Hanan D. Trotman

Stress and neurodevelopmental processes in the emergence of psychosis

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.

Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study

BACKGROUND Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) 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. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, 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 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 analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects 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 hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research.

The impact of a family history of psychosis on age-at-onset and positive and negative symptoms of schizophrenia: A meta-analysis

The results of research on the relation of family history (FH) of psychosis with clinical presentation in schizophrenia have been mixed. To date, there have been no comprehensive reviews that have examined this body of research. The current review quantitatively evaluates research on the relation of FH with two aspects of schizophrenia, age-at-onset and symptom presentation. Studies investigating the influence of a FH on age-at-onset (N=15 studies), age-at-onset and sex (N=12 studies), and/or positive (N=11 studies) and negative symptoms (N=12 studies) in patients with schizophrenia were included in the meta-analyses. Results showed that FH has a small but significant impact on age-at-onset as well as negative symptoms. Of most interest was the finding that sex differences in age-at-onset are not observed in samples with a FH. Furthermore, there was a significant interaction between FH and sex with respect to negative symptoms. The findings of the current review are discussed in light of the diathesis-stress model. Theoretical assumptions and empirical research are reviewed to support the notion that FH influences susceptibility and presentation through similar mechanisms. Implications of the current findings, limitations of the review, and directions for future research are highlighted.

Defining, operationalizing and measuring the duration of untreated psychosis: advances, limitations and future directions

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.

Gesture behavior in unmedicated schizotypal adolescents

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.

Neurocognition and Conversion to Psychosis in Adolescents At High-Risk

This study examined neurocognitive predictors of conversion to Axis I psychosis among adolescents at high-risk for psychosis (AHRP). There were no significant differences in neurocognitive performance between adolescents at high-risk for psychosis who converted (AHRP+) and adolescents at high-risk for psychosis who did not convert (AHRP-). Within-sex comparisons revealed a relation between risk status and performance among females, with AHRP+ performing below AHRP-, but this effect did not hold for males. Between-sex comparisons revealed AHRP- males performed worse than AHRP- females on several measures. Across groups, males performed better than their female counterparts on select measures. Results are discussed in terms of implications for use of neurocognitive profiles as bio-risk markers of psychosis, while considering sex differences.

Stress and the Prodromal Phase of Psychosis

Stress plays a role in most conceptualizations of the etiology of psychotic disorders. This is based on extensive research showing an association between the incidence of psychosis and psychosocial stress exposure (e.g., stressful life events and trauma) both in childhood and the weeks preceding a psychotic episode. There is also evidence of increased sensitivity to stressful events and dysregulation of biological stress systems. To better understand the relation of stress with the initial emergence of psychosis, research has increasingly focused on the psychosis prodrome, the period of functional decline that precedes clinical illness. Preliminary results suggest that increased incidence of early childhood trauma, heightened sensitivity to psychosocial stress, and dysregulation of biological stress response systems are present in the prodrome and associated with the onset and severity of psychosis. The current paper reviews this research and discusses the possible mechanisms responsible for these associations. This discussion includes the possible effect of stress on the hypothalamic-pituitary-adrenal [HPA] axis and hippocampus, and the role adolescent developmental changes may play in mediating this effect. Further longitudinal research combining clinical and biological measures of stress with techniques designed to assess developmental change in neural structure and function, cellular mechanisms, and genetic and epigenetic factors are critical for elucidating the role stress plays in the pathophysiology of psychotic illness.

Catechol-O-methyltransferase modulation of cortisol secretion in psychiatrically at-risk and healthy adolescents.

Objective Recent research implicates the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism in stress sensitivity, through modulation of hypothalamic-pituitary-adrenal (HPA) function. In healthy samples, Met homozygosity has been associated with greater HPA activity (i.e., cortisol) and stress sensitivity, though findings are mixed among clinical samples. To date, there are no reports examining baseline or longitudinal changes in HPA activity as a function of COMT genotype in youth. This study tested the hypothesis that COMT genotype would be associated with cortisol secretion in normal and at-risk adolescents; specifically, that COMT genotype would be linked in a dose-response manner such that Met homozygotes would have the highest salivary cortisol levels, followed by heterozygotes, then Val homozygotes. In addition, this study examined the relation of COMT genotype with longitudinal changes in cortisol. Methods This study examined the association of COMT with salivary cortisol across a 1-year period in healthy and at-risk adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision Axis II diagnoses. Results Results indicated higher cortisol levels for Met homozygotes (compared with heterozygotes and Val homozygotes) at the 1-year follow-up, and increased mean cortisol levels across a 1-year period among Met carriers, suggesting that COMT associates with differences in cortisol secretion during adolescence. Conclusion Findings are discussed with respect to COMT genotype as a potential genetic indicator of psychiatric risk that modulates developmental changes in HPA activity.

Impaired insight in patients with newly diagnosed nonaffective psychotic disorders with and without deficit features

Patients with schizophrenia who have primary, enduring negative symptoms, or the deficit syndrome, have poorer psychosocial functioning but lesser clinical distress compared with nondeficit patients. Poor awareness of impairment in patients with deficit schizophrenia may contribute to this seeming contradiction. We hypothesized that poor insight would be present early in the course of illness in deficit patients, and that those with deficit features would have greater impairment in insight than those without deficit features. One-hundred one first-episode patients with nonaffective psychotic disorders were categorized into deficit (n=31) and nondeficit (n=70) groups. The deficit patients had significantly poorer insight than nondeficit patients when rated using a self-report questionnaire, and nearly significantly poorer insight rated by clinical researchers. Further, this effect remained for self-rated insight and reached statistical significance for researcher-rated insight after controlling for positive, negative, and general psychopathology symptoms. These results suggest that the treatment of deficit patients may be particularly complicated by poor insight.

Developmental mechanisms in the prodrome to psychosis

Psychotic disorders continue to be among the most disabling and scientifically challenging of all mental illnesses. Accumulating research findings suggest that the etiologic processes underlying the development of these disorders are more complex than had previously been assumed. At the same time, this complexity has revealed a wider range of potential options for preventive intervention, both psychosocial and biological. In part, these opportunities result from our increased understanding of the dynamic and multifaceted nature of the neurodevelopmental mechanisms involved in the disease process, as well as the evidence that many of these entail processes that are malleable. In this article, we review the burgeoning research literature on the prodrome to psychosis, based on studies of individuals who meet clinical high risk criteria. This literature has examined a range of factors, including cognitive, genetic, psychosocial, and neurobiological. We then turn to a discussion of some contemporary models of the etiology of psychosis that emphasize the prodromal period. These models encompass the origins of vulnerability in fetal development, as well as postnatal stress, the immune response, and neuromaturational processes in adolescent brain development that appear to go awry during the prodrome to psychosis. Then, informed by these neurodevelopmental models of etiology, we turn to the application of new research paradigms that will address critical issues in future investigations. It is expected that these studies will play a major role in setting the stage for clinical trials aimed at preventive intervention.