Margaret M. McClure

Predicting schizophrenia patients' real-world behavior with specific neuropsychological and functional capacity measures.

BACKGROUND Significant neuropsychological (NP) and functional deficits are found in most schizophrenia patients. Previous studies have left questions as to whether global NP impairment or discrete domains affect functional outcomes, and none have addressed distinctions within and between ability and performance domains. This study examined the different predictive relationships between NP domains, functional competence, social competence, symptoms, and real-world behavior in domains of work skills, interpersonal relationships, and community activities. METHODS Two hundred twenty-two schizophrenic outpatients were tested with an NP battery and performance-based measures of functional and social competence and rated for positive, negative, and depressive symptoms. Case managers generated ratings of three functional disability domains. RESULTS Four cognitive factors were derived from factor analysis. Path analyses revealed both direct and mediated effects of NP on real-world outcomes. All NP domains predicted functional competence, but only processing speed and attention/working memory predicted social competence. Both competence measures mediated the effects of NP on community activities and work skills, but only social competence predicted interpersonal behaviors. The attention/working memory domain was directly related to work skills, executive functions had a direct effect on interpersonal behaviors, and processing speed had direct effects on all three real-world behaviors. Symptoms were directly related to outcomes, with fewer relationships with competence. CONCLUSIONS Differential predictors of functional competence and performance were found from discrete NP domains. Separating competence and performance provides a more precise perspective on correlates of disability. Changes in specific NP or functional skills might improve specific outcomes, rather than promoting global functional improvement.

Correlations of functional capacity and neuropsychological performance in older patients with schizophrenia: evidence for specificity of relationships?

BACKGROUND Neuropsychological (NP) performance is a consistent correlate of everyday functioning in schizophrenia, but it is unclear whether relationships between individual NP ability areas and domains of everyday functioning are general or specific. Assessments of real-world everyday functioning may be influenced by environmental and social factors (e.g., social security, disability status, opportunities and restrictions in living situations). This study examined the specificity of the relationships between different NP abilities and performance-based measures of social and living skills. METHODS 181 ambulatory older (age>50) patients with schizophrenia were examined with NP tests measuring episodic and working memory, executive functioning, verbal fluency, and processing speed. All subjects performed tasks examining social (Social Skills Performance Assessment: SSPA) and everyday living (UCSD Performance Based Skills Assessment: UPSA) skills. RESULTS Using canonical analysis, the NP variables were used to predict the functional capacity measures. The analysis found that 37% of the variance in the functional capacity and NP measures was shared, X(2) (54)=106.29, p<.001. Two canonical roots described the cognitive variables and the roots were differentially associated with everyday living and social skills. The root loading on processing speed, episodic memory, and executive functions were associated with UPSA scores, while the root loading on working and episodic memory and verbal fluency were associated most strongly with social competence. IMPLICATIONS Social and everyday living skills deficits in patients with schizophrenia may reflect generally independent domains of functional outcome, linked through cognitive performance. The data suggest that somewhat different cognitive processes are associated with these two domains of functional capacity, although there appears to be some overlap, which may be due to the nature of the NP tests employed.

Context Processing in Schizotypal Personality Disorder: Evidence of Specificity of Impairment to the Schizophrenia Spectrum

Working memory abnormalities, which are particularly pronounced on context processing tasks, appear relatively specific to schizophrenia spectrum illnesses compared with other psychotic disorders. However, the specificity of context processing deficits to schizotypal personality disorder (SPD), a prototype of schizophrenia, has not been studied. The authors administered 3 versions of the modified AX Continuous Performance Test and an N-back working memory test to 63 individuals with SPD and 25 with other personality disorders, as well as 42 healthy controls. For the AX Continuous Performance Test standard and degraded versions, there was a significant Trial Type x Delay x Group interaction, as SPDs made significantly more errors reflecting poor maintenance of context and fewer errors reflecting good maintenance of context. SPDs also demonstrated poor performance on the N-back, especially at the 2-back condition. Context processing errors and N-back accuracy scores were related to disorganization symptoms. These findings, which are quite similar to those previously reported in patients with schizophrenia, suggest that context processing deficits are specific to the schizophrenia spectrum and are not a reflection of overall psychopathology.

The Effects of Guanfacine on Context Processing Abnormalities in Schizotypal Personality Disorder

BACKGROUND The signature of impaired cognition in people with schizotypal personality disorder (SPD) may be centrally related to working memory impairments. Guanfacine, an alpha2A agonist that acts post-synaptically in the prefrontal cortex (PFC), has shown potential for reducing working memory limitations in other populations. This study examined the potential of guanfacine for improving context processing, a feature of working memory, in SPD. METHODS 29 individuals with SPD entered into a 4-week, randomized parallel-design, double-blind, placebo-controlled trial of guanfacine treatment, followed by a 4-week open-label extension. A modified version of the AX-Continuous Performance Test (AX-CPT) was administered. On this task, evidence of intact context processing includes few BX errors (false cue, correct probe) and higher levels of AY errors (correct cue, false probe). RESULTS At the end of double-blind treatment, participants treated with guanfacine demonstrated a significant reduction in BX errors and a small but significant increase in AY errors, a pattern that was not seen in the participants treated with placebo. CONCLUSIONS SPD participants improved in their context processing toward a normal response bias, making fewer BX and more AY errors, after being treated with guanfacine.

Pergolide Treatment of Cognitive Deficits Associated with Schizotypal Personality Disorder: Continued Evidence of the Importance of the Dopamine System in the Schizophrenia Spectrum

Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D1 and D2 receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.

Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder.

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2–4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen’s d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

Age-associated differences in cognitive performance in older community dwelling schizophrenia patients : Differential sensitivity of clinical neuropsychological and experimental information processing tests

Cognitive dysfunction is a common feature of schizophrenia and deficits are present before the onset of psychosis, and are moderate to severe by the time of the first episode. Controversy exists over the course of cognitive dysfunction after the first episode. This study examined age-associated differences in performance on clinical neuropsychological (NP) and information processing tasks in a sample of geriatric community living schizophrenia patients (n=172). Compared to healthy control subjects (n=70), people with schizophrenia did not differ on NP tests across age groups but showed evidence for age-associated cognitive worsening on the more complex components of an information-processing test. Age-related changes in cognitive function in schizophrenia may be a function of both the course of illness and the processing demands of the cognitive measure of interest. Tests with fixed difficulty, such as clinical NP tests, may differ in their sensitivity from tests for which parametric difficulty manipulations can be performed.

CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals

To the Editors: The CACNA1C gene codes for the pore-forming a1C subunit of the L-type voltage-gated calcium channel and plays an important role in synaptic plasticity, memory formation, learning and behavior (Bhat et al., 2012). The CACNA1C rs1006737 variant has been associated with bipolar disorder (BD) (Ferreira et al., 2008) and schizophrenia (Nyegaard et al., 2010). Furthermore, the same allele has been associated with increased hippocampal and prefrontal activity during emotional processing and executive cognition, respectively (Bigos et al., 2010), reduced bilateral hippocampal activation during episodic memory recall (Erk et al., 2010), increased paranoid ideation (Roussos et al., 2011), and increased expression of CACNA1C mRNA in human brain (Bigos et al., 2010). Psychosis is an overlapping feature of both schizophrenia and BD, and it has been suggested to represent a clinical manifestation of shared genetic liability between these two psychiatric illnesses (Craddock et al., 2009). In this study, we provide further support of this notion by replicating our previous findings (Roussos et al., 2011) and demonstrating that rs1006737 is also a risk factor for schizotypal personality disorder (SPD). Healthy subjects were recruited from the first (n=530) and second (n=334) wave of the Learning on Genetics of Schizophrenia (LOGOS) study. The recruitment of healthy controls (n=48) and SPD patients (n=50) has been described elsewhere (McClure et al., 2008). Briefly, the majority of SPD patients (90%) were recruited through advertisement in local newspapers and the remaining through referrals from outpatient psychiatric clinics at the Bronx Veterans Affairs Medical Center and Mount Sinai Medical Center. Participants provided written informed consent in accordance with the Institutional Review Board guidelines. All participants were evaluated by doctoral-level clinical psychologists with the Structured Interview for DSM-IV Personality (SIDP-IV) (Pfohl et al., 1997), and diagnoses were reached in a consensus meeting with an expert diagnostician (M.M.M.). The overall symptom-severity score for the cohort of patients with SPD was calculated based on each of the nine DSM-IV symptom criteria for SPD on a 4-point Likert-type scale (0=absent, 0.5=mild, 1.0=moderate, and 2.0=severe) grouped into three composite scores: cognitive impairment, interpersonal deficits, and paranoia. Subjects in the LOGOS cohort were assessed with the Schizotypal Traits Questionnaire (STQ). Table 1 describes the demographic characteristics of the LOGOS and SPD cohorts. All subjects were of Caucasian ancestry on the basis of self-report, as well as using a panel of ancestry informative unlinked markers. Table 1 Demographic and clinical characteristics of the LOGOS cohorts I and II and the SPD patients group. Genotyping was performed blind to phenotype measures by K-Biosciences (Herts, UK; ) as described elsewhere (Roussos et al., 2011). Call rate was 0.992, and no deviation from the Hardy–Weinberg Equilibrium was observed in any cohort (Table 2). Association analysis for qualitative (disease status in the SPD cohort) and quantitative traits (STQ in the LOGOS, and cognitive impairment, interpersonal deficits and paranoia in the SPD cohorts) was conducted with the UNPHASED package ( ) (Dudbridge 2008). Analysis of the demographic variables was performed based on Student’s t-test or the nonparametric Mann–Whitney–Wilcoxon test using SPSS (version 20; IBM, Armonk, NY). Table 2 Association analysis of rs1006737 and STQ in the LOGOS cohorts I and II and the SPD patients group. The rs1006737 ‘A’ allele was associated with the Paranoid Ideation subscale in the LOGOS I (p=5.0 × 10−4) and II (p=0.03) cohorts. Combined analysis of both cohorts showed a significant association for Paranoid Ideation (p=5.0 10−5) and Unusual Experiences (p=0.03). The same allele increased the risk for SPD (p=0.03, OR=1.91) and was associated at a trend level with Paranoia in the SPD patient group (p=0.053) (Table 2). The rs1006737 is associated with increased paranoid ideation as measured by the STQ in two distinct cohorts of healthy individuals, with SPD, and with the subphenotype of paranoia within the SPD patient group at a trend level. One limitation of our study is the small size of the SPD cohort, and further examination of the relationship between this single nucleotide polymorphism (SNP) and the schizotypal domains is warranted in future studies. However, the replication of previous results (Roussos et al., 2011) of increased schizotypy, as well as the same directionality of the effect (same risk allele), in all our cohorts and the existing literature in schizophrenia and BD, makes less likely that our SPD findings are a statistical artifact. These findings are consistent with the notion that common genetic risk factors for psychiatric disorders are penetrant in non-clinical and spectrum individuals. Furthermore, they provide a plausible link between enhanced genetic risk through inheritance of CACNA1C genotypes and the development of schizophrenia and BD through a “psychosis pathway”, which involves increased schizotypy in the clinical phenotype.

Pharmacological Approaches to the Management of Cognitive Dysfunction in Schizophrenia

Cognitive dysfunction is a core feature of schizophrenia as deficits that are present in the majority of patients with schizophrenia frequently precede the onset of other symptoms and persist even after other symptoms have been effectively treated. The use of atypical antipsychotics has produced some small improvements, although the need for adjunctive treatment specifically targeting cognitive dysfunction is gaining widespread acceptance. Animal models and some small clinical trials have yielded results that are promising but not definitive. Psychosocial interventions have also met with some success in ameliorating some cognitive limitations. The mixed results of pharmacological interventions are most likely to be as a result of a combination of methodological flaws of many studies, poor outcome measures, dose administration effects and problems with the agents themselves.

Visual–spatial working memory performance and temporal gray matter volume predict schizotypal personality disorder group membership

BACKGROUND Prior work shows individuals with schizotypal personality disorder (SPD) evince temporal lobe volume abnormalities similar to schizophrenia but sparing of prefrontal cortex, which may mitigate psychosis and the severe neurocognitive impairments observed in schizophrenia. This study examined the extent to which frontal-temporal gray matter volume and neurocognitive performance predict: (1) SPD group membership in a demographically-balanced sample of 51 patients and 37 healthy controls; and (2) symptom severity in SPD. METHODS Dimensional gray-matter volume (left frontal-temporal regions (Brodmann area (BA) 10, 21, 22)) and neurocognitive performance on key memory tasks (California Verbal Learning Test (CVLT), Dot Test, Paced Auditory Serial Addition Test (PASAT)), all salient to schizophrenia-spectrum disorders were examined in a multi-variable model. RESULTS Middle temporal gyrus (BA21) volume and spatial-working memory (Dot Test) performance were significant predictors of SPD group membership likelihood, with poorer working-memory performance indicating increased probability of SPD membership. Combining across regional volumes or cognitive measures resulted in fair-to-good discrimination of group membership, but including neurocognitive and non-collinear regional volume measures together resulted in a receiver-operating-characteristic (ROC) curve with improved diagnostic discrimination. Larger BA10 volume in dorsolateral prefrontal cortex (DLPFC) significantly predicted less symptom severity in SPD. CONCLUSIONS These findings suggest that temporal lobe volume and spatial-working memory performance are promising biological/phenotype markers for likelihood of SPD classification, while greater DLPFC volume may serve as a protective factor.