[1] 11w HPA axis functioning associated with transition to psychosis: Combined DEX/CRH test

[1] 125w We investigated functioning of the hypothalamic-pituitary-adrenal (HPA) axis in 12 young people at ultra high risk for developing psychosis, using the combined dexamethasone corticotrophin releasing hormone (DEX/CRH) test. Over a two year period, three of the 12 participants developed an acute psychosis. Descriptive analysis of the data indicated that contrary to expectations, participants who did not make the transition to psychosis had on average higher cortisol levels at the latter stages of the test, as well as a greater severity of depression and anxiety symptoms, than participants who subsequently developed psychosis. These preliminary results suggest that dysregulated HPA-axis functioning in individuals at high risk for psychosis may be associated more with comorbid depression symptoms than factors specifically related to the process of emerging psychosis illness.

[1] 75w The diathesis-stress model of schizophrenia contends that a combination of factors, including genetic liability, abnormal maturation, early exposures, and stress combine to affect the abnormal substrate thought to underlie schizophrenia (Corcoran et al., 2003;Walker and Diforio, 1997). Indeed some research has suggested that stress and the associated rise in cortisol may be associated with increased psychopathology via a dynamic process involving increased dopamine activity and atrophy of cells in the hippocampus (Thompson et al., 2004).

[2] 169w One method of directly investigating the effect of stress in psychosis is the use of specific challenge tests that measures the response of the hypothalamic-pituitary-adrenal (HPA) axis, one of the major systems mediating the physiological stress response. Meta-analyses of HPA-axis functioning in schizophrenia using the dexamethasone suppression test (DST) suggest a higher rate of cortisol non-suppression (Yeragani, 1990), although there is substantial variation in findings, likely reflecting methodological differences and heterogeneity in symptom presentation and medication status. The combined dexamethasone/corticotrophin releasing hormone (DEX/CRH) test provides both a more sensitive test of the HPA-axis than the DST alone, as well as a model for the body's response to stressors. In this challenge, dexamethasone is ingested the evening before the test, which acts to suppress activation of the HPA-axis. The following afternoon, CRH is ingested and plasma levels of cortisol and ACTH are measured to gain an indication of the responsiveness of the system to CRH. Only one study to date has examined the DEX/CRH response in patients with schizophrenia (Lammers

[3] 104w 0022-3956/$ -see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2005.11.010 et al. , 1995). Compared to healthy controls, patients had elevated cortisol, but not ACTH levels, although further analysis indicated that unmedicated patients released significantly more cortisol than their medicated counterparts. While these results further suggest hypercortisolism in schizophrenia, a similar response to the DEX/ CRH test has been observed in a number of psychiatric disorders, including major depression and bipolar disorder (Heuser et al., 1994;Schmider et al., 1995). Altered glucocorticoid feedback regulation therefore may be associated with acute illness processes, and the psychosocial stress that accompanies such episodes, irrespective of diagnosis.

[4] 74w In order to further elucidate the relationship between stress response and the pathophysiology of psychosis, it may be of special value to test HPA-axis reactivity during the sub-threshold stage of illness, prior to the onset of the first episode of psychosis. We applied the DEX/ CRH test in a small, specialized sample of individuals at ultra high risk of developing psychosis in order to assess whether HPA dysregulation is evident during the prodromal period.

[1] 210w Over a two year period from baseline assessment, three of the 12 participants (all male) developed an acute psychotic illness, in each case meeting the DSM-IV diagnostic criteria for schizophrenia. Description of the baseline clinical characteristics of the participants who did, and did not, make the transition to psychosis is presented in Table 1. Non-transition participants reported higher levels of anxiety and depression (7 out of 9 had ratings P the highest value among the transi-tion group) and more life events than their subsequently psychotic counterparts (7 out of 9 scored P the highest value among the transition group), however negative symptoms were lower compared to the transition subjects (6 out of 9 non-transition participants had ratings < the lowest value in the transition group). Four participants were taking anti-depressant medication at 0 20 40 60 80 100 120 140 160 180 1 2 3 4 5 6 Sample Time Cortisol Assay (ng/ml) Subject 1 (T) Subject 2 (T) Subject 3 (T) Subject 4 (NT) Subject 5 (NT) Subject 6 (NT) Subject 7 (NT) Subject 8 (NT) Subject 9 (NT) Subject 10 (NT) Subject 11 (NT) Subject 12 (NT) Fig. 2. Individual cortisol assay values. Note: T, transition subject/ NT, non-transition subject. Subjects receiving anti-depressant medication: 1, 2 10, 11.

[2] 19w the time of testing: sertraline 100 mg/d (one transition, one non-transition) and citalopram 30 mg/d (one transition, one non-transition).

[3] 98w For the DEX/CRH test, mean cortisol levels were equivalent between the groups at baseline and during the early stages of the test, although higher mean cortisol levels were apparent among participants that did not subsequently make the transition to psychosis, peaking at 60 min (see Fig. 1). As several subjects were taking antidepressants at the time of the test, individual cortisol levels are also presented to indicate the range of responses (see Fig. 2). Inspection of ACTH levels were largely equivalent between groups across all timepoints, although elevated for the non-transition group at 60 min (see Fig. 1).

[1] 90w While only tentative conclusions can be drawn from this study due to the small sample size and the heterogeneity of risk factors for psychosis, the results suggest that non-transition participants had higher cortisol levels during the latter stages of the DEX/CRH test than their contempories who subsequently made the transition to psychosis. Interestingly, the non-transition group also reported more severe depression and anxiety symptoms at the time of the test, as well as a greater number of life events and hassles, although negative symptoms were less prominent in this group.

[2] 336w These results are somewhat contrary to expectations, however the association between depression and an augmented response to the DEX/CRH test is well established (e.g., Hatzinger et al., 2002;Heuser et al., 1994;Kunugi et al., 2004). It is likely that among young people at high risk for developing psychosis, increased severity of depression symptoms and perceived psychosocial stress may mediate HPA-axis deregulation, more so than specific processes associated with the emergence of psychotic illness. However as the HPA-axis challenge in this study was conducted at baseline assessment, prior to participants making the transition to psychosis, conclusions regarding the relationship between emerging acute illness and altered glucocorticoid feedback regulation are limited. This is particularly the case given that two of the transition subjects, and two of nine nontransition participants, were receiving anti-depressant medication at the time of the test, though all were neuroleptic naı ¨ve. Prospective, longitudinal studies are required to assess changes in HPA-axis functioning associated with the transition from a prodromal phase through to an acute first episode of psychosis and on to more enduring forms of disorder. Furthermore, the inclusion of a healthy comparison group is necessary in order to place the response of both the transition and non-transition groups in a meaningful context. This study was especially limited by a small and clinically heterogeneous sample, although the latter reflects the nature of this 'at risk' patient population. The invasiveness and demands of the DEX/CRH test make it difficult to recruit participants for such studies, a difficulty magnified here given the complexity of identifying young people at ultra high risk of psychosis. Utilizing dexamethasone challenge tests at multiple time points, including at the time of transition to psychosis is the challenge for future research to determine whether HPA-axis function changes over the prodromal period. The results of this study provide an initial indication that the nature of the biological stress response in those at ultra high risk of psychosis may be influenced more by depression and perceived psychosocial stress than disease processes associated with emerging psychosis.

[1] 187w Participants were recruited from the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia, a service designed for young people aged 14-30 years who are at ultra high risk (UHR) of developing psychosis. Eligibility for treatment requires clients to meet criteria for at least one of three groups: trait and state risk factors (e.g., a first degree relative with a DSM-IV psychotic disorder or schizotypal personality disorder, as well as a significant decrease in mental state or functioning for a period of at least one month, evidenced by a reduction in Global Assessment of Functioning (GAF) Scale score of 30 points or more from pre-morbid level); attenuated psychotic symptoms (e.g., presence of ideas of reference, magical thinking, perceptual disturbance, paranoid ideation, or odd behavior and appearance held with a reasonable degree of conviction and occurring at least several times per week); and/or brief, limited intermittent psychotic symptoms (e.g., attenuated psychotic symptoms of less than a weeks' duration which resolve spontaneously) (see Phillips et al., 2002 for further details). Each participant provided informed consent to participate in the study, which was approved by the local ethics committee.

[2] 84w Twelve young people (10 male, 2 female) who met the UHR for psychosis criteria participated. The mean age was 19.4 years (SD = 3.6 years; range = 15-25 years). All participants were single and studying fulltime at secondary school (6) or university (6). Diagnostically, four participants met the criteria for trait and state risk factors, one had experienced brief intermittent psychotic symptoms and 11 had attenuated symptoms. All participants were neuroleptic naı ¨ve, however four were taking anti-depressant medication at the time of testing.

[3] 189w At baseline, psychopathology interviews were administered including the SCID-IV (First et al., 1996), the Brief Psychiatric Rating Scale (BPRS: Overall and Gorman, 1962), the Scale for the Assessment of Negative Symptoms (SANS: Andreasen, 1982), the Hamilton Depression (Hamilton, 1960) and Anxiety Rating Scales (Hamilton, 1959), and the GAF (APA, 1994). The experience of recent life events was obtained using both the Life Event Interview Schedule (LEIS; Ventura, 1999) and a questionnaire assessing the severity of minor stressors (the Hassles Scale: Kanner et al., 1981). Participants were clinically assessed at monthly intervals for 12 months post-baseline and again in 12-months time, with those making the transition to psychosis identified at 24 months. Transition to psychosis was defined as the presence of severe psychotic symptoms (e.g., hallucinations, delusions or formal thought disorder rated as severe on the corresponding scales from the BPRS) occurring at least several times per week and persisting for longer than a week (see Phillips et al., 2002). These criteria do not correspond to DSM-IV diagnostic criteria, however those subjects who made the transition to psychosis each met the diagnostic criteria for a DSM-IV psychotic disorder (see below).

[4] 138w The DEX/CRH test was administered to participants following baseline clinical assessment. At 23.00 h, 1.5 mg of dexamethasone was orally ingested. The following day, 100 lg CRH was administered intravenously as a bolus at 15.02 h to participants resting supine on a bed in a soundproof room (from 14.30). Venous blood samples (7 mls) were drawn from the arm via a butterfly cannular at 14.50 (baseline), 15. 00, 15.30, 15.45, 16.00 and 16.15 h for determination of cortisol and ACTH levels. Saline was flushed through the cannular to keep the line open and ensure that participants were not disturbed during the testing procedure. Cortisol was assayed using a previously reported procedure (Engler et al., 1988) and ACTH sent to a commercial laboratory for testing. The small sample size precluded any statistical analyses, therefore only qualitative data is presented.