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Keywords:

  • anxiety severity;
  • depression severity;
  • DHEAS;
  • Hamilton depression score;
  • Hospital Anxiety and Depression Scale

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Abstract  Although numerous studies have identified a correlation between dehydroepiandrosterone sulfate (DHEAS) levels and anxiety or depression, those findings remain controversial. The purpose of the present study was to determine whether a correlation exists between depression severity and anxiety severity and serum DHEAS concentrations in medication-free patients experiencing a major depressive episode. Twenty-eight medication-free major depressive outpatients (Hamilton Rating Scale for Depression 17 [HAM-D 17] score ≥17) were enrolled consecutively. Plasma DHEAS levels of all subjects were measured. Blood from subjects was drawn at 0900–1100 h Depression severity was assessed with the HAM-D 17 and the Hospital Anxiety and Depression Scale (HADS) depression subscale. Anxiety was assessed using the HADS anxiety subscale. Serum concentrations of DHEAS were measured immediately following the HAM-D 17 and HADS assessments. A significant, positive correlation was identified between HADS anxiety subscale total score and morning serum DHEAS concentration (P = 0.013) after controlling for age, gender and body mass index (BMI). No statistically significant correlations were found between depression ratings and morning serum DHEAS concentrations. This preliminary study provides pilot data indicating that morning serum DHEAS concentrations were positively correlated with HADS anxiety subscale score (anxiety severity) after controlling for age, gender and BMI in medication-free outpatients experiencing a major depressive episode. It is not known if morning serum DHEAS levels would show similar or dissimilar changes in non-depressed subjects. The present result needs subsequent replication.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

A number of studies have demonstrated a correlation between depression and anxiety in humans and some sexual steroid hormones, such as dehydroepiandrosterone (DHEA),1 dehydroepiandrosterone sulfate (DHEAS), estrogen and progesterone, but the findings are still controversial.2–4 Dehydroepiandrosterone sulfate is a neuroactive steroid created by the brain and adrenal glands.5,6 Although a number of studies indicated that DHEAS could result in persistent anxious and depressive symptoms, other studies obtained contrary findings.2,7–9 The purpose of the present preliminary study was to determine whether a correlation exists between morning serum DHEAS concentrations and anxiety or depression severity in patients experiencing major episodes of depression.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Subjects

The Ethics Committee of Chang Gung Memorial Hospital approved this study. The benefits and possible side-effects of this trial were explained to each recruited subject. Each enrolled subject signed a written consent form.

Medication-free outpatients who met the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th edition; DSM-IV), for major depressive disorders were consecutively enrolled. Medication-free patients were defined as follows: (i) patients who had not taken illegal drugs and who had no alcohol dependence or abuse within 6 months prior to the study; (ii) patients not taking fluoxetine, risperidole consta, clozapine and apripirazole within 4 weeks prior to the study; (iii) patients not taking antipsychotics, antidepressants, alprazolam, carbamazepine, diltiazem, insulin, metformin, morphine, or valproate therapy within 2 weeks prior to the study;10–12 (iv) patients who did not undergo DHEA or DHEAS therapy, hormone replacement therapy (HRT) or who had taken birth control pills within 2 weeks prior to the study; and (v) patients who did not receive electroconvulsive therapy (ECT) within 24 weeks prior to the study.13

A final inclusion criterion was total score ≥17 on the Hamilton Rating Scale for Depression 17 (HAM-D 17).14 Then the same psychiatrist using the structured Mini-International Neuropsychiatric Interview (MINI),15,16 which is a short structured diagnostic interview for DSM-IV psychiatric disorders used to eliminate other psychopathologies, interviewed each subject.

Exclusion criteria were as follows: (i) pregnancy, suspected pregnancy, or nursing; (ii) bipolar disorder or schizophrenia; (iii) history or presence of clinically significant hepatic, cardiovascular, or renal disease, diabetes or any other serious medical condition that might compromise the survey; (iv) history or presence of a bipolar disorder or a significant Axis II disorder that would interfere with survey participation; (v) history or presence of any psychotic disorder, including psychotic depression; and (vi) history or presence of any organic mental disorder.

Design

Depression severity of the subjects was assessed using the HAM-D 17 and Hospital Anxiety and Depression Scale (HADS) depression subscale.17 Anxiety severity was then measured using the HADS anxiety subscale. Their serum DHEAS levels were determined immediately following the HAM-D 17 and HADS assessments. Blood from subjects was drawn at 0900–1100 h.

Outcome measures

A radioimmunoassay technique using a commercially available kit (DSL-2700, Webster, TX, USA) was utilized to measure DHEAS levels; intra- and interassay variation coefficients were both <10%.

Statistical analyses

Continuous variables were compared using Student’s t-test or paired-samples t-test and correlated utilizing partial correlation. Categorical variables were compared using the χ2 test. Two-tailed P < 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Table 1 presents demographic, depression and anxiety ratings, and morning plasma DHEAS levels for the 28 enrolled patients. Of the 28 patients, nine were male and 19 were female (mean age, 33.2 ± 10.6 years; range, 18–54 years). Mean body mass index (BMI) was 23.1 ± 4.9 kg/m2 (range, 6.6–33.2 kg/m2). Mean duration of depression was 5.9 ± 7.1 months (range, 0.5–24 months). Thirteen subjects were diagnosed with their first major depressive episode and 15 subjects were diagnosed with depression recurrence.

Table 1.  Clinical details for 28 outpatients experiencing a major episode of depression
 Mean ± SDRange
  1. BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; HADS, Hospital Anxiety and Depression Scale; HAM-D 17, 17-item Hamilton Rating Scale for Depression.

Age (years)33.2 ± 10.618–54
Gender
 Male 9 
 Female19 
BMI (kg/m2)23.1 ± 4.96.6–33.2
Duration of depression (months)5.9 ± 7.10.5–24
Mean morning plasma DHEAS levels (ng/mL)1540.0 ± 1107.0323–4757
Mean HAM-D 17 total score26.6 ± 5.817–39
Mean HADS depression subscale total score11.7 ± 4.91–20
Mean HADS anxiety subscale total score12.5 ± 3.63–19
Mean HADS total score24.2 ± 7.76–36

Mean plasma DHEAS level was 1540.0 ± 1107.0 ng/mL. Mean HAM-D 17 total score was 26.6 ± 5.8; mean HADS depression subscale total score was 11.7 ± 4.9; mean HADS anxiety subscale total score was 12.5 ± 3.6; mean HADS total score was 24.2 ± 7.7. On independent-sample t-test, no significant difference existed between male and female subjects for plasma DHEAS levels (t = 0.202; P = 0.842), HAM-D 17 total score (t = −0.129; P = 0.899), HADS total score (t = −0.373; P = 0.713), HADS depression subscale total score (t = −0.616; P = 0.547) and HADS anxiety subscale total score (t = 0.098; P = 0.923). No significant difference existed for the following variables between subjects diagnosed with first-time major depressive episode and subjects diagnosed with recurring depression: plasma DHEAS levels, t = −0.373; P = 0.689; HAM-D 17 total score, t = 0.432; P = 0.670; HADS total score, t = −1.077; P = 0.292; HADS depression subscale total score, t = −1.142; P = 0.264; and, HADS anxiety subscale total score, t = −0.747; P = 0.462. After controlling for age, gender and BMI, no significant correlation was identified between plasma DHEAS levels and HAM-D 17 ratings score (r = 0.111; P = 0.599), HADS ratings score (r = 0.275; P = 0.184), HADS depression subscale score (r = 0.096; P = 0.649), or the scores for HAM-D 17 items. Additionally, no significant correlation was observed between plasma DHEAS levels and duration of depression after controlling for age, gender and BMI (r = 0.102; P = 0.629).

Table 2 shows the correlations between depression severity, anxiety severity and plasma DHEAS level. A significant and positive correlation existed between HADS anxiety subscale total score and morning plasma DHEAS concentration (r = 0.491, P = 0.013; Fig. 1) after controlling for age, gender and BMI.

Table 2.  Correlations for 28 outpatients experiencing a major episode of depression after controlling for age, gender and body mass index
 HAM-D17 total scoreHADS depression subscale total scoreHADS anxiety subscale total scoreHADS total score
  • DHEAS, dehydroepiandrosterone sulfate; HADS, Hospital Anxiety and Depression Scale; HAM-D 17, 17-item Hamilton Rating Scale for Depression.

  • *

     P < 0.05.

Morning plasma DHEAS level (ng/mL)r = 0.111r = 0.096r = 0.491r = 0.275
P = 0.599P = 0.649P = 0.013*P = 0.184
image

Figure 1. Correlations between Hospital Anxiety and Depression Scale (HADS) anxiety subscale total score and morning plasma dehydroepiandrosterone sulfate (DHEAS) levels of 28 outpatients experiencing a major episode of depression after controlling for age, gender and body mass index.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

This preliminary study provides pilot data indicating that morning serum DHEAS concentrations were positively correlated with HADS anxiety subscale score (anxiety severity) after controlling for age, gender and BMI in medication-free outpatients experiencing a major depressive episode. Some studies have demonstrated that DHEAS could result in anxious symptoms; however, other studies obtained contrary findings.2,9 An animal study suggested that elevated brain cortical DHEAS can result in anxiety in ovarectomized rats.18 Spivak et al. determined that plasma DHEAS levels were elevated in male patients with combat-related post-traumatic stress disorders.9 Paoletti et al. proposed that DHEAS is an anxiety-inducing steroid.19 In the central nervous system (CNS), some studies showed that DHEAS has mildly agonistic activity at gamma-aminobutyric acid-A (GABA-A) receptors but most studies showed that DHEAS has antagonistic activity at GABA-A receptors; such regulation of the central GABA-A receptors by DHEAS can result in anxiety symptoms.6–9,20,21 However, other studies showed that DHEAS has anxiolytic and antidepressant effects via several plausible mechanisms, for example antagonistic activity on N-methyl D-aspartate receptors, enhancement of serotonin neurotransmission, counteracting glucocorticoid actions, and agonistic action on sigma 1 receptors.2

Although no correlation was found between depression severity and morning plasma DHEAS concentrations in patients experiencing a major episode of depression in the present study, the results of other studies suggest that DHEAS is associated with depression.13,22–24 Maayan et al. found that high basal levels of DHEAS play a role in the resistance to electroconvulsive shock and perhaps ECT in depressed humans.13 T’Sjoen et al. examined 236 men (aged >70 years) in a community-based sample in 1977, and determined that higher Geriatric Depression Scale (GDS) scores were related to higher DHEAS levels.24 Barrett-Connor et al., who examined 699 women (aged 50–89 years) in a community-based sample, determined that DHEAS levels were inversely correlated with depressive symptoms.23 A study of 394 randomly selected community-dwelling women >65 years by Yaffe et al. obtained results similar to those obtained by Barrett-Connor et al.22,23

Several possible explanations exist for the conflicting results in the literature. The first likely explanation is that patient age and/or gender varied among studies. Several studies confirmed age- and gender-based differences and an age-related decline in DHEAS concentrations.25–27 The age range of subjects in the present study was young for severe depression because only medication-naive depressive patients were enrolled. After controlling for BMI, age and gender, the present study has demonstrated that morning DHEAS plasma concentrations were significantly and positively correlated with HADS anxiety subscale total score. The second reason for the differing results is that some medications can be correlated with altered DHEAS concentrations.10,11 Subjects on antipsychotics, antidepressants, anxiolytic, mood stabilizers, diltiazem, insulin, metformin, and morphine were excluded in the present study, but not in other studies.10,11 Third, visceral fat and medical conditions, such as diabetes, can be correlated with altered DHEAS concentrations.11,26,28,29 Visceral fat is associated with hypothalamic–pituitary–adrenocortical (HPA) hyperactivity.29 Fourth, smoking can influence the HPA-axis activity, but some studies demonstrated that DHEA and DHEAS levels in smokers and non-smokers did not differ.30 Most previous studies, including the present study, did not control for all morbid medical conditions, visceral fat or smoking.

The present study had several methodological limitations. First, sample size was small. Second, DHEAS plasma levels in non-depressed subjects were not measured. Such data can help clarify whether low plasma DHEAS levels are linked to diagnosis. Third, no objective assessments of anxiety severity other than HADS anxiety subscale, such as the Hamilton Rating Scale for Anxiety, were used.31 Fourth, this study lacked control for waist circumference (WC); this shortcoming can confound study results. WC, a proxy for visceral fat, should be measured because visceral fat is associated with HPA hyperactivity.29,32 Fifth, the present study did not measure cortisol. Ferrari et al. found an elevated cortisol-DHEAS ratio in drug-free depressed patients.33

This preliminary study provides pilot data indicating that morning serum DHEAS concentrations were positively correlated with HADS anxiety subscale score (anxiety severity) after controlling for age, gender and BMI in medication-free outpatients experiencing a major depressive episode. It is not known if morning serum DHEAS levels would show similar or dissimilar changes in non-depressed subjects. The result needs subsequent replication. Furthermore, clarifying the specific characteristics of DHEA and DHEAS regulation in depressed patients is also likely to be critical to an improved understanding of the possible beneficial effects of DHEA and DHEAS treatments in this patient group.2

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The authors would like to thank Chih-Ken Chen, MD, PhD, for his valuable discussions on statistical analysis, and technical writing instructor Ted Knoy, National Chiao Tung University, for his valuable revisions.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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