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.
Importance Neurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the “near-psychotic”, prodromal, clinical high-risk (CHR) state is necessary to develop accurate predictors of psychosis and more effective and potentially preventative treatments. Objective Identify core neurocognitive dysfunctions associated with the CHR phase, and measure the ability of neurocognitive tests to predict the transition to psychosis. Determine if the neurocognitive deficits are robust or explained by potential confounders. Design Case control study. Baseline neurocognitive functioning collected from 2008–2012 in the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). Setting A consortium of eight university-based, outpatient programs studying the psychosis prodrome in North America. Participants CHR individuals (n=689) and healthy controls (HCs, n=264) consisting of 137 male and 127 female HC and 398 male and 291 female CHR individuals ages 12–35. Interventions or Exposures A naturalistic, observational study. Main Outcome and Measure(s) Neurocognitive differences between those who did and did not transition to psychosis, differences between medicated and unmedicated groups, and time to conversion. Nineteen neuropsychological tests and four factors derived from factor analysis. Results The factors were Executive Function/Visual-Spatial, Verbal, Attention/Working Memory, and Declarative Memory. Amongst widespread mild to moderate impairments, CHR individuals were significantly impaired compared to HCs on Attention/Working Memory and Declarative Memory. CHR converters had large Declarative Memory and Attention/Working Memory deficits (Cohen’s d = ~0.8, p <.001) compared with controls and were significantly worse on these dimensions than non-converters. In Cox regression, impaired Declarative Memory and high Verbal (premorbid) ability in addition to age, site and positive psychotic symptoms, significantly predicted time to conversion in those who later transitioned to psychosis. The pattern of impairments could not be accounted for by premorbid or current general cognitive ability, medications, current depression, alcohol or cannabis abuse. Conclusions and Relevance Neurocognitive impairment is a robust characteristic of CHR individuals, especially those who later develop psychosis. Tests tapping verbal and visual declarative memory and attention/working memory were most sensitive to imminent psychosis amongst those at CHR. Interventions targeting the enhancement of neurocognitive functioning are warranted in this population.
Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research on the manifestation of these symptoms in 22q11.2DS patients, and no studies of differences in prodromal symptom patterns between genetically and behaviorally defined at-risk groups. In this study, demographically-matched groups of 23 SPD, 23 22q11.2DS, and 23 control participants were administered the Structured Interview for Prodromal Syndromes (SIPS). Both risk groups showed elevated positive, negative, disorganized, and general prodromal symptoms, as well as elevations on 10 of the same individual symptom items, relative to the control group. Approximately 60% of individuals in the 22q11.2DS group and 70% of individuals in the SPD group met symptom criteria for a prodromal psychosis syndrome. The 22q11.2DS group scored significantly higher than the SPD group on the “decreased ideational richness” item and showed a trend toward greater motor abnormalities. The results suggest that these two high-risk groups are similar in prodromal symptom presentation, possibly as a result of overlapping causal mechanisms, and that standardized measures of prodromal syndromes like the SIPS can be used to identify 22q11.2DS patients at greatest risk for conversion to psychosis.
The psychosis prodrome, or period of clinical and functional decline leading up to acute psychosis, offers a unique opportunity for identifying mechanisms of psychosis onset and testing early intervention strategies. We summarize major findings and emerging directions in prodromal research and provide recommendations for clinicians working with individuals suspected to be at high risk for psychosis. The past two decades of research have led to three major advances. First, tools and criteria have been developed that can reliably identify imminent risk for a psychotic disorder. Second, longitudinal clinical and psychobiological data from large multisite studies are strengthening individual risk assessment and offering insights into potential mechanisms of illness onset. Third, psychosocial and pharmacological interventions are demonstrating promise for delaying or preventing the onset of psychosis in help-seeking, high-risk individuals. The dynamic psychobiological processes implicated in both risk and onset of psychosis, including altered gene expression, cognitive dysfunction, inflammation, gray and white matter brain changes, and vulnerability-stress interactions suggest a wide range of potential treatment targets and strategies. The expansion of resources devoted to early intervention and prodromal research worldwide raises hope for investigating them. Future directions include identifying psychosis-specific risk and resilience factors in children, adolescents, and non-help-seeking community samples, improving study designs to test hypothesized mechanisms of change, and intervening with strategies that better engage youth, their environmental contexts, and neurodevelopmental targets to improve functional outcomes. Prospective research on putatively prodromal samples has the potential to substantially reshape our understanding of mental illness and our efforts to combat it.
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