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a
Department of Psychiatry, Erciyes University School of Medicine, Talas Road, 38039-Kayseri, Turkey
Department of Nuclear Medicine, Erciyes University School of Medicine, Talas Road, 38039-Kayseri, Turkey
c
Department of Endocrinology, Erciyes University School of Medicine, Talas Road, 38039-Kayseri, Turkey
Abstract
Leptin is a product of the obese gene and plays an important role in the regulation of body weight and food intake. Weight and appetite are
frequently altered in depression. So far, inconsistent results have been reported in terms of leptin levels in depression. Therefore, the authors
investigated serum leptin levels in patients with depression and in healthy controls, and whether there was any alteration throughout
antidepressant treatment. Female patients showed significantly higher leptin levels than those of the control females both before and after the
response to antidepressant treatment, whereas no difference was found between the male patients and the male controls. The improvement
from depression with antidepressant treatment caused a further elevation on the leptin levels, in both female and male patients. These findings
confirm an increase in leptin levels in depressive patients and presence of a sexual dimorphism. Moreover, clinical response to antidepressant
treatment seems to have an additional increasing effect on leptin levels.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Antidepressant treatment; Gender; Leptin; Major depression
1. Introduction
Leptin is a protein synthesised in the adipose tissue and is
the product of obese (ob) gene. Studies show that leptin
levels can be predicted with four independent parameters:
body mass index, percent body fat, gender and glycerol
concentration in blood (Hennessey, 2003). Leptin is
believed to be a messenger from adipose tissue to the brain,
which acts by binding to specific receptors in the
hypothalamus, and decreases food intake and increases
energy expenditure (Jequier, 2002). It exerts its anorexigenic
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2. Methods
2.1. Subjects
Thirty-six inpatients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria
for major depressive disorder (recurrent) (DSM-IV; American Psychiatric Association, 1994) and who were all
reported to have a decrease in appetite during the present
depressive episode were included in the study (mean
ageFSD: 39.81F11.15, range: 1855). Two independent
specialists in Psychiatry (EE, SS) diagnosed the patients.
They were selected from those who were refereed to the
inpatient setting from the psychiatric outpatient clinic. The
patients had been drug-free for at least 2 weeks. Exclusion
criteria for patients were: having taken electroconvulsive
therapy or lithium within the previous 6 months, having a
physical or psychiatric disease other than depression as
judged from their clinical and biochemical examinations,
having alcohol or drug abuse, or endocrine disorder
history, being above or below 15% of their ideal body
weight (i.e., BMI is 2025), and taking oral contraceptives
for female patients. The severity of clinical symptomatology was assessed by MontgomeryAsberg Depression
Rating Scale (Montgomery and Asberg, 1979), and all
patients had 25 or more scores in MADRS before the
treatment. The patients were treated by various antidepressant drugs in standard antidepressant doses for 6 to 10
weeks (5 of them were treated with amitriptyline, 15 with
venlafaxine, 7 with paroxetine, and 9 with fluoxetine) in
the psychiatric inpatient clinic by the two of the authors
(EE, SO), and a decrease of more than 50% in MADRS
scores was accepted as the response to the treatment. They
remained hospitalised for the full duration of the study and
the same authors made the follow-up examinations (EE,
SO). The patients did not take any additional drug or non-
3. Results
There were no significant differences in terms of age
(t=1.05, pN0.05) and BMI (t=1.06, pN0.05) between the
patients and the controls (Table 1). Serum leptin levels were
significantly higher in the patients before the antidepressant
treatment than those of the controls ( F=8.18; df=1, 50;
pb0.05). There was a significant effect of gender ( F=14.81;
df=1,50; pb0.001) and BMI ( F=22.72, df=1, 50; pb0.001)
on leptin levels. Age was not found to have any significant
effect on the leptin levels ( F=2.58; df=1, 50; pN0.05).
Leptin levels were significantly higher in women than in
men when all subjects were taken into consideration
( F=14.81; df=1, 50; pb0.001). In addition, it was found
that women had significantly increased leptin values
compared to men in both the patient and control groups.
For this reason, males and females were evaluated separately. The female patients had significantly higher leptin
levels compared to the control females both before and after
the treatment (pre-treatment mean valueFSD of the female
patients: 57.53F39.82 ng/ml, post-treatment mean valueFSD of the female patients: 65.31F37.38 ng/ml, mean
valueFSD of the female controls: 21.20F9.92 ng/ml;
F=7.66; df=1, 30; pb0.01 and F=14.33; df=1, 30;
pb0.001, respectively), while no difference was found
between the male patients and the male controls before or
after the treatment ( F=0; df=1, 17; pN0.05 and F=1.02;
df=1, 17; pN0.05, respectively) (Fig. 1).
The mean leptin levels were 38.95F39.93 ng/ml before
the treatment, and 45.47F39.40 ng/ml after the clinical
response to the antidepressant treatment in the patients.
There was a statistically significant difference in the leptin
levels between before and after the treatment in all patients
when taking the effects of gender, BMI and age into
consideration ( F=5.81; df=1,30; pb0.05) (Table 1). Gender
had no effect on the alteration in leptin with treatment
( F=0.44, df=1,30; pN0.05).
120
567
100
Women
Men
Total
80
60
40
20
0
Pre-treatment Post-treatment
Controls
Patients
Fig. 1. The gender difference in serum leptin levels of the patients and the
controls.
4. Discussion
The main findings of our study are: (i) female patients
have significantly higher leptin levels than those of the
control females both before and after the response to
antidepressant treatment, whereas no difference is found
between male patients and male controls, (ii) females have
significantly higher leptin values than males in both patients
(sevenfold) and healthy individuals (twofold), (iii) there is a
positive correlation between the severity of depression and
Table 1
Demographic features and leptin levels of the patients and controls
Patients
Age (year)
BMI (kg/m2)
MADRS score (before treatment)
MADRS score (after treatment)
Leptin level (ng/ml) (before treatment)
Leptin level (ng/ml) (after treatment)
Controls
Females (n=20)
Males (n=12)
Total (n=32)
Females (n=14)
Males (n=9)
Total (n=23)
38.10F10.96
26.74F4.88
37.45F6.51
10.30F3.48
57.53F39.82a
65.31F37.38c
42.66F11.34
23.92F3.58
31.08F5.05
8.16F3.63
8.0F9.06
12.40F7.36c
39.81F11.15
25.68F4.59
35.06F6.70
9.50F3.63
38.95F39.93b
45.47F39.40c
32.0F5.92
26.13F2.56
21.20F9.92
43.88F12.88
23.43F3.33
10.99F10.16
36.65F10.78
24.49F3.28
17.21F11.03
568
serum leptin levels, especially in women, and (iv) improvement from depression with antidepressant treatment is
associated with an increase in leptin levels in both female
and male patients.
4.1. Effect of depression on leptin levels
There is an ambiguity about the effects of depression on
leptin levels in the literature. Deuschle et al. (1996) reported
that leptin plasma concentrations did not differ between
depressed patients and healthy controls. Another study
reported higher nocturnal serum leptin levels in patients
with depression (Antonijevic et al., 1998). Kraus et al.
(2001) found that leptin levels were significantly lower in
both depression and schizophrenia compared to healthy
controls. The reason for this discrepancy may be the
differences in the clinical features of the patient groups or
in the time of blood sampling for leptin. The findings of this
study that an increase in leptin levels was observed in
depressive women compared to healthy women, and that the
severity of the depression was positively correlated to the
leptin levels suggest that depression may have some
increasing effects on serum leptin. Although it would be
expected that the reduced food intake and subsequent
weight loss in depression might be associated with
decreased leptin levels (Chan et al., 2003), how can we
explain this increase in depression?
As it was suggested in some previous reports (Antonijevic et al., 1998; Rubin et al., 2002), this increase in leptin
may be due to the hyperactive HPA system and enhanced
glucocorticoids, which are known to be the most consistent
biological correlates of major depression. Glucocorticoids
stimulate leptin gene expression and leptin production in the
adipocytes independently of their effects on food intake
(Cleare et al., 2001; Udden et al., 2003). However, since we
did not measure the HPA axis activity (through basal
cortisol levels or dexamethasone suppression test), our study
cannot directly point to the link between HPA activity and
serum leptin levels.
Another explanation for higher leptin levels in depression
may be that elevated leptin might contribute to HPA axis
hyperactivity in depression (Antonijevic et al., 1998), since
leptin was reported to elevate basal corticotropin releasing
hormone (CRH) release in rat hypothalamus (Schwartz et
al., 1996). Additionally, it can be thought that the presence
of bnormalQ or bincreasedQ leptin concentrations despite
decreased food intake could contribute to loss of appetite,
which is a foremost symptom of major depression
(Deuschle et al., 1996; Udden et al., 2003).
4.2. Gender effect on alterations of leptin levels
A sexual diergism in leptin levels has been consistently
reported, i.e., healthy women have higher leptin levels than
men (Licinio et al., 1998), suppression of the leptin by
arginin vasopressin administration is more considerable in
women than men (Rubin et al., 2002), and so on. The reason
of this gender inequity in terms of leptin remains to be
elucidated. A greater amount of subcutaneous and intraabdominal adipose tissue in women may be an important
determinant of the sex difference in leptin concentration
(Rubin et al., 2002). Furthermore, the differences in male
and female eating behaviours or upregulated leptin mRNA
in proportionally larger adipocytes of females have been
suggested for the sexual diergism (Hennessey, 2003).
Another explanation may be that testosterone may lead
leptin values to reduce in men, because testosterone reduces
leptin levels in hypogonadal men (Jockenhovel et al., 1997),
and leptin levels are inversely correlated with testosterone
levels in healthy nonobese men (Soderberg et al., 2001).
Nevertheless, there is a considerable divergence about
gender effect on leptin in the studies on depression. Some
studies report higher leptin levels in depressive patients than
in controls for both genders (Antonijevic et al., 1998), while
some report leptin increases only in depressive women, not
in men, in agreement with our result (Rubin et al., 2002). In
the present study, we also observed that the higher leptin
levels in depressive patients pertained mostly to women
rather than to men. However, taking into consideration the
small number of the patient and control groups, the result of
our study should be commented with great caution. If the
hypothesis that glucocorticoids stimulate the leptin production holds true, why glucocorticoids exert their leptinincreasing effects only in women? In a recent study,
dexamethasone has increased the plasma leptin levels only
in obese women, but not in obese men and in normal weight
subjects, unrelated to body fat distribution and insulin
sensitivity (Putignano et al., 2003). From this finding, one
can draw a conclusion that a greater sensitivity of female
adipose tissue to glucocorticoids may underlie the sexually
dimorphic pattern of leptin response to glucocorticoids.
4.3. Effect of antidepressant treatment on leptin levels
There are few studies investigating the effects of
antidepressants on leptin levels. In one study, mirtazapine
induced slight rise in leptin levels, while venlafaxine did not
affect it in depressed patients within 4 weeks (Kraus et al.,
2002). Another study found that 6-week treatment with
tricyclic agents or paroxetine did not have any effect on
leptin levels in contrast to our results (Hinze-Selch et al.,
2000). In a rat study, short-term fluoxetine treatment caused
plasma leptin levels to reduce (Dryden et al., 1999). In our
study, we used various antidepressants in the treatment of
depression and we preferred to evaluate the effect of
response to treatment on leptin levels. In contrast to our
initial expectation, we found a significant increase in leptin
levels by the therapeutic response to drug treatment, at least
in the short term. Given the finding that depressive patients
have already elevated leptin levels, how can we explain the
more elevated leptin values with the improvement from
depression?
5. Conclusion
The data of the study show the elevated leptin levels in
depressed females with decrease in appetite, but not in
depressed males. The reason for this gender diergism of
leptin may be a greater sensitivity of female adipose tissue
to glucocorticoids, which are known to be in higher levels in
depressed patients and to induce leptin production in the
adipocytes. Another conclusion of the study may be that
clinical response to antidepressant treatment has additional
increasing effect on leptin levels, rather than a normalizing
effect. This effect might be considered to be related to the
569
Acknowledgement
This study was supported by Erciyes University Research
Fund.
References
Ahima, R.S., Saper, C.B., Flier, J.S., Elmquist, J.K., 2000. Leptin
regulation of neuroendocrine systems. Front. Neuroendocrinol. 21,
263 307.
American Psychiatric Association, 1994. DSM: IV. Diagnostic and
Statistical Manual of Mental Disorders, 4th ed. American Psychiatric
Association, Washington, DC.
Antonijevic, I.A., Murck, H., Frieboes, R.M., Horn, R., Brabant, G.,
Steiger, A., 1998. Elevated nocturnal profiles of serum leptin in patients
with depression. J. Psychiatr. Res. 32, 403 410.
Atmaca, M., Kuloglu, M., Tezcan, E., Ustundag, B., Bayk, Y., 2002a.
Serum leptin and cholesterol levels in patients with bipolar disorder.
Neuropsychobiology 46, 176 179.
Atmaca, M., Kuloglu, M., Tezcan, E., Ustundag, B., Gecici, O., Firidin, B.,
2002b. Serum leptin and cholesterol values in the suicide attempters.
Neuropsychobiology 45, 124 127.
Bjorntorp, P., 2001. Do stress reactions cause abdominal obesity and
comorbidities? Obes. Rev. 2, 73 86.
Chan, J.L., Heist, K., DePaoli, A.M., Veldhuis, J.D., Mantzoros, C.S., 2003.
The role of falling leptin levels in the neuroendocrine and metabolic
adaptation to short-term starvation in healthy men. J. Clin. Invest. 111,
1409 1421.
Cleare, A.J., OKeane, V., Miell, J., 2001. Plasma leptin in chronic fatigue
syndrome and a placebo-controlled study of the effects of low-dose
hydrocortisone on leptin secretion. Clin. Endocrinol. 55, 113 119.
Deuschle, M., Blum, W.F., Englaro, P., Schweiger, U., Weber, B., Pflaum,
C.D., Heuser, I., 1996. Plasma leptin in depressed patients and healthy
controls. Horm. Metab. Res. 28, 714 717.
Dryden, S., Brown, M., King, P., Williams, G., 1999. Decreased plasma leptin
levels in lean and obese Zucker rats after treatment with the serotonin
reuptake inhibitor fluoxetine. Horm. Metab. Res. 31, 363 366.
Esler, M., Turbott, J., Schwarz, R., Leonard, P., Bobik, A., Skews, H.,
Jackman, G., 1982. The peripheral kinetics of norepinephrine in
depressive illness. Arch. Gen. Psychiatry 39, 295 300.
Hatzinger, M., 2000. Neuropeptides and hypothalamicpituitaryadrenocortical (HPA) system: review of recent research strategies in
depression. World J. Biol. Psychiatry 1, 105 111.
Hennessey, J., 2003. Leptin as fat orchestrator. Rev. Undergrad. Res. 2,
12 18.
Hinze-Selch, D., Schuld, A., Kraus, T., Kuhn, M., Uhr, M., Haack, M.,
Pollmacher, T., 2000. Effects of antidepressants on weight and on the
plasma levels of leptin, TNF-alpha and soluble TNF receptors: a
longitudinal study in patients treated with amitriptyline or paroxetine.
Neuropsychopharmacology 23, 13 19.
Hosoi, T., Okuma, Y., Wada, S., Nomura, Y., 2003. Inhibition of leptininduced IL-1b expression by glucocorticoids in the brain. Brain Res.
969, 95 101.
Jequier, E., 2002. Leptin signaling, adiposity, and energy balance. Ann.
N.Y. Acad. Sci. 967, 379 388.
570
Jockenhovel, F., Blum, W.F., Vogel, E., Englaro, P., Muller-Wieland, D.,
Reinwein, D., Rascher, W., Krone, W., 1997. Testosterone substitution
normalizes elevated serum leptin levels in hypogonadal men. J. Clin.
Endocrinol. Metab. 82, 2510 2513.
Kraus, T., Haack, M., Schuld, A., Hinze-Selch, D., Pollmacher, T., 2001.
Low leptin levels but normal body mass indices in patients with
depression or schizophrenia. Neuroendocrinology 73, 243 247.
Kraus, T., Haack, M., Schuld, A., Hinze-Selch, D., Koethe, D., Pollmacher,
T., 2002. Body weight, tumor necrosis factor system, and leptin
production during treatment with mirtazapine or venlafaxine. Pharmacopsychiatry 35, 220 225.
Leibowitz, S.F., Alexander, J.T., 1998. Hypothalamic serotonin in control
of eating behavior, meal size, and body weight. Biol. Psychiatry 44,
851 864.
Licinio, J., Negrao, A.B., Mantzoros, C., Kaklamani, V., Wong, M.L.,
Bongiorno, P.B., Negro, P.P., Mulla, A., Veldhuis, J.D., Cearnal, L.,
Flier, J.S., Gold, P.W., 1998. Sex differences in circulating human leptin
pulse amplitude: clinical implications. J. Clin. Endocrinol. Metab. 83,
4140 4147.
Ludwig, M., Klein, H.H., Diedrich, K., Ortmann, O., 2000. Serum leptin
concentrations throughout the menstrual cycle. Arch. Gynecol. Obstet.
263, 99 101.
Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to
be sensitive to change. Br. J. Psychiatry 134, 382 389.
Pariante, C.M., Miller, A.H., 2001. Glucocorticoid receptors in major
depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391 404.
Putignano, P., Brunani, A., Dubini, A., Bertolini, M., Pasquali, R.,
Cavagnini, F., 2003. Effect of small doses of dexamethasone on
plasma leptin levels in normal and obese subjects: a dose-response
study. J. Endocrinol. Invest. 26, 111 116.
Rayner, D.V., Trayhurn, P., 2001. Regulation of leptin production:
sympathetic nervous system interactions. J. Mol. Med. 79, 8 20.
Rubin, R.T., Rhodes, M.E., Czambel, R.K., 2002. Sexual diergism of
baseline plasma leptin and leptin suppression by arginine vasopressin in
major depressives and matched controls. Psychiatry Res. 113, 255 268.
Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P., Baskin, D.G.,
1996. Identification of targets of leptin action in rat hypothalamus.
J. Clin. Invest. 98, 1101 1106.
Soderberg, S., Olsson, T., Eliasson, M., Johnson, O., Brismar, K.,
Carlstrom, K., Ahren, B., 2001. A strong association between
biologically active testosterone and leptin in non-obese men and
women is lost with increasing (central) adiposity. Int. J. Obes. Relat.
Metab. Disord. 25, 98 105.
Stephens, T.W., Basinski, M., Bristow, P.K., Bue-Valleskey, J.M., Burgett,
S.G., Craft, L., Hale, J., Hoffmann, J., Hsiung, H.M., Kriauciunas, A.,
1995. The role of neuropeptide Y in the antiobesity action of the obese
gene product. Nature 377, 530 532.
Udden, J., Bjorntorp, P., Arner, P., Barkeling, B., Meurling, L., Rossner, S.,
2003. Effects of glucocorticoids on leptin levels and eating behaviour in
women. J. Intern. Med. 253, 225 231.
Yamada, J., Sugimoto, Y., Ujikawa, M., 1999. The serotonin precursor 5hydroxytryptophan elevates serum leptin levels in mice. Eur. J.
Pharmacol. 383, 49 51.