Heritable influences on amygdala and orbitofrontal cortex contribute to genetic variation in core dimensions of personality.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p<.01; r(g)=.23, p<.05, respectively). In addition, after adjusting for mean cortical thickness, genetic and nonshared-environmental correlations (r(e)) between left medial orbitofrontal cortex thickness and negative emotionality were also observed (r(g)=.34, p<.01; r(e)=-.19, p<.05, respectively). These findings support a model positing that heritable bases of personality are, at least in part, mediated through individual differences in the size of brain structures, although further work is still required to confirm this causal interpretation.

A multivariate twin study of hippocampal volume, self-esteem and well-being in middle-aged men.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men.

BACKGROUND: The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age. METHODS: Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. RESULTS: A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present. CONCLUSIONS: These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.

Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study.

OBJECTIVE: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the "exome" (all exons) and "spliceome" (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. METHODS: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. RESULTS: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. CONCLUSIONS: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery-oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceome-profiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry.

Apolipoprotein E genotype and memory in the sixth decade of life.

BACKGROUND: Virtually all adult studies of APOE genotypes and cognition have included individuals over 60. In older adults, epsilon 4 carriers may manifest greater cognitive asymmetries than non-epsilon 4 carriers even in the absence of overall mean differences. General cognitive ability may also be affected by aging and APOE genotype, but most studies have inadequately addressed this potential confound. The goals of this study were to examine, in middle age, the relationship of APOE genotype with episodic memory and verbal-visuospatial episodic memory asymmetries, after accounting for prior general cognitive ability. METHOD: We compared epsilon 4+ and epsilon 4- individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members. RESULTS: Compared with epsilon 4- individuals, epsilon 4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, epsilon 4 carriers had higher general cognitive ability than epsilon 4- individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability. CONCLUSIONS: Small, but significant, APOE-epsilon 4-related memory deficits appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-epsilon 4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.

Intelligence quotient and neuropsychological profiles in patients with schizophrenia and in normal volunteers.

BACKGROUND: The objective of this study was to examine neuropsychological performance at different intelligence quotient (IQ) levels in schizophrenia. METHODS: Thirty-six patients with schizophrenia were matched with 36 normal control subjects in two IQ groups: low average (81-94) and average (95-119). Performance level (IQ group main effects) and profile shape (IQ group x function interactions) were compared. RESULTS: Current IQ was lower than estimated premorbid intellectual ability in both patient groups. Patients also displayed poorer neuropsychological function than same-IQ control subjects, suggesting neuropsychological dysfunction beyond their already compromised IQ. Patients had different profile shapes than control subjects, but profile shapes were consistent within patients and control subjects at each IQ level. Patients at both levels had higher verbal and lower performance IQ than control subjects. Abstraction-executive function was one of the lowest neuropsychological scores in both patient groups. Average IQ patients had nonsignificantly better overall neuropsychological performance than low average control subjects, but the effect size (.43) was quite small relative to the IQ difference (effect size = 2.57). CONCLUSIONS: Neuropsychological patterns in schizophrenia tend to be consistent at different IQ levels. Even schizophrenia patients with normal current IQs manifest substantial neuropsychological compromise relative to their level of general intellectual ability. The results strengthen the argument that neurocognitive deficits are core deficits of schizophrenic illness.

Association of estrogen levels with neuropsychological performance in women with schizophrenia.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

Functional connectivity and working memory in schizophrenia: an EEG study.

A leading hypothesis suggests that schizophrenic patients suffer from a disconnection syndrome. A failure in functional connectivity curtails the cortical integration and network activation needed to perform working memory tasks. Simulations with neural network models also indicate that connectivity is crucial for simulation of working memory asks. Multichannel EEG correlation-coefficient estimations are considered as a reliable measurement of connectivity patterns among cortical regions. In this study EEG samples are obtained selectively at the delay epochs of a delayed response working memory task. Results of correlation-coefficient estimations indicate a lack of statistically significant changes between non-task and task conditions in frontal, certain parietal, temporal and central channels. These findings propose that schizophrenics probably "fail" to activate the neural networks of the fronto-temporal regions. These are the networks involved in computation of the working memory task. Interestingly also good performers schizophrenics failed to activate these networks suggesting that the connectivity function is more relevant to the disorder than to task performance. If distinct deficits in cortical network activations would correlate with mental disorders it would be relevant to diagnosis and treatment of psychiatric disorders.

Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading.

BACKGROUND: We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time. METHODS: In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter. RESULTS: Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group x gender interactions: the worse performance of the multiplex group was seen for females. CONCLUSIONS: These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.

Age and neuropsychologic function in schizophrenia: a decline in executive abilities beyond that observed in healthy volunteers.

BACKGROUND: Kraepelin originally conceptualized schizophrenia as a degenerative brain disorder. It remains unclear whether the illness is characterized by a static encephalopathy or a deterioration of brain function, or periods of each condition. Assessments of cognitive function, as measured by neuropsychologic assessment, can provide additional insight into this question. Few studies of patients with schizophrenia have investigated the effect of aging on executive functions, in an extensive neuropsychologic battery across a wide age range, compared to healthy volunteers. METHODS: We examined the interaction of aging and neuropsychologic function in schizophrenia through a cross-sectional study in patients (n = 87) and healthy control subjects (n = 94). Subjects were divided into three age groups (20-35, 36-49, and 50-75), and performance on an extensive neuropsychologic battery was evaluated. RESULTS: Compared to control subjects, patients with schizophrenia demonstrated similar age-related declines across most neuropsychologic functions, with the exception of abstraction ability, in which significant evidence of a more accelerated decline was observed. CONCLUSIONS: These results are consistent with previous reports indicating similar age effects on most aspects of cognition in patients with schizophrenia and healthy adults, but they support the hypothesis that a degenerative process may result in a more accelerated decline of some executive functions in older age in schizophrenia.

The paradox of normal neuropsychological function in schizophrenia.

Mounting evidence suggests that compromised neurocognitive function is a core feature of schizophrenia. However, some studies have found neuropsychologically normal schizophrenia patients. To address this apparent contradiction, we blindly rated individual neuropsychological profiles of 75 schizophrenia patients and 91 control participants on the basis of methods developed by L. J. Seidman, S. V. Faraone, W. S. Kremen, J. R. Pepple, M. J. Lyons, and M. T. Tsuang (1993). Almost one-quarter of the patients were classified as neuropsychologically within normal limits (WNL). Despite significantly worse neuropsychological performance, WNL patients had higher estimated premorbid ability than did controls. Compared to a subset of controls matched on overall neuropsychological function, WNL patients had higher estimated premorbid ability and current IQs. Our results favor the view that even neuropsychologically normal schizophrenia patients have compromised cognitive function relative to their presumed expected or premorbid level of intellectual ability.

Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis.

BACKGROUND: Schizophrenia is characterized by subcortical and cortical brain abnormalities. Evidence indicates that some nonpsychotic relatives of schizophrenic patients manifest biobehavioral abnormalities, including brain abnormalities. The goal of this study was to determine whether amygdala-hippocampal and thalamic abnormalities are present in relatives of schizophrenic patients. METHODS: Subjects were 28 nonpsychotic, and nonschizotypal, first-degree adult relatives of schizophrenics and 26 normal control subjects. Sixty contiguous 3 mm coronal, T1-weighted 3D magnetic resonance images of the brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter and cerebrospinal fluid (CSF) were segmented using a semi-automated intensity contour mapping algorithm. Analyses of covariance of the volumes of brain regions, controlling for expected intellectual (i.e., reading) ability and diagnosis, were used to compare groups. RESULTS: The main findings were that relatives had significant volume reductions bilaterally in the amygdala-hippocampal region and thalamus compared to control subjects. Marginal differences were noted in the pallidum, putamen, cerebellum, and third and fourth ventricles. CONCLUSIONS: Results support the hypothesis that core components of the vulnerability to schizophrenia include structural abnormalities in the thalamus and amygdala-hippocampus. These findings require further work to determine if the abnormalities are an expression of the genetic liability to schizophrenia.

Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study.

In a prior study of 54 relatives of patients with schizophrenia and 72 control participants, 3 neuropsychological functions met the criteria for risk indicators of the schizophrenia genotype: executive functioning, memory, and auditory attention. In an assessment of the stability of these findings, the sample was reexamined 4 years after the initial assessment. Three test scores were found to differ between groups (Immediate Verbal Memory, Delayed Verbal Memory, and Dichotic Listening Digits Detected) or to show a significant Group x Gender interaction (immediate and delayed verbal and visual memories). None of the test scores showed Group x Time interactions, suggesting that the discriminating power of the tests was stable over time. Evidence for deficits in working memory and rule learning on the object alternation test was also found. These results support the idea that neuropsychological dysfunction among relatives of patients with schizophrenia is a stable trait caused by the familial predisposition to schizophrenia.

Sex differences in self-reported schizotypal traits in relatives of schizophrenic probands.

We used the Schizotypal Personality Questionnaire to evaluate schizotypal traits in 44 normal volunteers and 40 non-psychotic, biological relatives of schizophrenic probands. Relatives endorsed more cognitive-perceptual traits than did controls; a group-by-sex interaction indicated that male relatives accounted for this difference. Although not statistically significant, a similar pattern was observed for interpersonal traits. Thus, elevated rates of some schizotypal traits appear to be more prominent in male than in female relatives of schizophrenic probands, at least when assessed by self-report. Subscale analysis indicated that differences were accounted for primarily by suspiciousness and ideas of reference, suggesting that paranoid-like phenomena from both the cognitive-perceptual and interpersonal factors may constitute an important dimension of schizotypy in relatives. Unlike previous studies, we did not find any differences in constricted affect or disorganization signs. Interviews and other non-self-report techniques are probably best suited for an assessment of these features, although the question remains as to whether the combination of both approaches might provide some incremental discriminatory power.

Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands.

Evidence of subtle neuropsychological deficits in relatives of schizophrenic probands (REL-SZs) suggests that these are risk indicators for schizophrenia, but little is known about whether neuropsychological performance in REL-SZs differs from that in other groups of relatives. We compared neuropsychological function in female REL-SZs (n = 39), relatives of primarily psychotic bipolar disorder probands (REL-BPs; n = 15), and a normal control group (n = 44). After adjustment for expected intellectual ability (based on reading recognition), REL-SZs showed deficits in verbal and visual memory (Wechsler Memory Scale-Revised logical memories, visual reproductions), and auditory attention (dichotic digits) compared with either REL-BPs or control subjects. Memory, but not dichotic listening differences remained significant after adjusting for current IQ; however, average effect sizes after controlling for either reading or IQ were roughly comparable for these three parameters (d = 0.80, 0.71, and 0.69, respectively). REL-BPs and control subjects showed little difference. Although both schizophrenic and bipolar patients often manifest neuropsychological dysfunction, these preliminary findings indicate subtle neuropsychological deficits only in REL-SZs. Such differences suggest different underlying processes; neuropsychological impairment may, in part, reflect an expression of genetic liability to schizophrenia but not bipolar disorder. Replication with a larger REL-BP sample and with male relatives is needed to evaluate the generalizability of the results.

Association of neuropsychological vulnerability markers in relatives of schizophrenic patients.

We investigated the association of neuropsychological risk indicators in a matched sample of first-degree relatives of schizophrenic patients (n = 54) and normal controls (n = 72). We focussed on three functions previously identified in a smaller, initial sample as putative risk indicators of the schizophrenia genotype: abstraction, verbal memory and auditory attention. The expanded sample of relatives displayed significantly lower scores than controls on abstraction, verbal memory and auditory attention. The relatives demonstrated significant intercorrelations among these three functions. The significant correlations among relatives between attention and verbal memory and between attention and abstraction differed significantly from these correlations among controls. We discuss how the use of multiple risk indicators may help us better identify those relatives that carry the schizophrenia genotype.

IQ decline during childhood and adult psychotic symptoms in a community sample: a 19-year longitudinal study.

OBJECTIVE: The goal of this study was to examine cognitive antecedents of psychosis by determining whether variability in IQ during childhood was predictive of psychotic symptoms in adulthood. METHOD: Deviant responder analyses were used to examine prospectively the relationship of IQ at ages 4 and 7 to psychotic symptoms at age 23 in 547 offspring from a community sample (National Collaborative Perinatal Project) that was unselected for psychiatric illness. The authors compared three hypotheses: that 1) low IQ, 2) large IQ fluctuations regardless of direction, or 3) large IQ declines would predict the presence of adult psychotic symptoms. RESULTS: The 10% of individuals with substantially larger than expected IQ declines from age 4 to 7 had a rate of psychotic, but not other psychiatric, symptoms at age 23 that was nearly seven times as high as the rate for other persons. Parental socioeconomic status and IQ at age 7 also predicted adult psychotic symptoms. However, when IQ at age 7, IQ decline between ages 4 and 7, and socioeconomic status were all included in a logistic regression analysis, only IQ decline remained significant. CONCLUSIONS: There is an increased likelihood of developing psychotic symptoms in adulthood for a subgroup of individuals with substantially greater than expected IQ declines during childhood. IQ decline is specific for psychotic symptoms, but follow-up assessment when the study participants are further into the age of risk will be necessary to determine specificity for schizophrenia. The authors discuss the implications of this early cognitive downturn for a neurodevelopmental view of schizophrenia.

Factor structure of the Wisconsin Card Sorting Test: dimensions of deficit in schizophrenia.

The aim of this study was to explore the factorial structure of the Wisconsin Card Sorting Test (WCST) and to identify the dimensions of deficit in schizophrenia. WCST scores in patients with schizophrenia and schizophrenia-related psychosis (n = 292), 1st degree relatives of schizophrenic patients (n = 91), and normal controls (n = 141) were subjected to a principal factor analysis followed by orthogonal rotation. This led to 3 factors, perseveration, failure to maintain set, and idiosyncratic sorting. The detected factor structure was found to be invariant across the schizophrenic and control subsamples. Moreover, it replicated previous findings from 2 smaller samples. Only perseverations and, to a lesser degree, idiosyncratic sorting appeared to differentiate schizophrenic patients from comparisons. Only perseveration had good sensitivity and specificity, as well as the most robust significant correlations with estimates of IQ, attention, and other measures of executive functioning. Thus, perseveration appears to be the most diagnostically useful and characteristic WCST feature of schizophrenia.

Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot magnetic resonance imaging study.

Substantial evidence suggests that nonpsychotic relatives of schizophrenia patients manifest subtle abnormalities in communication, eye movements, event-related potentials, and neuropsychological processes of attention, reasoning, and memory. We sought to determine whether adult relatives without psychosis or schizophrenia spectrum diagnoses might also have structural brain abnormalities, particularly in subcortical regions found to be impaired in patients with schizophrenia itself. Subjects were six sisters of schizophrenic patients and eleven normal female controls. Sixty contiguous 3 mm coronal, T1-weighted 3D magnetic resonance images (MRI) of the entire brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter was segmented using a semiautomated intensity contour mapping algorithm. Volumes were adjusted for total brain volumes. Adjusted gray matter subcortical volumes were significantly smaller in relatives than in controls in total hippocampus, right amygdala, right putamen, left thalamus, and brainstem. Relatives had significantly enlarged left and total inferior lateral ventricles. These results, though preliminary, suggest that some never-psychotic relatives of schizophrenic patients have abnormal brain structure. If replicated in a larger sample including both sexes, these results would suggest that the genetic liability to schizophrenia is also expressed as structural brain abnormalities.

Revisiting the factor structure for positive and negative symptoms: evidence from a large heterogeneous group of psychiatric patients.

OBJECTIVE: The factor structures of individual positive and negative symptoms as well as global ratings were examined in a diagnostically heterogeneous group of subjects. METHOD: Subjects were identified through a clinical and family study of patients with major psychoses at a VA medical center and evaluated with the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. For the examination of global-level factor structures (N = 630), both principal-component analysis and factor analysis with orthogonal rotation were used. Factor analysis was used for the examination of item-level factor structures as well (N = 549). RESULTS: The principal-component analysis of global ratings revealed three factors: negative symptoms, positive symptoms, and disorganization. The factor analysis of global ratings revealed a negative symptom factor and a positive symptom factor. The item-level factor analysis revealed two negative symptom factors (diminished expression and disordered relating), two positive symptom factors (bizarre delusions and auditory hallucinations), and a disorganization factor. CONCLUSIONS: The generation of additional meaningful factors at the item level suggests that important information about symptoms is lost when only global ratings are viewed. Future work should explore clinical and pathological correlates of the more differentiated item-level symptom dimensions.