From the psychosis prodrome to the first-episode of psychosis: No evidence of a cognitive decline.

Cognitive deficits have an important role in the neurodevelopment of schizophrenia and other psychotic disorders. However, there is a continuing debate as to whether cognitive impairments in the psychosis prodrome are stable predictors of eventual psychosis or undergo a decline due to the onset of psychosis. In the present study, to determine how cognition changes as illness emerges, we examined baseline neurocognitive performance in a large sample of helping-seeking youth ranging in clinical state from low-risk for psychosis through individuals at clinical high-risk (CHR) for illness to early first-episode patients (EFEP). At baseline, the MATRICS Cognitive Consensus battery was administered to 322 individuals (205 CHRs, 28 EFEPs, and 89 help-seeking controls, HSC) that were part of the larger Early Detection, Intervention and Prevention of Psychosis Program study. CHR individuals were further divided into those who did (CHR-T; n = 12, 6.8%) and did not (CHR-NT, n = 163) convert to psychosis over follow-up (Mean = 99.20 weeks, SD = 21.54). ANCOVAs revealed that there were significant overall group differences (CHR, EFEP, HSC) in processing speed, verbal learning, and overall neurocognition, relative to healthy controls (CNTL). In addition, the CHR-NTs performed similarly to the HSC group, with mild to moderate cognitive deficits relative to the CTRL group. The CHR-Ts mirrored the EFEP group, with large deficits in processing speed, working memory, attention/vigilance, and verbal learning (>1 SD below CNTLs). Interestingly, only verbal learning impairments predicted transition to psychosis, when adjusting for age, education, symptoms, antipsychotic medication, and neurocognitive performance in the other domains. Our findings suggest that large neurocognitive deficits are present prior to illness onset and represent vulnerability markers for psychosis. The results of this study further reinforce that verbal learning should be specifically targeted for preventive intervention for psychosis.

Facial affect recognition and social functioning among individuals with varying degrees of schizotypy.

Facial affect recognition (FAR) accuracy is impaired in schizophrenia and, to a lesser extent, in individuals at-risk for psychosis. Reduced reaction time and negative bias on FAR tasks are also evident in schizophrenia, though few studies have examined these measures in at-risk samples. Social dysfunction is associated with FAR deficits in schizophrenia and at-risk individuals. We aimed to elucidate the nature of FAR and social functioning among individuals from a non-clinical population reporting a range of schizotypal traits (i.e., risk for psychosis), and to examine whether FAR mediates the relationship between schizotypal traits and social functioning. Participants completed self-report measures assessing schizotypal traits and social functioning, and a computerized FAR task remotely via the Internet. High schizotypy individuals performed significantly worse than low schizotypy individuals on FAR total and neutral accuracy, demonstrated a negative bias, and reported significantly worse social functioning. Schizotypal traits were also negatively correlated with FAR performance and social functioning in the total sample. FAR accuracy did not mediate the direct relationship between schizotypal traits and social functioning. FAR may be an important social-cognitive endophenotype of psychosis risk with implications for understanding etiology of psychotic spectrum disorders, improving ways of identifying at-risk individuals, and developing preventive strategies.

Schizotypy and specificity of negative emotions on an emotional Stroop paradigm in the general population.

Attentional-interference using emotional Stroop tasks (ESTs) is greater among individuals in the general population with positive (versus negative) schizotypal traits; specifically in response to negatively (versus positively) valenced words, potentially capturing threat-sensitivity. Variability in attentional-interference as a function of subcategories of negatively valenced words (and in relation to schizotypal traits) remains underexplored in EST studies. We examined attentional-interference across negative word subcategories (fear/anger/sadness/disgust), and in relation to positive schizotypy, among non-clinical individuals in the general population reporting varying degrees of schizotypal traits. As hypothesized, performance differed across word subcategories, though the pattern varied from expectation. Attentional-interference was greater for fear and sadness compared to anger; and analogous for fear, disgust, and sadness. In the high schizotypy group, positive schizotypal traits were directly associated with attentional-interference to disgust. Attentional-interference was comparable between high- and low-positive schizotypy. Results suggest negative emotion subcategories may differentially reflect threat-sensitivity. Disgust-sensitivity may be particularly salient in (non-clinical) positive schizotypy. Findings have implications for understanding negative emotion specificity and variability in stimulus presentation modality when studying threat-related attentional-interference. Finally, disgust-related attentional-interference may serve as a cognitive correlate of (non-clinical) positive schizotypy. Expanding this research to prodromal populations will help explore disgust-related attentional-interference as a potential cognitive marker of positive symptoms.

Childhood household dysfunction, school performance and psychiatric care utilisation in young adults: a register study of 96†399 individuals in Stockholm County.

BACKGROUND: Exposure to childhood household dysfunction increases the risk of psychiatric morbidity. Although school performance also has been linked with psychiatric morbidity, limited research has considered school performance as a mediating factor. To address this gap in the literature, the current register study examined whether school performance mediates the association between childhood household dysfunction (experienced between birth and age 14 years) and psychiatric care utilisation in young adulthood. METHODS: We used a Swedish cohort of 96 399 individuals born during 1987-1991. Indicators of childhood household dysfunction were familial death, parental substance abuse and psychiatric morbidity, parental somatic disease, parental criminality, parental separation/single-parent household, public assistance recipiency and residential instability. Final school grades from the 9th year of compulsory school were used to create five categories. Estimates of risk of psychiatric care utilisation (measured as inpatient, outpatient and primary care) after the age of 18 years were calculated as HRs with 95% CIs. Mediation was tested with the bootstrap approach. RESULTS: Cumulative exposure to childhood household dysfunction was positively associated with psychiatric care utilisation. Specifically, individuals exposed to three or more indicators with incomplete school grades had the highest risk (HR=3.7 (95% CI 3.3 to 4.1) after adjusting for demographics), compared to individuals exposed to no indicators with highest grades. School performance was found to mediate the relationship. CONCLUSIONS: Our findings suggest that future efforts to prevent or mitigate the negative effects of childhood household dysfunction on psychiatric morbidity may benefit from integration of strategies that improve school performance among vulnerable youth.

Symptom trajectories and psychosis onset in a clinical high-risk cohort: the relevance of subthreshold thought disorder.

BACKGROUND: Prior studies have implicated baseline positive and negative symptoms as predictors of psychosis onset among individuals at clinical high risk (CHR), but none have evaluated latent trajectories of symptoms over time. This study evaluated the dynamic evolution of symptoms leading to psychosis onset in a CHR cohort. METHOD: 100 CHR participants were assessed quarterly for up to 2.5 years. Latent trajectory analysis was used to identify patterns of symptom change. Logistic and proportional hazards models were employed to evaluate the predictive value for psychosis onset of baseline symptoms and symptom trajectories. RESULTS: Transition rate to psychosis was 26%. Disorganized communication (i.e., subthreshold thought disorder) presented an increased hazard for psychosis onset, both at baseline (Hazard Ratio (95% CI)=1.4 (1.1-1.9)) and as a trajectory of high persistent disorganized communication (Hazard Ratio (95% CI)=2.2 (1.0-4.9)). Interval clinical data did not improve the predictive value of baseline symptoms for psychosis onset. CONCLUSIONS: High baseline disorganized communication evident at ascertainment tended to persist and lead to psychosis onset, consistent with prior behavioral and speech analysis studies in similar cohorts. Remediation of language dysfunction therefore may be a candidate strategy for preventive intervention.

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.

Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study.

OBJECTIVES: The familial ("genetic") high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. METHODS: We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13-25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. 'Genetic load' indexed number of affected family members relative to pedigree size. RESULTS: PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. CONCLUSIONS: Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed 'polygenic neurodevelopmental diathesis-stress model' whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies.

Assessing depression in youth at clinical high risk for psychosis: a comparison of three measures.

Depressive symptoms are prevalent among individuals at clinical high-risk (CHR) for psychosis. Prior studies have used the Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), and the "dysphoric mood" item of the Scale of Prodromal Symptoms (SOPS) to assess depressive symptoms in CHR samples. We compared the psychometric properties of these instruments in a CHR cohort, to support the selection of appropriate depressive symptoms measures in future studies and in clinical settings. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed through correlations with SOPS items that were expected or not expected to be related to depressive symptoms. Criterion validity was assessed by comparing scores between patients with and without a major depressive disorder diagnosis. We hypothesized based on the schizophrenia literature that the BDI would have superior internal consistency and discriminant validity compared to the HDRS, and that all three measures would show convergent validity and criterion validity. The BDI demonstrated superior internal consistency and construct validity in this at-risk sample. The BDI and HDRS differentiated patients with major depressive disorder, but SOPS dysphoria did not. This has implications for the choice of depression measures in future CHR studies and for the interpretation of past findings.

Integrating illness concerns into cognitive behavioral therapy for children and adolescents with inflammatory bowel disease and co-occurring anxiety.

PURPOSE: To examine the feasibility and preliminary benefits of an integrative cognitive behavioral therapy (CBT) with adolescents with inflammatory bowel disease and anxiety. DESIGN AND METHODS: Nine adolescents participated in a CBT program at their gastroenterologist's office. Structured diagnostic interviews, self-report measures of anxiety and pain, and physician-rated disease severity were collected pretreatment and post-treatment. RESULTS: Postintervention, 88% of adolescents were treatment responders, and 50% no longer met criteria for their principal anxiety disorder. Decreases were demonstrated in anxiety, pain, and disease severity. PRACTICE IMPLICATIONS: Anxiety screening and a mental health referral to professionals familiar with medical management issues is important.

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 Richardson's (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.

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.

The presentation of dermatoglyphic abnormalities in schizophrenia: a meta-analytic review.

Within a neurodevelopmental model of schizophrenia, prenatal developmental deviations are implicated as early signs of increased risk for future illness. External markers of central nervous system maldevelopment may provide information regarding the nature and timing of prenatal disruptions among individuals with schizophrenia. One such marker is dermatoglyphic abnormalities (DAs) or unusual epidermal ridge patterns. Studies targeting DAs as a potential sign of early developmental disruption have yielded mixed results with regard to the strength of the association between DAs and schizophrenia. The current study aimed to resolve these inconsistencies by conducting a meta-analysis examining the six most commonly cited dermatoglyphic features among individuals with diagnoses of schizophrenia. Twenty-two studies published between 1968 and 2012 were included. Results indicated significant but small effects for total finger ridge count and total A-B ridge count, with lower counts among individuals with schizophrenia relative to controls. Other DAs examined in the current meta-analysis did not yield significant effects. Total finger ridge count and total A-B ridge count appear to yield the most reliable dermatoglyphic differences between individuals with and without schizophrenia.

Schizotypal traits and neurocognitive functioning among nonclinical young adults.

Neurocognitive deficits and their relationship with symptoms have been documented in schizophrenia and at-risk samples. Limited research has examined relationships of schizotypal traits with cognitive functioning among nonclinical samples. To expand this literature and elucidate a dimensional model of psychosis-proneness, we examined the relationship of schizotypal traits with estimated intellectual functioning, simple and complex attention/working memory, verbal fluency and visuospatial abilities in a nonclinical sample of 63 young adults. As hypothesized, aspects of neurocognition were more closely associated with negative (than positive or disorganized) schizotypal traits. For the total sample, poorer visuospatial performance was associated with more negative and overall schizotypal traits. The magnitude of the majority of findings was strengthened after controlling for depression and anxiety. No other findings were significant. Results partially support Meehl's (1962, 1990) view that processes underlying schizophrenia are expressed along a continuum. Findings suggest a relationship of schizotypal traits with neurocognition that is differentiated by trait dimensions, beyond the contribution of general psychiatric symptoms. Findings have implications for better understanding etiology and potential risk factors for psychosis. While sex distribution did not enable direct examination of sex effects, evidence in the field argues for continued exploration of differential patterns by sex.

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/Alzheimer's/multiple sclerosis). We speculate a dose-response cortisol effect on symptoms, modulated by endogenous gonadal hormones via gene expression.

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

OBJECTIVE: Recent research implicates the catechol-O-methyltransferase (COMT) ValMet 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.

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.

Neuroanatomic substrates of sex differences in language dysfunction in schizophrenia: a pilot study.

OBJECTIVE: This pilot study investigated whether our previous findings of disrupted normal sexual brain dimorphisms in language-associated regions in schizophrenia were linked with our previously reported sex differences in language dysfunction in schizophrenia. METHOD: Nineteen adults with schizophrenia and 15 normal comparisons were tested on phonology, semantics and grammar and underwent structural MRI. RESULTS: Among males, left hippocampal and left planum temporale (PT) abnormalities were associated with phonological, semantic and grammar deficits, accounting for 17-52% and 27-33%, respectively, of variance in diagnostic group differences. Anterior cingulate gyrus was significantly associated with semantics. Among females, right Heschl's Gyrus (HG) and left PT were significantly associated with phonology, right HG with semantics and grammar and right hippocampus with semantics. CONCLUSIONS: These preliminary findings suggest disrupted sexual brain dimorphisms in schizophrenia are associated with sex-specific language deficits, and left hippocampal abnormalities, in particular, contribute to language dysfunction among men. Abnormalities in right cortical temporal regions showed stronger associations with language dysfunction among females.

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.

Sex differences in digit ratio (2D:4D) are disrupted in adolescents with schizotypal personality disorder: altered prenatal gonadal hormone levels as a risk factor.

The 2nd to 4th finger digit ratio (2D:4D) is a sexually dimorphic feature determined during gestation indexing prenatal androgen/estrogen levels. More 'feminized' 2D:4D phenotype has been demonstrated in schizophrenia versus same-sex controls. This study examined 2D:4D in adolescents with schizotypal personality disorder (SPD). Among normal controls, right 2D:4D was significantly greater (more feminized) in females than males. We replicated laterality effects; significant sex differences only on right. There were no significant sex differences among SPDs. Diagnostic group differences were restricted to White/Caucasian males with greater right 2D:4D in SPDs. Findings suggest disruptions in prenatal gonadal hormones in vulnerability for schizophrenia.