Background Studies of biomarkers of hypothalamic-pituitary-adrenal (HPA) activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy controls and individuals who meet clinical high risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be; a) elevated in the CHR group relative to controls, b) positively correlated with symptom severity, and c) most elevated in CHR patients who transition to psychotic level severity. Methods Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study (NAPLS). The present CHR sample included 256 individuals meeting Structured Interview for Prodromal Syndromes (SIPS) criteria, and 141 controls, all of whom underwent baseline assessment and measurement of salivary cortisol. Results Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance (ANCOVA) showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and ANCOVA revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared to healthy controls and CHR subjects who remitted. Conclusions The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of HPA activity in prediction of conversion to psychosis, and its relation with other biomarkers of risk, should receive attention in future research.

The notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored.

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Objective: Substantial converging evidence from schizophrenia researchers indicates that the duration of untreated psychosis (DUP) represents a modifiable predictor of outcome during the early course of schizophrenia. As DUP is increasingly assessed in research settings, focused attention should be given to the complexities of measurement of this critical construct. In this review, three aspects of measurement are addressed: (i) definition of DUP, (ii) operational criteria for the construct, and (iii) methods used for measurement. Recent advances, current limitations and future directions are discussed.Methods: Inclusion of published articles for this systematic review was based on two recent seminal meta-analyses examining associations between DUP and outcomes. Other relevant articles were reviewed to glean information on standardized instruments used to date and limitations regarding measurement of DUP.Results: Whereas the general definition of the DUP construct has been quite consistent across research groups, considerable variability exists in the operationalizations of the onset and endpoint of DUP. Several standardized instruments have been developed to measure DUP, although many articles fail to discuss reliability and validity of measurements. The literature lacks comparative assessments of the relative reliability and validity of the various measures and methods used to assess DUP. Conclusions:Given the importance of DUP and implications for secondary prevention, the complicated measurement issues that arise in quantifying this construct are addressed. A number of important advances from a variety of research groups have made the systematic assessment of DUP feasible and of great value for early psychosis research. Yet, several limitations must be considered as measurement of DUP progresses.

The diagnostic boundaries between autistic-and schizophrenia-spectrum disorders have varied over the years, and some overlap in diagnostic criteria persists. The present study examined childhood and current signs of autistic disorder (AD) in adolescents with schizotypal personality disorder (SPD) or other personality disorders, as well as healthy controls. A structured interview was administered to rate participants' current symptoms. Participants' guardians were interviewed with the Autism Diagnostic Inventory-Revised (ADI-R), a clinical assessment of childhood and current autistic signs. Compared to both the other personality-disordered and healthy groups, adolescents with SPD were rated as having significantly more impairment on childhood and current social functioning, and having more unusual interests and behaviors. For the entire sample, impaired childhood social functioning and unusual interests and behaviors were associated with higher negative symptom scores. Current impairments in social functioning, unusual interests and behaviors, and communication were also linked with greater negative symptoms. However, neither childhood nor current autistic features significantly predicted later conversion to an Axis I psychotic disorder over the course of three years of follow-up. The findings indicate that past and current autistic signs are more common in adolescents with SPD, but neither current nor childhood autistic features are linked with conversion to psychosis.

There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet, similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that 1) CHR individuals manifest higher self-reported stress in response to both LE and DH, when compared to healthy controls (HC), 2) group differences in self-reported stress increase with age, 3) baseline self-reported stress is associated with follow-up clinical status, and 4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N= 314) reported exposure to more LE when compared to the HC group (N=162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the “prodromal” phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors.

Schizotypal personality disorder is characterized by interpersonal and verbal communication deficits. Despite the important role of gesture in social communication, no published reports examine the use of gesture by individuals with SPD. In this study, raters code gesture from videotaped interviews of unmedicated adolescents with SPD, other personality disorders, or no Axis II disorder. Results indicate that SPD adolescents show significantly fewer gestures but do not differ from the other groups in overall rate of movement. The findings are discussed in light of brain regions involved in dysfunction, parallels to schizophrenia, and treatment implications.

The notion that adolescence is characterized by dramatic changes in behavior, and often by emotional upheaval, is widespread and longstanding in popular western culture. In recent decades, this notion has gained increasing support from empirical research showing that the peri- and post-pubertal developmental stages are associated with a significant rise in the rate of psychiatric symptoms and syndromes. As a result, interest in adolescent development has burgeoned among researchers focused on the origins of schizophrenia and other psychotic disorders. Two factors have fueled this trend: 1) increasing evidence from longitudinal research that adolescence is the modal period for the emergence of “prodromal” manifestations, or precursors of psychotic symptoms, and 2) the rapidly accumulating scientific findings on brain structural and functional changes occurring during adolescence and young adulthood. Further, gonadal and adrenal hormones are beginning to play a more prominent role in conceptualizations of adolescent brain development, as well as in the origins of psychiatric symptoms during this period (Walker and Bollini, 2002; Walker et al., 2008). In this paper, we begin by providing an overview of the nature and course of psychotic disorders during adolescence/young adulthood. We then turn to the role of hormones in modulating normal brain development, and the potential role they might play in the abnormal brain changes that characterize youth at clinical high-risk (CHR) for psychosis. The activational and organizational effects of hormones are explored, with a focus on how hormone-induced changes might be linked with neuropathological processes in the emergence of psychosis.