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Aims: Alterations in cortisol and dehydroepiandrosterone sulfate (DHEA-S) levels are thought to play a role in the pathophysiology of neuropsychiatric disorders, including schizophrenia. The aim of this study was to investigate the role of serum cortisol and DHEA-S in the pathophysiology of schizophrenia.
Methods: Sixty schizophrenic patients, 70 healthy first-degree relatives, and 60 healthy volunteers were included. Sociodemographic characteristics, data regarding disease duration and severity, as well as ongoing and previous drug use were recorded. Serum cortisol and DHEA-S levels were measured.
Results: Serum cortisol and DHEA-S levels were significantly higher in the schizophrenia group compared with the first-degree relatives and controls (P < 0.05). Serum cortisol levels in the first-degree relatives were significantly higher than in the healthy controls (P < 0.05). There was no significant difference between the first-degree relatives and healthycontrols in terms of DHEA-S levels and between the three groups in terms of serum cortisol/DHEA-S ratios.
Conclusions: Elevated serum cortisol levels in schizophrenic patients might be associated with the role of cortisol in the pathophysiology of schizophrenia. Also, the elevation of serum cortisol levels in first-degree relatives compared to controls suggests that similar pathophysiological processes might have a role in individuals without any disease symptoms, but with a genetic predisposition for schizophrenia. Elevated serum DHEA-S levels might be the result of a compensatory response to elevated cortisol levels. Serum cortisol and DHEA-S levels may be used as a biological marker for the diagnosis of schizophrenia; however, further studies with larger sample sizes are warranted to support this finding.
HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) axis abnormalities play a key role in the cause and pathogenesis of many psychiatric disorders.1 The neuroendocrinologic system, particularly the HPA axis, has been a focus of interest for neurobiological studies aiming at elucidating the cause of schizophrenia.2 HPA axis abnormalities have been demonstrated by impaired adrenocorticotropic hormone (ACTH) and cortisol responses on the dexamethasone suppression test.3 Impaired HPA axis in schizophrenic patients has been suggested to be associated with abnormalities in enzyme and neurotransmitter systems involved in HPA axis regulation and/or structural abnormalities in the limbic system.4
HPA axis abnormalities may cause an increase in the baseline cortisol level. It has been demonstrated that serum baseline cortisol levels are increased in schizophrenic patients;2,5 however, there are also other studies with contrary findings.6 It has been reported that in addition to impaired HPA axis, symptoms such as stress, anger, and introversion7,8 or anti-psychotic drugs used during treatment9 may be associated with abnormalities in cortisol levels of schizophrenic patients.
Dehydroepiandrosterone sulfate (DHEA-S) is a neuroactive steroid interacting with N-methyl d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors.10 DHEA-S and DHEA both bind to sigma receptors that act as ion channels and modulate neuronal excitability and plasticity. Owing to these characteristics, these receptors serve as neuroprotective agents.11 In addition to being a neuroactive steroid, DHEA-S may also play a role in psychiatric disorders via its anti-glucocorticoid effect.12 Moreover, DHEA-S has a neuroprotective role against glutamate-induced neurotoxicity, and protects hippocampal cells from oxidative stress-induced damage via this mechanism.13
Strous and colleagues found that DHEA-S levels were significantly higher in schizophrenia patients compared with healthy controls and this result suggests that individuals in their first-episode of schizophrenia psychosis may develop a neurosteroid response to the first onset of psychosis.14 Thus, the aim of the current study was to investigate the role of serum cortisol and DHEA-S in the physiopathogenesis of schizophrenia by determining the serum cortisol and DHEA-S levels, as well as serum cortisol : DHEA-S ratios of schizophrenic patients, and their first-degree relatives.
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The mean age of schizophrenic patients (n = 60) was 36.31 ± 9.49 years, the mean age of first-degree relatives (n = 70) was 39.30 ± 11.00 years, and the mean age of the control group (n = 60) was 37.30 ± 9.94 years. The sociodemographic characteristics of the study groups are presented in Table 1.
Table 1. Sociodemographic characteristics of the study groups
| ||Schizophrenic patients (n = 60)||First-degree relatives (n = 70)||Controls (n = 60)|
|Age (years), mean ± SD||36.31 ± 9.49||39.3 ± 11.0||37.30 ± 9.94|
|Sex, n (%)|| || || |
| Female||29 (48.3)||31 (44.3)||30 (50.0)|
| Male||31 (51.7)||39 (55.7)||30 (50.0)|
|Marital status, n (%)|| || || |
| Married||35 (58.3)||43 (61.4)||38 (63.3)|
| Single||20 (33.3)||23 (32.9)||19 (31.7)|
| Divorced||4 (6.7)||2 (2.9)||3 (5.0)|
| Widowed||1 (1.7)||2 (2.9)||–|
|Educational status, n (%)|| || || |
| None||1 (1.7)||6 (8.6)||2 (3.3)|
| Primary||16 (26.7)||16 (22.9)||19 (31.7)|
| Secondary||13 (21.7)||12 (17.1)||6 (10.0)|
| High school||16 (26.7)||20 (28.6)||19 (31.7)|
| College/University||14 (23.3)||16 (22.9)||14 (23.3)|
There were no significant differences between the study groups in terms of sex, marital status, and educational levels.
The mean disease duration was 9.1 ± 3.2 years. Paranoid type schizophrenia was noted in 35 patients (58.3%), disorganized type in eight patients (13.3%), undifferentiated type in 12 patients (20.0%), and residual type in five patients (8.3%). Eleven patients (18.31%) were not receiving any medical treatment. The mean BPRS score of the patients was 18.0 ± 5.4.
The mean serum cortisol level was 428.15 ± 39.60 nmol/L in the schizophrenia group, 372.71 ± 34.71 nmol/L in the first-degree relatives, and 295.03 ± 31.03 nmol/L in the control group. Serum cortisol levels were significantly higher in the schizophrenia group as compared to the other two groups (P < 0.05). Serum cortisol levels in the first-degree relatives were significantly higher than the healthy controls (P < 0.05; Fig. 1). The optimal cut-off value of cortisol to predict diagnosis of schizophrenia was found as >375.22, with 65% sensitivity and 57.1% specificity (AUC 0.622, 95% confidence interval 0.533–0.705) (Fig. 2a).
Figure 2. Receiver operator characteristic (ROC) curves for (a) cortisol and (b) dehydroepiandrosterone sulfate (DHEA-S) to predict diagnosis of schizophrenia.
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The mean serum DHEA-S level was 7605.56 ± 732.75 nmol/L in the schizophrenia group, 6059.44 ± 591.43 nmol/L in the first-degree relatives, and 5166.51 ± 510.46 nmol/L in the control group. Serum DHEA-S levels were significantly higher in the schizophrenia group as compared to the other two groups (P < 0.05). There were no significant differences between the first-degree relatives and healthy controls in terms of serum DHEA-S levels (Fig. 3). Optimal cut-off value of DHEA-S to predict diagnosis of schizophrenia was found as >3457.64, with 83.3% sensitivity and 35.7% specificity (AUC 0.597, 95% confidence interval 0.507–0.682) (Fig. 2b).
The mean serum cortisol : DHEA-S molar ratio was 0.098 ± 0.152 in the schizophrenia group, molar ratio was 0.104 ± 0.108 in the first-degree relatives, and molar ratio was 0.078 ± 0.064 in the control group. There were no significant differences between the three groups in terms of serum cortisol : DHEA-S ratios.
There was no significant correlation of serum cortisol and DHEA-S levels, and serum cortisol : DHEA-S ratios with disease duration and severity in the schizophrenia group. The serum cortisol, DHEA-S levels, and serum cortisol : DHEA-S ratios were not significantly different according to sharing the same home or not, taking antipsychotic treatment or not and between schizophrenia types.
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Recently, studies on schizophrenia have increasingly focused on potential causative factors, such as structural and functional brain abnormalities. The assumption that alterations in cortisol and DHEA-S levels may have a role in changes in clinical presentation of several neuropsychiatric disorders, including schizophrenia, has been emphasized.
Controversial results have been found in studies investigating serum cortisol and DHEA-S levels and the underlying mechanism for changes in serum cortisol and DHEA-S levels in schizophrenia have not been fully elucidated. Zhang et al.18 suggested that the discrepancy in results between studies might have resulted from differences in tested material, sampling of patients at different stages of disease progression, the effects of anti-psychotic drugs on cortisol levels, and the effects of other accompanying metabolic or endocrine disorders. In an attempt to eliminate these factors, we paid special attention to ensure a stable dose regimen for the last 2 months in schizophrenic patients on anti-psychotic treatment, to also include patients without anti-psychotic treatment in the schizophrenia group, to include schizophrenic patients without any active psychotic symptoms, to obtain blood samples at the same time of day in all groups, as well as to exclude individuals with any medical or endocrine disorders. Patients receiving benzodiazepines or any estrogen-containing drugs affecting cortisol levels were excluded from the study.
In some studies, serum cortisol levels have been shown to be increased in schizophrenic patients compared to healthy controls; however, it has been reported that this increase is not directly associated with the pathophysiology of schizophrenia.3,19 Some studies have suggested that elevated serum cortisol levels are associated with the negative symptoms of the disease.7,8 In contrast, Walder et al.5 and Kaneko et al.2 reported that elevated cortisol levels were associated with the positive symptoms of the disease. There are also studies reporting no significant differences between the schizophrenic patients and healthy controls in terms of cortisol levels.6,20 In another study, cortisol, androgen, and estrogen levels of paranoid schizophrenia patients, whose drugs were discontinued for 2 weeks, were compared with controls and no significant differences were noted.21 Serum cortisol levels in the schizophrenia group were significantly higher than both first-degree relatives and controls in the current study, while no such difference was noted between patients with different types of schizophrenia. Our patient group consisted of both schizophrenic patients with and without anti-psychotic treatment, and anti-psychotic drug use was not associated with cortisol levels.
Gallagher et al. examined cortisol and DHEA levels over multiple time-points and reported that cortisol levels were significantly elevated in both patient groups compared with controls. However there was no evidence of a difference in the cortisol : DHEA ratio of the groups, despite an elevation in DHEA levels in schizophrenic patients compared with bipolar patients and controls.22 They concluded that an elevation in DHEA levels may represent a specific endocrine marker in schizophrenia. Di Michele and colleagues found significantly higher plasma DHEA plasma levels in schizophrenic subjects compared with healthy controls and non-significant correlation between DHEA plasma levels and psychopharmacological treatment dosages, suggesting that DHEA may have some role in the pathophysiology of schizophrenia.23
In agreement with our findings, it has been shown in many studies that serum cortisol levels are increased in schizophrenic patients.2,5 In contrast to previous studies, we also measured cortisol levels in the first-degree relatives of the patients. It is well known that genetic factors have a role in the cause of schizophrenia and family history is the most significant risk factor for schizophrenia.24 Significantly higher serum cortisol levels in the first-degree relatives compared to the healthy control group might be associated with the hereditary nature of the disease. It has been reported that various clinical conditions related to schizophrenia and anti-psychotic drugs may affect hormone levels.9 Contrary to this theory, we did not find an association of hormone levels with disease duration and severity, and anti-psychotic drug use. In comparison with the control group, higher serum cortisol levels in the first-degree relatives, who did not have any disease symptoms and were not receiving anti-psychotic treatment, but had a genetic predisposition for schizophrenia, suggested that physiopathologic processes leading to hypercortisolemia might originate from this shared genetic background. These findings supported the hypothesis that hypercortisolemia might play a role in the physiopathology of schizophrenia and might be used as a diagnostic biological marker. On the other hand, cortisol levels may be used as a predictive marker for schizophrenia in first-degree relatives of schizophrenic patients; however, further large-scale studies are warranted to support this finding.
It has been shown that DHEA-S is associated with cognitive functions and it has been proposed that DHEA-S may have a role in the physiopathology of schizophrenia.25,26 While a decrease in the DHEA-S level has been associated with cognitive impairment in some studies,27 Morrison et al.28 associated cognitive impairment with elevated DHEA-S levels. In a study in which patients received DHEA for the treatment of schizophrenia, it was demonstrated that elevated serum DHEA-S levels were associated with the level of disease improvement.29 As we did not find a significant correlation of serum DHEA-S levels with disease duration and severity, we concluded that the serum DHEA-S level might have increased in order to reduce the negative effects of increased cortisol, as previously suggested by Van Broekhoven et al.12
Ritsner et al.6 reported that serum cortisol : DHEA-S ratios in schizophrenic patients were higher compared to healthy controls. However, in that particular study, the authors did not compare patients with different types of schizophrenia. They associated elevated serum cortisol : DHEA-S ratios in schizophrenic patients with anxiety, anger, and hostility. It has been reported in some studies that elevated serum cortisol : DHEA-S ratios are directly proportional to disease duration in patients with schizophrenia and depression.6,30 There were no significant differences between schizophrenic patients, their first-degree relatives, and controls in terms of serum cortisol : DHEA-S ratios in the current study. There were no significant differences between patients with different types of schizophrenia in terms of cortisol : DHEA-S ratios. There was no correlation of serum cortisol : DHEA-S ratios with disease duration and severity. Moreover, absence of a difference between medicated/unmedicated patients and also difference among subtypes of schizophrenia may simply be the result of small sample sizes in our study rather than the true absence of a difference.
In order to minimize the diurnal variation in cortisol levels, we obtained the blood samples at the same time of the day from all subjects in our study. The HPA axis displays robust circadian variation throughout its hierarchical levels, from ACTH to glucocorticoids.31 Glucocorticoids are essential for the maintenance of homeostasis and enable the organism to prepare for, respond to and manage stress, either physical or emotional. Cortisol, the principal glucocorticoid in humans, is synthesized in the adrenal cortex. It is released into the circulation in a pulsatile and circadian pattern.32 But the hormones like cortisol and DHEA-S in our study were determined at a single time-point. This investigation method is a limitation of our study, along with a lack of looking at the potential confounding effects of body mass index or prolactin levels. However, measurement of cortisol in consecutive blood samples obtained at different times of day can also provide further insight to the physiopathologic process because cortisol is released at varying levels throughout the day.
The environmental factors may affect the serum cortisol and DHEA-S levels and it has been shown that massive stress may activate the HPA axis.33,34 Furthermore, Young et al. showed that the HPA profiles of the symptomatic parents and their children were not different.35 In our study, the serum cortisol and DHEA-S levels of first-degree relatives did not significantly change with sharing the same home or not. Thus, we believe that stress as a result of relatives sharing the same environment with schizophrenia patients did not affect the results of our study.
In conclusion, elevated serum cortisol levels in schizophrenic patients might be associated with the role of cortisol in the physiopathology of schizophrenia. Elevated serum cortisol levels in first-degree relatives might be associated with the hereditary nature of schizophrenia. This finding suggests that similar physiopathologic processes occurring in the same genetic background might have a role in this increase. Elevated serum DHEA-S levels might have occurred as a compensatory response to elevated cortisol levels. Serum cortisol and DHEA-S levels may be used as a biological marker for the diagnosis of schizophrenia; however, further studies with larger sample sizes are warranted to support this finding.