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This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Risk-based decision making is altered in people with schizophrenia and in people with cannabis use compared to healthy controls; the pattern of risk-assessment in people with co-occurring schizophrenia and cannabis dependence is poorly understood. This study examined measures of risk-taking and decision-making in people with and without schizophrenia and/or cannabis dependence.Participants with schizophrenia (n=24), cannabis dependence (n=23), schizophrenia and co-occurring cannabis dependence (n=18), and healthy controls (n=24) were recruited from the community via advertisements and completed a one-visit battery of symptom, risk-based decision making, gambling behavior, cognitive, and addiction assessments. This report presents self-assessments of self-mastery, optimism, impulsivity, and sensation seeking and a behavioral assessment of risk (Balloon Analog Risk Task [BART]).On self-report measures, participants with schizophrenia and co-occurring cannabis dependence were intermediate between those with only cannabis dependence or only schizophrenia on ratings of self-mastery, sensation-seeking, and impulsivity. There were no group differences on ratings of optimism. Their behavior on the BART was most similar to participants with only cannabis dependence or healthy controls, rather than to participants with only schizophrenia.People with schizophrenia and co-occurring cannabis dependence may represent a unique group in terms of risk-perception and risk-taking. This has implications for interventions designed to influence health behaviors such as motivational interviewing.

There is increasing evidence that psychological factors (e.g., defeatist performance beliefs, trait negative affect) contribute to poor functional outcome in people with schizophrenia. In the current study, we evaluated whether multiple psychological factors predict poor functional outcome in individuals with schizophrenia, and whether associations between psychological variables and functional outcome persist even after accounting for neuropsychological impairment and negative symptoms.100 patients meeting diagnostic criteria for schizophrenia or schizoaffective disorder and 78 demographically matched healthy control subjects completed self-report psychological measures, neuropsychological testing, and clinical rating scales.Self-report scales assessing negative affectivity, defeatist performance beliefs, anhedonia, and behavioral inhibition were significantly correlated with functional outcome in people with schizophrenia. Neuropsychological impairment was associated with vocational outcome, whereas most of the self-report measures were related to social outcome. Defeatist performance attitudes were not correlated with neuropsychological performance.Self-report measures predict variance in functional outcome beyond measures of clinical symptomatology and neuropsychological impairment. Findings indicate that psychological factors may be meaningful targets for psychosocial interventions aimed at improving functional outcome in schizophrenia.

Sustained attention deficits and high rates of smoking are often observed in patients with schizophrenia. This has led to the hypothesis that patients may smoke as an attempt to ameliorate cognitive deficits related to abnormal nicotinic structure and function. Continuous performance tasks (CPT) are often used to index sustained attention deficits in patients with schizophrenia, however, there are important differences between tasks that may impact performance in smokers and nonsmokers with schizophrenia differently. The Conners' CPT (C-CPT) has a high signal-to-noise ratio and is commonly used to assess impulsivity. The CPT-Identical Pairs (CPT-IP) has a low signal-to-noise ratio and is commonly used to assess negative symptoms in patients with schizophrenia. We sought to determine whether there were differences of sustained attention between patient smokers vs. nonsmokers, and if one CPT would provide a better separation of sustained attention between groups. Results revealed that both instruments detect more impaired sustained attention deficits in patient smokers compared to nonsmokers. Patient smokers performed significantly worse on the majority of the CPT-IP composite scores compared to the C-CPT composite scores. These results do not support the self-medication theory, as patient smokers performed worse than patient nonsmokers. Researchers studying sustained attention in schizophrenia may wish to consider the CPT-IP over the C-CPT, as well as control for smoking status.

The current study examined the psychometric properties of the Brief Negative Symptom Scale (BNSS), a next-generation rating instrument developed in response to the NIMH sponsored consensus development conference on negative symptoms. Participants included 100 individuals with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who completed a clinical interview designed to assess negative, positive, disorganized, and general psychiatric symptoms, as well as functional outcome. A battery of anhedonia questionnaires and neuropsychological tests were also administered. Results indicated that the BNSS has excellent internal consistency and temporal stability, as well as good convergent and discriminant validity in its relationships with other symptom rating scales, functional outcome, self-reported anhedonia, and neuropsychological test scores. Given its brevity (13-items, 15-minute interview) and good psychometric characteristics, the BNSS can be considered a promising new instrument for use in clinical trials.

Objective To examine the structural integrity of the dorsolateral prefrontal-basal ganglia–thalamocortical circuit in people with the deficit form of schizophrenia. Method A three-dimensional structural MRI sequence was used to conduct morphometric assessments of cortical and subcortical regions in deficit and nondeficit outpatients with schizophrenia and healthy controls. Results The superior prefrontal and superior and middle temporal gyral gray matter volumes were significantly smaller in the deficit versus the nondeficit group and normal control groups. There were no significant group differences in examined subcortical structures. Conclusion People with deficit schizophrenia are characterized by selective reductions in the prefrontal and temporal cortex.

Background Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia. Method Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial. Results There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p = .45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p = .048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30 mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed. Conclusion Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45–50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.

To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia.Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study.In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects.Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Several clinical studies have found an inverse relationship between clinical symptoms and peripheral oxytocin (OT) levels in people with schizophrenia. As oxytocin is a putative treatment for schizophrenia, the effect of repeated dosing of OT on OT levels, clinical symptoms and the relationship between the two is of interest. In a, randomized, double blind, parallel group 3 week study (N=28) with daily administration of intranasal OT (20 IU twice daily) or placebo (PBO), we examined the effect of OT administration on the correlation between the change in peripheral OT levels and change in clinical symptoms in patients with schizophrenia. At baseline, there were no significant treatment group differences in OT levels. There were no significant associations between baseline OT levels and any symptom measures. After 3 weeks of OT/PBO dosing, there was no significant difference in the magnitude of change in OT levels between the two treatment groups. Correlations between changes in peripheral OT levels and changes in the BPRS total and negative symptom scores were not different between treatment groups. Larger studies are needed to examine the effect of exogenous OT on peripheral OT levels and the relationship between the latter and clinical symptoms. Clinical Trials.gov=NCT00884897.

Objective: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range (∼40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. Method: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. Results: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls (p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics (p

Background Cognitive deficits compromise quality of life and productivity for individuals with schizophrenia and have no effective treatments. Preclinical data point to the kynurenine pathway of tryptophan metabolism as a potential target for pro-cognitive drug development. We have previously demonstrated association of a kynurenine 3-monooxygenase (KMO) gene variant with reduced KMO gene expression in postmortem schizophrenia cortex, and neurocognitive endophenotypic deficits in a clinical sample. KMO encodes kynurenine 3-monooxygenase (KMO), the rate-limiting microglial enzyme of cortical kynurenine metabolism. Aberration of the KMO gene might be the proximal cause of impaired cortical kynurenine metabolism observed in schizophrenia. However, the relationship between KMO variation and cognitive function in schizophrenia is unknown. This study examined the effects of the KMO rs2275163C>T C (risk) allele on cognitive function in schizophrenia. Methods We examined the association of KMO polymorphisms with general neuropsychological performance and P50 gating in a sample of 150 schizophrenia and 95 healthy controls. Results Consistent with our original report, the KMO rs2275163C>T C (risk) allele was associated with deficits in general neuropsychological performance, and this effect was more marked in schizophrenia compared with controls. Additionally, the C (Arg452) allele of the missense rs1053230C>T variant (KMO Arg452Cys) showed a trend effect on cognitive function. Neither variant affected P50 gating. Conclusions These data suggest that KMO variation influences a range of cognitive domains known to predict functional outcome. Extensive molecular characterization of this gene would elucidate its role in cognitive function with implications for vertical integration with basic discovery.

The relationship between gluten sensitivity and schizophrenia has been of increasing interest and novel mechanisms explaining this relationship continue to be described. Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels schizophrenia (2.9 ± 7.7 vs. 1.3 ± 1.3, p = 0.046, controlled for age). Additionally, we examined symptoms within the schizophrenia group and found that while positive symptoms are significantly lower in people who have elevated antigliadin antibodies (AGA; 4.11 ± 1.36 vs. 6.39 ± 2.99, p = 0.020), no robust clinical profile differentiates between positive and negative antibody groups. Thus, identifying people in schizophrenia who may benefit from a gluten-free diet remains possible by blood test only.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Patients with schizophrenia demonstrate a generalized deficit across multiple cognitive domains. However, it is unknown whether this deficit is largely due to lower intelligence, or if there is an impact of schizophrenia which cannot be accounted for by measures of general intellectual ability (GIA). We created four IQ-matched strata of equal width between 89 healthy volunteers (HC) and 77 patients with schizophrenia (SZ) who had very similar IQ and reading scores within each stratum, then compared each stratum's performance on the MATRICS Consensus Cognitive Battery (MCCB). We hypothesized that any patient impairment on the MCCB after matching on IQ would be evidence that GIA does not fully explain the general deficit seen in schizophrenia. We found that patients showed evidence of greater neuropsychological impairment than what would be expected based solely on their IQ and reading ability scores. Further, this deficit was stronger in some cognitive domains than others, namely, processing speed and social cognition. These results suggest the presence of a distinction between GIA and generalized neuropsychological impairment that was consistent in magnitude across all patients, regardless of IQ.

article i nfo Background: Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfac- tory identification as well as positive and negative symptoms in people with schizophrenia. Methods: Individuals with schizophrenia or schizoaffective disorder (n=28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. Results: All 28 participants completed the clinical trial. Odor identification performance significantly im- proved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleas- ant smells. UPSIT score (F=5.20, df=1,23, p=0.032) and subscore for pleasant smells (F=4.56, df=1,23, p=0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxy- tocin was well tolerated during the three week trial. Conclusion: Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of pos- itive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov). Published by Elsevier B.V.

The purpose of this study was to examine the cognitive and clinical correlates of the MATRICS Consensus Cognitive Battery (MCCB) which was originally developed to be an endpoint for cognitive enhancement clinical trials. In a sample of 117 people with schizophrenia and 77 healthy control participants we found the following: a) the MCCB was highly sensitive to the type and level of impairment typically observed in schizophrenia, b) the MCCB composite score was highly correlated with WASI Estimated Full Scale IQ score, c) that the MCCB domain scores were generally moderately-highly intercorrelated, d) that MCCB performance was minimally related to clinical symptom type and severity, and e) the MCCB is sensitive to employment status with better performance in employed vs. unemployed patients. These data support the validity of the MCCB as a sensitive measure of cognitive impairment in schizophrenia and suggest that MCCB performance is relevant for functional outcome. The data also suggest that the MCCB domain scores may offer limited resolution on discrete cognitive functions.

People with schizophrenia who have current substance use disorder (SUD) are generally excluded from clinical trials for the following reasons: safety/side effect risk, concern about adherence to the study protocol (Kreyenbuhl et al., 2011) and avoidance of confounds to efficacy evaluations (Buchanan et al., 2010). Patients with a past history of SUD are generally not excluded, but may represent a population with similar potentially unfavorable characteristics. To evaluate the possible consequences of this differential exclusion practice, we examined baseline symptoms of participants with substantial lifetime substance use and compared to participants with no substantial lifetime substance use in a sample of 15 outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria) enrolled in a controlled clinical trial of an adjunct weight loss medication (Kelly et al., 2011; Boggs et al., 2012). This analysis includes the full sample of patients enrolled in the clinical trial, which was prematurely terminated because of withdrawal of the experimental compound; thus, within-study sample bias did not influence our findings. Participants were 18–55 years old, with stable psychiatric symptoms, treated with a second generation antipsychotic for ≥eight weeks (same dose for ≥four weeks), overweight or obese, with a Calgary Depression Scale (Addington et al., 1992) total score ≤7, no history of hospitalization for depression or suicidal thoughts or behavior in the prior six months, and no substance dependence (DSM-IV criteria) within the prior six months other than caffeine or nicotine and no substance abuse within the prior month. Current drug use status was confirmed by urine and blood tests and self-report. SUD history was evaluated using the Structured Clinical Interview for DSM-IV Disorders, with more detailed information on alcohol, heroin, methadone, barbiturates, cocaine, amphetamines, cannabis, hallucinogens, inhalants, and nicotine use from the modified Addiction Severity Index (ASI) interview (McLellan et al., 1980). The ASI collects information on use in the prior 30 days and number of years of lifetime use. Substantial lifetime substance use was defined as ≥5 years of past use ≥4 times per week or with binging or problematic use in which normal activities are compromised. Current schizophrenia symptoms were assessed with the Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms. There were no significant differences in participants’ socio-demographic characteristics. Both patient groups were comparable in demographic characteristics and cigarette smoking. The ten participants with substantial lifetime substance use had more severe current positive symptoms and less severe negative symptoms than the five participants without a substantial history of substance use (Table 1). Table 1 Psychiatric characteristics of 15 people with schizophrenia without current substance use disorder and with or without substantial lifetime substance use. This study has several limitations, including very small sample size, which precluded any statistical control for potential confounding factors, and substance use based on retrospective self-report without objective corroboration. Future studies are warranted with larger sample sizes, objective assessments of substance use, and clear distinctions between substance use groups to validate our findings. These findings suggest that more attention be given to past history of substance use in people without a current SUD who enroll in clinical trials. Persisting effects from prior substance use may adversely affect response to treatment, leading clinicians to add or change medications, when a more appropriate action might be evaluation of prior substance use. In addition, prior substance use is a risk factor for relapse to present substance use or abuse, with potential adverse effects on current treatment response. Therefore, all clinicians should pay attention to lifetime, not just current, co-occurring SUDs. Future research should consider the inclusion of participants with lifetime substance use, even if substantial, in order to improve the external validity of their studies, and account for lifetime substance use in their analysis plan.

We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.

The increased mortality rate of persons with schizophrenia has been ot" concern for several decades and is known to be 2-3 times higher than the general population. The relative risk of developing cardiovascular disease may be approximately 5 times higher than the general population. This risk may be rising, possibly due to newer medications. While second-generation antipsychotics (SGAs) offer many advantages over conventional antipsychotics, some may have serious long-term health consequences associated with use. All patients with medical or pharmacy assistance treated with clozapine in the State of Maryland (inpatients and outpatients) and N1 patients treated with risperidone as inpatients prior to December 31, 2000 were examined for date and cause of death by the Social Security Death Index and death record acquisition. During this time period 3,095 people with schizophrenia were included of which 152 (~5%) were found to be deceased. The mean age of death was significantly younger in patients who have been treated with clozapine vs. risperidone (59.2 vs. 72.9 years; p