body fat (34 680.9 4392.3 vs 27 692.5 458.7 mm2, respectively; d.f. ¼ 13, P < 0.12) and subcutaneous fat (21 449.1 2195.1 vs 20 204.0 2028.9 mm2, respectively; d.f. ¼ 13, P < 0.68) were no different between schizophrenics and controls. However, patients with schizophrenia had over three times as much intra-abdominal fat (IAF) as did normal controls (13 232.0 2666.5 vs 3879.9 571.9 mm2, respectively; d.f. ¼ 13, P < 0.005). Yet, there was no difference in IAF distribution between those patients who were drug naive (n ¼ 7) and those who were drug-free (n ¼ 8; 12


442.4 9762.6 vs 14 133.9 11 656.8 mm2, respective1y; d.f. ¼ 19, P < 0.76). Although there was a positive correlation between age and visceral fat distribution in patients with schizophrenia (r ¼ 0.71, d.f. ¼ 13, P < 0.003), there were no other significant correlations.

Discussion From our study it would appear that patients with schizophrenia have (1) a higher BMI and WHR, (2) higher plasma levels of cortisol, and (3) over three times as much IAF, than do normal age- and sex-matched controls. Our results have shown that certain patients with schizophrenia have grade 1 (25 – 30 kg=m2) obesity.32 This finding in one sense concurs with that of Allison et al33 who observed that, while some patients with schizophrenia were underweight, a significant percentage were obese, yet their results failed to differentiate between those who were drug-free and those who were drugnaive and therefore their findings may be explicable in terms of prior neuroleptic exposure which in certain instances is associated with weight gain in a significant proportion of patients.34,35 In contrast to the study by Allison et al,33 roughly half of our patients were drug-naive while the others were drug-free for clinically significant periods of time. Indeed, a sub-analysis of these two groups indicated that they had similar amounts of IAF. This study also showed that patients with schizophrenia had higher plasma cortisol levels than normal controls, which may reflect abnormalities of the feedforward and=or feedback limbs of the hypothalamic-pituitary-adrenal (HPA) axis.36 In terms of the former, high levels of corticotropinreleasing hormone (CRH),37,38 have been found to be increased in the cerebrospinal fluid of patients with schizophrenia. Despite having normal corticotropin and cortisol responses to CRH39 pretreatment with low-dose dexamethasone results in a subtle HPA axis dysregulation becoming manifest, as is indicated by greater than normal responses of cortisol to exogenously applied CRH.40 Further evidence of an overactive HPA axis comes from the observation by Van Cauter et al41 in that, unlike normal volunteers, patients with schizophrenia fail to lower plasma levels of cortisol between midnight and 04:00 h. In terms of the feedback axis, the rates of dexamethasone non-suppression are similar in patients with negative and positive symptom schizophrenia though certainly higher than that of the general population.42 The net effect, of such HPA axis dysregulation may be to induce a relative though chronic increase in plasma levels of cortisol. Whilst the endocrine literature is replete with descriptions of the physical consequences of excessive cortisol,43 it is only recently that similar observations have been made in patients with psychiatric disorders. For example, Michelson and his colleagues44 have shown that pre-menopausal women with depression have lowered bone mineral density while Delva et al45 Halbriech and Palter46 have shown similar findings in schizophrenia. Rosmond et al47 have recently

139 demonstrated that certain types of personality disorders had significantly higher WHRs as compared to controls though the metabolic and endocrine profiles did differ between the three clusters of disorders chosen for study. Furthermore, Thakore et al,23 using CT scanning have observed that melancholic depressives have twice the amount of intra-abdominal fat as do normal controls. The most likely pathophysiological mechanism underlying this increase in visceral obesity in depressives is hypercortisolaemia.48 In health, lipoprotein lipase (LPL) is the primary enzyme responsible for laying down fat.17 Glucocorticoids and cortisol increase lipoprotein lipase activity which is found to be two to four times more densely concentrated within intraabdominal fat stores as opposed to subcutaneous fat depots.49 Furthermore, the density of type 2 glucocorticoid receptors, a subtype of steroid receptor acted upon by cortisol in order to effect its message, is two to four times higher in visceral fat depots vs subcutaneous fat stores.50 Therefore, excessive levels of plasma cortisol will result in an increase in LPL activity which may account for the high levels of visceral fat deposition observed in depression. Our patients with schizophrenia were hypercortisolaemic in comparison to control subjects, thereby providing one explanation for the observed increase in IAF distribution. While BMI is an accepted measure of overall ‘fatness’, it is not a good indicator of regional fat distribution which in turn has some predictive validity in terms of developing illnesses associated with the metabolic syndrome.51 WHR is far better at determining the levels of visceral fat than BMI52 and our patients had significantly higher WHRs than did our healthy volunteers. Yet a possible explanation for our findings is the fact that our patients had an elevated BMI and that the higher levels of visceral fat were a consequence of this. Against this are the findings of Enzi et al53 who have found that healthy volunteers with BMIs 26 have less intra-abdominal fat (3700 mm2 in females and 5600 mm2 in males) than our patients with schizophrenia (13 232 mm2). Therefore, it would appear that the increase in visceral fat is not merely a ‘mass effect’ of a raised BMI. Finally it is difficult to draw conclusions from this study as its limitations include, a relatively small sample size, the fact that patients and controls were not matched for BMI and lastly, a single venepuncture was used to collect plasma cortisol. Despite these shortcomings our study has shown that patients with schizophrenia, be they drug-naive or drugfree, have higher levels of intra-abdominal fat than normal controls. Reduced life expectancy is a well-recognized association with central obesity and may help to explain why patients with schizophrenia die prematurely.

Acknowledgements This study was supported in part by an Independent Research Grant from Pfizer Ltd. International Journal of Obesity


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