Dysfunction In Schizophrenia Patients Research Articles

Association of elevated levels of peripheral complement components with cortical thinning and impaired logical memory in drug-naïve patients with first-episode schizophrenia

Schizophrenia has been linked to polymorphism in genes encoding components of the complement system, and hyperactive complement activity has been linked to immune dysfunction in schizophrenia patients. Whether and how specific complement components influence brain structure and cognition in the disease is unclear. Here we compared 52 drug-naïve patients with first-episode schizophrenia and 52 healthy controls in terms of levels of peripheral complement factors, cortical thickness (CT), logical memory and psychotic symptoms. We also explored the relationship between complement factors with CT, cognition and psychotic symptoms. Patients showed significantly higher levels of C1q, C4, factor B, factor H, and properdin in plasma. Among patients, higher levels of C3 in plasma were associated with worse memory recall, while higher levels of C4, factor B and factor H were associated with thinner sensory cortex. These findings link dysregulation of specific complement components to abnormal brain structure and cognition in schizophrenia.

Differences in olfactory dysfunction and its relationship with cognitive function in schizophrenia patients with and without auditory verbal hallucinations.

Olfactory discrimination dysfunction has been observed in patients with schizophrenia (SCZ), but its relationship with cognitive function has not been clarified. The purpose of this study was to examine the differences in olfactory identification function in SCZ patients with and without auditory verbal hallucinations (AVHs) and its relationship with cognitive function. Olfactory identification function was measured in 80 SCZ patients with AVHs, 57 SCZ patients without AVHs, and 87 healthy controls (HC). Clinical symptom scores and neuropsychological measures were also administered to all corresponding subjects. Compared to HC, SCZ patients showed significant deficits in olfactory identification and cognitive function, but there were no differences in olfactory identification dysfunction and cognitive dysfunction between the two subgroups. In the non-AVHs subgroup only, poorer Olfactory Stick Identification Test for Japanese (OSIT-J) scores were significantly and positively correlated with total and delayed recall (Bonferroni correction, p < 0.002). Stepwise regression analysis revealed that factors affecting olfactory identification impairment differed in the two SCZ patient subgroups. In conclusion, this study highlights the commonality of olfactory identification dysfunction in SCZ patients and the importance of olfactory assessment of different subtypes of SCZ patients.

Associations of polycyclic aromatic hydrocarbons, water-soluble ions and metals in PM2.5 with liver function: Evidence from schizophrenia cohort

BackgroundFine particulate matter (PM2.5) was reported to impact liver function, but the roles of specific PM2.5 chemical components remained to be explored. Besides, severe liver dysfunction in schizophrenia patients deserves attention. ObjectiveTo investigate the associations of short-term PM2.5 components with liver function in schizophrenia patients. MethodsA repeated-measures study based on schizophrenia cohort including 1023 visits (n = 446) was conducted during 2017–2020. Liver function was reflected by 10 indicators including liver enzymes, proteins and bilirubin et al. Monitoring data of PM2.5 and its components, including 16 polycyclic aromatic hydrocarbons (PAHs), 4 water-soluble ions and 10 metals were collected. Linear mixed effect and Bayesian kernel machine regression (BKMR) models were used to evaluate the single and combined effects of PM2.5 components (0–3 day) on liver function in schizophrenia patients. ResultsSeveral PAHs were significantly associated with liver enzymes, while water-soluble ions and metal components had almost no association. Specifically, with per interquartile range (IQR) increased in Fluoranthene, levels of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) increased by 2.06 %, 5.07 %, 4.94 % and 5.56 %, respectively. An IQR increases in Benzo[a]pyrene was significantly associated with 6.62 %, 3.67 % and 7.83 % increase in ALT, AST and GGT. Almost all PAHs, sulfate, nitrate, ammonium, Sb, Al, As, Pb, Mn and Tl were positively associated with albumin (ALB). Phenanthrene was associated with increased levels of direct bilirubin (DBIL) and total bilirubin (TBIL). The combined effects of significant PM2.5 components on ALP, GGT, ALB, globulin (GLOB), ratio of albumin to globulin (A/G), TBIL and total bile acid (TBA) were found by BKMR, respectively. ConclusionsFindings highlight the short-term combined effects of PM2.5 components, especially PAHs, on liver function in schizophrenia patients, which contribute to the management of PM2.5 sources including combustion activities and traffic emissions as well as improving schizophrenia comorbidities.

Cross-disorder and disorder-specific deficits in social functioning among schizophrenia and alzheimer's disease patients.

BackgroundSocial functioning is often impaired in schizophrenia (SZ) and Alzheimer’s disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive.Materials and methodsUsing data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis.ResultsAs compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen’s d’s 0.81–1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen’s d’s 0.65–1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen’s d’s 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p’s <0.001), even more so than severity of disease.ConclusionsAD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.

Amantadine in the Treatment of Sexual Inactivity in Schizophrenia Patients Taking Atypical Antipsychotics-The Pilot Case Series Study.

Sexual dysfunctions in people with schizophrenia are more severe than in the general population and are an important element in the treatment of schizophrenia. The mechanism of sexual dysfunction in patients treated for schizophrenia may be related to the side effects of antipsychotic drugs (hyperprolactinemia, suppression of the reward system), but it may also be related to the pathogenesis of schizophrenia itself. The aim of the study was to present the possibility of using amantadine in the treatment of sexual dysfunction in schizophrenia without the concomitant hyperprolactinemia. In an open and naturalistic case series study, five men treated for schizophrenia in a stable mental state were described. All patients reported a prolonged lack of sexual desire and sexual activity prior to treatment with amantadine. After exclusion of hyperprolactinemia, patients received amantadine 100 mg in the evening. Sexual dysfunction was assessed using subscales of the 14-point Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14). On subsequent visits after 1, 2 and 3 months of administration of amantadine, an improvement in sexual functioning was observed in all patients. Although this is only the preliminary report, amantadine may become a new indication for the treatment of sexual dysfunction in schizophrenia patients.

Correlations between age, biomedical variables, and cognition in patients with schizophrenia

ObjectiveTo illustrate the influence of clinical variables on cognition performance in patients with schizophrenia (SCZ). MethodsUsing the 66nao Brain Training device (a novel measurement tool), the cognitive performance of 99 patients with SCZ was evaluated. Patients were diagnosed by the ICD-10 diagnostic criteria for SCZ, and their age were 16–68 years old. Furthermore, we explored the relationship between age, biomedical variables and specific cognitive domains in patients with SCZ. Patients were divided into two groups: various of cognitive domains impairment group and non-impairment group according to the norm scores. All data were analyzed using RStudio Version 1.0.44 (RStudio, Inc.) ResultsPatients with SCZ had obvious cognitive impairment in total and five subdomains of cognitive function. We found that 1) SCZ patients with impaired cognitive total score experienced significant older age and longer illness duration compared with those with normal cognitive total score. 2) SCZ patients with impaired memory experienced significant older age compared with those with normal memory. 3) SCZ patients with impaired attention showed significant lower serum triglyceride (TG) level compared with those with normal attention. 4) SCZ patients with impaired flexibility performed significant longer illness duration compared with those with normal flexibility. 5) SCZ patients with impaired cognitive agility performed significant older age, longer duration, and higher systolic blood pressure (SBP) compared with those with normal cognitive agility. 6) The age, illness duration and SBP in patients with impaired time perception were marginally different from those of subjects with normal time perception. ConclusionThere are five dimensions (memory, attention, flexibility, cognitive agility, and time perception) of cognitive dysfunction in SCZ patients. Age, illness duration, TG, and SBP might play vital roles in various subdomains of the cognitive deficits respectively in patients with SCZ.

The Visual Word Form Area compensates for auditory working memory dysfunction in schizophrenia

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.

T132. RETINAL GANGLION CELLS DYSFUNCTIONS IN SCHIZOPHRENIA PATIENTS

BackgroundStructural and functional retinal anomalies are documented in neurologic, substance use and psychiatric disorders. In schizophrenia, flash electroretinogram (fERG) measures have revealed photoreceptors, bipolar cells and retinal ganglion cells (RGC) dysfunctions. To date, no study has explored RGC using a pattern electroretinogram (pERG) protocol as recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV) standards for RGC measurements. We aim to study retinal functional responses of the photoreceptors and RGC in schizophrenia patients in comparison with healthy controls.MethodsfERG conducted in scotopic (dark-adapted 0.01 and dark-adapted 3.0 ERG) and photopic conditions (light-adapted 3.0 ERG) and pERG were recorded in schizophrenia patients (n=29) and healthy controls (n=29). PERG provides the measurements of 2 waves: the P50 wave which arises in RGC with a contribution of bipolar cells and relates to the spatial distribution and density of the RGC bodies and the N95 wave which represents ganglion cell activity.ResultsfERG results showed a decrease in the b-wave amplitude (t(51)=-3.4, p<.05, d=0.63) (dark-adapted 0.01 ERG), a-wave amplitude (t(48)=4.7, p<.001, d =1.33) (dark-adapted 3.0 ERG), b-wave amplitude (t(48)=-2.8, p<.005, d=0.78) (dark-adapted 3.0 ERG), a-wave amplitude (t(52)=2.8, p<.001, d=0.29) (light-adapted 3.0 ERG) in schizophrenia patients compared to controls. We found as well a significant decrease of the a-wave implicit time (t(52)=-2.5, p<.05, d =1.19) (light-adapted 3.0 ERG) in schizophrenia patients compared to controls. pERG results showed a significant increase of the P50 (t(55)=2.1, p<.05, d=0.55) and a significant increase of the N95 implicit time in schizophrenia patients compared with controls (t(55)=4.2; p<.001, d=0.66).DiscussionOur results replicate previous findings regarding photoreceptors and bipolar cells dysfunction in schizophrenia patients. pERG results demonstrate a delay in transmission of action potentials by the ganglion cells along the visual pathway via the optic nerve and the lateral geniculate nucleus to the visual cortex in schizophrenia patients which could support alterations in cerebral visual processing in schizophrenia.

M181. DEVELOPMENTAL PROGRESSION OF INTERNEURON NETWORK DEFICITS IN A 15Q13.3 MICRODELETION MOUSE MODEL – A GLIMPSE ON ADOLESCENT PRIMING FOR SCHIZOPHRENIA?

BackgroundSchizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthoodMethodsImmunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures.ResultsWe initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenia-linked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice.DiscussionIn this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention.

Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome

Our previous study showed that metabolic abnormalities reduced the levels of brain-derived neurotrophic factor (BDNF) and deteriorated cognitive performance in patients with schizophrenia. Inflammation may play a key role in this process. Omega-3 fatty acids have been documented to ameliorate inflammation. Therefore, we hypothesized that omega-3 fatty acids may be of value in enhancing BDNF levels and improving cognitive function in patients with schizophrenia with metabolic syndrome (MetS). We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The enzyme-linked immunosorbent assay was used to measure the plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). Of the 80 patients who consented to the study, 72 completed this 12-week RCT. The primary outcome was the changes from baseline to 12 weeks in clinical characteristics and the levels of BDNF, CRP, IL-6 and TNF-α. There was a significant correlation between omega-3 fatty acid treatment and enhanced delayed memory factor in the RBANS assessment (Fgroup×time = 6.82; df = 1, 66; P = 0.01) when the patients completed this study. Along with cognitive improvement, omega-3 fatty acids enhanced BDNF (Fgroup×time = 4.93; df = 1, 66; P = 0.03) and reduced CRP (Fgroup×time = 17.11; df = 1, 66; P < 0.01), IL-6 (Fgroup×time = 9.71; df = 1, 66; P < 0.004) and TNF-α (Fgroup×time = 6.71; df = 1, 66; P = 0.012) levels after 12 weeks of treatment. The changes in BDNF levels are negatively correlated with the changes in TNF-α levels (r = −0.37, P = 0.03) but not with the changes in CRP and IL-6 levels. Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on cognitive function in patients with MetS, which is paralleled by enhanced BDNF levels.

The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine

BackgroundUse of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction.MethodsA total of 91 schizophrenia patients treated with olanzapine monotherapy participated in this study. A power spectral analysis of heart rate variability was used to assess ANS activity. The TaqMan system was used to genotype seven single nucleotide polymorphisms (SNPs) in CYP1A2 (rs2069514 and rs762551), UGT1A4 (rs2011425), and ABCB1 (rs1045642, rs1128503, rs2032582, rs2235048).ResultsSympathetic nervous activity was significantly higher in individuals with the UGT1A4 rs2011425 G allele than in those with the UGT1A4 rs2011425 non-G allele (sympathetic activity, p = .001). Furthermore, sympathetic nervous activity was also significantly associated with UGT1A4 rs2011425 genotype as revealed by multiple regression analysis (sympathetic activity, p = .008).ConclusionsWe suggest that the UGT1A4 rs2011425 polymorphism affects olanzapine tolerability because it is associated with the observed side effects of olanzapine in schizophrenia patients, namely sympathetic dysfunction.

The remediation effects of working memory training in schizophrenia patients with prominent negative symptoms

ABSTRACTIntroduction: Negative symptoms, particularly amotivation and anhedonia, are important predictors of poor functional outcome in patients with schizophrenia. There has been interest in the efficacy and mechanism of non-pharmacological interventions to alleviate these symptoms. The present study aimed to examine the remediation effect of working memory (WM) training in patients with schizophrenia with prominent negative symptoms.Methods: Thirty-one schizophrenia patients with prominent negative symptoms were recruited and assigned to either a WM training group or a treatment-as-usual (TAU) control group. The WM training group underwent 20 sessions of training using the dual n-back task over one month. A functional neuroimaging paradigm of the Affective Incentive Delay (AID) task was administered before and after the training intervention to evaluate the remediation effect of the intervention.Results: Our results showed that the WM training group demonstrated significant improvement in the WM training task and inattention symptoms. Compared with the TAU group, increased brain activations were observed at the right insula and the right frontal sub-gyral after WM training in the training group.Conclusions: These findings support the efficacy of WM training in ameliorating hedonic dysfunction in schizophrenia patients with prominent negative symptoms.

Retinal ganglion cells dysfunctions in schizophrenia patients with or without visual hallucinations

The electroretinogram has revealed photoreceptor, bipolar cell, and, in one prior study, retinal ganglion cell (RGC) dysfunction in schizophrenia. The structural abnormalities of the RGC are well documented in schizophrenia and such abnormalities have been associated with visual hallucinations (VH) in neurological disorders. The goals of this study were: 1) to examine the functional responses of photoreceptors and RGC in schizophrenia patients in comparison with healthy controls; and 2) to compare the extent of retinal dysfunction in schizophrenia patients with or without VH.We recorded the flash electroretinogram in scotopic and photopic conditions, and the pattern electroretinogram, in schizophrenia patients (n = 29) and healthy controls (n = 29). Schizophrenia patients were divided in two groups: schizophrenia patients with VH (VH group, n = 12) and schizophrenia patients with auditory hallucinations or no hallucinations (AHNH group, n = 17).Our results replicate previous findings regarding photoreceptor dysfunction in schizophrenia. PERG results showed a significant increase of the P50 implicit time in schizophrenia patients compared with controls (t(55) = 2.1, p < .05, d = 0.55) and a significant increase of the N95 implicit time in schizophrenia patients compared with controls (t(55) = 4.2; p < .001, d = 0.66). We found an increased rod b-wave implicit time (dark-adapted 0.01 ERG) in the VH group compared to the AHNH group and to the control group, which was associated with lifetime VH score.Our results demonstrate a slowing of RGC signaling in schizophrenia patients, which could affect the quality of visual information reaching the visual cortex. The implications of the data for understanding VH in schizophrenia are discussed.

Memory and cognition in schizophrenia.

Episodic memory deficits are consistently documented as a core aspect of cognitive dysfunction in schizophrenia patients, present from the onset of the illness and strongly associated with functional disability. Over the past decade research using approaches from experimental cognitive neuroscience revealed disproportionate episodic memory impairments in schizophrenia (Sz) under high cognitive demand relational encoding conditions and relatively unimpaired performance under item-specific encoding conditions. These specific deficits in component processes of episodic memory reflect impaired activation and connectivity within specific elements of frontal-medial temporal lobe circuits, with a central role for the dorsolateral prefrontal cortex (DLPFC), relatively intact function of ventrolateral prefrontal cortex and variable results in the hippocampus. We propose that memory deficits can be understood within the broader context of cognitive deficits in Sz, where impaired DLPFC related cognitive control has a broad impact across multiple cognitive domains. The therapeutic implications of these findings are discussed.

F64. DISRUPTION IN WORKING MEMORY GATING OBSERVED IN SCHIZOPHRENIA

BackgroundWorking memory and cognitive control deficits are hallmarks of schizophrenia. It is not known specifically how gating mechanisms that regulate memory may be disrupted in schizophrenia. Gating mechanisms determine what task-relevant information is selected into working memory while distractors are left out (input gating) and which items stored in working memory are selected for the rule or goal at hand (output gating). The current study investigated whether patients are able to perform the same cognitive control task that is able to dissociate input and output gating processes in a general population, and explored whether schizophrenia patients inappropriately use suboptimal cognitive control strategies (e.g. output gating when input gating can be used).MethodsPatients (n=5) with schizophrenia or schizoaffective disorder were recruited from the Providence VAMC. Participants completed a computer-based cognitive control task. In this task, participants remembered a target item from a sequence of two items in order to select a response. A context (rule) cued which item was relevant to remember, and was presented first in the stimulus sequence (context first) or last (context last). On selective trials, one item in the trial was relevant. On global trials, both items in the trial were relevant.ResultsPatients were able to complete the task with minor modifications to adjust for ability to understand the task rules. Preliminary results of reaction time data suggest that patients were challenged at increased cognitive load. Patients performed poorly on trials where participants could use only an input gating strategy (selective first). Preliminary data also suggest that performance in patients tended to be slightly worse for selective first trials where the distractor was presented before the relevant item (i.e. on trials where input gating would be required to keep the distractor out of working memory).DiscussionThe current study supports the feasibility of using the cognitive control task selected to investigate gating mechanisms in the schizophrenia patient population. Preliminary data suggest disruption in the ability for patients to optimally use gating strategies and handle cognitive load. Future research will seek to reproduce these preliminary results in a larger sample, as well as compare patient performance to an age-matched control population directly. By understanding how gating mechanisms are disrupted in the patient population, we may be able to better develop therapeutic interventions such as cognitive training strategies to treat cognitive dysfunction in schizophrenia patients.

The effects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients

The effects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients

Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study

BackgroundIt has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs.MethodsWe performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales.ResultsD-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower.ConclusionIt was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity.Trial registrationUMIN Clinical Trials Registry (number UMIN000000468). Registered 18 August 2006

Metabolic adverse effects of olanzapine on cognitive dysfunction: A possible relationship between BDNF and TNF-alpha

ObjectiveThere is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia. MethodsA sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program’s Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunosorbent assay for 108 patients and 47 controls. ResultsAmong the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=−2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than those without MetS. There was a negative correlation between the BDNF and TNF-alpha levels in the patients (r=−0.196, P=0.042). ConclusionOur findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha.

Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia.

Aberrant gamma-band (30-80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on γEP and γPL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20 mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1 ms, 85 dB clicks in 250-0.5 s trains at a frequency of 40 Hz; 0.5 s inter-train interval) was used to assess γEP and γPL. SZ patients had reduced γEP and γPL; memantine enhanced γEP and γPL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for γEP and γPL: greater memantine sensitivity on γEP and γPL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

65. Effects of NMDA Receptor Antagonism in Patients With Schizophrenia: Improvement in Markers of Cortical Oscillatory Dynamics

Abstract Background: NMDA receptor-associated oscillations in the gamma frequency band (30–80 Hz) are thought to underlie a variety of cognitive processes known to be disrupted in patients with schizophrenia (SZ). NMDA receptor functioning can be assessed in subjects by measuring evoked power and phase synchronization of gamma frequency oscillations in response to auditory steady state stimulation (ASSR). Therefore, both evoked power and phase synchronization of gamma frequency have promising applications as translational biomarkers for procognitive therapeutics. In previous work, we reported the low-to-moderate affinity NMDA-receptor antagonist, memantine, enhanced prepulse inhibition of startle and mismatch negativity in SZ patients. Here, we report the effects of a single dose of memantine on evoked power and phase synchronization of ASSR obtained in our previous study. Methods: SZ patients (n = 18; M:F=11:7; mean age = 37.7 years; range:21–48) and healthy comparison subjects (n = 14; M:F = 10:4; age = 26.6 years; range:19–36) completed 2 test days separated by 1 week. On each test day, subjects received either memantine 20 mg (p.o.) or placebo in a double-blind, randomized, counterbalanced, within-subject, crossover design. The ASSR paradigm was used to measure evoked gamma power and phase locking in response to 40 Hz click trains. Results: Patients with SZ had reduced evoked gamma power and phase locking, consistent with previous reports (main effect of group - Power: F = 5.89, df = 1.30, P < .025; Phase locking: F = 12.47, df 1.30, P < .0015). Memantine-enhanced evoked power and phase locking in both SZ and healthy comparison subjects (drug effect - Power: F = 6.40, df 1.30, P < .02; Phase locking: F = 8.49, df 1.30, P <.007). Memantine effects on both gamma power and phase locking were also significant when groups were matched for age (Ps < .005 and .0008, respectively). Memantine-associated enhancement of gamma power and phase locking in SZ patients correlated negatively with age (Ps < .0015 and .005, respectively). Significant relationships were also identified in patients between memantine effects on gamma power and phase locking (r = .74, P < .0005), gamma power and mismatch negativity (r = .54, P < .025), and phase locking and prepulse inhibition of startle (r = −.59, P < .027). Conclusion: A single dose of memantine normalized biomarkers of cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Our ongoing studies will clarify whether these acute changes are associated with beneficial clinical and functional outcomes and whether they predict enduring pro-cognitive effects. These data suggest gamma band ASSR parameters can be used as translational endpoints in early-phase clinical trials and in procognitive drug discovery.