Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

A number of different groups measuring the HPA axis at rest have observed hypercor-tisolaemia and elevated ACTH levels in schizophrenia though this is not a universally reported finding [3-9]. There are probably a number of reasons why this is the case but the 3 most likely are differences in methodology, patients were receiving antip-sychotic medication at the time of testing, or patients had been abruptly withdrawn from medications in order to produce a 'medication-free' scenario. Antipsychotics dampen activity of the HPA axis and such actions may occur via or independently of their actions on various monoaminergic systems [10]. Support that schizophrenia itself may be associated with increased HPA axis activity has come from endocrine and neuroimaging studies in drug-naive first-episode patients (10% larger pituitary volume) and high-risk subjects (who showed a 20% increase of developing psychosis with each further 10% increase in pituitary size) [11].

Dynamic challenges of the HPA axis have also provided conflicting results probably for the same reasons quoted above. That aside, the dexamethasone suppression test (dexamethasone normally inhibits the secretion of ACTH and cortisol) is abnormal in nearly 50% of subjects with schizophrenia [12] though this is not a very sensitive test as such findings have also been shown in post-traumatic stress disorder [13] and Alzheimer's disease [14]. Delta-9-tetrahydro-cannbinol, an active cannabis ingredient, when given to subjects with schizophrenia results in high cortisol levels and can cause a heightening of positive, negative and cognitive symptoms [15]. ACTH increases are greater in patients than matched controls when metabolic stress is induced centrally by 2-deoxy-D-glucose (2-DG) [5] while some investigators have shown that CRH-stimulated ACTH and cortisol are normal; however, pretreatment with dexamethasone leads to increased cortisol secretion in patients with established schizophrenia [16].

Vasopressinergic function is altered in schizophrenia as is indicated by the higher than expected rates of syndrome of inappropriate antidiuretic hormone section [17, 18]. Furthermore, osmotic stimuli [19] resulted in patients secreting greater amounts of ACTH and cortisol despite secreting similar amounts of AVP, while Jansen and Gispen-de Wied [20] subjected patients to psychosocial and physical stressors but found that only the former resulted in a blunted cortisol response. Metoclopramide is unique in its ability to stimulate AVP release and does so without altering plasma intracellular glucose deprivation, osmolality, or peripheral haemodynamics [9, 21-24]. Walsh et al. [25] have shown that metoclopramide induced patients to secrete higher levels of ACTH and cortisol though AVP responses were similar in first-episode drug-naive patients and their matched controls, a finding that may be explained by the fact that conditions of chronic stress increase pituitary responsiveness to AVP [26].

Altered stress responses in schizophrenia may have genetic underpinnings as is suggested by the findings that unaffected siblings of those with schizophrenia have exaggerated ACTH responses to stress [27], while Myin-Germeys et al. [28] have shown that those at high risk have increased behavioural sensitivity to daily life stressors. Brunelin et al. [29] have shown that 2-deoxyglucose induces a greater release of ACTH and homovanillic acid (a breakdown metabolite of dopamine and nora-drenaline) in patients with schizophrenia with siblings have a response intermediate to probands and controls.

Lack of or poorly functioning GR can also lead to an overactive HPA axis and such changes have been seen in subjects with schizophrenia. i.e. GR mRNA numbers in the frontal cortices, amygdala and hippocampus (dentate gyrus, CA1, CA3 and CA4) [30, 31] although these changes also occur in other psychiatric illnesses such as bipolar disorder and major depression [32]. Further evidence of GR dysfunction may come from the observation that acutely administered dexamethasone leads to growth hormone release in healthy controls; a response dependent upon dexamethasone acting on GR located within the hypothalamus [33]. In schizophrenia, Thakore et al. [34] have shown that dexamethasone-induced growth hormone responses are blunted, indicating either a central reduction or dysfunction of GR.

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