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. METHODS: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology. RESULTS: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm3) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm3) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). CONCLUSION: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

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. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

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. 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.

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 α4ß2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4ß2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. DESIGN: A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4ß2-specific effects while minimizing adverse effects. SETTING: Outpatient clinics. PARTICIPANTS: A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention Varenicline. MAIN OUTCOME MEASURES: Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention. RESULTS: A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose). CONCLUSIONS: Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits.

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. OBJECTIVES: To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. DESIGN: Case-control postmortem and clinical study. SETTING: Maryland Brain Collection, outpatient clinics. PARTICIPANTS: Postmortem specimens from schizophrenia patients (n = 32) and control donors (n = 32) and a clinical sample of schizophrenia patients (n = 248) and healthy controls (n = 228). MAIN OUTCOME MEASURES: Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). RESULTS: In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. CONCLUSION: Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.

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. One previous clinical trial showed superiority of adjunctive dipyridamole, an adenosine reuptake inhibitor, compared to placebo in ameliorating positive symptoms in schizophrenia patients. OBJECTIVES: The aim of this study was to examine the effects of dipyridamole monotherapy of 200 mg/day on positive and negative symptoms, with the goal of determining dosing for future adjunctive studies in schizophrenia. METHODS: Twenty symptomatic schizophrenia participants were randomized to a 6-week double-blind trial comparing olanzapine (20 mg/day) to dipyridamole monotherapy (200 mg/day). Thirteen participants completed the treatment phase (eight on dipyridamole; five on olanzapine). RESULTS: The olanzapine group showed a trend (p = 0.08) for superiority on BPRS total scores (mean ± SD: total BPRS score decreasing from 36.8 ± 2.3 at week 1, to 33.2 ± 5.5 at the end of the study). The mean total BPRS scores decreased from 36.4 ± 5.3 to 34.0 ± 7.7 in the dipyridamole group. CONCLUSIONS: Although these pilot data do not support a significant antipsychotic effect of dipyridamole monotherapy, the results provide some evidence for examining dipyridamole (200 mg/day) as adjunct to symptomatic antipsychotic-treated schizophrenia patients.

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. Twenty schizophrenia patients and 24 healthy comparison smokers participated in a double-blind, placebo-controlled, crossover, randomized functional magnetic resonance imaging study comparing nicotine vs placebo patch on sustained attention, using the rapid visual information-processing task. Schizophrenia patients had impaired visual sustained attention accuracy and processing speed (all P's <.001) and showed significantly reduced activation in the frontal-parietal-cingulate-thalamic attention network compared with healthy comparison subjects. Nicotine administration enhanced accuracy and processing speed compared with placebo (all P's ≤.006), with no drug × diagnosis interactions. However, schizophrenia patients' task performance remained impaired during the nicotine condition, even when compared with healthy comparison subjects in the placebo condition (all P's ≤.01). Nicotine exerted no significant reversal of the impaired attention network associated with schizophrenia. Activations in brain regions associated with nicotine-induced behavioral improvement were not significantly different between patients and comparison subjects. Thus, nicotine transiently enhanced sustained attention similarly in schizophrenia patients and in healthy comparison smokers. The neural mechanisms for this nicotinic effect in schizophrenia appear similar to those for healthy comparison subjects. However, nicotine, at least in a single sustained dose, does not normalize impaired sustained attention and its associated brain network in schizophrenia. These findings provide guidance for developing new treatment strategies for the sustained attention deficit in schizophrenia.

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. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.

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. A total of 69 inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind, placebo-controlled, randomized clinical trial. Of them, 33 participants were randomized to risperidone and 36 were randomized to placebo. There was no significant group difference in the predefined response criteria. There were modest group differences for Brief Psychiatric Rating Scale (BPRS) positive symptoms, which were significant in the completer analysis (F=5.70; df=1, 70.3; p=0.02; ES=0.27) but not the intent-to-treat (ITT) analyses (F=3.01; df=1, 77.5; p=0.09; ES=0.19). A similar pattern was found for the BPRS total score, with the completer analysis showing a significant improvement in the risperidone group (F=5.21; df=1, 64.9; p=0.03; ES=0.27), whereas the ITT analysis was not significant (F=3.52; df=1, 71.3; p=0.06; ES=0.22). In addition, there was a small, but significant, group difference for negative symptoms, as measured by the SANS total score, which favored the risperidone group (F=5.67; df=1, 78.7; p=0.02; ES=0.24). There were no significant group differences on safety measures, including neuropsychological test and extrapyramidal symptom scores. A significant elevation of prolactin in the risperidone group was observed. The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients. The study results are discussed in the context of previous double-blind studies of adjunctive risperidone. (clinicaltrials.gov, trial number: NCT00056498).

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). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.

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. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function.

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. METHODS: Two speed discrimination experiments were conducted in a within-subject design. In experiment 1, the stimulus duration was 150 msec to minimize the chance of eye-tracking occurrence. In experiment 2, the duration was increased to 300 msec, increasing the possibility of eye movement intrusion. Regular eye-tracking performance was evaluated in a third experiment. RESULTS: At 150 msec, speed discrimination thresholds did not differ between schizophrenia patients (n = 38) and control subjects (n = 33). At 300 msec, patients had significantly higher thresholds than control subjects (p = .03). Furthermore, frequencies of eye tracking during the 300 msec stimulus were significantly correlated with speed discrimination in control subjects (p = .01) but not in patients, suggesting that eye-tracking initiation may benefit control subjects but not patients. The frequency of eye tracking during speed discrimination was not significantly related to regular eye-tracking performance. CONCLUSIONS: Speed discrimination, per se, is not impaired in schizophrenia patients. The observed abnormality appears to be a consequence of impairment in generating or integrating the feedback information from eye movements. This study introduces a novel approach to motion perception studies and highlights the importance of concurrently measuring eye movements to understand interactions between these two systems; the results argue for a conceptual revision regarding motion perception abnormality in schizophrenia.

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. Frequency-specific sensory gating may be less complex than the P50 response, and therefore closer to the direct genetic effects, and thus a more valid endophenotype. OBJECTIVES: To compare the gating of frequency-specific oscillatory responses with the gating of P50 and to compare their heritabilities. DESIGN: We explored single trial-based oscillatory gating responses in people with schizophrenia, their relatives, and control participants from the community. SETTING: Outpatient clinics. PARTICIPANTS: Persons with schizophrenia (n = 102), their first-degree relatives (n = 74), and control participants from the community (n = 70). MAIN OUTCOME MEASURES: Gating of frequency-specific oscillatory responses, gating of the P50 wave, and their heritability estimates. RESULTS: Gating of the theta-alpha-band responses of the control participants were significantly different from those with schizophrenia (P < .001) and their first-degree relatives (P = .04 to .009). The heritability of theta-alpha-band gating was estimated to be between 0.49 and 0.83 and was at least 4-fold higher than the P50 heritability estimate. CONCLUSIONS: Gating of the theta-alpha-frequency oscillatory signal in the paired-click paradigm is more strongly associated with schizophrenia and has significantly higher heritability compared with the traditional P50 gating. This measure may be better suited for genetic studies of the gating deficit in schizophrenia.

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. Previous work has shown a reduced predictive pursuit response to a briefly masked (i.e., invisible) moving object in schizophrenia. However, the overt awareness of target removal can confound the measurement. METHODS: This study employed a novel method that covertly stabilized the moving target image onto the fovea. The foveal stabilization was implemented after the target on a monitor had oscillated at least for one cycle and near the change of direction when the eye velocity momentarily reached zero. Thus, the subsequent pursuit eye movements were completely predictive and internally driven. Eye velocity during this foveally stabilized smooth pursuit was compared among schizophrenia patients (n = 45), their unaffected first-degree relatives (n = 42), and healthy comparison subjects (n = 22). RESULTS: Schizophrenia patients and their unaffected relatives performed similarly and both had substantially reduced predictive pursuit acceleration and velocity under the foveally stabilized condition. CONCLUSIONS: These findings show that inability to maintain internal representation of the target motion or integration of such information into a predictive response may be the specific brain deficit indexed by the smooth pursuit endophenotype in schizophrenia. Similar performance between patients and unaffected relatives suggests that the refined predictive pursuit measure may index a less complex genetic origin of the eye-tracking deficits in schizophrenia families.

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. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.

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. We hypothesized that if NRG1 influences PPI in rodents, then it should have a similar effect on PPI in humans. METHODS: We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping was completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls. RESULTS: Rs3924999 genotype was significantly associated with PPI (p = .003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p = .02) and controls (p = .02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p = .85). Schizophrenia patients had reduced PPI compared to control subjects (p = .04). Neither single nucleotide polymorphism was associated with schizophrenia (all p > .37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p = .05). CONCLUSIONS: A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations.

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. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African-American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European-American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side-effect profile of the atypical antipsychotic drugs in children may be much different than that in adults.

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. METHOD: Fifty-nine schizophrenia patients and 17 healthy comparison subjects were tested on both P50 suppression and prepulse inhibition. P50 suppression was measured using paired clicks with 500-msec interstimulus intervals. Prepulse inhibition was measured by using a series of prepulse-pulse pairs with interstimulus intervals ranging from 30 to 500 msec. RESULTS: Patients showed reduced P50 suppression and prepulse inhibition in relation to healthy comparison subjects. Concordance analysis showed that abnormal P50 suppression and abnormal prepulse inhibition do not necessarily occur together. Prepulse inhibition was most prominent at the 120-msec interstimulus interval, which was not correlated to P50 suppression. At the 500-msec interstimulus interval, prepulse inhibition was significantly but negatively correlated to P50 suppression. Prepulse inhibition at the other interstimulus intervals was not correlated with P50 suppression. CONCLUSIONS: These neurophysiological measures lack robust and direct relationships and likely mark independent aspects of abnormal brain inhibitory functions in schizophrenia.

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. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. METHODS: Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val158Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). RESULTS: There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. CONCLUSION: Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia.

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. Patients and SSPD relatives performed significantly worse than non-SSPD relatives and SSPD and non-SSPD community controls. No differences in performance were observed among non-SSPD relatives and SSPD and non-SSPD community controls. Results suggest a continuum in which risk for schizophrenia-related cognitive impairments is highest among patients and SSPD relatives, intermediate among non-SSPD relatives, and lowest among SSPD and non-SSPD community controls. Results suggest that SSPD in the absence of a family history of psychosis may be a phenocopy.