Ikwunga Wonodi

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.

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.

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.

Association between Val108/158 met polymorphism of the COMT gene and schizophrenia

Schizophrenia is a complex disorder with a multifactorial polygenic inheritance with several genes conferring susceptibility at many genetic locations, each with a small effect. An attractive candidate gene for schizophrenia is the catechol‐O‐methyltransferase (COMT) gene, which is a modulator of dorsolateral prefrontal cortical function. A missense G to A mutation in this gene that results in a substitution of Methionine (Met) for Valine (Val) at codon 108/158 (Val108/158 Met) has recently been identified in association to schizophrenia. We compared allele frequencies of the variant Val allele between 96 schizophrenia cases and 80 normal controls. We selected controls from a similar pool to cases in ethnicity and gender. The frequency of the Val allele was significantly higher in schizophrenia cases compared to controls (0.620 vs. 0.506; P = 0.043). Calculation of the population attributable risk suggests that the Val allele accounts for as much as 23% of schizophrenia in this population (range: 3–38%). These results provide support for a role of this variant in the etiopathophysiology of schizophrenia.

Specific motion processing pathway deficit during eye tracking in schizophrenia: A performance-matched functional magnetic resonance imaging study

BACKGROUND The neural mechanisms underlying smooth pursuit eye movement (SPEM) abnormalities in schizophrenia are not well understood. Previous evidence suggests that a deficit in the processing of internal representations of object motion (extraretinal motion) contributes to SPEM deficits in patients. Functional magnetic resonance imaging (fMRI) activation was compared between patients and control subjects to determine whether schizophrenia patients exhibit abnormal cerebral activation in regions associated with extraretinal motion processing during SPEM. METHODS Patients and control subjects were selected based on matched performance in the closed-loop gain. Despite similar performance on closed-loop pursuit gain, patients showed consistent deficits in extraretinal motion based on predictive pursuit. In the magnet, subjects were tested using a traditional smooth-pursuit task that elicits closed-loop response. RESULTS Patients had reduced pursuit-related activation in several known extraretinal motion processing areas including frontal and supplemental eye fields, medial superior temporal cortex, and anterior cingulate. Patients also showed increased activation in medial occipitotemporal cortex. CONCLUSIONS These results provide functional anatomic evidence supporting reduced function in the extraretinal motion processing pathway in schizophrenia. Increased activation in medial occipitotemporal cortex suggests an increased dependence on immediate retinal motion information, which may be used to compensate for reduced extraretinal signaling during sustained visual tracking.

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.

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.

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, Fishers 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, Fishers 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.

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. We compared the frequency of the DRP‐2 *2236T > C polymorphism between subjects with (n = 117) and without (n = 72) schizophrenia, and then further evaluated whether the association was specific for the deficit (n = 24) and nondeficit (n = 93) forms of schizophrenia. In both Caucasians and African‐Americans, the C allele occurred more frequently in schizophrenia cases than controls, with this difference achieving statistical significance in Caucasians (C allele frequency: 42.0% in cases vs. 25.0% in controls, P = 0.014) but not African Americans (52.6% in cases vs. 50.0% in controls, P = 0.93). In Caucasians, the frequency of the C allele was significantly higher in both the deficit (allele frequency 53.3%, P = 0.009) and nondeficit (39.2%, P =0.050) forms of schizophrenia compared to controls (allele frequency 25.0%). We conclude that the DRP‐2 *2236 C allele may mark another polymorphism in DRP‐2, or in a nearby gene, that may influence susceptibility to schizophrenia.

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).