Serum Levels of Neuroactive Steroids in First-Episode Antipsychotic-Naïve Schizophrenic Patients and Its Correlation with Aggression: A Case-Control Study

IntroductionIt 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 brainto-plasma levels of roughly 6.5.9 Of note, DHEA-S acts on several neurotransmitter systems including gammaaminobutyric acid (GABAA) and N-methyl-D-aspartate receptors,10 thus regulating neuronal excitability via ligandgated ion channels.11 The hormone, DHEA, also protects neurons against oxidative stress, glutamate, and betaamyloid protein toxicity.12The 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 GABAA 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 drugnai've 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 GABAa 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. …