Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients

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Abstract

Dehydroepiandrosterone (DHEA) and its sulfate derivative DHEA-S are neurosteroids, produced in the brain, and neuroactive steroids, produced in the adrenals and affecting the brain. We compared the ratios of serum cortisol/DHEA or DHEA-S in schizophrenia patients with normal subjects, and determined the correlation of these ratios with psychopathology and distress. Early morning plasma concentrations of DHEA, DHEA-S, and cortisol were determined by radioimmunassay in 40 medicated schizophrenia inpatients, and 15 healthy subjects with similar age and sex distribution. Subjects were assessed for psychopathology using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS), anxiety, anger, emotional and somatic distress levels. Schizophrenia inpatients demonstrated significantly higher levels of state and trait anxiety, anger expression index, emotional and somatic self-reported distress scores. Cortisol/DHEA and cortisol/DHEA-S ratios were significantly higher in schizophrenia patients than in healthy comparison subjects. Both ratios correlated positively with age and duration of illness; cortisol/DHEA-S ratio also showed positive association with age of illness onset. When age, illness duration and age of onset were controlled, cortisol/DHEA-S ratio significantly correlated with severity of depression (MADRS, r=0.33, p=0.048), state and trait anxiety (r=0.43, p=0.008 and r=0.40, p=0.014, respectively), trait anger (r=0.41, p=0.012), angry temperament (r=0.46, p=0.004), anger expression index (r=0.36, p=0.033), and hostility (r=0.42, p=0.010). No significant association was found between these ratios and severity of psychopathology, and type or dosage of antipsychotic agents. Thus, elevated cortisol/DHEA and/or cortisol/DHEA-S ratios in schizophrenia patients are positively associated with higher scores for anxiety and anger, depression and hostility, age and age of onset/duration of illness, but are independent of severity of psychopathology (PANSS) and antipsychotic treatment.

Introduction

Both clinical and biological data indicate that schizophrenia patients are impaired in their biological response to stress Nuechterlein et al., 1994, Walker and Diforio, 1997, Jansen et al., 2000. This is associated with dysregulated hypothalamic–pituitary–adrenal (HPA) axis (Jakovljevic et al., 1998), and a blunted cortisol response to the stress of speaking in public Jansen et al., 1998, Jansen et al., 2000.

Dehydroepiandrosterone (DHEA) is a major circulating steroid and serves as a precursor for both androgenic and estrogenic steroids. Its sulfated form (DHEA-S) is the most abundant steroid found in the body Baulieu and Robel, 1996, Kroboth et al., 1999. It is considered both a neurosteroid, being produced in the brain, as well as a neuroactive steroid, produced in the adrenals and having its effect on the brain (Baulieu and Robel, 1996). The synthesis of DHEA requires only two steroid-metabolizing enzymes: cholesterol side-chain cleavage enzyme (CYP11A1) and 17α-hydroxylase/17,20 lyase (CYP17). DHEA sulfotransferase (SULT2A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2)—determines the capacity of the human adrenal to produce DHEA-S (Rainey et al., 2002). Brain DHEA(S) (Corpechot et al., 1981) levels exceed their respective concentrations in plasma. The neurosteroidogenesis in the brain is independent of the peripheral production; brain DHEAS was not influenced by adrenal stimulation or inhibition with adrenocorticotropic hormone (ACTH) or dexamethasone, respectively, and increased 2 days after the stressful event of adrenalectomy and orchiectomy (Corpechot et al., 1981). Although most of the biochemical pathways involved in the synthesis of neurosteroids in brain and periphery have been identified, the mechanisms that regulate the activity of the neurosteroid-producing cells are still largely unknown. Progress in defining the mechanisms that regulate DHEA(S) production has been hampered because adrenal secretion of DHEA(S) is absent or low in all mammals except primates (Rainey et al., 2002). It has been shown in the brain that GABA, by activating the GABAA receptor complex, inhibits the activity of neurosteroidogenic enzymes (Do-Rego et al., 2000). Recently, advances have been made in understanding the neuroactive role of DHEA and DHEA-S in the central nervous system Arlt et al., 2000, Stoffel-Wagner, 2001. Since DHEA has memory-enhancing effects Roberts et al., 1987, Flood et al., 1992, Migues et al., 2002, it has been hypothesized that DHEA has neuroprotective effects on cognition (Wolf and Kirschbaum, 1999) and that its age-related decline may be related to declining cognitive function associated with age in the elderly. These neurosteroids exhibit a variety of properties including anti-stress properties Hu et al., 2000, Boudarene and Legros, 2002 and reduction of neurodegeneration Majewska, 1992, Lapchak and Araujo, 2001. More specifically, DHEA and DHEA-S may act as an endogenous restraint against corticosterone: DHEA-S blocks the neurotoxic effects of corticosterone on hippocampal cells (Kimonides et al., 1999). DHEA also protects neurons against glutamate and beta amyloid–protein toxicity (Cardounel et al., 1999), excitatory amino acid-induced neurotoxicity (Kimonides et al., 1998), and numerous other insults resulting in oxidative stress. In addition to antiglucocorticoid actions, DHEA and DHEA-S increase neuronal excitability, enhance neuronal plasticity and appear to have antagonistic effects on central gamma-aminobutyric acid (GABA) mechanisms (Majewska, 1992), its increase the number of NMDA receptors in rat brain (Wen et al., 2001). Previous studies have shown that levels of these hormones may be associated with feelings of “well-being” and enjoyment of “leisure” activities (Johnson et al., 2002), although we found elevated DHEA, DHEA-S and cortisol circulatory levels in severely depressed patients compared to controls (Maayan et al., 2000).

DHEA and DHEA-S are mainly synthesized in the adrenal gland and their levels decrease markedly with age(Morley et al., 1997) particularly in post-menopausal women (Skalba et al., 2003), along with the attenuated activity of the adrenal gland. The levels in elderly populations are reduced to 20% to 30% of peak levels in young adulthood Orentreich et al., 1992, Labrie et al., 1997, Nafziger et al., 1998. The developmental and age-related changes in DHEA(S) are not paralleled by any other steroid hormone, suggesting that the mechanisms regulating DHEA(S) formation are unique (Rainey et al., 2002). Among a non-clinical sample of 46 men aged 62–76, higher morning cortisol/DHEA ratio is associated with higher anxiety (r=0.46; p=0.004; (van Niekerk et al., 2001). Low levels of DHEA are also associated with Alzheimer's disease and multi-infarct dementia (Hillen et al., 2000).

Depressed patients showed significantly higher values of plasma DHEA-S and cortisol Takebayashi et al., 1998, Heuser et al., 1998, and higher cortisol/DHEA ratios than controls Goodyer et al., 1996, Michael et al., 2000, Young et al., 2002. Reported findings demonstrate increased morning plasma levels of DHEA and DHEA-S in untreated chronic combat-related PTSD (Spivak et al., 2000) and in anorexic and bulimic patients (Monteleone et al., 2001). Previous studies investigating DHEA blood levels in psychosis have demonstrated low DHEA levels Tourney and Hatfield, 1972, Oertel et al., 1974 observed by some particularly in the morning, (Tourney and Erb, 1979), higher DHEA-S levels in males (Oades and Schepker, 1994) as well as abnormal DHEA diurnal rhythms (Erb et al., 1981) and no differences in DHEA levels (Brophy et al., 1983).

In the presence of normal cortisol levels, a low DHEA level could result in functional hypercortisolaemia (Goodyer et al., 1996). As there is a wide interindividual variability in plasma DHEA-S levels (Thomas et al., 1994), cortisol/DHEA(S) ratios are more informative than DHEA(S) values alone Hechter et al., 1997, van Broekhoven and Verkes, 2003. To the best of our knowledge, no study has been conducted assessing the cortisol/DHEA-S and/or cortisol/DHEA ratios among schizophrenia patients in comparison to healthy controls. One could speculate that if biological response to stress is impaired among schizophrenia patients, it is possible that cortisol/DHEA and/or cortisol/DHEA-S ratios would be found elevated in schizophrenia patients as a result of stress associated with the illness. The aim of this study was, first, to compare the ratios of serum cortisol/DHEA or DHEA-S in schizophrenia patients with normal subjects, and, second, to determine the correlation between these ratios and psychopathology/distress properties within the patients.

Section snippets

Subjects

A total of 40 schizophrenia inpatients and 15 healthy volunteers participated in the study after providing written informed consent. The study was approved by the local ethics committee.

Of the patient sample, 38 were male, mean age was 38.0 (S.D.=11.1; range=20–57), 62.5% of the patients were never married and 35.2% had only primary school education. All patients had been admitted to psychiatric inpatient units and had DSM-IV diagnosis of schizophrenia. Mean age of onset, defined as age of

Steroid determination

Patients and normal volunteers were controlled for time of awakening, morning activity, caffeine consumption and smoking, factors that can affect morning cortisol levels. All participants were instructed to avoid morning exercises. Plasma samples of cortisol, DHEA and DHEA-S were collected between 8:00 and 9:00 am after 20 min of rest. Subjects were instructed to abstain from unusual physical activity or stress for a period of 24 h prior to blood sampling. Cortisol was measured by the TKCO1

Data analysis

The pentagonal model included five PANSS factors (positive, negative, activation, dysphoric mood and autistic preoccupation) (White et al., 1997) was used for analysis of symptoms of schizophrenia. The patient and control groups were compared on demographic, psychopathological, behavioral, and biological measures by using nonparamentric two-tailed Wilcoxon Rank-Sum test (since the data did not follow the normal probability distribution) and chi-square analysis, where appropriate. Results are

Results

The mean PANSS total score of schizophrenia patients was 68.4 (S.D.=19.8). The mean subscale scores were positive scale, 11.6 (S.D.=5.0), negative scale, 17.3 (S.D.=5.8), activation factor, 10.6 (S.D.=4.0), dysphoric mood, 9.9 (S.D.=3.8) and autistic preoccupation, 7.9 (S.D.=2.9). The MADRS mean score was 8.6 (S.D.=7.1).

Hormonal characteristics of patients were not significantly associated with gender (F=0.10, df=2.40, p=0.86), so they were pooled into a single group. Table 1 compares hormonal

Discussion

The first aim of this study was to compare the ratios of serum cortisol/DHEA or DHEA-S in 40 medicated schizophrenia inpatients with 15 healthy control subjects. We also wanted to determine the correlation of these ratios with psychopathology and distress properties. The main findings of the present study indicated that: (1) the cortisol/DHEA and cortisol/DHEA-S ratios were higher in schizophrenia patients than healthy comparison subjects, (2) elevated cortisol/DHEA and/or cortisol/DHEA-S

Acknowledgements

The authors acknowledge the dedicated editorial assistance of Rena Kurs.

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