Dr Thomas Ljung Department of Heart and Lung Diseases, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden (fax: 46 31 826540; e-mail: email@example.com).
Abstract. Ljung T, Ahlberg A-C, Holm G, Friberg P, Andersson B, Eriksson E, Björntorp P (Sahlgrenska University Hospital and University of Göteborg, Göteborg, Sweden). Treatment of abdominally obese men with a serotonin reuptake inhibitor: a pilot study. J Intern Med 2001; 250: 219–224.
Objective. To investigate the effects of a selective serotonin reuptake inhibitor (SSRI) on the neuroendocrine and autonomic nervous system perturbations found in abdominal obesity.
Design. Treatment for 6 months with citalopram and for 6 months with placebo using a double-blind, cross-over design, with a 2-month wash-out period between treatment periods.
Subjects. Sixteen healthy men, 45–60 years, moderately obese and with an abdominal fat distribution.
Measurements. Anthropometry, three different depression rating scales, serum lipids, testosterone, IGF-I, oral glucose tolerance test (OGTT), pituitary stimulation with corticotropin releasing hormone (CRH), arithmetic stress test, and excretion of cortisol and metoxycatecholamines in urine, collected during 24 h.
Results. Cortisol concentrations in the morning were low before treatment, indicating a perturbed function of the hypothalamic-pituitary-adrenal (HPA) axis. After treatment with citalopram morning cortisol concentrations rose to normal. Cortisol concentrations after stimulation with CRH or stress were elevated by citalopram treatment, but urinary cortisol excretion was unchanged. The glucose concentrations after OGTT (120 min) tended to be reduced, with unchanged insulin concentrations, whilst other metabolic values did not change during treatment. Heart rate after administration of CRH, and during laboratory stress test, decreased by treatment with citalopram. Diurnal urinary excretion of metoxycatecholamines tended to decrease. Neither body mass index nor waist/hip circumference ratio decreased. Depression scores were within normal limits before treatment and did not change.
Conclusion. The results of this pilot study indicate improvements in the regulation of neuroendocrine-autonomic systems as well as metabolism in abdominal obesity during treatment with an SSRI.
Mental depression is associated with a number of neuroendocrine abnormalities, including changes in the hypothalamic-pituitary-adrenal (HPA) activity, and growth hormone secretion; tentatively, also the production of sex steroids may be aberrant. An increase in the activity of the sympathetic nervous system is often observed . Most of these changes seem to be state dependent, i.e. they are normalized upon treatment with antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) [2, 3].
Subjects with abdominal obesity have repeatedly been reported to show traits of depression [4–7, A-C. Ahlberg et al. 2001, unpublished data]. They also show neuroendocrine abnormalities, reminiscent of those in depression. The activity of the HPA axis is aberrant, resulting in low morning cortisol levels [8–11] and a reduced dexamethasone induced suppression of cortisol release . Serum levels of growth hormone and, in males, sex steroids are reduced [6, 9]. There are signs of an increased activity of the sympathetic nervous system activity in terms of elevated heart rate, blood pressure and excretion of catecholamine metabolites. This is occurring in parallel with signs of perturbations of the regulation of the HPA axis  and has been suggested to be induced as a compensation for a malfunctioning HPA axis . Another common feature in depression and abdominal obesity is an increased risk for onset of type 2 diabetes [13–15].
The peripheral endocrine abnormalities, resulting from the neuroendocrine perturbations, may be involved in the pathogenesis of abdominal obesity and its associated metabolic and haemodynamic risk factors . We therefore hypothesized that treatment with an SSRI would correct the associated neuroendocrine and endocrine abnormalities, also in nondepressed subjects with abdominal obesity, with resulting improvement of the somatic risk factor pattern.
This problem was tested in a pilot study in which men with abdominal obesity were treated with citalopram, an SSRI with antidepressant efficacy. Citalopram was chosen because it does not exert any marked effects on food intake and body weight, and as it is devoid of affinity for the noradrenaline transporter and for noradrenergic and cholinergic receptors .
Materials and methods
Sixteen moderately obese men (BMI 26.5–34.7) were selected for the study after recruitment by advertisements. Selection criteria were age 45–60 years, absence of clinically manifested diabetes and a waist/hip circumference ratio (WHR) > 1.0. Thirteen of these 16 men have participated in a previous study where they were compared with controls having a similar BMI but a WHR < 1.0 (11), and they volunteered to participate in this treatment study. Men using psychotropic or adrenoceptor blocking drugs were not included. All men were apparently healthy and reported moderate alcohol consumption.
The subjects were informed orally and in writing, informed consent was obtained, and the study was approved by the Ethics Committee of the University of Göteborg.
The men were treated for 6 months with citalopram (H. Lundbeck A/S, Copenhagen-Valby, Denmark) and for 6 months with placebo using a double-blind, cross-over design, with a 2-month wash-out period between treatment periods. In order to minimize side-effects, treatment started with 10 mg day–1, which was increased to 20 mg after 1 week. After 2 weeks, and for the rest of the trial, the dose was 40 mg day–1. The dose was taken in the morning. The normal dose of citalopram, when treating depression, is 20 mg day–1 and the recommended maximum dose is 60 mg day–1.
Before treatment, and at the end of the two treatment periods before tapering medication, the men underwent a number of test procedures.
A psychiatric interview was performed, without the knowledge of other test results, in which the Hamilton Depression Scale (HDS), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Beck Depression Inventory (BDI) were used .
Oral glucose tolerance test (OGTT) was performed in the over night fasting state at 9 a.m. with 100 g glucose dissolved in water ingested within 5 min. Blood glucose and plasma insulin were measured via a patent intravenous catheter before and 30, 60, 90 and 120 min after glucose administration.
On another morning at 9 a.m. a pituitary stimulation with corticotropin releasing hormone (CRH) was performed. An intravenous catheter was inserted, and then the subjects rested for 30 min in a recumbent position. At 9 a.m. 100 μg CRH [Corticorelin (human) as trifluoroacetate, Ferring, Kiel, Germany] was administered intravenously. Blood samples for adrenocorticotropic hormone (ACTH) and cortisol were collected 15 min before CRH was injected, immediately before and then 15, 30, 60, 90 and 120 min after the CRH injection.
Arithmetic stress test was performed as previously described . In short, an intravenous catheter was inserted and then the subjects rested for 30 min in a recumbent position. The men were sitting comfortably during the stress test, forced calculation for 10 min, and thereafter. Blood pressure and pulse rate were recorded 15 min before commencing the stress test, immediately before and then 10, 20, 30 and 40 min after start. Blood samples for ACTH and cortisol were drawn at the same points of time.
Body weight was measured to the nearest 0.1 kg with the men in underwear, and the height to the nearest 0.5 cm. The waist circumference was measured horizontally midway between the lowest rib and iliac crest, and hip circumference as the widest circumference in the gluteal region. The waist/hip circumference ratio (WHR) was then calculated. Blood pressures were measured after 5 min rest in the supine position with a mercury sphygmomanometer. The average of two measurements with 1 min interval was used.
Glucose was determined by a commercially available enzymatic method and insulin by radioimmunoassay (Phadebas, Pharmacia, Uppsala, Sweden). Serum lipids were determined as described in . Total serum testosterone was determined by a nonextraction method where testosterone bound to bovine serum albumin was used as the antigen (testosterone RIA, ICN Medicals, Costa Mesa, CA, USA). Insulin-like growth factor I (IGF-I) was measured with a nonextraction radioimmunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), ACTH by an immunoassay method (Nichols Institute Diagnostics) and cortisol by radioimmunoassay (Orion Diagnostica, Turkku, Finland). Metoxycatecholamines in urine, collected during 24 h, were determined by high-performance liquid chromatography .
The estimated treatment effects (values after citalopram-period compared with values after placebo-period) were analysed with paired t-test, and P < 0.05 was considered significant. Adjustments for any period effects made no significant difference in results. Area under the curve (AUC) was calculated as the mean of all included values. The software of the Macintosh system was utilized (Statview 4.0 FPU) and results were double checked by a statistician using the SAS System (Statistical Analysis System, Cary, NC, USA).
Table 1 shows the results of anthropometric, haemodynamic and metabolic measurements, at the end of the treatment periods before tapering medication, after 6 months placebo and after 6 months citalopram. Neither BMI nor WHR decreased. After citalopram treatment heart rate was lower during challenges by CRH and laboratory stress. The glucose concentrations during OGTT, after 120 min, tended to be reduced after treatment with citalopram (P < 0.10) whilst insulin concentrations did not change.
Table 1. Anthropometric, haemodynamic and metabolic variables for the 16 men after treatment with placebo and after treatment with citalopram
Table 2 shows the results of endocrine measurements, at the end of the treatment periods. After citalopram treatment cortisol concentrations in the morning became higher (P < 0.05). Cortisol concentrations during stimulation with CRH (Fig. 1; P < 0.05) and with stress (Fig. 2; P < 0.05) were also increased whilst ACTH concentrations during stimulation with CRH (Fig. 1) and with stress (Fig. 2) remained unchanged. The urinary excretion of catecholamine metabolites tended to decrease (Table 2, P=0.06) after treatment with citalopram.
Table 2. Endocrine variables for the 16 men after treatment with placebo and after treatment with citalopram
The sum scores ranged from 0 to 9 in all three depression scales used and the mean sum showed for HDS 3.1 (SD 2.7), for MADRS 1.8 (SD 2.7), and for BDI 4.0 (SD 2.9) before treatment and did not change after treatment (not shown).
No serious side-effects during treatment were reported.
This small pilot trial suggests that administration of the SSRI citalopram to abdominally obese men influences HPA activity, sympathetic activity, and insulin sensitivity. None of these men were depressed, suggesting that the neuroendocrine and autonomic effects observed were not secondary to an effect on mood. No reduction in weight was observed, suggesting that the effects were also not secondary to an effect on food intake.
Most of these men have participated in a previous study where they were compared with controls and shown to have lower than normal morning cortisol concentrations . This has been observed previously to be associated with abdominal obesity [6, 8–11], and is probably a sign of deranged diurnal regulation of cortisol secretion by the HPA axis, which normally is most active in the morning. This condition also seems to be associated with a decreased plasticity of cortisol secretion, as revealed by various challenge tests [1, 9, 11].
Lower morning cortisol values in men with higher WHR has been reported previously [8–10]. Explanations for this have included insensitive adrenals or a decreased 21-hydroxylase activity which would direct cortisol precursors mainly into synthesis of adrenal androgens . Other possibilities might be increased activity of 11β-hydroxysteroid dehydrogenase, which converts cortisol to inactive cortisone . Based on other studies [9, 24] we believe that morning cortisol decrease is an early sign of a perturbed function of the HPA axis. This may or may not be associated with elevated urinary cortisol excretion [8, 9] depending on the ‘stage’ in the HPA perturbations and might also involve gender differences.
After treatment with citalopram, morning cortisol concentrations were elevated and no longer different from that observed in controls in a previous study , suggesting a change towards normalization of HPA axis activity. It is well known that serotonin exerts a stimulatory influence on the HPA axis; in line with this, infusion of citalopram to healthy males has previously been shown to induce a transient increase in cortisol release . Measurements of morning cortisol concentrations in serum was undertaken after intake of the morning dose of citalopram; hence, it cannot be excluded that the increase in morning serum concentrations of cortisol was because of this acute facilatory effect of serotonin reuptake inhibition on cortisol release. The fact that citalopram also stimulated cortisol responses to CRH and stress however, suggests that the treatment influenced also the regulation of the HPA axis, making it more dynamic. Given the differences observed when abdominally obese men have been compared with controls with respect to HPA axis activity , the effect of citalopram on cortisol release may be seen as a normalization. Likewise, it is well established that treatment with an SSRI may lead to a normalization of HPA activity in depressed patients .
Glucose concentrations after 120 min during OGTT tended to be lower after treatment with citalopram, whilst insulin concentrations remained unchanged. These findings possibly indicate an improved glucose tolerance. As this tendency for decrease in glucose was accomplished with similar insulin concentrations, this might be interpreted to mean an increased sensitivity to insulin. Fluoxetine, a serotonin reuptake inhibitor with anorectic effects, has previously been reported to improve insulin sensitivity, independently of weight loss, in obese type 2 diabetic patients [26, 27].
Heart rate, in stimulated states, in these abdominally obese men decreased after citalopram treatment. Previous studies suggest that citalopram and other SSRIs may cause a modest reduction in heart rate in depressed patients, and, tentatively, also in healthy controls [28, 29] but data are not unanimous [25, 30, 31]. The significant reduction in heart rate, and the tendency for a reduction in the urinary excretion of catecholamine metabolites, observed in this study, suggest that citalopram induced a reduction in the activity of the sympathetic nervous system in this group of men. In order to investigate if the effect of citalopram on heart rate is more pronounced in patients with abdominal obesity (or depression) than in healthy controls, further studies are warranted.
In summary, potentially beneficial changes in HPA axis regulation, the sympathetic nervous system and metabolic factors were seen in these men with abdominal obesity and multiple risk factors but without depressive symptoms. These results in a pilot study seem of sufficient interest to encourage further studies.
The authors thank Marie-Louise Norberg, Carola Gustafsson, Raija Saikkonen and Birgitta Odén for their dedicated clinical work and Per Tanghøj, H Lundbeck AS Biostatistics Department, Copenhagen Denmark, for statistical advice.