Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms.

BACKGROUND: Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder. METHODS: Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor. RESULTS: Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN. CONCLUSIONS: These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).

A tale of two sites: Differential impairment of frequency and duration mismatch negativity across a primarily inpatient versus a primarily outpatient site in schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best replicated neurophysiological deficits in schizophrenia, with reduced amplitude reflecting impaired information processing at the level of supratemporal auditory cortex. Differential patterns of MMN dysfunction according to deviant types have been reported across studies, with some research groups showing impairment in duration MMN but not frequency MMN, and other research groups reporting both findings. We evaluate the hypothesis that recruitment setting, reflecting current functional status, might be an important determinant of the pattern of MMN dysfunction. Here, we evaluated patterns of MMN dysfunction, along with tone matching and neuropsychological performance in subjects drawn from 1) a predominant inpatient/residential care setting (Nathan Kline Institute) and 2) a predominant outpatient setting (Columbia University). As predicted, compared to healthy controls, deficits in duration MMN were observed across sites, whereas deficits in frequency MMN/tone matching were confined to the chronic inpatient setting. Within patients, the frequency MMN deficit was highly correlated with impairments in tone matching ability across sites (r=-0.52, p<0.0001), as well as impairments in verbal learning (r=-0.54, p<0.0001). Responses to standard stimuli in the MMN paradigm were assessed using measures of alpha evoked power and inter-trial coherence (ITC). While deficits in alpha ITC were observed across sites (both p<0.05), deficits in alpha power were observed at the inpatient (p=0.001) but not outpatient (p=0.2) site. Overall, these finding indicate that impairments of frequency MMN generation and response power to standard stimuli could be particularly linked to forms of schizophrenia that are associated with poor functional outcome.

Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia.

Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (θ)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and θ-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (α) and beta (ß) frequency ranges. PCP treatment also significantly reduced α-frequency response to standard stimuli while increasing θ-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to θ-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.

Developmental trajectory of mismatch negativity and visual event-related potentials in healthy controls: Implications for neurodevelopmental vs. neurodegenerative models of schizophrenia.

Sensory processing deficits are core features of schizophrenia, reflected in impaired generation of event-related potential (ERP) measures such as auditory mismatch negativity (MMN) and visual P1. To understand the potential time course of development of deficits in schizophrenia, we obtained MMN to unattended duration, intensity and frequency deviants, and visual P1 to attended LSF stimuli, in 43 healthy individuals ages 6 to 25years (mean 17), and compared results to data from 30 adult schizophrenia patients (mean age 38). We analyzed "time-domain" measures of amplitude and latency, and event-related spectral perturbation (ERSP, "time-frequency") to evaluate underlying neurophysiological mechanisms. Duration and intensity MMN amplitudes increased from childhood to late adolescence, while frequency MMN reached maximum amplitude during early development. As reported previously, in ERSP analyses, MMN activity corresponded primarily to theta-band (4-7Hz) activity, while responses to standards occurred primarily in alpha (8-12Hz) across age groups. Both deviant-induced theta and standard-induced alpha activity declined significantly with age for all deviant types. Likewise, visual P1 also showed an amplitude decline over development, reflecting a reduction in both evoked power and ITC. While MMN "difference" waveform ERP data suggest failure of maturation in schizophrenia, MMN ERSP analyses instead support a neurodegenerative process, as these isolate responses to deviants and standards, showing large low-frequency evoked power for both in children. Neurodegenerative processes are also supported by large visual P1 amplitudes and large low-frequency evoked power in children, in contrast with adult schizophrenia. Sensory processing deficits in schizophrenia may be related to accelerated synaptic pruning.

Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia.

Mismatch negativity (MMN) is among the best established biomarkers of cortical dysfunction in schizophrenia. MMN generators are localized primarily to primary and secondary auditory regions, and are known to reflect activity mediated by cortical N-methyl-d-aspartate-type glutamate receptors (NMDAR). Nevertheless, mechanisms underlying MMN generation at the local circuit level remain incompletely understood. This review synthesizes recent advances in circuit-level conceptualization of MMN based upon neuro-oscillatory findings. In the neuro-oscillatory (aka event-related spectral perturbation, ERSP) approach, responses to sensory stimuli are decomposed into underlying frequency bands prior to analysis. MMN reflects activity primarily in theta (4-7Hz) frequency band, which is thought to depend primarily upon interplay between cortical pyramidal neurons and somatostatin (SST)-type local circuit GABAergic interneurons. Schizophrenia-related deficits in theta generation are also observed not only in MMN, but also in other auditory and visual contexts. At the local circuit level, SST interneurons are known to maintain tonic inhibition over cortical pyramidal interneurons. SST interneurons, in turn, are inhibited by a class of interneurons expressing vasoactive intestinal polypeptide (VIP). In rodents, SST interneurons have been shown to respond differentially to deviant vs. standard stimuli, and inhibition of SST interneurons has been found to selectively inhibit deviance-related activity in rodent visual cortex. Here we propose that deficits in theta frequency generation, as exemplified by MMN, may contribute significantly to cortical dysfunction in schizophrenia, and may be tied to impaired interplay between cortical pyramidal neurons and local circuit SST-type GABAergic interneurons.

Investigating the potential genetic association between RANBP9 polymorphisms and the risk of schizophrenia.

Schizophrenia is a serious mental disorder that is affected by genetic and environmental factors. As the disease has a high heritability rate, genetic studies identifying candidate genes for schizophrenia have been conducted in various populations. The gene for human Ran­binding protein 9 (RANBP9) is a newly discovered candidate gene for schizophrenia. As RANBP9 is a small guanosine­5'­triphosphate­binding protein that interacts with the disrupted in schizophrenia 1 protein, it is considered to be an important molecule in the pathogenesis of schizophrenia. However, to date, no study has examined the possible association between the genetic variations of RANBP9 and the risk of schizophrenia. In the present study, it was hypothesized that RANBP9 variations may influence the risk of schizophrenia. In order to investigate the association between RANBP9 polymorphisms and the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormalities, a case­control association analysis was performed. Using a TaqMan assay, five single­nucleotide polymorphisms and an insertion/deletion variation within the start codon region of RANBP9 were genotyped. Five major haplotypes were identified in 449 patients with schizophrenia and 393 unrelated healthy individuals as controls (total, n=842). However, the association analyses revealed no associations between all genetic variants and schizophrenia and SPEM abnormality. To the best of our knowledge, this is the first study to investigate an association between RANBP9 polymorphisms and schizophrenia and SPEM abnormality. The findings of allele frequencies and association results in this study may aid in further genetic etiological studies in schizophrenia in various populations.

NCAM140 and pCREB Expression after Tianeptine Treatment of SH-SY5Y Cells.

OBJECTIVE: Antidepressants Modulate Neuronal Plasticity. Tianeptine, An Atypical Antidepressant, Might Be Involved In The Restoration Of Neuronal Plasticity; It Primarily Enhances The Synaptic Reuptake Of Serotonin. Ncam140 Is Involved In Neuronal Development Processes, Synaptogenesis And Synaptic Plasticity. We Investigated The Effect Of Tianeptine On The Expression Of Ncam140 And Its Downstream Signaling Molecule In The Human Neuroblastoma Cell Line Sh-sy5y. METHODS: NCAM protein expression was measured in human neuroblastoma SH-SY5Y cells that were cultivated in serum-free media and treated with 0, 10, or 20 µM tianeptine for 6, 24, or 72 hours. NCAM140 expression in the tianeptine treatment group was confirmed by Western blot, and quantified through measurement of band intensity by absorbance. CREB and pCREB expression was identified after treatment with 20 µM tianeptine for 6, 24, and 72 hours by Western blot. RESULTS: Compared to cells treated for 6 hours, cells treated with 0 or 10 µM tianeptine for 72 hours showed a significant increase in NCAM140 expression and cells treated with 20 µM tianeptine showed a significant increase after 24 and 72 hours. The pCREB level in cells treated with 20 µM tianeptine increased in time-dependent manner. CONCLUSION: Our findings indicated that the tianeptine antidepressant effect may occur by induction of NCAM140 expression and CREB phosphorylation.

Genetic association analysis of CNR1 and CNR2 polymorphisms with schizophrenia in a Korean population.

Located on 6q15 and 1p36.11, cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) genes are considered to be a positional and functional candidate gene for the development of mental disorders such as schizophrenia because CNR1 is known as a regulator of dopamine signaling in the hippocampus and the cerebral cortex. However, few genetic studies have been carried out to investigate an association of CNR1 and CNR2 polymorphisms and the risk of schizophrenia. In this study, although the result indicates that CNR1 and CNR2 variations are unlikely to influence schizophrenia susceptibility in a Korean population, the findings would provide meaningful information for further genetic studies.

Lack of association between DISC1 polymorphisms and risk of schizophrenia in a Korean population.

The DISC1 gene is considered to be a strong candidate gene for the development of schizophrenia. This study examines the association of DISC1 polymorphisms with schizophrenia in a Korean population. Although we fail to discover convincing evidence that DISC1 affects schizophrenia development, our findings may be useful for further genetic studies.

Genetic association analysis of ERBB4 polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population.

The human receptor tyrosine-protein kinase erbB-4 (ERBB4) gene mediates neuregulin 1 (NRG1) signaling, and is involved in neuronal migration and differentiation. Despite the potential significance of ERBB4 in the development of schizophrenia, relatively few genetic studies for the association of ERBB4 with schizophrenia were performed in the populations including Ashkenazi Jews, Americans including Caucasians and African Americans, and Han Chinese. In this study, differences in ERBB4 variations were investigated to determine association with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Seven polymorphisms in ERBB4 gene were genotyped in 435 schizophrenia cases and 390 unrelated healthy controls. In order to investigate the relationship between ERBB4 and the risk of schizophrenia and SPEM abnormality, differences in SNP and haplotype distribution were analyzed using logistic and multiple regression analyses. However, we failed to replicate the associations reported by previous studies in other populations. Although statistically not significant, the tendency towards associations between ERBB4 polymorphisms and the risk of schizophrenia and SPEM abnormality in this study from a Korean population would be helpful for further genetic etiology studies in schizophrenia.

Lack of associations of neuregulin 1 variations with schizophrenia and smooth pursuit eye movement abnormality in a Korean population.

Schizophrenia is a serious and disabling mental disorder with a high heritability rate. The human neuregulin 1 (NRG1) on 8p12 has been implicated as a candidate gene for schizophrenia. However, controversial results of the associations of NRG1 polymorphisms with schizophrenia and related phenotypes have been reported. In this study, four NRG1 single nucleotide polymorphisms, three in the promoter region, and one nonsynonymous in coding region, were genotyped in a total of 825 subject including 435 schizophrenia cases and 390 normal controls of Korean ethnicity. Although logistic association analysis of NRG1 polymorphisms and haplotypes with schizophrenia showed a nominal association in rs4623364G > C (P = 0.04), the significance disappeared after corrections for multiple testing (corrected P > 0.05). Additional case/control and multiple regression analyses in schizophrenia patients using a method that measures the smooth pursuit eye movement (SPEM) function globally based on natural logarithmic values of the signal/noise ratio also showed no association between NRG1 variants and SPEM abnormality among patients with schizophrenia (P > 0.05). Despite the need for further replications in other cohorts, our findings provide additional supporting information that four variants in NRG1 investigated in this study may not be associated with schizophrenia and its related SPEM function in a Korean population.

Determinants of the blood lead level of US women of reproductive age.

OBJECTIVES: Blood lead concentration of an infant is largely affected by maternal blood lead recycling. This study aimed to identify sociodemographic, lifestyle, and nutritional determinants for blood lead levels (BLLs) of women of reproductive age in the United States. METHODS: Subjects (n = 4,394) were women (20-49 years old) included in the most recent complete National Health and Nutritional Survey (NHANES III). Certain sociodemographic, lifestyle and nutritional determinants for BLL were identified. RESULTS: The BLL of reproductive age women was 1.78 microg/dL geometric mean, The BLL was inversely associated with poverty income ratio and education level, hematocrit, intake of thiamine, and serum levels of folate, and positively associated with ethnicity (Black, Hispanic), living in urban areas or the Northeast region, age, alcohol consumption, cigarette smoking, serum protoporphyrin, and intake of pyridoxine, iron, and folate. Subjects in the lowest decile for serum ascorbic acid had significantly higher BLLs than those in the 2nd through 8th deciles. CONCLUSION: Infants born to women who smoke, drink and maintain poor nutritional status for selected nutrients are at a greater risk of lead toxicity than those born to other women. Nutritional manipulation of thiamine, ascorbic acid and folate may impact BLL in women.