Research on serious mental disorders, particularly psychosis, has revealed highly variable symptom profiles and developmental trajectories prior to illness-onset. As Dante Cicchetti pointed out decades before the term “transdiagnostic” was widely used, the pathways to psychopathology emerge in a system involving equifinality and multifinality. Like most other psychological disorders, psychosis is associated with multiple domains of risk factors, both genetic and environmental, and there are many transdiagnostic developmental pathways that can lead to psychotic syndromes. In this article, we discuss our current understanding of heterogeneity in the etiology of psychosis and its implications for approaches to conceptualizing etiology and research. We highlight the need for examining risk factors at multiple levels and to increase the emphasis on transdiagnostic developmental trajectories as a key variable associated with etiologic subtypes. This will be increasingly feasible now that large, longitudinal datasets are becoming available and researchers have access to more sophisticated analytic tools, such as machine learning, which can identify more homogenous subtypes with the ultimate goal of enhancing options for treatment and preventive intervention.

Childhood adversity is associated with poor mental and physical health outcomes across the life span. Alterations in the hypothalamic–pituitary–adrenal axis are considered a key mechanism underlying these associations, although findings have been mixed. These inconsistencies suggest that other aspects of stress processing may underlie variations in this these associations, and that differences in adversity type, sex, and age may be relevant. The current study investigated the relationship between childhood adversity, stress perception, and morning cortisol, and examined whether differences in adversity type (generalized vs. threat and deprivation), sex, and age had distinct effects on these associations. Salivary cortisol samples, daily hassle stress ratings, and retrospective measures of childhood adversity were collected from a large sample of youth at risk for serious mental illness including psychoses (n = 605, mean age = 19.3). Results indicated that childhood adversity was associated with increased stress perception, which subsequently predicted higher morning cortisol levels; however, these associations were specific to threat exposures in females. These findings highlight the role of stress perception in stress vulnerability following childhood adversity and highlight potential sex differences in the impact of threat exposures.

OBJECTIVES/SPECIFIC AIMS: Negative symptoms of schizophrenia, including motivational deficits, social withdrawal, poverty of speech, decreased emotional reactivity, and psychomotor retardation, have been shown to be most predictive of functional impairment and poor outcome in patients with schizophrenia. Furthermore, these symptoms tend not to be responsive to antipsychotic medications. Inflammation could be one mechanism underlying these difficult to treat symptoms. METHODS/STUDY POPULATION: Three cohorts of patients, reflecting different phases of disease, were studied. One cohort was comprised of a sample of patients with deficit schizophrenia (characterized by primary and enduring negative symptoms; n=17), nondeficit patients (n=39), and healthy controls (n=28). ANOVA and multivariate general linear models were used to compare groups, and linear regression models were used to examine relationships between inflammatory cytokines and negative symptoms. The second cohort was comprised of 80 individuals at clinical high risk for psychosis from the North American Prodromal Longitudinal Study. Linear regression models examined the relationship between baseline inflammatory markers and subsequent negative symptoms at follow-up visits up to 2 years. The third cohort consisted of patients with treatment-resistant schizophrenia (TRS) on clozapine (n=10). Correlations were performed to examine relationships between inflammatory markers and negative symptoms. In a subgroup of patients from this third sample, resting state functional connectivity analyses were performed on fMRI data to explore relationships between inflammatory markers and connectivity in brain reward circuitry. RESULTS/ANTICIPATED RESULTS: In a sample of patients with the deficit syndrome of schizophrenia (n=17), a subtype of the disorder characterized by primary and enduring negative Symptoms, tumor necrosis factor (TNF) was significantly increased relative to nondeficit patients (n=39) and healthy controls (n=28; F2,57=3.51, p=0.036), and predicted total negative symptoms (β=0.31, p=0.012), alogia (β=0.30, p=0.024), and blunted affect (β=0.31, p=0.018) items of the Positive and Negative Symptom Scale in linear regression models while controlling for antipsychotics. In another sample of individuals at clinical-high risk for psychosis (n=80), baseline concentrations of TNF significantly predicted negative symptoms, including anhedonia, apathy, and loss of interest in linear regression models, at the 6-month (β=0.25, p=0.011) and 12-month follow-up (β=0.39, p=0.001). Interleukin (IL)-1 receptor antagonist also predicted these symptoms at the 6-month follow-up (β=0.21, p=0.037). In a third sample (n=10) of patients with TRS treated with clozapine, IL-1β was correlated with passive/apathetic social withdrawal (r=0.657, p=0.039) and disturbance of volition (r=0.686, p=0.029) items of the Positive and Negative Symptom Scale and the global avolition-apathy scores of the Scale for the Assessment of Negative Symptoms (r=0.751, p=0.012). Finally, in a small subsample (n=5) of patients from this TRS cohort for whom we collected fMRI data, we found resting-state functional connectivity from a right nucleus accumbens seed to a cluster in medial prefrontal cortex. We found relationships between higher inflammation and decreased connectivity for TNF (r=−0.64) and CRP (r=−0.89). DISCUSSION/SIGNIFICANCE OF IMPACT: Taken together, these preliminary data show the predicted relationship between inflammatory markers and negative symptoms and demonstrate the reproducibility of TNF and other monocytic-derived cytokines as reliably elevated in schizophrenia and associated with negative symptoms across samples of patients with schizophrenia and individuals at high risk for psychosis. Cytokines may exert their effects via their impact on brain reward circuitry, and could represent novel treatment targets for motivational deficits and negative symptoms of schizophrenia.

The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12–23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p = .001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p < .001). A similar period of stagnation was apparent for role functioning, but to a lesser extent (p = .007). The results remained consistent when we accounted for the time to conversion. Our findings suggest that CHR-C start lagging behind CHR-NC in social and role functioning in adolescence, followed by a period of further stagnation in adulthood.

Accumulating behavioral and genetic research suggests that most forms of psychopathology share common genetic and neural vulnerabilities and are manifestations of a relatively few core underlying processes. These findings support the view that comorbidity mostly arises, not from true co-occurrence of distinct disorders, but from the behavioral expression of shared vulnerability processes across the life span. The purpose of this review is to examine the role of the prefrontal cortex (PFC) in the shared vulnerability mechanisms underlying the clinical phenomena of comorbidity from a transdiagnostic and ontogenic perspective. In adopting this perspective, we suggest complex transactions between neurobiologically rooted vulnerabilities inherent in PFC circuitry and environmental factors (e.g., parenting, peers, stress, and substance use) across development converge on three key PFC-mediated processes: executive functioning, emotion regulation, and reward processing. We propose that individual differences and impairments in these PFC-mediated functions provide intermediate mechanisms for transdiagnostic symptoms and underlie behavioral tendencies that evoke and interact with environmental risk factors to further potentiate vulnerability.

Background: Schema Theory proposes that the development of maladaptive schemas are based on a combination of memories, emotions and cognitions regarding oneself and one's relationship to others. A cognitive model of psychosis suggests that schemas are crucial to the development and persistence of psychosis. Little is known about the impact that schemas may have on those considered to be at clinical high risk (CHR) of developing psychosis. Aims: To investigate schemas over time in a large sample of CHR individuals and healthy controls. Method: Sample included 765 CHR participants and 280 healthy controls. Schemas were assessed at baseline, 6 and 12 months using the Brief Core Schema Scale (BCSS). Baseline schemas were compared to 2-year clinical outcome. Results: CHR participants evidenced stable and more maladaptive schemas over time compared to controls. Schemas at initial contact did not vary amongst the different clinical outcome groups at 2 years although all CHR outcome groups evidenced significantly worse schemas than healthy controls. Although there were no differences on baseline schemas between those who later transitioned to psychosis compared to those who did not, those who transitioned to psychosis had more maladaptive negative self-schemas at the time of transition. Associations between negative schemas were positively correlated with earlier abuse and bullying. Conclusions: These findings demonstrate a need for interventions that aim to improve maladaptive schemas among the CHR population. Therapies targeting self-esteem, as well as schema therapy may be important work for future studies.

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.

Deterioration in premorbid functioning is a common feature of schizophrenia, but sensitivity to psychosis conversion among clinical high-risk samples has not been examined. This study evaluates premorbid functioning as a predictor of psychosis conversion among a clinical high-risk sample, controlling for effects of prior developmental periods. Participants were 270 clinical high-risk individuals in the North American Prodrome Longitudinal Study—I, 78 of whom converted to psychosis over the next 2.5 years. Social, academic, and total maladjustment in childhood, early adolescence, and late adolescence were rated using the Cannon–Spoor Premorbid Adjustment Scale. Early adolescent social dysfunction significantly predicted conversion to psychosis (hazard ratio = 1.30, p = .014), independently of childhood social maladjustment and independently of severity of most baseline positive and negative prodromal symptoms. Baseline prodromal symptoms of disorganized communication, social anhedonia, suspiciousness, and diminished ideational richness mediated this association. Early adolescent social maladjustment and baseline suspiciousness together demonstrated moderate positive predictive power (59%) and high specificity (92.1%) in predicting conversion. Deterioration of academic and total functioning, although observed, did not predict conversion to psychosis. Results indicate early adolescent social dysfunction to be an important early predictor of conversion. As such, it may be a good candidate for inclusion in prediction algorithms and could represent an advantageous target for early intervention.

The observations of family members as well as the results of past research suggest that a variety of developmental pathways can precede the onset of schizophrenia in early adulthood. In this article, we describe recent findings from our research on the childhood precursors of schizophrenia. Taken together, the results indicate that childhood behavioral, emotional, and motoric dysfunction occur at a higher rate in preschizophrenia subjects when compared to control subjects. Further, there are developmental changes as well as significant variability among schizophrenia patients in the nature and severity of childhood impairment. Drawing on the prevailing diathesis-stress model, we explore the moderating role that stress exposure and reactivity may play in the expression of the organic diathesis for schizophrenia. Specifically, we consider the role of the biological stress response in the production of developmental changes and individual differences in the pathways to schizophrenia. Given extant models of dopamine involvement in the neuropathology of schizophrenia, stress-induced Cortisol release may alter the expression of subcortical abnormalities in dopamine neurotransmission. Thus, we present a neural mechanism for the hypothesized behavioral sensitivity to stress exposure in schizophrenia, and explore the capacity of the model to account for the changing behavioral manifestations of vulnerability.

Normal adolescent development is often accompanied by transient emotional and behavioral problems. For most individuals with postpubertal-onset adjustment problems, there is a resolution by early adulthood and relative stability through the adult life span. But for a minority, adjustment problems escalate during adolescence and portend the development of serious mental illness in adulthood. In this article, we explore adolescent behavioral changes and neurodevelopmental processes that might contribute to stress sensitivity and vulnerability for the emergence of the mental disorders. Of particular interest is the role that hormonal changes might play in the expression of genetic vulnerabilities for psychopathology. Drawing on recent findings from clinical research and behavioral neuroscience, we describe the ways in which postpubertal hormones might alter brain function and, thereby, behavior. It is concluded that there are both activational and organization effects of hormones on the adolescent brain, and these contribute to developmental discontinuities in behavioral adjustment. Implications for adult psychopathology and preventive intervention are discussed.