Deborah J. Walder

Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia

BACKGROUND There is substantial evidence of dysregulation of cortisol secretion, hippocampal abnormalities, and memory deficits in schizophrenia and other psychotic disorders. Research also suggests that cortisol secretion augments dopaminergic activity, which may result in increased symptom expression in this clinical population. METHODS We examined the relations among cortisol release, cognitive performance, and psychotic symptomatology. Subjects were 18 adults with schizophrenia or schizoaffective disorder, seven with a nonpsychotic psychiatric disorder, and 15 normal control subjects. Tests of memory and executive function were administered. Cortisol was assayed from multiple saliva samples. RESULTS Findings indicated the following: 1) patients with psychotic disorders scored below the comparison groups on the cognitive measures; 2) for the entire sample, cortisol levels were inversely correlated with performance on memory and frontal tasks; and 3) among patients, cortisol levels were positively correlated with ratings of positive, disorganized, and overall symptom severity, but not with negative symptoms. CONCLUSIONS The present results suggest that abnormalities in the hypothalamic-pituitary-adrenal axis and hippocampal systems play a role in observed cognitive deficits across populations. Among psychotic patients, elevated cortisol secretion is linked with greater symptom severity.

Developmental changes in cortisol secretion in normal and at-risk youth.

Adolescence is associated with an increase in the rate of certain psychiatric symptoms, and it is typically the developmental period when prodromal features of the major psychiatric disorders emerge. This is especially true of schizophrenia, with the majority of patients showing a marked postpubertal rise in schizotypal signs that predates the onset of clinical symptoms in early adulthood. Cross-sectional studies of youth have revealed a positive correlation between age and saliva cortisol level, suggesting a normative maturational increase in activity of the hypothalamic-pituitary-adrenal (HPA) axis. It has been hypothesized that this increase may trigger the expression of symptoms in vulnerable individuals. The present longitudinal study measured cortisol secretion and its relation with symptom development in samples of youth with schizotypal personality disorder (SPD), other personality disorders, or no Axis II disorder. The findings indicate moderate stability in cortisol levels across a 2-year period, with a longitudinal increase in cortisol levels over time. Cortisol levels at the first and second assessments were correlated with the severity of SPD symptoms at follow-up. The results are consistent with the notion that the HPA axis undergoes a postpubertal maturational process that moderates the expression of psychiatric symptoms.

The relations among putative biorisk markers in schizotypal adolescents: minor physical anomalies, movement abnormalities, and salivary cortisol.

BACKGROUND Evidence suggests that prenatal insult may play a role in the etiology of psychotic disorders. Minor physical anomalies (MPA) are an indicator of abnormal fetal development and are elevated in individuals at genetic and behavioral risk for psychosis. Yet, there has been little empirical research on the relationships between MPAs and other neurobiological risk indicators. We hypothesized that the frequency of MPAs (an external marker of prenatal central nervous system [CNS] disruption) would be associated with two other biomarkers suggestive of disruptions in fetal neurodevelopment: movement abnormalities (an indicator of striatal abnormalities) and heightened cortisol secretion (an indicator of hypothalamic-pituitary-adrenal [HPA]/hippocampal function). METHODS Participants with schizotypal personality disorder (SPD; n = 39) and both normal (n = 47) and other personality disorders (n = 28) control subjects were administered structured diagnostic interviews and assessed for MPAs, movement abnormalities, and salivary cortisol. RESULTS Schizotypal personality disorder participants showed significantly greater MPAs and movement abnormalities and higher cortisol than both the normal and other personality disorders groups. Hierarchical linear regression analyses revealed that higher rates of MPAs were linked with greater movement abnormalities and salivary cortisol. CONCLUSIONS The findings suggest that MPAs serve as a marker of neurodevelopmental abnormalities that affect striatal and hippocampal regions.

Markers of Basal Ganglia Dysfunction and Conversion to Psychosis: Neurocognitive Deficits and Dyskinesias in the Prodromal Period

BACKGROUND Movement abnormalities and cognitive deficits may represent external markers of an underlying neural process linked with the early etiology of psychosis. As basal ganglia function plays a governing role in both movement and cognitive processes, an understanding of the relationship between these phenomena stands to inform etiologic conceptualizations of vulnerability and psychotic disorders. METHODS In this investigation, trained raters coded movement abnormalities in videotapes from structured interviews of adolescents and young adults with a prodromal risk syndrome (n = 90). The participants were administered a neuropsychological battery including measures of verbal comprehension, perceptual organization, immediate/delayed auditory memory, and an estimate of full-scale intelligence quotient. Diagnostic status was followed for a 2-year period utilizing structured clinical interviews, during which time 24 high-risk participants (26.66%) converted to an Axis I psychotic disorder. RESULTS Elevated dyskinetic movements in the upper-body region were correlated with deficits in domains of verbal comprehension, perceptual organization, and both immediate and delayed auditory memory. Further, discriminant function analyses indicated that baseline movement abnormalities and neurocognitive deficits significantly classified those high-risk participants who would eventually convert to a psychotic disorder (72.3%). CONCLUSIONS Results support a common cortico-striato-pallido-thalamic circuit irregularity, underlying both movement abnormalities and cognitive deficits in individuals at high risk for psychosis. Models incorporating external markers of progressive basal ganglia dysfunction may enhance detection and preventive intervention for those high-risk individuals most in need of treatment.

Prenatal maternal stress predicts autism traits in 6½ year-old children: Project Ice Storm

Research implicates prenatal maternal stress (PNMS) as a risk factor for neurodevelopmental disorders; however few studies report PNMS effects on autism risk in offspring. We examined, prospectively, the degree to which objective and subjective elements of PNMS explained variance in autism-like traits among offspring, and tested moderating effects of sex and PNMS timing in utero. Subjects were 89 (46F/43M) children who were in utero during the 1998 Quebec Ice Storm. Soon after the storm, mothers completed questionnaires on objective exposure and subjective distress, and completed the Autism Spectrum Screening Questionnaire (ASSQ) for their children at age 6½. ASSQ scores were higher among boys than girls. Greater objective and subjective PNMS predicted higher ASSQ independent of potential confounds. An objective-by-subjective interaction suggested that when subjective PNMS was high, objective PNMS had little effect; whereas when subjective PNMS was low, objective PNMS strongly affected ASSQ scores. A timing-by-objective stress interaction suggested objective stress significantly affected ASSQ in first-trimester exposed children, though less so with later exposure. The final regression explained 43% of variance in ASSQ scores; the main effect of sex and the sex-by-PNMS interactions were not significant. Findings may help elucidate neurodevelopmental origins of non-clinical autism-like traits from a dimensional perspective.

Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome

Sex differences in age at onset, symptomatology, clinical course (see Walker et al., 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study prospectively examined sexual dimorphisms in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12-36.8years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings help elucidate early course of vulnerability for, and maximally sensitive and specific etiological and prediction models of, psychosis conversion. Findings highlight the importance of considering sexually differentiated predictors of longitudinal course and outcome, in the context of emerging risk profiles. This may optimize efforts at early identification and individually tailored preventive interventions targeting different neurobiological markers/systems and/or cognitive-behavioral approaches. We speculate a contemporary, multidimensional model of psychosis risk that posits a role of sexually dimorphic, genetically linked influences that converge with a modulating role of gonadal hormones (see Walder et al., 2012) across a temporally sensitive neurodevelopmental trajectory towards conferring risk.

Efficacy of social cognition remediation programs targeting facial affect recognition deficits in schizophrenia: A review and consideration of high-risk samples and sex differences

Schizophrenia patients suffer from significant social functioning deficits. Social cognition, particularly facial affect recognition (FAR), is an important predictor of functional outcome. Recently, investigators developed numerous social cognition remediation programs targeting FAR deficits with the goal of improving social functioning and quality of life in schizophrenia patients. This article builds on Horan et al.s (2008) comprehensive review and Kurtz and Richardsons (2012) meta-analysis of a broad range of social cognition remediations, by systematically reviewing efficacy of empirically based remediations in schizophrenia specifically targeting FAR (across 23 studies), and their potential functional benefits. We describe each FAR-based social cognition remediation program, which may aid clinical scientists and clinicians in selecting programs for further study and practice. We critically evaluate limitations of FAR remediation programs and applications. Our review concludes FAR remediation programs are strongly efficacious in improving FAR performance and functional status in schizophrenia. Importantly, we provide rationale for and recommend that future research consider (as yet underexplored) sexual dimorphisms in FAR remediation effects, and examine FAR remediation in clinical high-risk for psychosis populations. The goal is to mitigate deficits, perhaps hinder illness onset, and individually tailor treatments across the psychosis continuum in a way that maximally aids those in greatest need.

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.

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.

Biological sex and menstrual cycle phase modulation of cortisol levels and psychiatric symptoms in a non-clinical sample of young adults.

Prior research examined the complex, bidirectional interplay of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal axes and their roles in (clinical) cognitive/behavioral functions. Less well understood are contemporaneous relationships in non-clinical samples. This pilot study explored cortisol in relation to psychiatric symptoms/personality as a function of self-reported menstrual cycle phase and sex differences in a non-clinical, young adult sample. Consistent with literature and hypotheses, cortisol levels were lowest during early-follicular, intermediary during late-follicular, and highest during mid-luteal phases (not significant), and greater among males than early-follicular females. An acute stressor uniformly affected cortisol across phases and sex, though magnitude and time course differed. Psychiatric symptoms were greater among early-follicular/late-follicular females versus males, and early-follicular and/or late-follicular versus mid-luteal. Contrary to hypotheses, positive psychotic-like symptoms were greater among males than (mid-luteal) females. Cortisol inversely related to early-follicular symptoms, and directly related to late-follicular/mid-luteal symptoms. Results suggest menstrual cycle phase modulates non-clinical psychiatric symptomatology and HPA activity. Findings tentatively bolster a dimensional/continuum model of psychopathology with implications for understanding neurobiological underpinnings and risk/protective factors for mental/physical health conditions, particularly those marked by sex differences and neuroendocrine dysfunction (depression/schizophrenia/Alzheimers/multiple sclerosis). We speculate a dose-response cortisol effect on symptoms, modulated by endogenous gonadal hormones via gene expression.