Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

Introduction: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent.

Clozapine in Reducing Aggression and Violence in Forensic Populations.

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders.

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia.

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.

Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder.

Context: The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder.

Objective: Because α4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans.

Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.

Context: Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway.

Dipyridamole monotherapy in schizophrenia: pilot of a novel treatment approach by modulation of purinergic signaling.

Background: Emerging data indicate the neuromodulator adenosine may play a role in the therapeutics of schizophrenia. Adenosine A(2A) receptor stimulation exerts a functional antagonism at postsynaptic D(2) receptors. Data from animal models relevant to schizophrenia support a therapeutic effect of modulating adenosinergic transmission in the ventral striatum.

Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia.

The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10.

Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine.

The large numbers of partial clozapine responders represent a major therapeutic challenge. Unfortunately, there are no clear data to support how best to treat these patients. This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine.

Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia.

The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the alpha7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine).

Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia.

Sustained attention abnormality in schizophrenia is usually refractory to available treatment. Nicotine can transiently improve sustained attention in schizophrenia patients, although its neural mechanisms are unknown. Understanding the neural basis of this effect may lead to new treatment strategies for this cognitive deficit.

Is motion perception deficit in schizophrenia a consequence of eye-tracking abnormality?

Background: Studies have shown that schizophrenia patients have motion perception deficit, which was thought to cause eye-tracking abnormality in schizophrenia. However, eye movement closely interacts with motion perception. The known eye-tracking difficulties in schizophrenia patients may interact with their motion perception.

Sensory gating endophenotype based on its neural oscillatory pattern and heritability estimate.

Context: The auditory sensory gating deficit has been considered a leading endophenotype in schizophrenia. However, the commonly used index of sensory gating, P50, has low heritability in families of people with schizophrenia, raising questions about its utility in genetic studies. We hypothesized that the sensory gating deficit may occur in a specific neuronal oscillatory frequency that reflects the underlying biological process of sensory gating.

Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.

Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM.

Nicotine effect on prepulse inhibition and prepulse facilitation in schizophrenia patients.

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design.

Refining the predictive pursuit endophenotype in schizophrenia.

Background: To utilize fully a schizophrenia endophenotype in gene search and subsequent neurobiological studies, it is critical that the precise underlying physiologic deficit is identified. Abnormality in smooth pursuit eye movements is one of the endophenotypes of schizophrenia. The precise nature of the abnormality is unknown.

Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition.

Background: Neuregulin 1 (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia. A widely used surrogate measure of psychosis in animal models, PPI is considered a schizophrenia endophenotype.

Tardive dyskinesia in children treated with atypical antipsychotic medications.

Recent years have witnessed increased antipsychotic treatment of children despite limited long-term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic-naïve patients (n = 80) with similar age, sex ratio, and diagnoses.

Independent domains of inhibitory gating in schizophrenia and the effect of stimulus interval.

Objective: Patients with schizophrenia are known to have inhibitory gating deficits in the suppression of evoked potential P50 response to repeated stimuli and the prepulse inhibition of the startle response. In the current study, the authors aimed to determine whether these two inhibitory gating measures are related in schizophrenia patients or whether abnormal P50 suppression and abnormal prepulse inhibition are independent neurophysiological characteristics of schizophrenia. The authors hypothesized that the relationship of the two measures may vary as a function of interstimulus intervals of stimulus presentations.

Lack of association between COMT gene and deficit/nondeficit schizophrenia.

Background: The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states.

Deficits on the Continuous Performance Test within the schizophrenia spectrum and the mediating effects of family history of schizophrenia.

Individuals with schizophrenia spectrum personality disorders (SSPD) and schizophrenia show similar cognitive impairments. The authors examined the contributions of SSPD symptoms and familial risk for schizophrenia to impairments on the Continuous Performance Test--Identical Pairs Version. Participants included 103 schizophrenia patients, 66 first-degree relatives (29 SSPD), and 103 community controls (26 SSPD) screened for family history of psychosis.

Effects of repeated amphetamine administration on antisaccade in schizophrenia spectrum personality.

Repeated amphetamine administration is used to examine the responsivity of cerebral dopaminergic systems. Schizophrenia spectrum personality (SSP) provides a unique opportunity to study the pathophysiology of schizophrenia because of shared neurobiology without the confounding factors of acute psychosis and psychotropic exposure. Previously we noted that on repeated amphetamine administration, dyskinesia and SSP symptoms were less likely to worsen in SSP than in healthy volunteers.

Psychopathological and cognitive correlates of tardive dyskinesia in patients treated with neuroleptics.

Even though new cases of TD are on the decline in North America and other western countries, TD remains a public health concern for patients with chronic schizophrenia, PAD, and for nonpsychiatric patients treated with dopamine receptor antagonists. The new generation of atypical antipsychotic medications is believed to pose less risk for TD. However, identifying the cognitive and disease-related correlates of TD should equip clinicians with the necessary tools to reduce the prevalence of this iatrogenic movement disorder.

Reliability of a portable head-mounted eye tracking instrument for schizophrenia research.

Smooth pursuit eye movement (SPEM) abnormalities are some of the most consistently observed neurophysiological deficits associated with genetic risk for schizophrenia. SPEM has been traditionally assessed by infrared or video oculography using laboratory-based fixed-display systems. With growing interest in using SPEM measures to define phenotypes in large-scale genetic studies, there is a need for measurement instruments that can be used in the field.

Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia.

A previous study has shown an association between the *2236T > C allele polymorphism of the dihydropyrimidinase-related protein 2 (DRP-2) gene and schizophrenia in a Japanese sample [Nakata et al. (2003); Biological Psychiatry 53:571-576]. DRP-2 is an important molecule in guiding neuronal development and its gene is located in 8p21, a chromosomal region that was previously shown to have significant linkage to schizophrenia and to several deficit symptoms of schizophrenia.