Kathryn E. Lewandowski

Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder

BACKGROUND Neurocognitive dysfunction in schizophrenia (SZ), bipolar (BD) and related disorders represents a core feature of these illnesses, possibly a marker of underlying pathophysiology. Substantial overlap in domains of neuropsychological deficits has been reported among these disorders after illness onset. However, it is unclear whether deficits follow the same longitudinal pre- and post-morbid course across diagnoses. We examine evidence for neurocognitive dysfunction as a core feature of all idiopathic psychotic illnesses, and trace its evolution from pre-morbid and prodromal states through the emergence of overt psychosis and into chronic illness in patients with SZ, BD and related disorders. METHOD Articles reporting on neuropsychological functioning in patients with SZ, BD and related disorders before and after illness onset were reviewed. Given the vast literature on these topics and the present focus on cross-diagnostic comparisons, priority was given to primary data papers that assessed cross-diagnostic samples and recent meta-analyses. RESULTS Patients with SZ exhibit dysfunction preceding the onset of illness, which becomes more pronounced in the prodrome and early years following diagnosis, then settles into a stable pattern. Patients with BD generally exhibit typical cognitive development pre-morbidly, but demonstrate deficits by first episode that are amplified with worsening symptoms and exacerbations. CONCLUSIONS Neuropsychological deficits represent a core feature of SZ and BD; however, their onset and progression differ between diagnostic groups. A lifetime perspective on the evolution of neurocognitive deficits in SZ and BD reveals distinct patterns, and may provide a useful guide to the examination of the pathophysiological processes underpinning these functions across disorders.

Anxiety and depression symptoms in psychometrically identified schizotypy.

The neurodevelopmental vulnerability for schizophrenia appears to be expressed across a dynamic continuum of adjustment referred to as schizotypy. This model suggests that nonpsychotic schizotypic individuals should exhibit mild and transient forms of symptoms seen in full-blown schizophrenia. Given that depression and anxiety are reported to be comorbid with schizophrenia, the present study examined the relationship of psychometrically defined schizotypy with symptoms of depression and anxiety in a college student sample (n=1258). A series of confirmatory factor analyses indicated that a three-factor solution of positive schizotypy, negative schizotypy, and negative affect provided the best solution for self-report measures of schizotypy, anxiety, and depression. As hypothesized, the model indicated that symptoms of depression and anxiety are more strongly associated with the positive-symptom dimension of schizotypy than with the negative-symptom dimension. This is consistent with studies of schizophrenic patients and longitudinal findings that positive-symptom schizotypes are at risk for both mood and non-mood psychotic disorders, while negative-symptom schizotypes appear more specifically at risk for schizophrenia-spectrum disorders.

Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual‐spatial ability, non‐verbal reasoning, and planning skills. 22q11DS is also associated with behavioral and psychiatric abnormalities, including a markedly elevated risk for schizophrenia. Research findings indicate that people with schizophrenia, as well as those identified as schizoptypic, show specific cognitive deficits in the areas of sustained attention, executive functioning, and verbal working memory. The present study examined such schizophrenic‐like cognitive deficits in children and adolescents with 22q11DS (n = 26) and controls (n = 25) using a cross‐sectional design. As hypothesized, 22q11DS participants exhibited deficits in intelligence, achievement, sustained attention, executive functioning, and verbal working memory compared to controls. Furthermore, deficits in attention and executive functioning were more pronounced in the 22q11DS sample relative to general cognitive impairment. These findings suggest that the same pattern of neuropsychological impairment seen in patients with schizophrenia is present in non‐psychotic children identified as at‐risk for the development of schizophrenia based on a known genetic risk marker.

Relationship of neurocognitive deficits to diagnosis and symptoms across affective and non-affective psychoses

INTRODUCTION Neurocognitive dysfunction is believed to be a core feature of schizophrenia and is increasingly recognized as a common symptom dimension in bipolar disorder. Despite a copious literature on neurocognition in these disorders, the relationship amongst neurocognition, symptoms, and diagnosis remains unclear. We examined neurocognitive functioning in a cross-diagnostic sample of patients with psychotic disorders. Based on previous findings, it was hypothesized that neurocognitive functioning would be impaired in all three patient groups, and that groups would be similarly impaired on all neuropsychological measures. Additionally, we predicted that negative symptoms but not positive, general, or mood symptoms, would be associated with neurocognitive functioning. METHOD Neurocognitive functioning and symptoms were assessed in participants with schizophrenia (n=25), schizoaffective disorder (n=29), or bipolar disorder with psychosis (n=31), and in healthy controls (n=20). RESULTS Neurocognitive functioning was significantly impaired in all patient groups, and groups did not differ by diagnosis on most measures. A series of linear regressions revealed that negative symptoms (but no other clinical symptom) predicted poorer executive functioning across groups. Diagnosis was not a significant predictor of any neurocognitive variable. DISCUSSION Neurocognitive deficits were pronounced in this cross-diagnostic sample of patients with psychotic disorders, and did not differ by diagnosis. Neurocognitive dysfunction may represent a symptom dimension that spans diagnostic categories, and may reflect shared pathogenic processes. As neurocognitive dysfunction is among the strongest predictors of outcome in patients, efforts to treat these deficits, which have shown promise in schizophrenia, should be extended to all patients with psychosis.

Psychopathology, social adjustment and personality correlates of schizotypy clusters in a large nonclinical sample

INTRODUCTION Correlational methods, unlike cluster analyses, cannot take into account the possibility that individuals score highly on more than one symptom dimension simultaneously. This may account for some of the inconsistency found in the literature of correlates of schizotypy dimensions. This study explored the clustering of positive and negative schizotypy dimensions in nonclinical subjects and whether schizotypy clusters have meaningful patterns of adjustment in terms of psychopathology, social functioning, and personality. METHODS Positive and negative schizotypy dimensional scores were derived from the Chapman Psychosis-Proneness Scales for 6137 college students and submitted to cluster analysis. Of these, 780 completed the NEO-PI-R and Social Adjustment Scale-self report version, and a further 430 were interviewed for schizophrenia-spectrum, mood, and substance use psychopathology. RESULTS Four clusters were obtained: low (nonschizotypic), high positive, high negative, and mixed (high positive and negative) schizotypy. The positive schizotypy cluster presented high rates of psychotic-like experiences, schizotypal and paranoid symptoms, had affective and substance abuse pathology, and was open to experience and extraverted. The negative schizotypy cluster had high rates of negative and schizoid symptoms, impaired social adjustment, high conscientiousness and low agreeableness. The mixed cluster was the most deviant on almost all aspects. CONCLUSIONS Our cluster solution is consistent with the limited cluster analytic studies reported in schizotypy and schizophrenia, indicating that meaningful profiles of schizotypy features can be detected in nonclinical populations. The clusters identified displayed a distinct and meaningful pattern of correlates in different domains, thus providing construct validity to the schizotypy types defined.

Categorical vs dimensional classifications of psychotic disorders

OBJECTIVE Both categorical and dimensional methods appear relevant to classifying psychotic disorders; however, there is no clear consensus on the most appropriate categories and dimensions or on the best approach for constructing nosologic criteria that integrate these 2 methods. This review examines the evidence on specific dimensions and categories that would best characterize psychoses. METHOD Entries in the MEDLINE database between 1980 and 2011 were searched for studies of the dimensional and/or categorical structure of psychosis. Studies were included if samples represented a spectrum of psychotic disorders and dimensions/categories were empirically derived using principal components analysis, factor analysis, or latent class analysis. RESULTS Most dimensional studies observed 4 or 5 dimensions within psychosis, with positive, negative, disorganization, and affective symptom domains most frequently reported. Substance abuse, anxiety, early onset/developmental, insight, cognition, hostility, and behavioral/social disturbance dimensions appeared in some studies. Categorical studies suggested 3 to 7 major classes within psychosis, including a class similar to Kraepelins dementia praecox and one or more classes with significant mood components. Only 2 studies compared the relative fit of empirically derived dimensions and categories within the same data set, and each had significant limitations. CONCLUSION There is relatively consistent evidence on appropriate categories and dimensions for characterizing psychoses. However, the lack of studies directly comparing or combining these approaches provides insufficient evidence for definitive conclusions about their relative merits and integration. The authors provide specific recommendations for designing future studies to identify valid dimensions and/or categories of the psychoses and investigate hybrid approaches to model the structure of the underlying illnesses.

Relationship of Catechol-O-Methyltransferase to Schizophrenia and Its Correlates: Evidence for Associations and Complex Interactions

Converging lines of evidence suggest that the gene that codes for catechol-O-methyltransferase (COMT) may play a role in the etiology, neurodevelopment, and expression of schizophrenia. Dopamine dysregulation has long been implicated in schizophrenia pathogenesis, and COMT appears to play a role in dopamine functioning, especially in prefrontal cortex. Additionally, the COMT gene maps to the commonly deleted region on chromosome 22q11 in 22q11 deletion syndrome (22q11DS), a disorder associated with a highly elevated risk for the development of psychosis. An amino acid polymorphism (Val158Met) in the COMT gene affects the activity level of COMT, which affects the levels of available catecholamines in the brain. Val158Met has been found to predict performance on dopamine-mediated prefrontal tasks in healthy adults and patients with schizophrenia. While association and linkage studies have failed to provide conclusive evidence of a strong link between COMT genotype and schizophrenia, evidence linking neural functioning and behavioral output has been somewhat more promising. The present work examines evidence for the role of COMT in schizophrenia pathogenesis, and associations between COMT and cognitive and behavioral correlates of schizophrenia and related disorders. Additionally, evidence for complex interactions involving COMT is examined, including the utility of haplotype analysis and evidence for gene-by-gene and gene-by-environment interactions.

Aberrant cerebellar connectivity in motor and association networks in schizophrenia

Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the “cognitive dysmetria” and “dysmetria of thought” models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks) relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of schizophrenia.

Auditory hallucinations in a cross-diagnostic sample of psychotic disorder patients: a descriptive, cross-sectional study

BACKGROUND Auditory hallucinations (AH) are a cardinal feature of schizophrenia spectrum disorders. They are not disease specific, however, and can occur in other conditions, including affective psychoses. METHODS In this descriptive, cross-sectional study, we examined AH in relation to other psychotic symptoms, mood symptoms, illness severity, and functional status in 569 patients with psychosis (n = 172 schizophrenia, n = 153 schizoaffective disorder, n = 244 bipolar disorder with psychotic features). RESULTS A total of 323 (56.7%) patients reported a lifetime history of AH (75.6% of patients with schizophrenia, 71.9% schizoaffective disorder, and 34.0% bipolar disorder). The mean score for the hallucinations item (P3) of the Positive and Negative Syndrome Scale in the AH group was 3.66 ± 1.79, indicating mild to moderate state hallucinations severity. Auditory hallucinations were strongly associated with hallucinations in other sensory modalities and with the first-rank symptoms of delusions of control, thought insertion, and thought broadcasting. Multivariate analysis showed that AH were associated with lower education even after controlling for diagnosis, age, and sex. There was no association between AH and functional status as measured by the Multnomah Community Ability Scale. CONCLUSIONS Auditory hallucinations are associated with specific clinical features across the continuum of both schizophrenic and affective psychoses independent of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis.

Anxiety Disorder Comorbidity in Bipolar Disorder, Schizophrenia and Schizoaffective Disorder

Background: Reported rates of comorbid anxiety disorders in psychotic and mood disorders vary widely among studies. Sampling and Methods: We used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, to examine rates of comorbid anxiety disorders in patients with schizoaffective disorder (SZA; n = 153), bipolar I disorder (BP; n = 304) and schizophrenia (SZ; n = 174). Results: The rates of anxiety disorders in participants with SZA (30.1%), BP (22.4%) and SZ (16.7%) differed significantly [χ2(2) = 8.368, p = 0.015]. Among anxiety disorders, this effect was most pronounced for panic disorder (PD). PD rates were significantly higher in participants with SZA (15.7%) as compared to participants with BP (6.9%) and SZ [6.9%; χ2(2) = 10.879, p = 0.004]. Logistic regression models controlling for demographic and clinical characteristics confirmed that primary diagnosis (SZA, BP or SZ) was a significant predictor of PD comorbidity and approached significance in predicting the comorbidity of any anxiety disorder. Conclusions: Our findings suggest that patients with SZA have high rates of anxiety disorders. Clinicians treating patients with SZA should evaluate for anxiety disorder comorbidity, especially as anxiety symptoms may not be reported at first presentation.