Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (S) levels in medicated patients with major depressive disorder compared with controls

Journal of Affective Disorders 146 (2013) 205–212

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Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (S) levels in medicated patients with major depressive disorder compared with controls Hirofumi Kurita a,1, Hitoshi Maeshima b,1, Sayaka Kida b, Hisashi Matsuzaka a, Takahisa Shimano b, Yoshiyuki Nakano b, Hajime Baba b, Toshihito Suzuki a,b,n, Heii Arai a,b a b

Division of Psychiatry and Behavioral Sciences, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan Department of Psychiatry, Juntendo Koshigaya Hospital, Juntendo University Faculty of Medicine, 560, Fukuroyama, Koshigaya-shi, Saitama, Japan

a r t i c l e i n f o

abstract

Article history: Received 4 September 2012 Accepted 4 September 2012 Available online 26 October 2012

Background: There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD). Methods: Participants included 90 inpatients with MDD at the psychiatric ward of Juntendo University Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls (based on sex and age) included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second, correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis. Results: Serum DHEA levels were significantly increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were significantly decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. Multiple regression analysis showed that both hormones were affected by the age at onset of depression. Limitations: All subjects in the present study were on antidepressant medications. Conclusions: Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression, as DHEA administration has been found to be effective for the treatment of depression. Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression. However, DHEA/DHEA-S may be a poor indicator for evaluating severity of depression. & 2012 Elsevier B.V. All rights reserved.

Keywords: Dehydroepiandrosterone (DHEA) DHEA-S Major depressive disorder Sex differences

1. Introduction Women are more than twice as likely as men to be diagnosed with depression. (Scheibe et al., 2003; Sloan and Kornstein, 2003).

n Correspondence author at: Department of Psychiatry, Juntendo University Koshigaya Hospital, University Faculty of Medicine, 560 Fukuroyama, Koshigaya, Saitama 304 0032, Japan. Tel.: þ 81 48 975 0321; fax: þ 81 48 975 3022. E-mail address: [email protected] (T. Suzuki). 1 These authors contributed equally to this work.

0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.09.004

Accumulating evidence suggests the presence of gender differences in clinical symptoms, course of illness, personality traits, treatment-seeking behaviors, and response to antidepressants in depression (Scheibe et al., 2003; Sloan and Kornstein, 2003; Halbreich and Kahn, 2007; Keers and Aitchison, 2010). Women were found to experience more vegetative and atypical symptoms, anxiety, and anger than men (Scheibe et al., 2003; Halbreich and Kahn, 2007). Pharmacological studies have suggested that women show a superior response to selective serotonin reuptake inhibitors (SSRIs) and have fewer adverse drug reactions to SSRIs

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than men (Sloan and Kornstein, 2003; Keers and Aitchison, 2010), which is consistent with the close relationship between estrogen and serotonergic neural transmission, although this topic remains controversial. Estrogen not only affects the production of serotonin but also the expression and binding of serotonin to its receptors and transporters within the serotonin pathway. However, less attention has been given to gender differences in the endocrinologic features of depression, except for the role of estrogen in augmenting serotonergic transmission in the brain. In addition to accumulating findings regarding the role of estrogen in depression, findings regarding the role of adrenal androgen levels in depression have been reported. These findings include data on dehydroepiandrosterone (DHEA) and its sulfoconjugated derivative (DHEA-S), which are secreted from the adrenal cortex and testis (Nieschlag et al., 1973). DHEA and DHEA-S are precursors to sex hormones and are converted to androgens and estrogens in peripheral tissues (Labrie et al., 1997). DHEA-S is the most abundant steroid hormone in the body with a concentration 250 and 500 times higher than that of DHEA in men and women, respectively (Nieschlag et al., 1973; Labrie et al., 1997). Under normal circumstances, DHEA is secreted synchronously with cortisol in response to corticotropin releasing hormone (CRH). Circulating endogenous DHEA and DHEA-S levels have been associated with diseases such as lupus, cancer, and diabetes, as well as other factors, including diet and exercise (Kroboth et al., 1999; Salek et al., 2002). They are also neuroactive in the brain (Corpechot et al., 1981; Majewska et al., 1990) and play an important role in controlling mood (Herbert, 1998). They have the potential to clinically influence the central nervous system and possibly affect stress levels, mental health, and psychiatric disorders. Changes in levels of DHEA or in the cortisol/DHEA ratio have been associated with the pathophysiology of depression with a hyperfunction of the hypothalamic– pituitary–adrenal (HPA) axis. To date, in terms of differences in levels of DHEA-S based on gender, concentrations of these steroids are much higher in men than in women (Sulcova et al., 1997; Yamaji and Ibayashi, 1969; Goldman and Glei, 2007). A recent longitudinal study also showed that basal plasma DHEA-S levels are higher and show a more pronounced decline with age for men than women (Tannenbaum et al., 2004). Accumulating evidence has reported alterations of serum levels of adrenal androgens in patients with MDD. To our knowledge, however, there has been little evidence linking sex-specific alterations in DHEA and DHEA-S. The aims of the present study were (1) to explore differences in serum levels of DHEA and DHEA-S between MDD patients and controls separately for men and women and (2) to assess the correlation between two adrenal androgens and clinical symptoms of MDD, and the influence of clinical factors on serum levels of adrenal androgens in patients with MDD separately for men and women.

2. Methods 2.1. Participants A total of 90 inpatients with MDD (44 men, mean age, 50.7 years, range, 32–70 years; 46 women, mean age, 51.3 years, range, 34–68 years) were recruited from Juntendo Koshigaya Hospital between May 2006 and May 2012. All patients were hospitalized for mixed anxiety-depressive symptoms and met the Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV-TR) criteria for MDD. Patients had either suffered a single episode or recurrent depressive episodes. Patients were excluded if they had a history of other psychiatric disorders including delusions, severe or acute medical illnesses,

neurological disorders, or the use of drugs that may cause depression. Patients showing clinical evidence of dementia or with Mini-Mental State Examination (MMSE) scores o24 were also excluded. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D) on admission. All patients were on antidepressant medication, but were still considered to be in a depressive state at the time of the study. Patients were receiving antidepressant therapy, including SSRIs, serotonin and noradrenaline re-uptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), at the required dose to obtain an optimal clinical response with minimal side effects. The following antidepressive agents were prescribed alone or in combination: TCAs in 34 cases, SSRIs in 21 cases, SNRI in 14 cases, and other antidepressants in 11 cases. The daily dosage of antidepressants administered on admission was converted to the equivalent dose of imipramine (e.g., the imipramine 25 mg equivalent was set at 5 mg of paroxetine, 10 mg of mianserine, 25 mg of amitriptyline, 25 mg of amoxapine, 25 mg of fluvoxamine, and 50 mg of trazodone; Inagaki and Inaba, 2006). The age at onset of a first depressive episode, number of depressive episodes, and duration of last depressive episode were confirmed via medical records. Depressive symptoms were assessed using HAM-D on admission, and symptoms were categorized into four groups: ‘‘anxiety somatization’’ (total score for psychic anxiety, somatic anxiety, somatic symptoms, general somatic symptoms, hypochondriasis and insight), ‘‘cognitive disturbance’’ (total score for feelings of guilt, suicide, agitation, derealization, paranoid symptoms, and obsessional and compulsive symptoms), ‘‘retardation’’ (total score for depressed mood, work and activities, retardation, and genital symptoms), and ‘‘sleep disturbance’’ (total score for early insomnia, middle insomnia, and late insomnia; Feighner et al., 1993). A total of 128 healthy participants (50 men, mean age, 45.9 years, range, 32–72 years; 78 women, mean age, 49.2 years, range 33–71 years) were recruited as a control group. All controls were working at least part-time or were students and did not have any history of depression, dementia, or other neuropsychiatric diseases. All control subjects underwent an annual medical examination including a complete laboratory examination. Results revealed no signs of physical or mental illness. Controls with MMSE scores o24 were excluded. The present study was approved by the Medical Ethics Committee of Juntendo University and was performed in accordance with the regulations outlined by Juntendo University. All participants provided written informed consent after the study had been fully explained.

2.2. Procedures We compared serum DHEA and DHEA-S levels between patients with MDD and matched controls in men and women, respectively. Blood samples were taken at 07:00–08:00, before breakfast, and collected during both the follicular and luteal phases of the menstrual cycle in female patients and controls. Blood was centrifuged immediately after it was drawn and stored at  80 1C until use. We performed single point measurements. Serum levels of DHEA and DHEA-S were all measured at the SRL Laboratory (Tokyo, Japan). For DHEA, a radioimmunoassay (RIA) was used (DPC DHEA, Diagnostic Products Corporation, Los Angeles, CA, USA). For DHEA-S, a chemiluminescent immunoassay (CLEIA) was used (Access DHEA-S, Beckman Coulter KK, Tokyo, Japan). The detection limits for DHEA and DHEA-S were 0.064 ng/ ml and 11 ng/ml, respectively. Inter- and intra-assay coefficients of variation were 10.2 and 9.1% for DHEA, and 10.6% and 7.2% for DHEA-S, respectively.

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converted to imipramine equivalents. Mean scores on the HAM-D in the male and female MDD patients indicated moderate depression.

2.3. Statistical analysis Statistical analysis for serum levels of adrenal hormones was performed using two-way analysis of variance (ANOVA) with diagnosis (MDD vs. controls)  sex (men vs. women) used as variables and a significance level of p o0.05. For post-hoc comparisons within each sex group, data on each serum hormone level between MDD and controls were compared using the twotailed unpaired student t-test. Owing to multiple comparisons and to control the experiment-wise type I error rate across four primary significant tests, each single unpaired t-test was performed using the Bonferroni correction. The level at 0.05/2 ¼0.025 was adopted as a level of significance. Results with significant levels of p o0.10 are reported as trends. Correlations between serum DHEA and DHEA-S levels of patients and controls were assessed in each sex group using Pearson’s correlation coefficients associated with the Bonferroni adjusted p values. In addition, the relationship between serum DHEA and DHEA-S concentrations and HAM-D scores on admission was examined in each sex using Pearson’s correlation coefficients. Multiple regression analysis was conducted using serum hormones as dependent variables and age at onset of depression, number of depressive episodes, duration of last depressive episode, and daily dosage of antidepressants converted to the imipramine-equivalent dose as independent variables. Values are shown as mean 7standard deviation (SD). Statistical procedures were performed using Windows SPSS v15.1 (SPSS Japan Inc., Tokyo, Japan).

3.2. Comparison of serum DHEA, DHEA-s levels Data on hormone levels are shown in Tables 2 and 3. Serum DHEA concentrations were significantly increased in patients compared with controls (po0.001), whereas there were no significant differences in serum DHEA-S levels between patients with MDD and controls (Table 2). Comparison of each serum hormone between men and women in the control group showed that serum levels of DHEA-S (po0.001) were significantly higher in men than in women in the control group; no significant differences were seen for serum DHEA levels (p¼0.168) (Table 3). These findings suggested that gender differences in serum hormonal levels existed in the present study and were consistent with previous reports (Sulcova et al., 1997; Yamaji and Ibayashi, 1969; Tannenbaum et al., 2004; Goldman and Glei, 2007). Thus, the hormonal data of patients with MDD were evaluated separately for men and women (Table 3). In terms of serum DHEA levels, two-way ANOVA revealed a significant main effect for diagnosis (F(1, 214)¼1127.1, p¼0.019). No significant main effects for sex and sex x diagnosis interaction were revealed. Post-hoc analysis by unpaired t-test showed a significant increase of serum DHEA levels in both males (p¼0.004) and females (po0.001). Two-way ANOVA for serum DHEA-S levels showed a significant difference in the sex  diagnosis interaction (F(1, 211)¼13.0, po0.001), whereas no main effect for diagnosis Table 2 Serum hormones levels in patients with MDD and controls.

3. Results N ¼218

3.1. Subject characteristics Participant characteristics are shown in Table 1. No significant differences in mean ages, education years, or presumed IQ between the control and MDD groups in men and women were noted. Moreover, male and female patients with MDD did not differ significantly with respect to age at onset of a first depressive episode, number of depressive episodes, duration of last depressive episode, HAM-D at admission, or daily dosage of antidepressants

DHEA DHEA-S

Controls n¼ 128 Mean (SD)

MDD n¼90 Mean (SD)

2.32 (1.33) 1437.3 (1026.7)

4.01 (3.06) 1288.7 (1208.9)

Two-tailed unpaired student t-test p valuea o0.001 0.253

MDD, major depressive disorder; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; units, ng/ml. a

All patients with MDD vs. all controls.

Table 1 Subject demographics. Men

Age Education Presumed IQ Age of onset Number of depressive episodes Duration of last depressive episode Daily dose of antidepressantd HAM-D Anxiety somatization Cognitive disturbance Retardation Sleep disturbance

Women

Two-tailed unpaired student t-test

N ¼94 Controls n¼ 50 Mean (SD)

MDD n¼44 Mean (SD)

N ¼124 Controls n¼78 Mean (SD)

MDD n ¼46 Mean (SD)

45.9 (16.0) 14.4 (4.4) 103.3 (13.6) NA NA NA NA NA NA NA NA NA

50.7 (13.2) 14.6 (2.5) 103.7 (12.2) 44.9 (14.0) 1.5 (0.7) 12.4 (12.7) 133.5 (72.1) 15.9 (7.7) 4.6 (2.9) 2.2 (2.3) 6.4 (3.5) 1.7(1.5)

49.2 (5.1) 13.0 (3.1) 102.4 (10.4) NA NA NA NA NA NA NA NA NA

51.3 (13.7) 12.4 (2.4) 101.7 (13.0) 47.8 (13.9) 1.8 (1.4) 14.4 (10.6) 131.1 (86.3) 20.3 (8.9) 6.4 (2.9) 2.9 (2.4) 6.6 (3.2) 2.7(1.9)

NS, not significant; NA, not applicable; MDD, major depressive disorder; HAM-D, Hamilton Rating Scale for Depression. a

Male controls vs. female controls. Male patients with MDD vs. male controls. c Female patients with MDD vs. female controls. d Antidepressants were converted into imipramine-equivalent doses. b

p valuea

p valueb

p valuec

NS NS NS

NS NS NS

NS NS NS

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Table 3 Results of serum hormones levels. Men N ¼99

Women N ¼124

Statistical analysis

Controls

MDD

Controls

MDD

2  2 (diagnosis  gender) analysis of variance

n¼ 50

n¼ 44

n¼ 78

n¼ 46

Main effect of diagnosis

Main effect of gender

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

F

F

p value

DHEA levels 2.52 (1.63) 4.22 (3.73) 2.19 (1.08) 3.80 (2.25) 29.089 DHEA-S levels 2209.9 (1208.9) 1504.3 (878.6) 981.7 (512.7) 1082.5 (653.0) 0.568

Interaction

p value F

o0.001 1.550 0.215 0.589 4.014 0.295

0.026 12.965

Two-tailed unpaired student t-test

p value

p valuea p valueb p valuec

0.873 o 0.001

0.168 0.004 o 0.001 0.002

o0.001 0.342

MDD, major depressive disorder; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate. a b c

Male controls vs. female controls. Male patients with MDD vs. male controls. Female patients with MDD vs. female controls.

and sex was observed. By post-hoc analysis using the unpaired t-test, serum DHEA-S levels were significantly decreased in male patients compared with male controls (p¼0.002). In the correlation between serum DHEA and DHEA-S levels in patients with MDD, significant positive correlations were seen between serum concentrations of DHEA and DHEA-S (R¼0.626, po0.001) in male controls, whereas no significant correlations were seen between serum DHEA and DHEA-S levels (R¼0.290) in patients with MDD. In contrast, in female patients, there was a significant positive correlation between serum DHEA and DHEA-S levels in both controls (R¼0.320, po0.001) and patients with MDD (R¼0.509, po0.001). Unlike in male patients, the correlation between serum DHEA and DHEA-S remained significant in female patients. 3.3. Correlations between serum DHEA/DHEA-S and clinical symptoms of depression We found no significant correlations between serum DHEA concentrations or serum DHEA-S concentrations and total and subgroup scores on the HAM-D in patients with MDD. In addition, no significant correlations between serum DHEA/DHEA-S and HAM-D scores were seen in either male or female MDD patients (Table 4). Multiple regression analysis showed that age at onset had a significant negative effect on both serum DHEA (p ¼0.005) and DHEA-S levels (p¼0.008) (Table 5). However, number of depressive episodes, duration of last depressive episode, and imipramine-equivalent daily dosage of antidepressants had no significant effect on serum DHEA/DHEA-S levels. When analyzing separately for men and women, the influence of age at onset was not found on serum DHEA/DHEA-S levels in female patients with MDD. There was a trend for a significant negative effect of number of episodes of depression on serum DHEA-S levels in male patients with MDD (p¼0.088).

4. Discussion The aim of this study was to assess the significance of serum levels of adrenal androgens on depression in male and female patients with MDD separately for men and women. Significant differences in serum hormone levels in the control group between men and women in the present study suggested that a differential analysis of each gender was needed between patients and controls. Thus, data were analyzed separately for men and women. The present study showed a significant increase of serum DHEA levels in both males and females patients with MDD. Supporting evidence for high levels of DHEA has been previously

Table 4 Correlation between hormones and HAM-D scores in MDD subjects a. HAM-D total score All Subjects  0.021 Serum DHEA levels  0.167 Serum DHEA-S levels Men Serum DHEA levels Serum DHEA-S levels Women Serum DHEA levels Serum DHEA-S levels

Anxiety Cognitive somatization disturbance

Retardation Sleep disturbance

0.018

 0.069

0.128

 0.158

 0.194

 0.195

0.032

 0.226

 0.063

0.016

 0.072

0.047

 0.237

 0.194

 0.222

 0.253

 0.004

 0.217

0.121

0.136

 0.034

0.307

0.005

0.081

0.143

0.006

0.151

 0.061

MDD, major depressive disorder; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate. a Correlation between hormones in women subjects was performed using Pearson’s correlation coefficients.

reported in severely depressed patients (Hansen et al., 1982; Heuser et al., 1998; Fabian et al., 2001). However, other studies have found contrasting results that showed a reduction (Michael et al., 2000; Jozuka et al., 2003) or no significant change in DHEA levels in patients with depression compared with controls (Young et al., 2002; Kahl et al., 2006). Circadian variations in DHEA salivary concentrations have been reported to be blunted in adolescents (Goodyer et al., 1996) and adults (Osran et al., 1993) with MDD. Taken together, these studies suggest a possible abnormality in the metabolism of adrenal androgen during the development of depression. Wolkowitz et al. (1997, 1999) showed beneficial effects of DHEA administration on depression. Improvements in specific symptoms, including sadness, guilt, and discouragement, were closely associated with increases in circulating levels of DHEA (Wolkowitz et al., 1997, 1999). Although the pharmacological mechanisms underlying the antidepressant efficacy of DHEA are still undetermined, DHEA has been known to modulate neuronal excitability via its interaction with different

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Table 5 Results of multiple regression analysis. Serum DHEA levels

Serum DHEA-S levels

p value

b

p value

All Subjects Age of onset  0.452 Number of depressive episodes  0.188 Duration of last depressive episode 0.237  0.126 Daily dose of antidepressanta

0.005 0.204 0.114 0.421

 2.802  0.405 0.710  0.299

0.008 0.687 0.482 0.766

Men Age of onset  0.697 Number of depressive episodes  0.299 Duration of last depressive episode 0.261  0.267 Daily dose of antidepressanta

0.015 0.259 0.293 0.306

 0.761  0.464  0.008  0.135

0.009 0.088 0.973 0.599

Women Age of onset Number of depressive episodes Duration of last depressive episode Daily dose of antidepressanta

0.778 0.574 0.719 0.490

 0.059 0.237 0.001  0.082

0.797 0.299 0.998 0.717

b

 0.065  0.128  0.082  0.158

DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate. a

Antidepressants were converted into imipramine-equivalent doses.

neurotransmitter receptors. It has a direct and non-genomic action on membrane-receptors in the brain, and it functions as a neurosteroid. Specifically, DHEA modulates the neural transmission of the GABA-benzodiazepine receptor complex (GABA-BDZ receptor) and the NMDA receptor (Eser et al., 2006; Dubrovsky, 2006). Previous experimental studies have reported that DHEA is a negative non-competitive modulator for the GABA-BDZ receptor and inhibits GABA-induced chloride ion transport currents (Majewska et al., 1990; Demirgoren et al., 1991; Rupprecht and Holsboer, 1999; Spivak et al., 2000). Moreover, DHEA exerts antidepressant effects via its interaction with the sigma 1 receptor, which enhances the neurotransmission of noradrenaline and serotonin (van Broekhoven and Verkes, 2003). Apart from its neurochemical actions, DHEA has a potential anti-glucocorticoid action (Kalimi et al., 1994; Eser et al., 2006; Muller et al., 2006), and administration of DHEA has been reported to decrease plasma cortical levels (Wolkowitz et al., 1999). These previous studies support one plausible mechanism for the antidepressant effects of DHEA, although the exact mechanism in which DHEA antagonizes the effects of cortisol remains unclear. Thus, DHEA’s antidepressant effects are enhanced through noradrenaline and serotonergic neural systems and sigma1 receptors, or by counteracting glucocorticoid actions (Debonnel et al., 1996; Dubrovsky, 2005). Thus, an increase of plasma DHEA levels may be associated with the development of depression. With respect to serum DHEA-S levels, previous studies have shown a significant decrease in serum DHEA-S levels in MDD (Berr et al., 1996; Yaffe et al., 1998; Barrett-Connor et al., 1999; Scott et al., 1999; Ferrari et al., 2004; Markianos et al., 2007). The present study’s results also indicated a reduction in DHEA-S levels in male patients with MDD. However, several reports have shown an increase (Tollefson et al., 1990; Takebayashi et al., 1998; Assies et al., 2004; Hsiao, 2006a) or no change (Bicikova et al., 2000; Erdincler et al., 2004) in serum DHEA-S levels in MDD. Takebayashi et al. (1998) reported that higher levels of plasma DHEA-S and cortisol were observed in depressed patients, and that these levels returned to normal after antidepressant treatment. The reason for the possible decrease in DHEA-S levels in depressed males in our study remains unclear. Previous studies have not examined differences by gender. In our results, a reduction of DHEA-S levels was observed in males with MDD, whereas no significant differences were noted between female depressed patients and controls.

209

Unlike our findings for serum DHEA, sex differences in levels of DHEA-S have been reported previously (Yamaji and Ibayashi, 1969; Zumoff and Bradlow, 1980; Orentreich et al., 1984; Carlstrom et al., 1988; Sulcova et al., 1997; Tannenbaum et al., 2004). Most reports suggest a significantly higher concentration of serum DHEA-S in men compared with women. Potential underlying mechanisms of the sex differences in DHEA-S levels include the lower in vivo cleavage of DHEA-S, the testicular contribution to DHEA-S levels, and high sulfotransferase (SULT)2A1 activity in men (Zumoff and Bradlow, 1980; Carlstrom et al., 1988). In addition, a difference in basal levels of serum DHEA-S, a sex-specific alteration of serum DHEA-S, has been observed in pathological conditions in humans (Jakubowicz et al., 1995; Tilvis et al., 1999; Mazat et al., 2001). Jakubowicz et al. (1995) reported that serum DHEA-S levels were significantly increased with a reduction of body weight in obese men, but not in women. There has also been a stronger association between the DHEA-S levels and morbidity and mortality in men (Tilvis et al., 1999; Mazat et al., 2001). The present study also showed a similar result with a lower level of serum DHEA-S in depressed men only. In addition, there was a trend for a significant negative effect of number of episodes of depression on serum DHEA-S levels in male patients with MDD. Goldman and Glei (2007) reported that lower levels of DHEA-S are associated with increases in depressive symptoms among men, whereas there was no significant association among women. These findings suggest that endogenous DHEA-S levels are related to health outcomes for men, but not women. In addition, correlation analysis showed a different result between male and female patients with MDD. The significant positive correlation between serum DHEA and DHEA-S levels in controls disappeared in male patients with MDD, whereas a significant correlation was observed in both women controls and women MDD patients. This finding may suggest deterioration in the physiological relationship between two adrenal androgens under a depressive condition in men. To the best of our knowledge, a few studies with simultaneous measurement of DHEA and DHEA-S have been reported in depression. Scott et al. (1999) reported a lower serum DHEA-S level, but not DHEA level, in depressed patients who were not receiving any treatment. This finding is, in part, consistent with our results. There was, however, a controversial result with a reduced DHEA level, but not DHEA-S level in patients with major depression (Jozuka et al., 2003). A lack of association of between serum DHEA and DHEA-S levels has been observed in other physical conditions including septic shock (Arlt et al., 2006), systemic lupus erythematosus (Hedman et al., 1989), and drug administration studies (Murakami et al., 1993; Nestler et al., 1994). These findings suggest that DHEA-S levels may not always reflect biological activity of circulating DHEA. Considering our results, data may reflect a downward regulation of activity in DHEA sulfotransferase in tissues regulating the equilibrium between DHEA and DHEA-S in patients with depression, although no specific evidence to support an alteration in the rate of sulfurylation was found. Chabraoui et al. (1991) recommended measuring both DHEA and DHEA-S to better understand their regulation. Sulcova et al. (1997) indicated that DHEA measurements cannot be a substitute for DHEA-S levels and vice versa. Thus, additional studies are required to investigate whether the lack of association of DHEA and DHEA-S occurs in depressed patients. Taken together with our results, serum DHEA-S functions as a biological marker for depression in men only. Although the mechanism of change in serum DHEA-S levels remains unknown, these findings may suggest that DHEA-S plays different physiological roles in men and women. Further studies are needed to examine possible sex differences in DHEA-S secretion and dynamics of the conversion of DHEA-S, which may occur in depressive states.

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Although significant changes in serum DHEA levels were seen in both male and female patients with MDD, and in serum DHEA-S levels of men compared with controls, no significant correlations were observed between serum hormone levels and total and subscores of HAM-D in either men or women. These findings may indicate that serum DHEA/DHEA-S levels are a poor indicator for evaluating the severity of depression, although levels of these hormones are increased in the development of depression. Barrett-Connor et al. (1999) showed a consistent result with our finding concerning the correlation with serum DHEA levels and HAM-D scores. In contrast, Hsiao (2006b) indicated that differences in pre- and post-treatment plasma DHEA levels were significantly and positively correlated with differences in preand post-treatment HAM-D scores following antidepressants, even though they showed a significant increase in DHEA levels in patients with MDD before treatment. In terms of the relationship between serum DHEA-S levels and depressive symptoms, there are controversial results. Some reports showed only DHEA-S levels were significantly and inversely associated with depressed mood, as assessed with the Beck Depression Inventory (Barrett-Connor et al., 1999) and with CES-D scale (Morsink et al., 2007). This finding is interesting, as a decreased DHEA-S level was associated with depressive symptoms. However, Hsiao, 2006a, 2006b found that a significant positive correlation was identified between serum DHEA-S concentrations and the HAM-D anxiety subscale, but not total score. Thus, there were controversial results regarding the correlation between serum DHEA/DHEA-S levels and scores of depressive symptoms. Some possible explanations exist for the conflicting results in previous reports. The first explanation is that age, gender, and HAM-D scores varied among studies. For example, other studies in the literature examined a change of serum hormones in the total number of patients and controls, but not in each gender separately. HAM-D scores in our study also were relatively lower than a previous study (Hsiao, 2006a, 2006b). In patients with more severe depressive symptoms, a significant positive correlation may be revealed. Our previous report (Satomura et al., 2011), however, showed a decrease of serum brain-derived neurotrophic factor (BDNF) level with a significant negative correlation between serum BDNF levels and HAM-D scores in MDD patients who showed a similar severity of HAM-D scores to our patients. Thus, subsequent studies are needed to address these conflicting results. The second plausible explanation is the difference in study designs, including sample size. Our sample size of MDD patients was relatively high, but all patients were treated with antidepressants. These conditions are different from previous reports (Hsiao, 2006a, 2006b). Multiple regression analysis showed that both DHEA and DHEA-S levels were inversely affected by the age of onset with depression. The results have to be considered with caution as longitudinal studies on aging have shown that plasma DHEA/DHEA-S concentrations (Orentreich et al., 1984; Sulcova et al., 1997) have progressively decreased with age. Plasma concentrations of DHEA and DHEA-S peak between the ages of 20 and 30 years in men and 20 and 40 years in women, and decline between the ages of 70 and 80 years (Carlstrom et al., 1988; Sulcova et al., 1997). Thus, the factor of age itself could markedly influence the finding that age at onset with depression was significantly associated with serum levels of DHEA/DHEA-S. In men, but not women, age at onset also influenced serum DHEA-S levels. Glei et al. (2004) showed a pronounced decline in DHEA-S levels with increasing age among men, but virtually no decline above age 60 for women. Such a sex difference in changes of serum adrenal androgens with age may influence our results. Again, additional studies are needed to address the conflicting results found in different studies. The present study has several limitations. First, the sample size was small, which limits the statistical power of the analysis. Second, all patients were treated with antidepressants, which

might have influenced serum levels of the hormones measured. Salek et al. (2002) showed that changes in hormone concentrations of serum DHEA/DHEA-S levels may be related to the remission of depression rather than to a direct effect of the antidepressant, as different changes in serum DHEA/DHEA-S levels have been shown between remitted and non-remitted depressed patients following 12 weeks of antidepressant therapy (Fabian et al., 2001). Hsiao (2006b) showed plasma DHEA levels were significantly decreased from baseline to remission after antidepressant treatment. In addition, a decrease of DHEA-S levels was revealed only in males with depression in the present study, although no significant difference was seen in the daily dosage of antidepressants between men and women. Multiple regression analysis also showed that serum DHEA/DHEA-S levels were not significantly affected by the daily dose of antidepressants. However, the influence of medication on serum DHEA/DHEA-S concentrations cannot be completely denied. Further investigations of drug-naı¨ve patients and follow-up studies will be necessary. Third, the effect of age, sex, and menstrual cycle phase on endogenous pituitary–adrenocortical responsiveness has been reported in humans (Born et al., 1995; Kirschbaum et al., 1999; Keenan et al., 2009). Further research is needed to replicate the findings in this study and to extend our follow-up data with respect to the influence of sex and aging on specific hormone levels. In conclusion, we found a significant increase of serum DHEA levels in both male and female MDD patients compared with controls. Serum levels of DHEA-S were significantly decreased in depressed men only. Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression. However, our findings suggest distinct characteristics for these hormones between men and women with MDD. In addition, no significant correlation was observed between serum hormone levels of DHEA and DHEA-S and HAM-D scores in either men or women.

Conflict of interest All authors declare that they have no conflicts of interest.

Role of funding source This research was supported in part by a grant from the Research Support Foundation of Juntendo Institute of Mental Health.

Acknowledgment This research was supported in part by a grant from the Research Support Foundation of Juntendo Institute of Mental Health.

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