Department of Psychiatry Nanjing Brain Hospital and Nanjing Medical University, Nanjing, China, and Department of Biomedical Science, University of Sheffield, Sheffield, UK
Department of Psychiatry Nanjing Brain Hospital and Nanjing Medical University, Nanjing, China, and Department of Biomedical Science, University of Sheffield, Sheffield, UK
Department of Radiological Science, Nanjing Brain Hospital and Nanjing Medical University, Nanjing
Clinical Science Centre, Nanjing Brain Hospital and Nanjing Medical University, Nanjing
Department of Biomedical Science, University of Sheffield, Sheffield
Correspondence: Gavin P. Reynolds, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. Tel: (0) 114 222 4662; fax: (0) 114 276 5413; e-mail: g.p.reynolds{at}sheffield.ac.uk
Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To assess the effects of antipsychotic drug therapy on abdominal fat deposition, on insulin and leptin secretion, and on circulating glucose and lipids.
Method Abdominal body fat was determined by magnetic resonance imaging in a group of previously untreated patients with schizophrenia, before and after 10 weeks antipsychotic drug treatment. Body mass and blood concentrations of glucose, insulin, leptin and lipids were also measured.
Results Significant increases in both subcutaneous and intra-abdominal fat were identified after antipsychotic drug treatment. A three-fold increase in leptin secretion as well as significant increases in levels of circulating lipids and non-fasting glucose were also identified.
Conclusions Patients first receiving antipsychotic drugs experience substantial deposition of both subcutaneous and intra-abdominal fat, reflecting a loss of the normal inhibitory control of leptin on body mass. Along with fat deposition, the increase in levels of fasting lipids and in non-fasting glucose may provide early signs of drug-induced progression towards the metabolic syndrome.
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INTRODUCTION |
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METHOD |
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A total of 46 patients were recruited (27 men and 19 women). All patients received dietetically balanced hospital meals (daily energy intake: men 10.5 MJ (2500 kcal), women 9.2 MJ (2200 kcal)), occasionally supplemented by gifts from relatives, and had the opportunity for an hours physical exercise each day. All patients were rated using the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987) for the assessment of clinical psychotic symptoms by the senior psychiatrist (Z.-J.Y.) trained in its use. A minimum PANSS score of 60 was acceptable on admission; improvement after antipsychotic drug treatment was expressed by percentage change over baseline PANSS scores.
Control group
The control group consisted of hospital staff well matched for age (26.9
years, s.d.=50) and gender (22 men, 16 women) with the patient group, and were
all apparently healthy after assessment by physical examination, blood
screening and urine test. None had any history of treatment for
neuropsychiatric disorders.
Experimental measures
Body fat indicators
Weight, height, and waist and hip circumferences were measured, and the
body mass index (BMI) and waist:hip ratio (WHR) were calculated for all
patients on admission and weekly for 10 weeks. The same measurements were made
on the control group members. Waist circumference was measured midway between
the lower rib margin and the iliac crest, and hip circumference was measured
at the level of the widest circumference. Measurement of abdominal
subcutaneous fat (SUB) and intra-abdominal fat (IAF; visceral fat) was
performed by magnetic resonance imaging (MRI) on subgroups of participants (40
patients and 22 controls) with a whole-body scanner (Siemens Magnetom 8) using
a 0.2 T magnetic field and an inversion recovery pulse sequence (inversion
time 0.25 ms, repetition time 500 ms, and echo time 20 ms; field of view 380
mm3, matrix 192 x 256). One single transverse scan was taken
halfway between the lower rib margin and the iliac crest with the participant
lying supine. This site was determined by palpation approximately at the level
of L4/L5 vertebra. Slice thickness was 10 mm and one scan took approximately 6
min. Image analyses to determine the abdominal fat used the techniques
described by Seidell et al
(1990). Scans were taken
within 36 h of admission and after 10 weeks.
Biochemical indicators
Blood was taken for testing from the patients on admission and after 10
weeks of antipsychotic treatment. Whole venous blood samples were taken into
tubes containing ethylenediamine tetra-acetic acid (EDTA) at approximately
06.30 h following overnight fasting, and 2 h after breakfast for non-fasting
plasma glucose measurement. After centrifugation at 2500 g at 4°C for 5
min, plasma supernatants were collected and immediately stored at
80°C prior to assay. The samples were processed randomly and masked
to diagnosis. Plasma glucose concentration was assayed by an automated glucose
oxidase method. Measures of lipids total high-density lipoprotein
(HDL) and low-density lipoprotein (LDL) cholesterol and triglycerides
were determined by standard clinical biochemistry laboratory assays. Fasting
plasma insulin was measured with a 125I-insulin radioimmunoassay
kit (National Health Institute, Beijing, China) in duplicate for each
participant. The intra- and interassay coefficients of variation were below
3%. A leptin immunoradiometric kit (ACTIVE Human Leptin Coated-Tube
Immunoradiometric Assay Kit DSL-23100, Diagnostic Systems Laboratories,
Webster, TX, USA) was used to determine total fasting plasma leptin levels in
duplicate. The intra- and interassay coefficients of variation were below
4%.
Data analysis
All statistical analyses were performed using the Statistical Package for
the Social Sciences, version 10.0. Initial analysis involved univariate
analysis of variance (ANOVA) to compare the study groups, and
repeated-measures analysis to determine the effects of treatment on body fat
and biochemical indicators. Except where significant interaction terms were
observed, the results are reported as t-tests. Values are given as
mean (standard deviation). Significance levels are for two-tailed tests;
P values below 0.05 were regarded as significant. Antipsychotic dose
was converted to chlorpromazine equivalents (risperidone dose x 100).
Correlations between biochemical indicators and clinical parameters and
features were examined by Spearman rank correlation. Stepwise multiple
regression was used for analysis of the influence of weight and fat indicators
and clinical features on plasma leptin levels.
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RESULTS |
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Weight and fat indicators
Initial comparisons between the control and patient groups showed no
significant difference between the two. Values for the control group were:
average weight 60.7 kg (s.d.=9.6); BMI 21.6 kg (s.d.=2.3); WHR 0.81
(s.d.=0.07); SUB 102.9 cm2 (s.d.= 51.6); and IAF 47.3
cm2 (s.d.=13.8). The general absence of any gendergroup
interaction indicated that this effect held true within the genders except for
a significant interaction term for WHR (F=6.03, P=0.016),
reflecting a lower WHR in female controls 0.77 (s.d.=0.06) compared with
female patients (t=2.469, P=0.019). There were significant
increases in all weight and fat indicators after 10 weeks antipsychotic
treatment in the patient group (Table
2). This showed significant interactions with gender for SUB
(F=5.675, P=0.022), and particularly for IAF
(F=13.727, P=0.001) and WHR (F=11.574,
P=0.001), but not for BMI, reflecting substantially greater changes
in the male group than in the female group. Thus no significant change in WHR
and SUB was apparent for the female patients after treatment; significant
differences between males and females were found for the changes in WHR
(t=3.496, P=0.001), SUB (t=2.2, P=0.038)
and IAF (t=3.941, P=0.0001).
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Biochemical indicators
No significant difference in fasting plasma leptin or fasting plasma
insulin levels was found between the control group and patients on admission:
controls, plasma insulin 17.19 mIU/l (s.d.=18.84), t=0.295,
P=0.769; plasma leptin 11.07 ng/ml (s.d.=11.39), t=71.546,
P=0.127. Insulin, however, showed a significant gendergroup
interaction (F=8.664, P=0.004), reflecting the higher values
observed in female patients (t=2.056, P=0.049).
There was a substantial elevation in plasma leptin in the patient group after 10 weeks treatment as well as within gender subgroups (Table 3). No significant difference in plasma insulin was found after 10 weeks of treatment. There was no significant difference in fasting plasma glucose levels before and after treatment either in all patients or in the gender subgroups. However, after 10 weeks of treatment, a significant increase in non-fasting plasma glucose concentration was found. Substantial and significant differences were also observed in total and LDL cholesterol and triglycerides. No clear gender difference in response to treatment was apparent in glucose measures, leptin, insulin or lipid markers, as there was no significant interaction. Similarly, the lack of significant treatmentdrug type interactions in ANOVA indicated no significant difference between risperidone and chlorpromazine in their effects on any of these measures or on body fat indicators. However, there were significant gender differences in leptin levels in the control group at baseline assessment (males 5.77 ng/ml (s.d.=4.99) v. females 18.35 ng/ml (s.d.=13.69); t=3.511, P=0.003) and in the patient group both at baseline (t=5.061, P=0.0001) and after treatment (t=3.107, P=0.004).
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Correlation of body fat indicators with clinical features, outcome and biochemical indicators
Within the MRI-determined baseline body fat indicators, only IAF was
positively correlated with age (r=0.463, P=0.003) in the
patient group but not significantly in the control group (r=0.201,
P=0.37). There was no significant correlation between the changes in
body fat and clinical features, including age and antipsychotic dose. The
biochemical markers also showed no significant correlation with these clinical
features (data not shown). Patients showed a substantial decrease in PANSS
scores over 10 weeks treatment (see
Table 1); however, the change
in BMI was not significantly correlated with this clinical improvement
(r=0.223, P=0.137).
In the control group there was no significant relationship between plasma leptin levels and body fat, although a trend to increased SUB with increased leptin was apparent (r=0.384, P=0.078). In patients, initial leptin concentrations correlated significantly with BMI at baseline (r=0.33, P=0.03), and with SUB but not IAF measurements at baseline (r=0.73, P=0.0001). Leptin, both on admission and after 10 weeks, correlated inversely with the percentage change in SUB (r=0.505, P=0.002; r=0.467, P=0.005) but not with that in IAF. Moreover, this change in SUB but not in IAF was also strongly correlated with fasting insulin concentrations at baselineline base (r=0.523, P=0.001) and after 10 weeks treatment (r=0.537, P=0.001). To elucidate further the influences on plasma leptin in schizophrenia, stepwise multiple regression was performed with body fat indicators, gender, age, drug type and antipsychotic dose included as independent variables; only gender and baseline SUB were significantly associated with initial leptin (ß=0.64, t=4.928, P=0.0001), whereas after 10 weeks leptin was only significantly related to gender.
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DISCUSSION |
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It is well established that antipsychotic drug treatment can induce substantial weight gain, with different drugs having greater or lesser effects, and the greatest increases occurring with atypical antipsychotics (reviewed by Allison et al, 1999; Taylor & McAskill, 2000). Inevitably, most studies undertaken in the context of drug trials have assessed patients who had previously received antipsychotic drug treatment. Such treatment confounds the effects of drugs over the period of the study by elevating values of baseline weight and related metabolic measures by amounts dependent on the drug (or drugs) previously received. In addition, the difficulty in distinguishing correlates of disease from the consequences of drug treatment means that it is possible that schizophrenia itself can be a risk factor for the metabolic syndrome (Ryan & Thakore, 2002). Hence the importance of studies in drug-naïve patients. We observed that initial antipsychotic treatment has a substantial effect on weight and fat deposition.
The mechanisms underlying this antipsychotic-drug induced weight gain are
likely to be multifactorial. Antagonism of the serotonin receptor
5-HT2C, for which several antipsychotic drugs, particularly
olanzapine and clozapine, have high affinity, is a strong candidate as the
receptor is known to influence appetite and thereby weight gain
(Nonogaki et al,
1998). Association of a polymorphism of the 5-HT2C
receptor gene with antipsychotic drug-induced weight gain provides further
evidence of the importance of the receptor in this process
(Reynolds et al,
2002). However, effects at other receptors, including dopamine
D2, -adrenoceptors and particularly the histamine
H1 receptor (Kroeze et
al, 2003), have also been implicated.
Leptin changes
Leptin is a hormone secreted by adipose tissue to have effects at receptors
in the hypothalamus that result in the control of food intake. Deficits in
leptin or leptin receptors result in overeating and obesity, indicating the
importance of the hormone in body mass homoeostasis. The increase in fat
deposition observed here occurred despite a substantial elevation in levels of
circulating leptin, indicating that leptin control of fat deposition in
patients receiving antipsychotic treatment is awry. This is likely to occur
because the drugs block other receptors, e.g. 5-HT2C, that interact
with the effects of leptin in the hypothalamus
(Nonogaki et al,
1998). However, the inverse correlation between SUB increases and
leptin levels suggests that some remaining influence of leptin on subcutaneous
fat deposition is present. These results are certainly consistent with
previous findings of elevated leptin concentrations in antipsychotic-treated
patients with schizophrenia (Herran et
al, 2001) and appear likely to be a consequence of
subcutaneous fat deposition, over which leptin normally imparts most
regulatory control (Cnop et al,
2002).
Weight gain and hyperglycaemia
The accumulation of intra-abdominal fat seen in patients in this study may
well be the first indication of increasing risk of diabetes, since this
measure is correlated with insulin resistance
(Cnop et al, 2002).
Certainly there is growing evidence that the treatment of schizophrenia,
particularly with clozapine and olanzapine, may impair glucose metabolism and
increase the risk of diabetes (Henderson,
2002; Newcomer et al,
2002). We observed that an increase in non-fasting glucose
concentration emerged after 10 weeks treatment. This finding may
provide the first indications of impaired glucose utilisation, which has been
reported in patients treated chronically with risperidone, as well as more
profound effects following olanzapine and clozapine
(Newcomer et al,
2002). More speculatively, this developing insulin resistance,
along with the observations of central fat deposition and the substantial and
significant increases in blood lipid levels, may reflect early signs of
progression towards the metabolic syndrome.
Drug-induced weight gain and clinical improvement
The changes in weight and/or body fat indicators do not appear to be
related to clinical improvement in this study. Our finding is consistent with
the absence of any significant relationship between weight gain and symptom
improvement in another, larger, sample of similar patients
(Zhang et al, 2003),
despite reports that weight gain is positively correlated with symptom
improvement following clozapine and olanzapine
(Czobor et al, 2002).
However, consistent with our findings, the latter report found no relationship
between weight gain and symptom improvement in patients receiving risperidone.
In addition, it is difficult to eliminate artefactual results from such
studies; poor nutrition and low weight may be a consequence of more severe
symptoms, and such patients may show greater increases in both symptom
improvement and weight gain following treatment.
Although the findings reported here describe the consequences of just 10 weeks treatment with common antipsychotics, they do provide indicators of a developing morbidity associated with weight gain. Such studies need to be extended to determine the longer-term consequences of antipsychotic drug treatment in previously drug-naïve patients, and to differentiate better the effects of different drugs. However, the potential that substantial subcutaneous and visceral fat deposits (particularly the latter) may have in developing insulin resistance leading to the metabolic syndrome suggests that all should be done to minimise this drug-induced weight gain and its impact. This may include dietary counselling (Meltzer, 2001), routine screening for diabetes (Henderson, 2002) or even, in the future, genetic testing for liability (Reynolds et al, 2002). Consideration of the different severities of weight gain associated with different drugs (Allison et al, 1999) should, of course, be an important factor in choosing appropriate drug treatments.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication May 20, 2003. Revision received August 4, 2003. Accepted for publication September 3, 2003.
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