More recently, these features have been reported among individuals who are at increased risk for psychosis due to clinical features and/or genetic liability . Moreover, at-risk individuals who later develop full psychosis show even greater increases in basal cortisol and pituitary volume , suggesting that increased HPA axis activity may signal risk for worsening illness. In parallel with this research, studies show that at-risk individuals report greater exposure and sensitivity to a range of psychosocial stressors, including major life events, childhood trauma, and minor daily stressors . However, there has been a paucity of studies examining the concordance between psychosocial stress or exposure/distress and HPA axis function; as such, the extent to which individuals on the psychosis spectrum exhibit ‘abnormal’ HPA axis responses to psychosocial stressors is unclear. That is, the increases in basal cortisol observed in those with, and at-risk for, psychosis may represent eithera ‘normal/ adaptive’ response to the high levels of psychosocial stressors reported in these populations , orhyper responsivity of the HPA axis , characterised by an increase in cortisol greater than that expected in a healthy individual . Alternatively, the elevated basal cortisol levels observed may be partially independent of psychosocial stress exposure/distress , and instead reflect individual-level factors such as genetic predisposition to HPA axis hyperactivity or metabolic abnormalities ,cannabis grow tent the latter being more common among individuals at clinical high-risk for psychosis , who present features consistent with the prodromal phase of illness.

Two recent studies of at-risk individuals support the ‘increased concordance’ hypothesis: Using the experience sampling method, siblings of psychosis patients showed more pronounced increases in salivary cortisol in response to unpleasant events relative to controls , whilst a further study reported a stronger association between retrospectively-reported stressful life events and basal cortisol in CHR youth compared to controls . In contrast, lower cortisol responses during psychosocial stress or tasks have observed in CHR individuals and young adults with high schizotypy traits relative to controls; a pattern consistent with that observed in patients with chronic schizophrenia . Together, these findings tentatively suggest that naturally-occurring psychosocial stressors are associated with greater cortisol increases in at-risk individuals compared to healthy controls, whereas the response to experimentally-induced psychosocial stressors is blunted. However, the degree to which HPA axis responses to laboratory-based stressor tasks are relevant to psychosis aetiology is unclear. Studying the effect of naturally-occurring stressors on HPA axis function is methodologically complex. Unlike studies using experimentally-induced stressor tasks, the lapse of time between stressor exposure and cortisol measurement may be considerable. Whilst elevations in cortisol levels following stressor exposure appear to decrease over time , early life events and trauma exposure are associated with HPA dys regulation later in life, suggesting long term effects of stress exposure . A related issue is that stress measures and cortisol samples may not be collected on the same day, particularly when studies have large assessment batteries spanning several days. It is possible that day-to-day variations in perceived stress might influence both retrospective reporting of stressful events and cortisol levels, such that greater concordance is observed when measures are collected on the same day.

However, to our knowledge, this has yet to be investigated. Determining the extent to which HPA axis responsivity in at-risk youth predicts clinical outcome is important, as such work might ultimately help to identify individuals at increased risk of illness progression by virtue of being more sensitive to the effects of psychosocial stress, enabling targeted interventions. Utilising data from the North American Prodrome Longitudinal Study 2 [NAPLS 2, ] we investigated whether psychosocial stressors, basal cortisol levels, and stressor-cortisol concordanceat the baseline assessment differed across healthy controls and CHR subgroups defined on the basis of their clinical presentation at the two-year follow-up . Based on previous studies, we hypothesised that CHR youth who later converted to psychosis would show greater exposure and distress in relation to psychosocial stressors,elevated basal cortisol, and higher stressor-cortisol concordance relative to healthy controls; we also anticipated that CHR non-converters would be intermediate to CHR converters subgroups and healthy controlson these measures. In all analyses we controlled for a range of potential confounders , and additionally explored the effect of lapse-of-time between assessments on stressor-cortisol concordance.NAPLS 2 is a consortium of eight research sites examining CHR youth, the aims and recruitment methods for which are detailed elsewhere . Briefly, CHR subjects were help-seeking individuals who met criteria for one or more prodromal syndromes:attenuated psychotic symptoms;brief intermittent psychotic symptoms; or substantial functional decline combined with a first degree relative with a psychotic disorder, or schizotypal personality disorder in individuals younger than 18 years. Prodromal syndromes were assessed using the Criteria of Prodromal Syndromes , based on the Structured Interview for Prodromal Syndromes [SIPS ], conducted by clinically-trained interviewers; psychiatric diagnoses were determined via the Structured Clinical Interview for DSM-IV . CHR individuals who had met criteria for an Axis I psychotic disorder were not eligible for inclusion; treatment with antipsychotic medication was permitted provided that full psychotic symptoms were not present at the time of medication commencement.

Healthy controls were recruited from the community and had no personal history or first-degree relative with psychosis and did not meet criteria for any prodromal syndrome. All participants were aged between 12 – 35 years at recruitment. Exclusion criteria for both groups included substance dependence in the past six months, neurological disorder, or full-scale IQ < 70.Ethical approval was provided by Institutional Review Boards at each NAPLS site , all participants provided informed consent or assent. The current sample includes 662 participants for whom variables of interest at baseline and clinical status at follow-up were available. At baseline, participants provided information on sociodemographic factors and potential confounders, completed stress measures, and collected saliva samples. Where possible, saliva was collected on the same day as daily stressor, life event and childhood trauma measures . However, in some in cases , the baseline assessment was interrupted that lead to a substantial delayin the completion of all measures. In such instances, the remaining baseline measures were collected when the participant was able to return and complete the schedule, with clinical assessments repeated to confirm CHR status. All participants were included in the analysis which accounted for timelapse between assessments. Prodromal symptoms were assessed via the SIPS at 12- and 24-month follow-up assessments and used to categorise CHR subgroups [see Table 1 for details ].Participant date of birth, sex, and ethnicity were assessed via self report, the latter was subsequently collapsed to a four-level variable . Cannabis use was assessed via a structured interview . For the purposes of the current investigation we created a binary variable indexing current use . Details of all prescribed psychotropic medications were obtained at the baseline assessment via self-report, pharmacy records,grow lights for cannabis and/or medical records. Binary variables were created for current antipsychotic use and current psychotropic use , irrespective of type, dose, or data source.The 58-item, Daily Stress Inventory , was used to determine the presence of minor stressors occurring within the past 24 -hs. Participants indicated whether they experienced each stressor and the level of distress elicited by each endorsed stressor . Total distress scores were then divided by the total exposure scoreto obtain an average distress per item score . Life events were assessed via the Psychiatric Epidemiology Research Interview Life Events Scale , modified to exclude life events of lesser relevance to youth. The 59 events can be classified as independent or dependent . Interviewers recorded how often each of the 59 events had occurred in the participant’s lifetime and the associated level of distress ; participants could report multiple exposures to the same event , where the maximum occurrence for any single life event in the NAPLS cohort was four. An average life event distress score was derived by dividing the total distress score by the total exposure score . Participants additionally completed the Childhood Trauma and Abuse Scale , a semi-structured interview examining experiences of physical, sexual, and psychological abuse, and emotional neglect, occurring prior to age 16 . Each trauma type was scored as absent/present with a binary variable indexing any form of trauma derived.At the research session, participants provided three saliva samples with a mean salivary cortisol value subsequently derived when two or more samples were available . The median time of collection for the three samples was 1107 h , 1207 h , and 1300 h , respectively. The mean cortisol value, which is highly correlated with area under the curve values , was computed to provide consistency with previous publications.

Participants were instructed to avoid consumption of caffeine, alcohol, or dairy products after 1900 h on the day before sampling; individuals who reported non-compliance with these instructions were not excluded as previous analyses performed on a subset of the cohort found no association with these variables and cortisol levels . Use of nonprescription medications over the past 24 hours was assessed via self-report. Samples were stored at -20 °C, and rapidly thawed and centrifuged prior to assay using a highly sensitive enzyme immuno assay . All samples were assayed in duplicate with intra- and inter-assay coefficients of variation less than 10% and 15%, respectively.All analyses were performed using Stata Version 15 . The number of days between stress measure completion and cortisol collection could not be computed for ∼6% of the sample due to missing assessment dates. In such cases, missing values for the three time-lapse variables were imputed using the median number of days across the entire sample. The imputed data variables were used in all subsequent analyses. Ladder and gladder commands were used to identify transformations yielding normally distributed continuous variables. Subsequently, age, cortisol, daily stressor average distress scores, and life event exposure scores were log-transformed, daily stressor exposure scores were square-root transformed, whilst life event average distress scores did not require transformation. There were no transformations that could improve the distribution of the assessment time-lapse variable, therefore a five-level categorical variable was created cortisol collected before stress measurement;assessments completed on the same day;cortisol 1-10 days after stress measurement;cortisol 11-30 days after; and cortisol > 30 days after. Next, we examined correlations between salivary cortisol and sampling variables, namely, time of first sample collection, number of samples collected , and use of non-prescription medications in past 24 hours. To remove the influence of relevant factors , cortisol values for the entire sample were regressed on sampling time, cough/cold medication use, and corticosteroid use to obtain standardised residuals. The resulting variable was used for all subsequent analyses. Group differences in demographic variables were examined using one-way analysis of variance, Kruskall Wallis, and chi-squared tests. To identify potential confounders, associations among demographic factors, cortisol, and psychosocial stress measures were examined using within-group Pearson’s correlations , biserial correlations , and chi-squared tests . Associations of group status with basal cortisol and psychosocial stressors were next examined, with adjustment for factors that were found in the above steps to be significantly associated with basal cortisol and/or any stressor in any group. Analyses of covariance , were employed for basal cortisol and continuous stressor measures, with estimated means and standard errors derived from these models. For trauma exposure, a logistic regression model was used to test the association with group status ; pairwise comparisons and adjusted trauma prevalence rates and associated SEs for each group were derived from the logistic model. All pairwise comparisons were performed with Sidak correction for multiple testing. To test whether stressor-cortisol concordance was moderated by time-lapse between assessments, correlations between cortisol and psychosocial stressors were examined within each time-lapse category. Linear regression models were used to test associations between individual psychosocial stressors and salivary cortisolin each group. Owing to multicollinearity, each stressor was examined in a separate model; all models were adjusting for potential confounders identified in the above steps. To facilitate comparison of stressor-cortisol concordance across groups, from these adjusted models, we obtained standardised beta coefficients for each psychosocial stress measure and computed SEs for these coefficients [SEStβ = SEβ ]. Stβ coefficients for each stressor were then pooled using the ‘meta’ command to obtain an overall measure of stressor-cortisol concordance.Of the 457 CHR individuals included in the current study,showed a remission of CHR symptoms,remained symptomatic, experienced a progression of positive symptoms, and 69converted to psychosis.