East Asian Arch Psychiatry 2017;27:79-84

ORIGINAL ARTICLE

Dr Ram K. Solanki, MD (Psychiatry), Department of Psychiatry, Sawai Man Singh Medical College, Jaipur, Rajasthan, India.
Dr Parag Sharma, MD (Psychiatry), Department of Psychiatry, Sawai Man Singh Medical College, Jaipur, Rajasthan, India.
Dr Alok Tyagi, MD (Psychiatry), Department of Psychiatry, Sawai Man Singh Medical College, Jaipur, Rajasthan, India.
Dr Chitra Singh, MD (Psychiatry), Department of Psychiatry, Sawai Man Singh Medical College, Jaipur, Rajasthan, India.

Address for correspondence: Dr Parag Sharma, Psychiatric Centre, Sawai Man Singh Medical College and Hospital, Jaipur, India. Email: parag1989.11@gmail.com

Submitted: 7 November 2016; Accepted: 23 March 2017

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Introduction

It has largely been implicated that schizophrenic patients have higher level of perceived stress and impaired coping strategies and that psychosocial stress plays a role in the development and course of psychotic disorders.¹ The biological response to stress is then mediated through the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system and invokes a number of adaptive behavioural and physiological changes.² In response to the stressors, neural signals are converted into an endocrine response at the level of the hypothalamus leading to activation of the pituitary gland and finally release of corticosteroids by the adrenal gland. Cortisol and dehydroepiandrosterone sulfate (DHEA-S) are the 2 major circulating neurosteroids that have their effect on the brain. Cortisol exerts widespread actions on the central nervous system including regulation of gene transcription, cellular signalling, modulation of synaptic structure and neurotoxicity. On the contrary, DHEA and its sulfated form (DHEA-S) are the major circulating neurosteroids that have neuroprotective,^3,4 antioxidant,⁵ and anti-inflammatory⁶ effects on the brain. 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. Dehydroepiandrosterone has potent antiglucocorticoid actions on the brain and can protect hippocampal neurons from glucocorticoid-induced neurotoxicity.⁷ In acute stress, and in response to the level of adrenocorticotropic hormone (ACTH), serum levels of DHEA rise parallel to serum cortisol levels.

In humans, the concentration of DHEA-S is much higher than cortisol and DHEA concentration⁸ with brain- to-plasma levels of roughly 6.5.⁹ Of note, DHEA-S acts on several neurotransmitter systems including gamma- aminobutyric acid (GABA^A) and N-methyl-D-aspartate receptors,¹⁰ thus regulating neuronal excitability via ligand- gated ion channels.¹¹ The hormone, DHEA, also protects neurons against oxidative stress, glutamate, and beta- amyloid protein toxicity.¹²

The evidence for HPA axis dysfunction has been reviewed in the context of the stress-diathesis model of schizophrenia.¹³ Overactivation of this axis leads to altered blood levels of cortisol (glucocorticoid), and is associated with greater symptom severity and poor response to antipsychotics.¹⁴ Interestingly, cortisol level falls following an acute psychotic exacerbation, possibly attributed to antipsychotic treatment.¹⁵ A systematic review by Pariante¹⁶ noted an increase in pituitary volume during the prodromal phase, decrease in volume in chronically ill patients and then an increase as a result of antipsychotic medication intake (typical antipsychotics). Further, administration of DHEA was beneficial in patients with depression and anxiety and in schizophrenic patients with negative symptoms.¹⁷

Compared with healthy controls, DHEA-S levels were elevated,^18,19 or no different²⁰ in schizophrenic patients. The state of the psychotic illness, duration of untreated psychosis (DUP), and medication may explain these inconsistencies. Duration of untreated psychosis is defined as the time from manifestation of the first psychotic symptom to initiation of adequate antipsychotic drug treatment. These findings further strengthen the role of neurosteroids in onset and maintenance of schizophrenia.

Of particular interest is the potential role of neurosteroid modulators of GABA^A receptors in the neurobiological mechanisms of aggressive behaviour.²¹ It has been shown in animal models that neurosteroids are related to aggressive behaviour and they may be implicated in aggressive behaviour among humans. One study of drug- naïve schizophrenic individuals showed that high DHEA-S level correlated with low lifetime history of aggression score, i.e. trait aggression, wherein the role of central GABA^A receptors has been postulated.¹⁹ An extensive literature search did not reveal any study focusing on neurosteroid level and state aggression rather than trait aggression.

To exclude the effect of medication and trait aggression, we aimed to explore the blood level of these neurosteroids and ascertain its correlation with state aggression and psychopathology in first-episode antipsychotic-naïve (FEAN) schizophrenic patients.

Methods

Study Population

The present study was approved by the Institutional Review Board and conducted between 1 June 2015 and 30 May 2016. The study population consisted of individuals with schizophrenia admitted to an emergency ward at a psychiatric centre in Jaipur, India. Written informed consent was obtained from participants or from a parent or guardian wherever appropriate. Thirty male or female patients aged between 18 and 55 years having FEAN schizophrenia were included in the study. The diagnosis was confirmed by 2 senior consultant psychiatrists (RKS and AT) according to the ICD-10 criteria for schizophrenia.

Patients with diabetes, impaired thyroid function, asthma, or who were prescribed steroid medications or oral contraceptives (verified by means of clinical examination, routine laboratory investigations and previous medical records) were excluded from the study. Patients with any surgery involving the adrenals or an ACTH-secreting tumour were also excluded. Co-morbid psychiatric disorders including affective disorder and substance use disorder were excluded due to different aetiopathogenesis.

In this study, 20 age- and gender-matched healthy individuals with no history of psychiatric or medical illness served as a control group. Hospital staff as well as healthy second-degree relatives (not first-degree relatives) of a patient with no history of psychiatric illness in the family served as further controls.

Clinical Assessment

Following recruitment, all admitted patients were evaluated using psychometric scales that included Positive and Negative Syndrome Scale (PANSS),²² Clinical Global Impression Scale (CGI-S),²³ and the Modified Overt Aggression Scale (MOAS).²⁴ In accordance with the MOAS, an aggressive behaviour constituted either verbal aggression (e.g. shouting angrily and making clear threats), physical aggression against self (e.g. minor burns, mutilation, deep cuts, and fracture), physical aggression against an object or property (e.g. throwing objects, smashing a window, and setting fire), or physical aggression against other people (e.g. striking, kicking, pushing, and attacking others causing physical injury). The patient’s aggressive behaviour over the past week was noted in all 4 domains, the sum in each domain multiplied by a factor and weighted sums formed the total score.

Apart from de-escalation, all patients were administered adequate quantities of benzodiazepines to control the illness and no antipsychotic in any form was administered prior to blood sampling (i.e. antipsychotic-naïve).

Blood Sampling

Blood samples from all recruited patients and controls were obtained between 8:30 am and 9:30 am after 20 minutes of rest in a comfortable environment. All recruits were advised to avoid exercise and caffeine 24 hours prior to blood collection. A 20 mL sample of venous blood was withdrawn using all septic precautions into plain tubes for the collection of serum. Serum cortisol and DHEA-S levels were then analysed in the Central Laboratory, Sawai Man Singh Medical College and Hospital, Jaipur, India.

Statistical Analysis

The patient and control groups were compared for socio- demographic, clinical, behavioural, and biological measures using SPSS (Windows version 20.0; IBM Corp, Armonk [NY], United States). Data were presented as mean ± standard deviation or standard error. Student’s t test and Pearson Chi-square test were used to test for associations between variables. Group × gender effects on serum cortisol and DHEA-S levels were tested using analysis of variance (ANOVA) with main factors of group (controls, patients) and gender (male, female). Post-hoc tests were performed using the Tukey’s honestly significant difference test wherever appropriate. A significance level of α = 0.05 was applied to all tests.

Results

In the patient sample, their mean (± standard deviation) age was 24.3 ± 5.4 years and 60% were male, the corresponding figures in the control population being 27.9 ± 6.1 years and 65%. All patients were admitted to an emergency psychiatric ward with an ICD-10 diagnosis of schizophrenia. Mean age of onset of illness was 22.3 years, thus the mean DUP in our study sample was approximately 2 years. Clinical features of the patients are shown in Table 1.

Serum levels of DHEA-S and cortisol were measured in all 30 participating patients (Table 2). Baseline DHEA-S level but not cortisol level was significantly higher in schizophrenic patients than the controls. The serum cortisol (p = 0.17) and DHEA-S (p = 0.29) levels did not vary in relation to age. Males and females also did not show any statistical difference in the levels of serum cortisol (p = 0.78), serum DHEA-S (p = 0.34), or MOAS (p = 0.78). No gender difference in values was noted in the patient group (p = 0.93) but female controls had significantly lower serum DHEA-S than males (p < 0.01). Age and gender showed no correlation with serum cortisol level in either group. One-way ANOVA and Tukey’s post-hoc analysis showed no correlation of DUP with serum DHEA-S (p = 0.31), serum cortisol (p = 0.11) or MOAS (p = 0.48) score. Table 3 shows correlations between baseline biological and clinical variables in FEAN schizophrenic patients.

Discussion

Our results provide data about the clinical variables in FEAN schizophrenic patients. The mean age of patients was 24.3 years and the serum cortisol and DHEA-S levels did not vary in relation to age. Similarly, males and females did not show any statistical difference for measures of serum cortisol, serum DHEA-S, or MOAS. The DUP in our study sample was 2 years, fairly high compared with that in high- income countries. Further, the DUP had no correlation with serum cortisol, serum DHEA-S, or MOAS. Importantly, this reveals that serum level of neurosteroids does not fluctuate with increasing duration of schizophrenia. Other studies in schizophrenic patients have not identified any association between violence at presentation and DUP, but have emphasised the role of substance abuse, affective disorder, and number of hospitalisations in the pathophysiology of aggression.^25,26 Nonetheless, a recent meta-analysis²⁷ concluded that longer DUP was associated with a higher homicide rate among patients with psychosis, prior to receiving treatment. Our findings may be explained by the fact that we excluded substance abuse and our patients were admitted for the first time.

This study adds to our knowledge that FEAN schizophrenic patients may demonstrate significantly higher blood levels of the neurosteroid DHEA-S and such elevation is negatively correlated with aggressive behaviour (as assessed by the MOAS). Since healthy males showed higher DHEA-S levels than healthy females, this difference faded with first-episode schizophrenia where the gender difference was absent with male and female patients demonstrating similarly higher levels of DHEA-S. A comparatively higher elevation of DHEA-S may be a reason for a better prognosis of schizophrenia in females. Additionally, DHEA-S has been reported to increase oestrogen level in women. This further strengthens our argument for a neuroprotective function of DHEA-S.^28,29

Previous studies assessed aggression using a lifetime history of aggression³⁰ rating scale that provides a life history of aggression and not acute aggression. Therefore MOAS is a better measure of aggression in schizophrenic patients as it identifies the severity of aggression over the last 7 days, i.e. a measure of acute aggression, not trait aggression (i.e. lifetime history of aggression).

It has been found that neurosteroids are positive modulators of the GABA^A receptor. The GABA^A receptor is a heteropentameric protein that can be constituted from various subunits. Modulators (including neurosteroids) of α subunit can cause various effects on aggressive behaviour depending on the serum neurosteroid level, with high levels having anti-aggressive effects and vice versa.³¹

In contrast, serum cortisol levels had no significant correlation with aggression (degrees of freedom = 5, p = 0.44). This raises questions about our understanding of the mechanism of action of different neurosteroids in the brain. It can be deduced from the above discussion that a higher level of serum DHEA-S acts as a compensatory, neuroprotective, and anti-aggressive factor in FEAN schizophrenic patients. Nonetheless we did not measure DHEA level and therefore we exclude the possibility of altered DHEA in these patients. It may be speculated that as the illness progresses, the level of DHEA-S declines and thus the neuroprotection offered by these neurosteroids is lost leading to heightened aggression over time in schizophrenia. Chronic schizophrenic patients often demonstrate diminished neurosteroid levels, elevations of which, achieved by augmentative administration of DHEA, correlate with clinical improvement in negative symptoms, mood, anxiety, and depression. Overall, the authors believe that DHEA-S levels affect aggression and prognosis to some extent, though the exact mechanism of this biological interaction remains unclear. The question remains whether there is a biological mediator that can precisely correlate with clinical symptoms in first presentation of schizophrenia and direct the further course of illness.

This may be the first study that attempted to identify a biological mediator of acute aggression in FEAN schizophrenic patients after controlling for possible confounders, i.e. substance abuse, medicated schizophrenics, affective state, intellectual disability, and other psychoses. Further studies should focus on longitudinal assessment of neurosteroids and aggression in schizophrenia. The use of DHEA-S as an endophenotypic marker in schizophrenia should also be further evaluated.

Limitations

A larger sample may have revealed more significant findings but stringent exclusion criteria to address only

FEAN schizophrenic individuals made this difficult. Serial blood measurements over the course of the day would have excluded the effects of diurnal variation of neurosteroids. Smoking also influences serum cortisol levels but is more prevalent in schizophrenic patients. Excluding smokers would have provided better results.

Conclusion

Patients with first-episode schizophrenia showed significantly higher DHEA-S levels in blood compared with healthy controls. Serum DHEA-S level has an inverse relationship with aggression and its higher elevation in females is a marker for a good prognosis. This measure may serve as a biological adaptive mechanism that antagonises the neuronal damage caused by cortisol in the hippocampus. Results from this study may add to our existing knowledge about schizophrenia and suggest treatment implications for the future. Nonetheless the complex interaction between neurosteroids, dopamine pathways, and neurotransmitters in the brain warrants further investigation.

Acknowledgements

We would like to thank Dr Vijay Choudhary and Dr Ajitabh Soni for their assistance in preparing this manuscript.

Declaration

All authors have disclosed no conflicts of interest.

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