clozapine remains an ultimate option for patients with treatment resistant schizophrenia ( kane 2012 ) .
efficacy of clozapine against positive symptoms of schizophrenia was confirmed in numerous studies and meta - analyses ( chakos et al .
2001 ) , including analysis published by the cochrane library ( asenjo lobos et al .
however , treatment with clozapine is associated with very severe metabolic side - effects ( newcomer 2005 ) .
clozapine - induced weight gain is very common ( wetterling 2001 ) , and so is impaired fasting plasma glucose levels . in patients with schizophrenia weight gain
is associated with impaired physical functioning and negative body appraisal ( bachmann et al . 2012 ) , both of which affect quality of life . while treatment with clozapine may reduce mortality by reducing suicide rate , mortality due to clozapine - associated weight gain will diminish reduction in the suicide rate almost entirely over 10  years by the increased mortality associated with weight gain of 10  kg ( fontaine et al .
also , obesity is linked with numerous secondary health problems ( pressure overload on lungs , joints and bones ) and is an important risk factor for life - threatening diseases , such as cardiovascular disease , type 2 diabetes and certain cancers .
several mechanisms are considered as taking role in clozapine - induced weight gain , including antagonism at histamine h1 receptors ( kroeze et al .
various receptors , including aforementioned 5-ht1b and 5-ht1c , regulate activity of the hypothalamic nuclei ( particularly the arcuate nucleus ( arc ) , which plays the key role in appetite regulation ) .
activity of arc is also regulated by several hormones of anorexigenic properties : leptin , pancreatic polypeptide ( pp ) , cholecystokinin ( cck ) , glucagon - like peptide-1 ( glp-1 ) , oxyntomodulin ( oxm ) , peptide yy ( pyy ) and the first discovered orexigenic substance - ghrelin ( druce et al . 2004 ) .
agouti - related peptide ( agrp ) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism and energy expenditure , thus leading to weight gain .
it was identified in 1997 based on its sequence similarity with agouti signaling peptide ( asip ) , a protein synthesized in the skin that controls coat color .
compared with asip , agrp is physiologically expressed in the hypothalamus ( shutter et al .
agrp is also expressed in the adrenal gland , testes , kidneys , and lungs .
agrp induces obesity by antagonism of the melanocortin receptors ( mc3-r and mc4-r , subtypes implicated in weight regulation , via metabolism and appetite control ) ( ollmann et al .
these neurons make peptides that potently stimulate food intake not only by increasing neuropeptide y ( npy ) signaling , but also by reducing melanocortin signaling via the release of agrp ( morton and schwartz 2001 ) .
activity of the agrp / npy neurons is modulated by leptin , released from the adipose tissue , and insulin .
the adiposity signals ( insulin and leptin ) are secreted in proportion to body fat content and act in the hypothalamus to inhibit anabolic and stimulate catabolic , effector pathways ( schwartz et al .
the increase of food intake following a single central administration of agrp is sustained for up to a week ( hagan et al . 2000 ) , while the response to npy is sustained over hours , rather than days .
this study was undertaken with the purpose to determine if patients with schizophrenia on clozapine monotherapy have higher fasting levels of agrp compared with healthy control . in order to provide more accurate measurements ,
biochemical and anthropometric measurements were combined with body composition determined using bioelectric impedance analysis ( bia ) , which provides accurate measurements of body fat , lean mass and body water ( bosy - westphal et al .
this is the first study to investigate such combination of these parameters in subjects with schizophrenia treated with clozapine .
data for 24 european caucasian adult hospitalized patients with paranoid schizophrenia ( 295.30 according to dsm - iv , f20.0 according to icd-10 ) was included into the study .
these subjects were on clozapine monotherapy for at least two months prior the assessments with a minimum dose of 100  mg / day .
most patients was in stable phase of the disease ( i.e. no acute psychosis ) .
control group was 24 healthy subjects and was gender- and age - matched with patients in the clozapine group .
health status of the control subjects was determined on the basis of basic physical examination , including vital signs and an interview .
all patients and volunteers included in the study expressed their written informed consent for participation in this study .
the blood samples for the chemistry panel were collected between 7  am and 8  am , after ensuring at least 8  h of overnight fasting .
glucose , lipids , calcium and uric acid levels were measured using a dirui cs-400 analyzer ( dirui , china ) .
homocysteine chemiluminescence assessments were performed using an immulite 2,000 analyzer ( siemens , germany ) , insulin immunochemistry assessments were performed using a cobas e411 analyzer ( roche diagnostics , switzerland ) and albumin levels were assessed using a cobas integra 800 analyzer ( roche diagnostics , switzerland ) .
levels of agrp were measured in blood serum using elisa ( enzyme - linked immunosorbent assay ) method . prior to assays ,
serum samples were stored at  80  c for up to 6  months .
elisa assays were performed using commercial kits ( intra - assay : cv < 10  % , inter - assay : cv < 12  % ) manufactured by raybiotech ( usa ) , according to protocol provided by its manufacturer ( all samples were 2-fold diluted ) . metabolic syndrome and abdominal obesity were defined according to international diabetes foundation ( idf ) criteria ( alberti et al .
kg / m , 2530  kg / m and 30  kg / m were defined as normal weight , overweight and obesity , respectively . raised triglycerides ( tga ) level 150  mg / dl and/or total cholesterol ( tc ) 200  mg / dl and/or reduced hdl cholesterol level < 40  mg / dl for men and < 50  mg / dl for women and/or raised ldl cholesterol level 135  mg / dl were interpreted as dyslipidemia .
corrected calcium was calculated using the formula : corrected calcium [ mg / dl ]  = measured total calcium [ mg / dl ]  + 0.8 ( 4.0  serum albumin [ g / dl ] ) .
insulin resistance was estimated from fasting glucose and insulin results by homeostasis model assessment and quicki index , using the formula : homa1-ir = ( fasting plasma glucose [ mg / dl ]  insulin [ mu / l])/405 . homa2-ir index was calculated using a calculator downloaded from http://www.dtu.ox.ac.uk .
quicki index ( lower numbers reflect greater insulin resistance ) was calculated using the formula : 1/(log ( fasting insulin [ mu / l ] ) + log ( fasting plasma glucose [ mg / dl ] ) ) .
height was measured with a wall - mounted height measure to the nearest 0.5  cm .
weight was measured with a spring balance that was kept on a firm horizontal surface .
subjects wore light clothing , stood upright without shoes and weight was recorded to the nearest 0.5  kg .
body mass index ( bmi ) was calculated as body weight in kilogram divided by the height in meter squared ( kg / m ) .
waist , abdominal and hip circumference was measured using a non - stretchable fiber measuring tape .
waist - to - hip ratio ( whr ) was calculated as waist circumference divided by hip circumference .
whr cut - off points were defined according to who recommendations ( 0.85 for women and 0.9 for men ) .
fat mass index ( fmi ) was calculated as total body fat in kilogram divided by the height in meter squared ( kg / m ) .
excess body fat according to fmi classification ranges were defined as fmi > 6 for men and fmi > 9 for women
body composition was measured using a maltron bf-906 body fat analyzer ( maltron , uk ) , single frequency bioelectrical impedance analyzer to determine resistance and reactance at 50  hz .
standard operating conditions were observed by a trained operator including preparation of the participant , electrode placement and operation .
the measurement using bia was taken immediately prior to anthropometry measurements with participants lying supine , in a rested state .
simple descriptive statistics ( means , standard deviations , 95  % confidence interval [ ci ] ) were generated for all continuous variables . for discrete variables number of patients and percentages are given .
skewed variables were transformed to follow normal distribution using log , square root , inverse square root or square transformation .
means , standard deviations , and confidence intervals are reported for non - transformed variables , results of tests are reported for transformed or non - transformed variables . if transformation resulted in normal distribution , two - tailed t - test
was used to assess inter - group differences , otherwise variables were analyzed using mann 
associations were tested by pearson s ( for variables with normal distribution ) or spearman 's ( for other variables ) correlation coefficients . the significant level was set at p < 0.05 .
for group of patients treated with clozapine the mean age was 38.812.6 and 39.912.3 for the control group ( p  = 0.62 ) . in both groups
there were 12 men and 12 women . in the clozapine group 12 subjects smoked cigarettes and 8 in the control group ( p  = 0.38 ) .
the mean duration of monotherapy with clozapine was 60.579.4 [ 95  % ci : 27.094.1 ] months and mean clozapine dose was 341.1148.6 [ 95  % ci : 278.4403.8 ] mg / day .
detailed results for anthropometric measurements and laboratory tests are shown in table  1 . 

table 1results of anthropometric measurements and laboratory testsclozapine 
 n  = 24control 
 n  = 24weight [ kg]78.114.2(72.184.1)72.615.1(66.278.9 ) 
 p  = 0.08 
 t  = 1.38bmi [ kg / m]27.13.6(25.528.6)24.83.5(23.326.2 ) 

p  = 0.01 
 t  = 2.25fmi [ kg / m]8.93.1(7.610.2)7.73.0(6.49.0 ) 
 p  = 0.09 
 t  = 1.38abdominal circumference [ cm]96.59.4(92.5100.4)85.511.6(80.690.3 ) 
 p <
0.001 
 z  = 3.58waist circumference [ cm]91.112.1(86.096.2)82.410.6(77.886.8 ) 
 p  = 0.005 
 z  = 2.66hip circumference [ cm]99.08.4(95.5102.5)95.97.1(92.998.9 ) 
 p  = 0.08 
 t  = 1.39whr0.920.08(0.880.95)0.860.08(0.820.89 ) 
 p  = 0.005 
 z  = 2.66sbp [ mm hg]121.713.6(115.9127.4)136.717.9(129.1144.2 ) 
 p  = 0.001 
 z  = 3.26dbp [ mm hg]81.28.5(77.684.8)82.812.1(77.687.9 ) 
 p  = 0.30 
 t  = 0.50uric acid [ mg / dl]4.51.4(3.95.1)4.31.3(3.74.8 ) 

t  = 0.57homocysteine [ mol / l]14.5    4.4(12.616.4)13.6    5.0(11.515.7 ) 
 p  =  0.25 
 t  =  0.67tc [ mg / dl]194.2    53.2(171.7216.6)216.6    65.3(189.0244.1 ) 

p  =  0.06 
 t  =  1.54hdl [ mg / dl]43.5    12.6(38.248.8)55.1    14.3(49.161.1 ) 
 p 
41.9(104.8140.3)128.3    39.7(111.5145.0 ) 
 p  =  0.29 
 t  = 0.54tga [ mg / dl]140.3    120.4(89.4191.1)104.3    81.4(69.9138.6 ) 

p  =  0.07 
 t  =  1.50fpg [ mg / dl]103.5    31.7(90.1116.8)87.8    11.7(82.892.7 ) 
 p  =  0.03 

t  = 1.88insulin [ u / ml]11.8    8.2(8.3 - 15.3)7.7    3.2(6.3 - 9.1 ) 
 p  =  0.02 
 t  = 2.08homa1-ir3.3    3.4(1.84.7)1.7    0.8(1.32.0 ) 
 p  =  0.009 
 t  = 2.46homa2-ir1.6    1.1(1.12.1)1.0    0.4(0.81.2 ) 
 p  =  0.01 
 t  = 2.26quicki0.15    0.01(0.140.15)0.16 
  0.01(0.150.16 ) 
 p  =  0.007 
 t  = 2.52corrected calcium [ mg / dl]8.6    0.9(8.29.0)8.7 
p  =  0.37 
 t  = 0.33data given as : mean    standard deviation ( 95  % ci)bmi  =  body mass index ; fmi  =  fat mass index ; whr  =  waist - to - hip ratio ; sbp  =  systolic blood pressure ; dbp  =  diastolic blood pressure ; tc  =  total cholesterol ; hdl  =  high density lipoproteins ; ldl  =  low density lipoproteins ; tga  =  triglycerides ; fpg  =  fasting plasma glucose ; homa1-ir  =  homoeostasis model assessment of insulin resistance 1 ; homa2-ir  =  homoeostasis model assessment of insulin resistance 2 ; quicki  =  quantitative insulin sensitivity check index results of anthropometric measurements and laboratory tests data given as : mean    standard deviation ( 95  % ci ) bmi  =  body mass index ; fmi  =  fat mass index ; whr  =  waist - to - hip ratio ; sbp  =  systolic blood pressure ; dbp  =  diastolic blood pressure ; tc  =  total cholesterol ; hdl  =  high density lipoproteins ; ldl  =  low density lipoproteins ; tga  =  triglycerides ; fpg  =  fasting plasma glucose ; homa1-ir  =  homoeostasis model assessment of insulin resistance 1 ; homa2-ir  =  homoeostasis model assessment of insulin resistance 2 ; quicki  =  quantitative insulin sensitivity check index we have found no inter - group differences for body composition analysis . detailed results for bia analysis are shown in table  2 . lean body mass was higher in men in the whole study sample ( 60.16.4 [ 95  % ci : 57.4 - 62.8 ] vs. 43.85.4 [ 95  % ci : 41.546.1 ] kg , t = 9.56 , p < 0.001 ) and in the clozapine group ( 59.65.7 [ 95  % ci : 56.063.3 ] vs. 45.37.0 [ 95  % ci : 40.9 - 49.8 ] kg , t = 5.48 , p < 0.001 ) .
similarly , basal metabolic rate was higher in men in the whole study sample ( 1,707.7182.3 [ 95  % ci : 1,630.71,784.6 ] vs. 1,337.3138.4 [ 95  % ci : 1,278.8 - 1,395.7 ] kcal / day , t  = 7.92 , p < 0.001 ) and in the clozapine group ( 1,701.2138.2 [ 95  % ci : 1,613.41,789.0 ] vs. 1,362.7173.0 [ 95  % ci : 1,252.71,472.5 ] kcal / day , t = 5.29 , p < 0.001 ) . 

n  =  24control 
 n  =  24total body fat [ kg]25.6    8.8(21.829.2)22.4    8.7(18.726.1 ) 
 p  =  0.10 
 t  =  1.25total body fat [ % ] 32.6    8.4(29.136.2)28.9    7.1(25.831.8 ) 
 p  =  0.06 
 t  =  1.67lean body mass [ kg]52.5    9.6(48.456.5)51.4    10.8(46.855.9 ) 
 p  =  0.36 
 t  =  0.36lean body weight [ % ] 67.6    8.1(64.271.0)71.1    7.1(68.174.1 ) 
 p  =  0.07 
 t  = 1.61total body water [ l]38.4    7.0(35.441.3)37.7    7.9(34.340.9)p  =  0.36 t  =  0.35total body water [ % ] 49.9    5.4(47.652.1)52.1    5.2(49.854.2 ) 
 p  =  0.09 
 t  =  1.42basal metabolic rate [ kcal / day]1,532.0 
p  =  0.39 
 t  =  0.26data given as : mean    standard deviation ( 95  % ci ) results of body composition analysis data given as : mean    standard deviation ( 95  % ci ) there were no significant difference for fasting serum levels of agrp between the clozapine group and the control group ( 15.008.65 [ 95  % ci : 11.3418.65 ] vs. 15.336.82 [ 95  % ci : 12.4518.22 ] pg / ml , t  = 0.32 , p  = 0.37 ) , see fig .  1 .
women had significantly lower levels of agrp in the whole study group ( 12.535.65 [ 95  % ci : 10.1414.92 ] vs. 17.808.66 [ 95  % ci : 14.1421.45 ] pg / ml , t  = 2.47 , p  = 0.009 ) and in the control group ( 12.905.77 [ 95  % ci : 9.2216.57 ] vs. 17.777.14 [ 95  % ci : 13.2322.31 ] pg / ml , t  = 1.82 , p  = 0.04 ) , but the difference was not significant for the clozapine group ( 12.175.75 [ 95  % ci : 8.5115.83 ] vs. 17.8210.28 [ 95  % ci : 11.28 - 24.36 ] pg / ml , t  = 1.64 , p  = 0.06).fig .
1mean fasting agrp serum levels [ pg / ml ] in subjects on clozapine and in the control group ( p  = 0.37 ; horizontal bars indicate means ) .
mean fasting agrp serum levels [ pg / ml ] in subjects on clozapine and in the control group ( p  = 0.37 ; horizontal bars indicate means ) .
for the whole study group significant correlations of agrp levels were found for total body fat [ % ] ( r  = 0.34 , p  = 0.02 ) , lean body mass [ kg ] ( r  = 0.38 , p  = 0.006 ) , lean body mass [ % ] ( r  = 0.34 , p  = 0.02 ) , body water [ l ] ( r  = 0.38 , p  = 0.006 ) , body water [ % ] ( r  = 0.34 , p  = 0.02 ) and homocysteine levels ( r  = 0.29 , p  = 0.04 ) .
for the clozapine group significant correlations of agrp levels were found for total body fat [ % ] ( r  = 0.48 , p  = 0.02 ) , basal metabolic rate ( r  = 0.42 , p  = 0.04 ) , lean body mass [ % ] ( r  = 0.49 , p  = 0.01 ) , body water [ % ] ( r  = 0.49 , p  = 0.01 ) . for the control group
significant correlations of agrp levels were found only for basal metabolic rate ( r  = 0.42 , p  = 0.04 ) . in the clozapine group
there were no significant differences for agrp levels between subjects with or without excess body fat ( based on fmi value ) ( p  = 0.59 ) , idf - defined metabolic syndrome ( p  = 0.33 ) , smokers and non - smokers ( p  = 0.15 ) , subjects with bmi < 25  kg / m and with bmi 25  kg / m ( p  = 0.09 ) , subjects with and without impaired fasting glucose ( p  = 0.16 ) , subjects with and without abdominal obesity ( p  = 0.11 ) , subjects with and without dyslipidemia ( p  = 0.09 ) , and subjects with and without homa-1ir defined insulin resistance ( p  = 0.07 ) . in the control group there were no significant differences for agrp levels between subjects with or without excess body fat ( based on fmi value ) ( p  =  0.20 ) , idf - defined metabolic syndrome ( p  =  0.44 ) , smokers and non - smokers ( p  =  0.35 ) , subjects with bmi < 25  kg / m and with bmi 25  kg / m ( p  = 0.12 ) , subjects with and without impaired fasting glucose ( p  = 0.36 ) , subjects with and without abdominal obesity ( p  = 0.10 ) , subjects with and without dyslipidemia ( p  = 0.37 ) , and subjects with and without homa-1ir defined insulin resistance ( p  = 0.13 ) . in the whole study group there was no significant differences for agrp levels between subjects with or without excess body fat ( based on fmi value ) ( p  = 0.30 ) , idf - defined metabolic syndrome ( p  = 0.43 ) , smokers and non - smokers ( p  = 0.29 ) , subjects with bmi < 25  kg / m and with bmi 25  kg / m ( p  = 0.39 ) , subjects with and without impaired fasting glucose ( p  = 0.29 ) , subjects with and without dyslipidemia ( p  = 0.11 ) , and subjects with and without homa-1ir defined insulin resistance ( p  = 0.33 ) . there was a significant difference for agrp levels between subjects with or without abdominal obesity ( 13.466.50 [ 95  % ci : 9.0917.83 ] vs. 16.926.93 [ 95  % ci : 12.7321.11 ] pg / ml , t  = 1.80 , p  = 0.04 ) .
the main objective of the present study was to find out whether there is a significant difference in fasting serum levels of agrp peptide between patients with schizophrenia on clozapine monotherapy and age- and sex - matched healthy controls .
we have found the difference was not significant ( clozapine : 15.008.65 , control : 15.336.82  pg / ml , p  = 0.37 ) .
we do not know pre - treatment values , so we can not determine whether and how this parameter changed during therapy with clozapine . to our knowledge ,
no data are available on the effect of clozapine on blood agrp concentrations in humans .
limited data are available for olanzapine , which has clinical and pharmacological properties similar to clozapine .
results of these studies show that treatment with olanzapine does not affect agrp levels ( basoglu et al .
however , in animal study it was demonstrated that administration of olanzapine or clozapine upregulates npy and agrp and downregulates proopiomelanocortin in the arcuate nucleus of the hypothalamus ( ferno et al .
we do not know studies demonstrating correlation between blood levels of agrp and levels in the hypothalamus , but since it was showed recently that agrp neurons are unique among hypothalamic neurons by being the predominant neuronal subtype situated outside the blood 
brain barrier ( olofsson et al . 2013 ) , we may assume that changes in hypothalamic expression are reflected in changes in blood levels .
the finding that women had significantly lower levels of agrp in the whole study group ( 12.535.65 vs. 17.808.66  pg / ml , p  = 0.009 ) and in the control group ( 12.905.77 vs. 17.777.14  pg / ml , p  = 0.04 ) , but not in the clozapine group ( 12.175.75 vs. 17.8210.28  pg / ml , p  = 0.057 ) , might indicate that the testes are important source of agrp , as shown previously ( shutter et al .
however , several more recent studies showed no difference between men and ( gavrila et al .
2001 ) , therefore it may indicate that plasma agrp levels reflect central agrp concentrations .
it was previously reported that total level of agrp is higher in obese subjects ( katsuki et al .
2001 ) , although in another study it has been demonstrated that agrp levels were lower in normal weight group compared with women with anorexia , probably due to increased leptin levels ( moriya et al .
we did not measure levels of leptin or acylated ghrelin , but we found in the same group of patients that there were no differences for desacyl ghrelin levels between patients taking clozapine and control group ( wysokiski et al .
while there was a significant difference in bmi values between the clozapine group and the control group , we found no differences between both groups for fmi values . compared with bmi ,
fmi is a better indicator of central obesity since it is much more sensitive to body fat content ( kelly et al .
moreover , there were no differences for any of the bia results between both groups .
these indicate that there was a substantial similarity between both groups in terms of body fat content , which is important considering that agrp levels may affect or result more from the amount of adipose tissue than from body weight per se .
on the other hand , we have found negative correlations between agrp levels and total body fat ( r  = 0.34 and  0.48 in the whole study group and clozapine group , respectively ) .
these may indicate the effect of leptin on the expression of agrp , but require further studies .
additionally , there were positive correlations with lean body mass ( r  = 0.38 and 0.49 in the whole study group and clozapine group , respectively ) , body water ( which amount is negatively correlated with the amount of body fat : r  = 0.96 , p  <  0.001 ) ( r  = 0.34 and 0.49 in the whole study group and clozapine group , respectively ) and basal metabolic rate ( r  = 0.42 both in the clozapine group and control group ) , also being in line with the above - mentioned mechanism . in animal studies
it has been found that high - fat diet leads to decreased expression of agrp in the hypothalamus , probably in the mechanism moderated by leptin ( staszkiewicz et al .
we have no detailed data on diet patterns of our study subjects , but reports are consistent that patients with schizophrenia consume higher amounts of high - fat foods compared with healthy population ( dipasquale et al .
. this might be one of the reasons why we have found no differences between our study groups . also ,
level of physical activity ( usually lower in hospitalized patients ) might affect mechanisms regulating agrp levels .
finally , another important factor is the effect of treatment mediated by other anabolic or catabolic neuropeptides . here , two most important peptides are leptin ( which decreases agrp levels ) and ghrelin ( which has opposite effect ) and have also been studied most extensively ( sentissi et al .
2008 ) . since both leptin and ghrelin ( andrews 2011 ) may regulate activity of agrp / npy neurons in the arcuate nucleus , effects of antipsychotics on these neuropeptides must be taken into consideration . therefore
, a study focused on interactions within this regulatory system would be very important for better understanding of this problem . based on our results
however , the low number of study subjects limited the probability of finding inter - group differences due to lack of statistical power . due to the cross - sectional study design causal relationships
can not be established and the effect of previous antipsychotic treatment can not be excluded .
dual - energy x - ray absorptiometry ( dxa ) should be used to measure body composition and adipose tissue mass more accurately .
due to complex structure of interactions between anabolic and catabolic neuropeptides , a longitudinal study comparing these interactions are crucial for understanding mechanisms of treatment - induced weight gain .
 aim : agouti - related peptide ( agrp ) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism , thus leading to weight gain . 
 the aim of the study was to find out if agrp level in subjects with schizophrenia on clozapine monotherapy is higher compared with healthy controls . 
 methodology : we determined fasting serum agrp levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy , age- and sex - matched controls . 
 biochemical and anthropometric measurements were combined with body composition analysis . 
 results : there was no difference for agrp levels between patients taking clozapine and control group ( 15.008.65 vs. 15.336.82  pg / ml , p  = 0.37 ) . 
 we found negative correlations between agrp levels and total body fat ( r  = 0.34 and  0.48 in the whole study group and clozapine group , respectively ) and positive correlations with lean body mass ( r  = 0.38 and 0.49 in the whole study group and clozapine group , respectively ) , body water ( r  = 0.34 and 0.49 in the whole study group and clozapine group , respectively ) and basal metabolic rate ( r  = 0.42 both in the clozapine and control groups ) . 
 there were no correlations with age , height , weight , body mass index , fat mass index , abdominal , waist or hip circumferences , waist - hip ratio , blood pressure , total cholesterol , hdl , ldl , triglycerides , uric acid , glucose , insulin , clozapine dose or treatment duration , duration of treatment with antipsychotics and markers for insulin resistance . 
 conclusion : we can not conclude that treatment with clozapine is associated with increased level of agrp . 
 we did not find previously described differences in agrp levels between obese and non - obese subjects or associations between agrp and various metabolic parameters . 
Introduction
Material and methods
Results
Discussion