Examining the psychobiological response to acute social stress across clinical stages and symptom trajectories in the early psychosis continuum.

The stress-vulnerability model has been repeatedly highlighted in relation to the risk, onset and course of psychosis, and has been independently studied in clinical high-risk (CHR) and first-episode psychosis (FEP) populations. Notable in this literature, however, is that there are few studies directly comparing markers of stress response across progressive stages of illness. Here we examined the psychobiological response to the Trier Social Stress Test in 28 CHR (mean age 19.1) and 61 FEP (age 23.0) patients, in order to understand the stage(s) or trajectories in which differences in subjective stress or physiological response occur. The overall clinical sample had greater perceived stress and blunted cortisol (FEP + CHR, n = 89, age 21.7) compared with healthy controls (n = 45, age 22.9). Additional analyses demonstrated elevated heart rate and systolic blood pressure in FEP compared with CHR, but there were no further differences in physiological parameters (cortisol, heart rate, or blood pressure) between stage- or trajectory-based groups. Together, this suggests that individual stress response markers may differentially emerge at particular stages en route to psychosis - and demonstrates how stage-based analyses can shed light on the emergence and evolution of neurobiological changes in mental illness.

A meta-analysis of blood and salivary cortisol levels in first-episode psychosis and high-risk individuals.

Dysregulated cortisol responses and glucose metabolism have been reported in psychosis. We performed a random-effects meta-analysis of cortisol responses in first-episode psychosis (FEP) and psychosis risk states, taking into consideration glucose metabolism. A total of 47 studies were included. Unstimulated blood cortisol levels were significantly higher (g = 0.48, 95 %CI: 0.25-0.70, p < 0.001) in FEP, but not in psychosis risk states (g = 0.39, 95 %CI: -0.42-1.21, p = 0.342), compared to controls. Cortisol awakening response (CAR) was attenuated in FEP (g = -0.40, 95 %CI: -0.68 - -0.12, p = 0.006), but not in psychosis risk states (p = 0.433). Glucose and insulin levels were positively correlated with unstimulated blood cortisol levels in FEP. Our meta-analysis supports previous findings of elevated blood cortisol levels and attenuated CAR in FEP. Future research should focus on identifying the common denominators for alterations in stress hormones and glucose metabolism.

Social Determinants of Health and Preclinical Glycemic Control in Newly Diagnosed First-Episode Psychosis Patients.

BACKGROUND: The abnormally high incidence of disorders of glucose metabolism (DGM) in psychotic-spectrum disorders (PSD) has often been attributed to the side effects of antipsychotics and unhealthy lifestyles. The influence of social determinants of health has been largely ignored, despite ample evidence linking social adversity with both PSD and DGM. The aim of this study is to examine the influence of well-established social determinants of health on preclinical levels of glycated hemoglobin (HbA1c) in a sample of first-episode psychosis (FEP) patients. METHODS: In a sample of newly admitted FEP patients, univariate analyses were used to select the main predictors of HbA1c levels from the following social determinants of health: childhood trauma, immigrant background, visible minority status, and indices of social and material deprivation. The predictors identified in the univariate analyses were tested in multivariate linear regression models including age, sex, BMI, depression, and physical anergia (proxy of sedentary behaviour) as covariates. RESULTS: Univariate analyses identified visible minority status and childhood physical abuse as predictors of HbA1c. After controlling for covariates, minority status significantly predicted higher levels of glycated hemoglobin (ß = 0.23; P = 0.01), and physical abuse had a marginally significant effect (ß = 0.23; P = 0.06). Other predictors were not significantly associated. CONCLUSION: FEP patients from a visible minority or who were victims of childhood physical abuse have higher levels of HbA1c at admission compared with other patients. This might suggest an increase in risk for the development of future DGM. If confirmed, preventive strategies could be tailored for these groups.

Severe childhood trauma and emotion recognition in males and females with first-episode psychosis.

AIM: Childhood trauma increases social functioning deficits in first-episode psychosis (FEP) and is negatively associated with higher-order social cognitive processes such as emotion recognition (ER). We investigated the relationship between childhood trauma severity and ER capacity, and explored sex as a potential factor given sex differences in childhood trauma exposure. METHODS: Eighty-three FEP participants (52 males, 31 females) and 69 nonclinical controls (49 males, 20 females) completed the CogState Research Battery. FEP participants completed the Childhood Trauma Questionnaire. A sex × group (FEP, controls) ANOVA examined ER differences and was followed by two-way ANCOVAs investigating sex and childhood trauma severity (none, low, moderate, and severe) on ER and global cognition in FEP. RESULTS: FEP participants had significantly lower ER scores than controls (p = .035). No significant sex × group interaction emerged for ER F(3, 147) = .496, p = .438 [95% CI = -1.20-0.57], partial η2  = .003. When controlling for age at psychosis onset, a significant interaction emerged in FEP between sex and childhood trauma severity F(3, 71) = 3.173, p = .029, partial η2  = .118. Males (n = 9) with severe trauma showed ER deficits compared to females (n = 8) (p = .011 [95% CI = -2.90 to -0.39]). No significant interaction was observed for global cognition F(3, 69) = 2.410, p = .074, partial η2  = .095. CONCLUSIONS: These preliminary findings provide support for longitudinal investigations examining whether trauma severity differentially impacts ER in males and females with FEP.

The effects of childhood adversity on treatment delays and its components in first-episode psychosis.

Apart from increasing risk for psychotic disorders, childhood adversity has been associated with worse outcomes. One way in which childhood adversity may worsen outcomes is by lengthening treatment delays, which are associated with negative impacts. We tested the influence of childhood trauma on treatment delays, measured as the duration of untreated psychosis (DUP), and its help-seeking and referral components, in a first-episode psychosis cohort (N = 203). We accounted for pertinent social (e.g., migrant status) and other determinants (i.e., age at onset, diagnosis, symptoms) of treatment delays. Multiple linear regression analyses revealed that for a one-unit increase in Childhood Trauma Questionnaire (CTQ) scores, average overall DUP increased by 25%. Higher CTQ scores also significantly predicted help-seeking and referral DUPs. Patients with schizophrenia-spectrum psychosis had longer help-seeking and total DUPs than those with affective psychosis. More severe positive symptoms predicted longer help-seeking DUPs, while more severe negative symptoms predicted longer referral DUPs. Indicators of social disadvantage did not affect DUP. Our results show that childhood trauma increases DUP by prolonging the help-seeking process and delaying access to mental healthcare even after help is sought. Early identification of psychosis among populations with trauma histories seems warranted and can likely positively impact outcomes.

Impact of childhood trauma on positive and negative symptom remission in first episode psychosis.

OBJECTIVE: Early life adversity is suspected to play an important role for onset and course of psychosis, but its relationship with longer-term clinical outcome is not entirely clear. In this longitudinal study, we investigated the impact of childhood trauma (CT) on positive and negative symptom remission in first episode psychosis (FEP) patients over two years. METHODS: A total of 210 FEP patients were assessed with the Childhood Trauma Questionnaire. Patients reporting moderate to severe trauma (CT; N = 114; 54.3%) were compared to those without trauma (N-CT; N = 96; 45.7%). Positive (PSR) and negative symptom remission (NSR) were determined monthly over 24 months following established criteria using the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Global Functioning was evaluated at baseline and 24 months of follow-up. RESULTS: Compared to N-CT patients, CT patients had achieved significantly lower rates of PSR at 12 months and significantly lower rates of NSR at 24 months. A dose-response relationship was observed between the number of trauma categories fulfilled and the number of patients not achieving PSR and NSR at these time points. Higher trauma scores were significantly associated with poor functioning and higher positive and negative symptom severity at 24 months, but not at baseline and 12 months of follow-up. CONCLUSION: Differential effects of CT on clinical outcome may not be apparent at psychosis onset, but only become evident through poor symptomatic remission and general functioning over time. Targeted diagnostic and therapeutic efforts after illness onset might limit these detrimental consequences.

Hippocampal activation during a cognitive task is associated with subsequent neuroendocrine and cognitive responses to psychological stress.

Increased activation of the hypothalamus pituitary adrenal (HPA) axis, marked by increased secretion of cortisol, is a biological marker of psychological stress. It is well established that the hippocampus plays an important role in the regulation of HPA axis activity. The relationship between cortisol (stress-related elevation or exogenous administration) and the hippocampal-related cognitive function is often examined. However, few human studies to date have examined the effect of stress on hippocampal activity and the interactions between stress-induced activation of the HPA axis and hippocampal function during different phases of cognitive function. On the basis of our previous work, we hypothesized that group differences in stress-sensitivity relate to differences in hippocampal-related stress-integration. To test this hypothesis, we conducted a functional MRI study using tasks known to involve the hippocampal formation: novel-picture encoding, psychological stress, and paired-picture recognition. On the basis of their cortisol responses to stress, we divided subjects into stress-responders (increase in cortisol, n = 9) and nonresponders (decrease in cortisol, n = 10). Responders showed higher hippocampal deactivation during the stress task and lower recognition scores due to a larger number of misses. Intriguingly, stress-responders showed significant differences in hippocampal activation already prior to stress, with higher levels of hippocampal activity during the picture encoding. Although effects of both cortisol and hippocampal activation on recognition were present in responders, similar effects were absent in the nonresponder group. Our results indicate that hippocampus plays an important role in adaptive behavioral responses. We hypothesize that states of hippocampal activation prior to stress might reflect states of vigilance or anxiety, which might be important for determining interindividual differences in subsequent stress response and cognitive performance.

Gender differences in childhood trauma in first episode psychosis: Association with symptom severity over two years.

Early life adversity is associated with increased risk for psychosis onset and poor clinical outcome. Male compared to female patients often show a more severe course of psychotic illness. The aim of the present study was to investigate gender differences in childhood trauma (CT) and their impact on symptomatic and functional outcome following psychosis onset. The study included 210 patients (144 men, 66 women) diagnosed with a first-episode of psychosis (FEP). Early adversity was assessed with the Childhood Trauma Questionnaire. Psychotic symptoms and general functioning were rated with the Brief Psychiatric Rating Scale and Global Assessment of Functioning scale at baseline, 12 and 24 months of follow-up in an established early intervention service. Male patients reported higher rates of physical or emotional neglect, whereas female patients indicated significantly higher rates of emotional abuse. More severe CT was related to higher levels of depression in women and to negative symptoms in men. Distinct CT effects were observed on positive and negative symptom severity and global functioning in male patients at 24 months. Emotional abuse was the strongest predictor of depression in both genders. In male patients only, emotional abuse predicted positive symptom severity and impaired global functioning, whereas emotional neglect predicted more severe negative symptoms. Our results suggest differences in CT experiences in male and female FEP patients, with a more pronounced impact on longer-term outcome in male patients. The findings support the notion that sex differences in stress vulnerability account for the relatively poor illness course in male psychosis patients.

Does an integrated outreach intervention targeting multiple stages of early psychosis improve the identification of individuals at clinical high risk?

AIMS: To explore the impact of a targeted case identification intervention, with training and education regarding first-episode psychosis and clinical high-risk syndromes, on the referral and identification of those at high risk. METHODS: Using a historical control design, referral information from pre-intervention and post-intervention periods was collected via administrative data and clinician notes from a catchment-based early psychosis service. RESULTS: A significant increase in the number of referrals sent to the service's clinical high-risk unit was observed following the intervention (P = 0.01). The proportion of referrals eligible was significantly higher post-intervention (P = 0.03), with the majority (26/44, 59.1%) referred via the first-episode psychosis service unit. CONCLUSIONS: An integrated outreach intervention for both first-episode psychosis and the clinical high-risk state was effective in increasing referrals of eligible cases to the service's at-risk unit. Rather than being stage-specific, targeted case identification strategies and service integration should span across the early stages of psychosis.

The Trier Social Stress Test in first episode psychosis patients: Impact of perceived stress, protective factors and childhood trauma.

Psychosis has been associated with abnormalities in hypothalamic-pituitary-adrenal axis functioning, which may emerge through heightened stress sensitivity following early life adversity - ultimately resulting in illness onset and progression. The present study assessed cortisol levels during an established psychosocial stress task and their association with current stress perception, putative protective factors and adverse childhood experiences in patients with a first episode of psychosis (FEP). A total of 100 volunteers participated in the study, 57 of whom were patients with a FEP (mean age 23.9 ± 3.8) and 43 healthy community controls (mean age 23.2 ± 3.9). Salivary cortisol, heart rate and blood pressure were measured at eight time points before and after the Trier Social Stress Test. Subjective stress and protective factors were assessed with the Perceived Stress Scale, the Self-Esteem Rating Scale and the Brief COPE. Early life adversity was assessed with the Childhood Trauma Questionnaire. Patients compared to controls showed significantly lower cortisol levels (F = 7.38; p = .008) throughout the afternoon testing period, but no difference in the cortisol response to the TSST. Heart rate was elevated and protective factors were lower in patients compared to controls. Attenuated cortisol levels were associated with higher levels of perceived stress, poor protective factors and more physical neglect during childhood. Our results suggest that attenuated baseline cortisol levels and not a blunted response during an acute stress task might be an indicator of heightened stress vulnerability and poor resilience in psychosis. The possible influence of childhood adversity and antipsychotic medication is discussed.

Individualized Prediction of Transition to Psychosis in 1,676 Individuals at Clinical High Risk: Development and Validation of a Multivariable Prediction Model Based on Individual Patient Data Meta-Analysis.

Background: The Clinical High Risk state for Psychosis (CHR-P) has become the cornerstone of modern preventive psychiatry. The next stage of clinical advancements rests on the ability to formulate a more accurate prognostic estimate at the individual subject level. Individual Participant Data Meta-Analyses (IPD-MA) are robust evidence synthesis methods that can also offer powerful approaches to the development and validation of personalized prognostic models. The aim of the study was to develop and validate an individualized, clinically based prognostic model for forecasting transition to psychosis from a CHR-P stage. Methods: A literature search was performed between January 30, 2016, and February 6, 2016, consulting PubMed, Psychinfo, Picarta, Embase, and ISI Web of Science, using search terms ("ultra high risk" OR "clinical high risk" OR "at risk mental state") AND [(conver* OR transition* OR onset OR emerg* OR develop*) AND psychosis] for both longitudinal and intervention CHR-P studies. Clinical knowledge was used to a priori select predictors: age, gender, CHR-P subgroup, the severity of attenuated positive psychotic symptoms, the severity of attenuated negative psychotic symptoms, and level of functioning at baseline. The model, thus, developed was validated with an extended form of internal validation. Results: Fifteen of the 43 studies identified agreed to share IPD, for a total sample size of 1,676. There was a high level of heterogeneity between the CHR-P studies with regard to inclusion criteria, type of assessment instruments, transition criteria, preventive treatment offered. The internally validated prognostic performance of the model was higher than chance but only moderate [Harrell's C-statistic 0.655, 95% confidence interval (CIs), 0.627-0.682]. Conclusion: This is the first IPD-MA conducted in the largest samples of CHR-P ever collected to date. An individualized prognostic model based on clinical predictors available in clinical routine was developed and internally validated, reaching only moderate prognostic performance. Although personalized risk prediction is of great value in the clinical practice, future developments are essential, including the refinement of the prognostic model and its external validation. However, because of the current high diagnostic, prognostic, and therapeutic heterogeneity of CHR-P studies, IPD-MAs in this population may have an limited intrinsic power to deliver robust prognostic models.

Sex differences in the cortisol response to awakening in recent onset psychosis.

A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has been suggested as a factor in the etiology and exacerbation of psychosis, but has not been reported consistently. Sex differences are apparent in many aspects of psychotic disorders and may explain some of the equivocation associated with the regulation of the HPA axis in the illness. The present study compared the cortisol response to awakening (CRA) in 27 patients (16 men and 11 women) with recent onset of psychosis (within the past 2 years) and 40 age and gender matched controls. Within the patient group, we also assessed the relationship between the CRA and positive and negative symptoms of psychosis, anxiety and depression. The CRA in patients was not significantly different from controls. However, within the patient group, we observed a significant sex difference, with a blunted cortisol response to awakening in men but not in women (F=7.26; p<0.002). This difference could not be explained by differences between male and female patients in awakening time, medication, or diagnosis of schizophrenia vs. affective psychosis. Cortisol levels were not related to symptom measures. Our findings demonstrate a dysregulation of the HPA axis in male patients with recent onset of psychosis. This sex specificity might be related to and explain in part the unfavorable course of the illness observed in men.

A study on negative and depressive symptom prevalence in individuals at ultra-high risk for psychosis.

BACKGROUND: Negative symptoms are known to be present in the prodromal stage of psychotic disorders, yet little is known about their prevalence. Studies examining the presence of negative symptoms in ultra-high risk (UHR) populations have shown some limitations, notably failing to control depression. The objective of this study was to examine the prevalence of negative symptoms in the presence of significant levels of depression and in the absence of such symptoms (primary negative symptoms) over 1 year and to examine differences in negative symptoms in psychosis converters and non-converters. METHODS: Participants were 123 individuals at UHR for the development of psychosis receiving follow-up for a period of 2 years. Negative symptoms and depression were measured using the Scale for the Assessment of Negative Symptoms and the Montgomery-Asberg Depression Scale at baseline, 6 and 12 months post-admission. RESULTS: At baseline, the prevalence of negative symptoms and primary negative symptoms was 76.4% and 32.7%, respectively. Whereas the prevalence of negative symptoms was significantly decreased at 6 months, the prevalence of primary negative symptoms was similar at all time points. Negative symptoms at baseline were not different between later converters and non-converters to psychosis. CONCLUSION: Our findings confirm the presence of secondary and primary negative symptoms in individuals at UHR, but suggest a differential trajectory of both measures over time. Future studies should include larger UHR groups and focus on the investigation of intra-individual changes in primary negative symptoms over time and further explore their potential role for psychosis conversion.

Outcome in patients converting to psychosis following a treated clinical high risk state.

AIM: We explored 2-year outcomes in a sample of clinical high risk (CHR) patients who converted to psychosis despite receiving interventions. METHODS: Of 167 CHR patients, 18 had converted to psychosis and received treatment for their first episode of psychosis in an early intervention service over 2 years. RESULTS: Compared to patients admitted directly to the same early intervention service without having been identified as CHR prior to onset of psychosis, CHR converters were in remission for fewer months (M = 5 vs M = 10); were more likely to be prescribed more than 1 antipsychotic medication (90% vs 68%) and to receive clozapine treatment (38% vs 2%) over 2 years. CONCLUSIONS: CHR patients who convert to psychosis may be inherently more resistant to comprehensive treatment and may have poorer outcomes. Conversion to psychosis from a state of CHR can be reduced to a rate of 10%-12% following interventions, yet outcomes for patients who convert despite such interventions remain unexplored.

The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men.

In aged and pathological populations, reduced hippocampal volume is frequently described in association with impairment of hippocampus-dependent cognitive processes and chronically elevated cortisol levels. Recent studies in young healthy subjects show a negative association between hippocampal volume and memory. The aim of the present study was to investigate the associations among hippocampal volume, cortisol levels and memory performance in a group of healthy young men. Hippocampal volume was determined by manual segmentation of high-resolution 3D Magnetic Resonance Images from 13 subjects. Stress-induced cortisol levels in response to the "Trier Social Stress Test" (TSST) as well as the cortisol response to awakening (CRA) over four weeks were assessed. Declarative memory performance was tested before and after exposure to the TSST. The results show that larger hippocampal volume was associated with a significantly stronger cortisol increase in response to the TSST and a significantly greater CRA. Moreover, larger hippocampal volume was associated with significantly lower memory performance before the TSST. Our results challenge the direction of the frequently observed relationships among hippocampal volume, cortisol reactivity and memory performance and question the relevance of findings in clinical and aged subjects for young healthy populations.

The neural diathesis-stress model of schizophrenia revisited: An update on recent findings considering illness stage and neurobiological and methodological complexities.

Over the past decade, our understanding of the role of stress in serious mental illness has become more sophisticated. In this paper, we revisit the neural diathesis-stress model of schizophrenia that was initially proposed in 1997 and updated in 2008. In light of cumulative research findings, we must now encompass evidence on the premorbid periods of psychosis, and our more nuanced understanding of hypothalamic-pituitary-adrenal (HPA) axis function and its association with neurodevelopmental, epigenetic, neurotransmitter, and inflammatory processes, as well as brain structure and function. Giving consideration to the methodological complexities that have become more apparent as research in this area has burgeoned, the various indices of HPA axis function, and the different stages of illness, we review relevant research published since the 2008 update of the model. We conclude by proposing an extended neural diathesis-stress model that addresses the broader neurobiological context of stress psychobiology in psychosis progression. Implications of this model for best practice, with regards to both future research and treatment strategies, are discussed.

Neuroanatomical and Symptomatic Sex Differences in Individuals at Clinical High Risk for Psychosis.

Sex differences have been widely observed in clinical presentation, functional outcome and neuroanatomy in individuals with a first-episode of psychosis, and chronic patients suffering from schizophrenia. However, little is known about sex differences in the high-risk stages for psychosis. The present study investigated sex differences in cortical and subcortical neuroanatomy in individuals at clinical high risk (CHR) for psychosis and healthy controls (CTL), and the relationship between anatomy and clinical symptoms in males at CHR. Magnetic resonance images were collected in 26 individuals at CHR (13 men) and 29 CTLs (15 men) to determine total and regional brain volumes and morphology, cortical thickness, and surface area (SA). Clinical symptoms were assessed with the brief psychiatric rating scale. Significant sex-by-diagnosis interactions were observed with opposite directions of effect in male and female CHR subjects relative to their same-sex controls in multiple cortical and subcortical areas. The right postcentral, left superior parietal, inferior parietal supramarginal, and angular gyri [<5% false discovery rate (FDR)] were thicker in male and thinner in female CHR subjects compared with their same-sex CTLs. The same pattern was observed in the right superior parietal gyrus SA at the regional and vertex level. Using a recently developed surface-based morphology pipeline, we observed sex-specific shape differences in the left hippocampus (<5% FDR) and amygdala (<10% FDR). Negative symptom burden was significantly higher in male compared with female CHR subjects (p = 0.04) and was positively associated with areal expansion of the left amygdala in males (<5% FDR). Some limitations of the study include the sample size, and data acquisition at 1.5 T. This study demonstrates neuroanatomical sex differences in CHR subjects, which may be associated with variations in symptomatology in men and women with psychotic symptoms.

The Clinic for Assessment of Youth at Risk (CAYR): 10 years of service delivery and research targeting the prevention of psychosis in Montreal, Canada.

AIM: In the context of an increasing focus on indicated prevention of psychotic disorders, we describe the operation of the Clinic for Assessment of Youth at Risk (CAYR) over 10 years, a specialized service for identification, monitoring and treatment of young individuals who meet ultra-high risk (UHR) criteria for psychosis, and its integration within the Prevention and Early Intervention Program for Psychosis (PEPP) in Montreal, Canada. METHODS: We outline rationale, development, inclusion and exclusion criteria, assessment, services offered, community outreach and liaison with potential referral sites, and our research focus on risk and protective factors related to the neural diathesis-stress model of psychosis. RESULTS: Between January 2005 and December 2014, CAYR has received 370 referrals and accepted 177 patients who met UHR criteria based on the Comprehensive Assessment for At Risk Mental States. Conversion rates to a first episode of psychosis were 11%. Our research findings point to high subjective stress levels, poor self-esteem, social support and coping skills, and a dysregulation of the hypothalamus-pituitary-adrenal axis during the high-risk phase. CONCLUSIONS: Our efforts at community outreach have resulted in increasing numbers of referrals and patients accepted to CAYR, highlighting the relevance of and need for a high-risk programme in the Montreal area. Patients with psychotic symptoms can be immediately assigned to the first-episode psychosis clinic within PEPP, which has likely contributed to the low conversion rates observed in the UHR group. Our research findings on stress and protective factors emphasize the importance of psychosocial interventions for high-risk patients.

Reduced hippocampal volume and hypothalamus-pituitary-adrenal axis function in first episode psychosis: evidence for sex differences.

BACKGROUND: Hippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms. METHODS: Fifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale. RESULTS: Male patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning. CONCLUSIONS: We propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.

Self-reported depressive symptoms and stress levels in healthy young men: associations with the cortisol response to awakening.

OBJECTIVE: There is evidence that clinical depression and negative mood are associated with elevated basal cortisol levels. Recently, measuring the cortisol response during the first hour in the morning with strict reference to the time of awakening was established as a reliable marker of individual adrenocortical activity. In studies using this marker, a relationship with self-reported stress levels and psychosomatic symptoms has been found. The goal of the present study was to investigate the association of self-reported depressive symptomatology with early morning free cortisol levels and their relationship to measures of stress. METHODS: We assessed the severity of depressive symptoms using the Hamilton Depression Inventory and chronic and acute stress perception in 40 healthy young men. Once a week, for 4 consecutive weeks, subjects provided saliva samples collected at 0, 30, and 60 minutes after awakening. RESULTS: Higher levels of depressive symptomatology were associated with a greater cortisol response after awakening. This association seemed to be stronger when only subjects in the nonclinical range of depression were included. Furthermore, cortisol levels and depressive symptomatology were significantly positively correlated with measures of chronic and acute stress perception. CONCLUSIONS: The present study extends earlier findings of hypothalamus-pituitary-adrenal axis hyperactivity in clinical depression to healthy young men with mild levels of depressive symptomatology. Measuring the cortisol response to awakening is proposed as an economical alternative to traditional approaches for determining basal hypothalamus-pituitary-adrenal axis activity. Associations between depressive symptomatology and chronic stress, as well as implications for future studies, are discussed.