Christopher Reist

Social cognition in schizophrenia: Relationships with neurocognition and negative symptoms

Despite the growing importance of social cognition in schizophrenia, fundamental issues concerning the nature of social cognition in schizophrenia remain unanswered. One issue concerns the strength of the relationships between social cognition and key features of the disorder such as neurocognitive deficits and negative symptoms. The current study employed structural equation modeling to examine three key questions regarding the nature of social cognition in schizophrenia: 1) Are social cognition and neurocognition in schizophrenia better modeled as one or two separate constructs? 2) Are social cognition and negative symptoms in schizophrenia better modeled as one or two separate constructs?, and 3) When social cognition, neurocognition, and negative symptoms are included in a single model, is social cognition more closely related to neurocognition or to negative symptoms? In this cross sectional study, one hundred outpatients with schizophrenia or schizoaffective disorder were administered measures of social cognition, neurocognition, and negative symptoms. A two-factor model that represented social cognition and neurocognition as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and neurocognition are distinct, yet highly related, constructs. Likewise, a two-factor model that represented social cognition and negative symptoms as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and negative symptoms are distinct constructs. A three-factor model revealed that the relationship between social cognition and neurocognition was stronger than the relationship between social cognition and negative symptoms. The current findings start to provide insights into the structure of social cognition, neurocognition, and negative symptoms in schizophrenia.

Shifting emphasis from pharmacogenomics to theragnostics

What will be the role of theragnostic patents in upstream and downstream biomarker research?

The Japanese version of the Barratt Impulsiveness Scale, 11th version (BIS-11) : Its reliability and validity

Abstract No instrument for assessing impulsiveness has been developed in Japan. After translating the Barratt Impulsiveness Scale 11th version (BIS‐11) into Japanese, we investigated reliability and validity in student (n = 34) and worker (n = 416) samples. To assess test–retest reliability, the intraclass coefficient between test and retest was calculated in the student sample. Internal consistency was examined by calculating Cronbachs alpha in the worker sample. To see factor validity, we examined by confirmatory factor analysis whether the three‐factor model, proposed by a previous report, fit the data. The results showed that the Japanese version of the BIS‐11 had excellent test–retest reliability and acceptable internal consistency reliability. In addition, the Japanese version was judged to have similar factor structure to the original one. The Japanese version of the BIS‐11 is a reliable and valid measure and has possible utility for assessing impulsiveness.

Social Cognition and Neurocognition: Effects of Risperidone, Olanzapine, and Haloperidol

Objective: This study examined the short-term effects of first- and second-generation antipsychotic medications on social cognition and basic cognition. Method: One hundred patients with schizophrenia or schizoaffective disorder participated in an 8 week, double-blind study of risperidone, olanzapine, and haloperidol. Participants were administered multiple measures of social cognition, basic cognition, and clinical symptoms at baseline, the end of week 4, and the end of week 8. Seventy-three patients completed the baseline assessment and at least one other assessment. Data were analyzed with mixed-effects analyses of covariance. For data reduction, the social cognitive measures were clustered into a summary score, and the cognitive measures were clustered into two summary scores: general cognitive ability and processing speed. (The effects on thinking of risperidone and olanzapine can be found at NCT00108368, www.clinicaltrials.gov.) Results: There were no treatment-related differences on any of the three summary scores. Social cognition did not show within-group changes over time either by itself or after control for the cognitive clusters. One cognitive score (general cognitive ability) increased during the study period for all three medication groups. Conclusions: The present study included a rather thorough assessment of social cognition and did not find any evidence of between-group or within-group effects of antipsychotic medication on social cognition.

Treatment-resistance to Clozapine in Association With Ultrarapid Cyp1a2 Activity and the C → A Polymorphism in Intron 1 of the cyp1a2 Gene: Effect of Grapefruit Juice and Low-dose Fluvoxamine

Antipsychotic response to clozapine varies markedly among patients with schizophrenia. The disposition of clozapine is dependent, in part, on the cytochrome P-450 (CYP) 1A2 enzyme in vivo. In theory, a very high CYP1A2 activity may lead to subtherapeutic concentrations and treatment resistance to clozapine. This prospective case study evaluates the clinical significance of ultrarapid CYP1A2 activity and a recently discovered single nucleotide (C → A) polymorphism in intron 1 of the CYP1A2 gene (CYP1A2*F) for treatment resistance to clozapine. In addition, we describe the effect of grapefruit juice or low-dose fluvoxamine (25–50 mg/d) coadministration on clozapine and active metabolite norclozapine steady-state plasma concentration and antipsychotic response.

CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite norclozapine steady-state concentration in patients with schizophrenia

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizo-phrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r s = −0.87, p < 0.01) and norclozapine (r s = −0.76, p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Citalopram Combined with Behavioral Therapy Reduces Cocaine Use: A Double-Blind, Placebo-Controlled Trial

Cocaine dependence continues to be a significant problem in the United States, without any approved pharmacotherapy. Promising findings from preclinical research on the effects of cocaine on serotonin lead to examination of selective serotonin reuptake inhibitors (SSRIs) as potential treatments for cocaine dependence with mixed results, possibly due to drug interactions or specifics of concomitant behavioral therapy. The purpose of this study was to examine whether the SSRI citalopram would reduce cocaine positive urines in a 12-week, double-blind placebo-controlled trial. Seventy-six cocaine dependent patients received either citalopram 20 mg per day or placebo along with cognitive behavioral therapy (CBT) and contingency management (CM). Citalopram treated subjects showed a significant reduction in cocaine-positive urines during treatment compared to placebo treated subjects. No differences were noted in retention between the two groups. Side effects reported for citalopram were mild, with none leading to discontinuation of study drug. Results of this study support further examination of citalopram in combination with behavioral therapy as a treatment for cocaine dependence.

β-Adrenergic blockade and emotional memory in PTSD

Emotional arousal has been shown to enhance memory, an effect that is blocked by propranolol suggesting that the noradrenergic system is important in the mechanism action. Because PTSD has as prominent features heightened arousal and distressing memories, the current study was undertaken to examine whether PTSD subjects differed from controls in emotional enhancement of memory. Seventeen subjects with PTSD and 21 controls received either placebo or 40 mg of propranolol prior to exposure to either an emotionally arousing or emotionally neutral, narrated slide story. Recall, measured 1 wk later, for the arousing story was enhanced and this effect was reduced by propranolol. PTSD and control subjects did not differ in the acquisition and retention of memories under emotionally arousing or emotionally neutral conditions, nor were differential effects of propranolol observed between the two groups.

Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia : An observational pharmacoepidemiology study from 1988 to 2002

Patients with schizophrenia are at increased risk for cardiovascular disease as a consequence of lifestyle habits, impaired access to health care, and, increasingly, due to metabolic side effects ostensibly attributed to second-generation antipsychotics (SGAs). There is little evidence, however, on the extent and temporal patterns of SGA-associated metabolic side effects. We longitudinally examined the differential prevalence rates of obesity, diabetes mellitus, and diabetic ketoacidosis among inpatients with schizophrenia compared with control inpatients without schizophrenia. The data were derived from the National Inpatient Sample, the largest all-payer inpatient care database in the United States consisting of 5 to 8 million inpatient hospital stays per year sampled to approximate a 20% sample of community hospitals from 1988 to 2002. Overlaid on these observations was the market penetration data for SGAs. In 1988, the net difference from controls in obesity prevalence among inpatients with schizophrenia was +4.7%; by 2002, this difference had widened to +14.7%. Similarly, a significant increase in net prevalence of diabetes mellitus and diabetic ketoacidosis was observed from 1988 to 2002 among schizophrenic inpatients. In conclusion, after the introduction of SGAs, patients with schizophrenia in the United States have experienced a striking net increase in the prevalence of obesity and diabetes mellitus. This is likely to significantly add to an already elevated risk for cardiovascular disease in this population. Further investigations are urgently required so that health policy can be appropriately amended for preventive measures.

Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians: Haplotype characterization and relevance of the 2-repeat allele†

The relationship of the dopamine D4 receptor gene (DRD4) to the behavioral trait of novelty seeking has not been uniformly consistent. A methodological shortcoming in previous studies may relate to the way different DRD4 variants were categorized. Because of evolutionary and functional (e.g., diminished potency to reduce cAMP) similarities between the 2‐ and 7‐repeat (2R, 7R) alleles of the DRD4, we suggest grouping of these two alleles together may facilitate detection of biologically meaningful and reproducible association findings with behavioral traits. We measured novelty seeking with the Tridimensional Personality Questionnaire (TPQ) in a community sample of Caucasian, Korean, and Filipino subjects (N = 171) who were subsequently characterized for the DRD4 variable number of tandem repeats (VNTR). In the Korean sample, those with a 2R and/or 7R allele scored significantly higher on novelty seeking scale (P < 0.05). By contrast, grouping the VNTR alleles by size (2, 3, 4 vs. 5, 6, 7), as has been done in similar studies of Asian subjects, was not significant. Using the extreme discordant phenotype (EDP) strategy in the pooled sample and selecting the individuals within the upper and lower decile, we observed a trend for association with higher novelty seeking in individuals who carry the 2R and/or 7R alleles (P = 0.06). We also confirmed that the 2R allele in the Korean and Filipino subjects was the result of a one‐step recombination event between the 4R and 7R alleles. This study suggests that genetic association analyses can benefit by consideration of the shared functional and evolutionary attributes of the DRD4 2R and 7R alleles.