Original article 165
Plasma orexin A, ghrelin, cholecystokinin, visfatin, leptin
and agouti-related protein levels during 6-week olanzapine
treatment in first-episode male patients with psychosis
Cengiz Basoglua, Ozgur Onerb, Cengiz Gunesc, Umit B. Semiza,
Alpay M. Atesa, Ayhan Algula, Servet Ebrinca, Mesut Cetina,
Omer Ozcana and Osman Ipcioglua
The objective of the study was to investigate the change of
body mass index (BMI), waist circumference, lipid profile,
leptin, ghrelin, orexin, visfatin, agouti-related protein, and
cholecystokinin levels during 6 weeks of olanzapine
treatment in newly diagnosed first-episode drug naive,
young adult, nonobese male patients with psychosis.
Twenty male participants who were all first-episode drug
naive psychotic patients without prominent affective signs
and symptoms and 22 healthy male controls of similar age
were included. BMI, waist circumference, fasting glucose,
and lipid profiles were measured, and Positive and
Negative Syndrome Scale and Brief Psychiatric Rating
Scale scores were obtained at baseline, during the second
and sixth week of treatment, and the aforementioned
neuropeptide levels were measured at baseline and during
the sixth week of treatment. Treatment was associated with
significant increases in BMI, waist circumference, serum
triglyceride, and low-density lipoprotein levels. BMI levels
increased more than 7% in over 75% of the patients. Leptin
increased, and ghrelin and orexin decreased significantly
Introduction
Schizophrenia is a chronic disorder that has devastating
effects on the individual and society. Antipsychotic
treatments generally reduce the psychotic symptoms
and usually allow the patient to experience functional
recovery in terms of academics, peer relations, and family
life. The advent of second generation (atypical) anti-
psychotic drugs (AAPs) has allowed for less drug
discontinuation in patients owing to more favorable side
effect profiles. However, most of these drugs have serious
metabolic side effects, such as insulin resistance, obesity,
and hyperlipidemia, for both short-term and long-term
use (McEvoy et al., 2005; Thakore, 2005; Wu et al., 2006;
Perez-Iglesias et al., 2007; Arango et al., 2008; Graham
et al., 2008; Kahn et al., 2008; Perez-Iglesias et al., 2009).
Furthermore, weight gain reduces patients’ compliance
to drug regimes, which may result in more frequent
relapses (Weiden et al., 2004). All antipsychotic drugs
do not have the same side effects; among atypical anti-
psychotics, clozapine leads to the greatest weight gain,
followed by olanzapine, risperidone, sertindole, quetia-
pine, and ziprasidone (Allison et al., 1999; Bobes et al.,
2003; Brixner et al., 2006).
0268-1315 
c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
with olanzapine treatment, whereas cholecystokinin,
visfatin, and agouti-related protein levels did not change
significantly. In conclusion, consistent with previous
studies, we found increased BMI, leptin and lipids during
olanzapine treatment. Association of neuropeptide level
changes with symptom improvement might be mediated
by the dopaminergic and serotonergic systems. Int Clin
Psychopharmacol 25:165–171  c 2010 Wolters Kluwer
Health | Lippincott Williams & Wilkins.
International Clinical Psychopharmacology 2010, 25:165–171
Keywords: agouti-related protein, cholecystokinin, first-episode psychosis,
ghrelin, leptin, olanzapine, orexin A, visfatin
a
Department of Psychiatry, GATA Haydarpaşa Training Hospital, bChild Psychiatry
Department, Dr Sami Ulus Children’s Hospital, Ankara and cDiyarbakır Military
Hospital, Diyarbakır, Turkey
Correspondence to Dr Cengiz Basoglu, Department of Psychiatry, GATA
Haydarpaşa Training Hospital, Uskudar 34668, Istanbul, Turkey
Tel: + 90 2165422020; fax: + 90 2163493517;
e-mail: cengizbasoglu@gmail.com
Received 23 June 2009 Accepted 12 January 2010
It has been shown that in newly diagnosed first-episode
patients, 90–100% of the participants taking olanzapine
gained more than 7% of the pretreatment weight in a
1 year follow-up period (Lieberman et al., 2005; Zipursky
et al., 2005; Green et al., 2006; McEvoy et al., 2007;
Strassnig et al., 2007; Saddichha et al., 2008), which is a
clinically significant rate (Marder et al., 2004). A recent
study suggested that the difference between haloperidol
and olanzapine may not be the final weight gain but
weight gain patterns, with olanzapine causing a signifi-
cantly higher weight gain in the first 3 months (Perez-
Iglesias et al., 2008a, 2008b). Short-term follow-up studies
conducted with first-episode patients reported consistent
results; it has also been suggested that the weight
gain associated with olanzapine treatment was more
prominent during the early weeks (Kinon et al., 2001;
Ratzoni et al., 2002).
Control of the food intake and regulation of weight gain
are influenced by a number of factors. Weight gain is
influenced by central nervous system hormones and
neuropeptides as well as gastrointestinal factors. The
hypothalamus, which uses peripheral signals including
DOI: 10.1097/YIC.0b013e3283377850
166 International Clinical Psychopharmacology 2010, Vol 25 No 3

neuropeptides to monitor the nutritional and energy impact of weight gain on neuropeptide levels is necessary
status of the body, controls the termination of meals to evaluate the direct effects of AAPs on these variables
(Valassi et al., 2008). The arcuate nucleus of the hypo- (see Ref. Jin et al., 2008).
thalamus, which contains neuropeptide Y (NPY) and
Several studies have investigated olanzapine related
agouti-related peptide (AGRP) neurons, is connected
changes in several anorexigenic and orexigenic neuro-
with the paraventricular nucleus and lateral hypothalamic
peptides in a single sample of first-episode drug naive
area (LHA). Anorexigenic peptides like insulin, leptin,
psychotic patients; however, these studies had confound-
and adiponectin that are secreted from the pancreas and
ing factors like the presence of obesity and metabolic
adipose tissue, signal that adiposity is high to the brain,
disorder before treatment. Therefore, the aim of this
whereas orexigenic peptides (orexins) convey the oppo-
study was to investigate changes in BMI, waist circum-
site message (Valassi et al., 2008). Many studies have
ference, lipid profile, leptin, ghrelin, orexin, visfatin,
revealed that orexins are associated with feeding, blood
AGRP, and CCK levels during a 6-week long olanzapine
glucose, arousal, and the maintenance of waking (Cai
treatment in newly diagnosed first-episode drug naive,
et al., 1999; Harris and Aston-Jones, 2006). Colecysto-
young adult, nonobese male patients with psychosis.
kinin, bombesin, and glucagons-like peptide, which are
secreted from the gastrointestinal tract, indicate a sense
of fullness through activation of the vagus sympathetic
Methods
afferents to the nucleus of tractus solitarius (Anubhuti,
A total of 27 patients were enrolled in the study. They
2006). Ghrelin is the only orexigenic gastrointestinal tract
were referred to an educational military health center
neuropeptide and increases almost 2-fold before meals to
owing to their psychotic behavior during their mandatory
induce hunger in humans. There is an inverse relation-
military service. All patients were hospitalized for
ship between ghrelin levels and body mass index (BMI)
6 weeks. Five patients left the study within the first
(Lopez et al., 2007). Obesity alters postprandial ghrelin
2 weeks; two patients exhibited manic symptoms, one
regulation (English et al., 2002). The actions of ghrelin
received electroconvulsive therapy, and two refused to
and leptin are opposite; low leptin and high ghrelin
complete the questionnaires. Participants were all first-
signals enhance NPY/AGRP release. NPY and AGRP are
episode, drug naive patients. All criteria for the diagnosis
potent orexigenic peptides. AGRP action involves melano-
of schizophrenia per the Diagnostic and Statistical Manual
cortin and orexin receptors (Lopez et al., 2007; Valassi
of Mental Disorders, Fourth Edition (DSM-IV) criteria
et al., 2008). Visfatin is a recently identified neuro-
except for the duration of the illness were fulfilled by all
peptide with a proposed insulin-like effect (Fukuhara
patients. None of the patients had prominent affective
and Matsuda, 2005).
signs and symptoms, therefore psychotic mood disorders
and schizoaffective disorder were ruled out. Treatment
The role of the neuropeptides, mentioned above, on
response was assessed by Positive and Negative Syn-
olanzapine induced weight gain has been investigated.
drome Scale (PANSS). The primary efficacy variable was
The most vigorously studied neuropeptide is leptin.
defined as a change in the PANSS total score (Kay et al.,
Several studies have reported that increased leptin levels
1987). Secondary efficacy parameters included changes in
are correlated with weight gain, but not necessarily with
the PANSS subscale scores: PANSS negative (N1-7 on
other metabolic parameters such as lipid profile (see Ref.
the PANSS), PANSS positive (P1-7 on the PANSS), and
Jin et al., 2008). Whether these are changes in ghrelin
general symptoms scores (G1-16 on the PANSS) from
and adiponectin with antipsychotic treatment is contro-
baseline to scores obtained at baseline, second, and sixth
versial. Although some studies have reported higher serum
weeks of treatment. Written informed consent was
ghrelin levels in patients using olanzapine (Murashita
obtained from each patient.
et al., 2005; Palik et al., 2005; Esen-Danaci et al., 2008),
others have not found these changes (Togo et al., 2004; Physical and neurological examinations were performed;
Tanaka et al., 2008). A recent 1-year follow-up study liver and kidney function tests were evaluated for all
showed that weight and BMI increased significantly in participants. Participants with normal results and without
patients using olanzapine, risperidone, or haloperidol. any of the following were admitted to the study:
Other parameters that increased were insulin, leptin and alcohol and substance abuse or dependence (other than
ghrelin plasma levels, but not adiponectin, resistin or smoking), having an important medical problem such as
visfatin (Perez-Iglesias et al., 2008a, 2008b). Leptin and Wilson’s disease, Down’s syndrome, malnutrition, dia-
insulin levels were correlated with BMI both at baseline betes mellitus, chronic renal failure, cancer, liver cirrhosis
and at follow-up, suggesting impaired insulin and leptin and thyroid diseases, known endocrinological illnesses,
signaling. Another study reported reduced serum adipo- BMI greater than 30, past history of psychosis and use
nectin in patients using olanzapine (Richards et al., 2006). of antipsychotic drugs, severe neurological disorders
Association of cholecystokinin (CCK), visfatin and AGRP such as epilepsy or use of antiepileptic drugs. Fasting
with olanzapine related weight gain has not been studied blood glucose levels were within normal limits for
extensively. It has been suggested that eliminating the all patients and controls. Treatment was started with

10 mg/day olanzapine and titrated up to 20 mg/day at the
end of the first week. All the patients were on 20 mg/day
olanzapine by the end of the sixth week. None of the
patients received additional drugs during the course of
the study.
Twenty-two male volunteers were enrolled as the control
group during their military service. These volunteers
were screened for DSM-IV Axis I and II diagnoses by
Structural Clinical Interview for DSM-IV Diagnosis I and
II, respectively, and none of them had any psychiatric
disorders. They also did not have a history of neurological
disorders or serious head trauma. The study was approved
of by the local ethical committees and informed consent
was obtained from all participating patients.
Weight and waist circumference were measured weekly in
the morning before breakfast. Samples were collected at
baseline at 8:00 a.m. for both patients and controls at the
start and in the sixth week of the treatment in patient
group. Venous blood was taken from the left forearm into
Vacutainer tubes containing potassium EDTA. About
50 U/ml aprotinin was added immediately and blood was
centrifuged at 1500 rpm for 15 min. Obtained plasma was
saved at –851C until the assay.
We estimated that the average total energy in daily
nutrient intake of the patient group was between 2800
and 3200 kCal because they were inpatients and were
eating meals provided by the hospital. However, it is not
possible to be completely certain that they did not eat
anything from outside the hospital as the Psychiatry
Department is an open facility.
Laboratory analysis
Venous blood samples were collected at baseline both in
patients and in the controls during the sixth week of
the treatment in the patient group in the morning
at 7:00 a.m. after 12 h of fasting. Serum triglyceride,
cholesterol and HDL cholesterol levels were determined
by conventional enzymatic photometric methods in the
Beckman-Coulter Synchron LX-20 Automated Analyser
(Beckman Coulter Inc., Palo Alto, California, USA).
VLDL cholesterol levels were calculated from triglyce-
ride levels. LDL cholesterol levels were estimated using
the Friedwald equation.
Ghrelin, AGRP, orexin A, and visfatin levels were
measured in the plasma fractions of venous blood
taken into the Vacutainer tubes containing potassium
EDTA and 500 U/ml aprotinin using an ELISA kit
(Phoenix Pharmaceuticals, Belmont, California, USA).
Serum ghrelin levels were measured using Enzyme
Linked Immunosorbent Assay (ELISA). The design of
this immunoassay kit is based on the principle of a
competitive enzyme immunoassay. It has a sensitivity of
0.078 ng/ml, and less than 5 and 14% intra-assay and
interassay variation, respectively. It has a detection range
Metabolic changes with olanzapine treatment Basoglu et al. 167
of 0–100 ng/ml. Plasma AGRP was measured using a
kit (ELISA). Sensitivity was 0.07 ng/ml, and the linear
range was between 0.09 and 0.61 ng/ml. Interassay and
intra-assay variation was less than 6 and 10%, respec-
tively. Plasma orexin A levels were measured using a
commercially available competitive enzyme immuno-
assay – Orexin A (Hypocretin-1) kit (human, mouse, rat)
(Phoenix Pharmaceuticals, Belmont, California, USA).
This kit specifically measures orexin A and does not cross
react with orexin-B. The minimum detectable concen-
tration of orexin A was 0.29 ng/ml (190 pg/ml). The assay
protocol was carried out in accordance with the manu-
facturer’s instructions. Using the provided standard
peptide, a curve where the known concentrations of
standard peptide and its corresponding optical density (at
450 nm) were plotted on the x and y axis, respectively,
was created. The optical density of the cerebrospinal
fluid sample was then determined and the corresponding
concentration of peptide read off the curve. The reading
for each sample was obtained in triplicate and the average
value obtained. Serum concentrations of visfatin were
assayed using a commercial ELISA kit with a lower limit
of sensitivity of 2.63 ng/ml and intra-assay and interassay
coefficients of variations of 5.2 and 5.8%, respectively.
Serum leptin levels were determined using a commer-
cially available radioimmunoassay kit from Phoenix
Pharmaceuticals. The assay is based on the competition
of 125I peptide and peptide binding to the limited
quantity of antibodies specific for the peptide in each
reaction mixture. This human kit is designed for amino
acids 57–92 of the human leptin molecule and gives
100% cross reactivity. It is sensitive for leptin levels
of 1–128 pg/tube. Plasma CCK octapeptide was mea-
sured with an EIA (enzyme immunoassay) kit (Phoenix
Pharmaceuticals). The range of the kit was 0–100 ng/ml.
The assay sensitivity was 0.08 ng/ml; the intra-assay and
interassay coefficients of variation for the assay control
were 4% and less than 15%, respectively.
Data analysis
BMI, waist circumference, fasting blood glucose, plasma
low-density and high-density lipoprotein, and triglyceride
levels were measured at baseline and during the second
and sixth weeks of treatment. Patient and control groups
were compared by one-way analysis of variance. Effects
of treatment on these variables were investigated with
repeated measure analysis of variance. Plasma leptin,
ghrelin, orexin, AGRP, visfatin, and CCK levels were
measured at baseline and at the sixth week of the
treatment, and pretreatment and posttreatment values
were compared with Wilcoxon signed-rank test as some
of these variables were not normally distributed. Cor-
relation of percent change of BMI and the neuropeptide
levels were computed by the Spearman correlation test.
For significant correlations among the change of neuro-
peptide levels and metabolic variables such as triglyceride
and fasting glucose, we reanalyzed the data using partial
168 International Clinical Psychopharmacology 2010, Vol 25 No 3

correlations to control the effect of BMI change. We
report the results when they are different from the
previous analysis.
Results
Mean and standard deviation of age and the measured
variables are summarized in Table 1. There was no signifi-
cant age difference between the control and patient
groups [F(1,41) = 2.5, P > 0.12].
The patient group had significantly higher baseline HDL
[F(1,41) = 23.7, P < 0.001] and ghrelin than controls
[F(1,41) = 5.5, P = 0.024]. There were no other signifi-
cant differences.
We found several significant treatment effects. BMI
[F(1,19) = 82.8, P < 0.001], waist circumference [F(1,19) =
48.9, P < 0.001], triglyceride [F(1,19) = 16.3, P < 0.001],
LDL [F(1,19) = 13.7, P = 0.002], and leptin (z = – 3.7,
P < 0.001) levels increased, and ghrelin (z = – 3.1,
P = 0.002) and orexin (z = – 2.4, P = 0.015) levels
decreased with olanzapine treatment. BMI increased 7%
or more in 75% of the patients. Fasting blood glucose,
HDL, CCK, AGRP, and visfatin levels did not change
significantly during the 6 weeks of olanzapine treatment.
Correlation analysis revealed that percent BMI and leptin
changes were not significantly correlated with percent
change of any neuropeptide. Correlation between percent
BMI and leptin changes was almost significant (r = 0.44,
P = 0.054), and there was a significant correlation bet-
ween percent triglyceride and leptin changes. However,
when the effect of BMI change was controlled with
partial correlations, the results were no longer significant
(P = – 0.29, P > 0.90). Percent changes of CCK, ghrelin,
AGRP, orexin and visfatin were significantly correlated
(Table 2). None of the neuropeptide levels and
triglyceride or fasting glucose changes was correlated.
PANNS total, positive, negative and general psycho-
pathology scores decreased significantly with 6 weeks of
olanzapine treatment, showing the effectiveness of the
treatment (Table 3).

Table 1 Age, BMI, metabolic variables, and neuropeptide levels of control group and baseline, second, and sixth week measurements
of the patient group
Patients

Controls Baseline Second week Sixth week

Age (years) 21.7 ± 1.1 21.2 ± 0.75

Smokers (%) 77.3 65.0
BMI* (kg/m2) 22.4 ± 2.0 22.0 ± 2.2 23.3 ± 2.1 24.4 ± 2.4
Waist circumference (cm)* 82.7 ± 7.13 78.7 ± 7.1 83.9 ± 6.1 87.3 ± 6.4
Fasting blood glucose (mg/dl) 76.2 ± 6.5 79.9 ± 6.3 76.1 ± 6.8 76.5 ± 10.8
LDL (mg/dl)** 90.1 ± 18.3 96.9 ± 34.2 119.1 ± 32.3 123.2 ± 35.6
HDL (mg/dl)w 31.9 ± 5.8 43.3 ± 9.1 54.8 ± 25.5 43.5 ± 7.3
Triglyceride (mg/dl)* 97.1 ± 48.7 89.5 ± 46.9 142.7 ± 95.7 152.4 ± 80.5
Leptin (ng/ml)* 2.8 ± 2.2 3.1 ± 2.3 8.4 ± 6.4
Cholecystokinin 0.35 ± 0.18 0.39 ± 0.19 0.29 ± 0.15
Ghrelin (pg/ml)**,z 8.1 ± 1.2 20.6 ± 24.5 7.9 ± 0.90
Orexin (pg/ml)*** 14.18 ± 33.7 18.9 ± 40.3 1.1 ± 0.65
AGRP (ng/ml) 4.8 ± 0.99 5.1 ± 1.5 4.7 ± 0.60
Visfatin (ng/ml) 69.6 ± 81.5 53.7 ± 23.9 53.8 ± 20.5

AGRP, agouti-related protein; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
*Significant change with treatment, P < 0.001.
**Significant change with treatment, P < 0.01.
***Significant change with treatment, P < 0.05.
w
Significant difference between patients and controls, P < 0.001.
z
Significant difference between patients and controls, P < 0.05.

Table 2 Correlations of measured percent changes during olanzapine treatment of neuropeptide levels with body mass index
Percent change Cholecystokinin Ghrelin Orexin AGRP Visfatin BMI Fasting glucose Triglyceride

Leptin – 0.009 – 0.405 – 0.185 – 0.245 – 0.454 0.436 0.107 0.517*

Cholecystokinin 0.692** 0.668** 0.835** 0.723** 0.250 0.068 – 0.017
Ghrelin 0.638** 0.692** 0.732** – 0.212 – 0.162 – 0.192
Orexin 0.517* 0.702** 0.050 0.032 – 0.026
AGRP 0.630** 0.141 – 0.089 – 0.063
Visfatin – 0.077 – 0.263 – 0.319
BMI 0.132 0.377
Fasting glucose 0.087

AGRP, agouti-related protein; BMI, body mass index.

*Correlation is significant at the 0.05 level (two-tailed).
**Correlation is significant at the 0.01 level.

Table 3 Change of PANNS total, positive symptoms, negative symptoms and general psychopathology scores with 6-week olanzapine
treatment
Baseline Second week
PANSS total 95.2 ± 14.8 70.0 ± 19.2
PANNS positive symptoms 21.4 ± 4.1 14.9 ± 4.5
PANSS negative symptoms 24.5 ± 8.5 17.3 ± 5.7
PANSS general psychopathology 49.4 ± 6.9 37.9 ± 11.0
PANNS, Positive and Negative Syndrome Scale.
Discussion
Olanzapine treatment significantly increased plasma
leptin level and decreased plasma ghrelin and orexin
levels, but did not change plasma CCK, visfatin, and
AGRP levels. The effect of olanzapine treatment on
the orexin and CCK levels has not been investigated
before. Our study indicated that BMI, waist circum-
ference, LDL, and triglyceride levels increased significantly
after 6 weeks of olanzapine treatment. Our results were
consistent with those of earlier studies dealing with first-
episode patients (Zipursky et al., 2005; Strassnig et al.,
2007). In a meta-analysis carried out by Jin et al. (2008),
leptin increased significantly with olanzapine treatment.
However, we did not find a significant correlation
between percent change of leptin and BMI with
treatment, which could be owing to the sample size used
because a statistical trend was seen. We found that
percent leptin and triglyceride changes were correlated,
consistent with the results of Atmaca et al. (2003).
However, this correlation was not significant when the
effect of BMI change was controlled.
Our results also indicated that ghrelin and orexin levels
decreased with treatment. Although some studies re-
ported lower ghrelin levels in patients taking antipsycho-
tic drugs (Togo et al., 2004; Hosojima et al., 2006; Tanaka
et al., 2008), others have reported increased (Murashita
et al., 2005; Palik et al., 2005; Esen-Danaci et al., 2008;
Perez-Iglesias et al., 2008a, 2008b) or unchanged levels
(Himmerich et al., 2005; Theisen et al., 2005). Interes-
tingly, ghrelin levels were significantly higher in the
patient group before treatment. It is difficult to interpret
this finding because earlier studies have not compared
pretreatment ghrelin levels in first-episode schizophrenia
patients with healthy controls. It has very recently been
shown that systemic ghrelin administration leads to
increased extracellular dopamine in the nucleus accum-
bens (Quarta et al., 2009). It can be speculated that high
ghrelin levels might be related to dopaminergic system
dysregulation in untreated patients. This issue must be
evaluated further in future studies. Orexin has been
investigated less extensively. It has recently been
reported that olanzapine induces activation of orexin
neurons in the LHA (Wallingford et al., 2008). Clozapine
activation of LHA orexin neurons has also been reported
(Fadel et al., 2002). It has been reported that orexin
levels are lower in obese individuals compared with
healthy controls (Komaki et al., 2001; Adam et al., 2002;
Metabolic changes with olanzapine treatment Basoglu et al. 169
Sixth week Percent change F (1,19) P
58.0 ± 24.4 37.2 ± 28.9 33.8 < 0.0001
11.3 ± 4.5 25.6 ± 44.8 41.3 < 0.0001
16.2 ± 7.4 44.3 ± 26.3 11.8 0.003
30.6 ± 13.9 36.7 ± 29.4 29.7 < 0.0001
Baranowska et al., 2005). In recent animal studies, olanza-
pine treatment was shown to be related to decreased
energy expenditure and sympathetic discharge, which
were associated with Orexin A positive neurons (Monda
et al., 2008; Stefanidis et al., 2008), although other findings
did not support this finding (Davoodi et al., 2009). We
did not find any changes in AGRP, visfatin and CCK
levels with olanzapine treatment. Consistent with our
finding, one recent study did not find a significant change
in visfatin after antipsychotic treatment (Perez-Iglesias
et al., 2008a, 2008b). Changes of AGRP and CCK with
olanzapine treatment have not been studied before. CCK
is more closely associated with short-term eating behavior
and may not be related with body weight (Lopez et al.,
2007). AGRP is a potent orexigenic, and leptin inhibits
its release (Anubhuti, 2006). It can be speculated that
high levels of leptin during olanzapine treatment might
inhibit AGRP release. This issue must be investigated in
future studies.
We found that percent changes of CCK, visfatin, AGRP,
ghrelin, and orexin were significantly and positively
correlated. On one hand, this was not surprising because
all of these neuropeptides are associated with food
intake and energy regulation. Although AGRP, ghrelin,
visfatin and orexin are orexigenic, CCK is anorexigenic.
Our results showed that levels of all of these neuro-
peptides decreased with olanzapine treatment and that
they were associated with weight gain. It can be
concluded that levels of orexigenic neuropeptides de-
creased appropriately (but were not correlated) with
weight gain. In contrast, the leptin level also increased, as
reported by earlier studies suggesting leptin resistance
(Jin et al., 2008).
The most significant limitation of the study was its small
sample size. However, the sample was quite homogenous in
terms of age, baseline BMI, and drug dose. Regarding the
sample size, some of the comments on the findings may be
more or less speculative. We included only male patients,
which made the sample even more homogenous, but,
clearly, our results may not be valid for women. The
strengths of our study included the investigation of several
neuropeptides in a single sample and the inclusion of same
sex controls with similar age distribution.
In conclusion, the results of this study indicated that
short-term olanzapine treatment was associated with
significant increases in BMI, waist circumference, serum
170 International Clinical Psychopharmacology 2010, Vol 25 No 3
triglyceride, and LDL levels. BMI levels increased more
than 7% in over 75% of the patients, which is alarming
when the serious outcomes of obesity are considered.
Leptin increased and ghrelin and orexin decreased
significantly with olanzapine treatment while CCK,
visfatin and AGRP levels did not change significantly.
Percent leptin change was associated with percent BMI
and triglyceride changes, but the correlation between
leptin and triglyceride change was not maintained when
the effects of BMI change was controlled. Future studies
to investigate the mechanisms of AAP induced weight
gain are necessary to develop effective agents to over-
come this important health risk.
Acknowledgement
There is no funding source supporting the study
submitted.
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