Neuropharmacological computational analysis of longitudinal electroencephalograms in clozapine-treated patients with schizophrenia using hierarchical dynamic causal modeling.

The hierarchical characteristics of the brain are prominent in the pharmacological treatment of psychiatric diseases, primarily targeting cellular receptors that extend upward to intrinsic connectivity within a region, interregional connectivity, and, consequently, clinical observations such as an electroencephalogram (EEG). To understand the long-term effects of neuropharmacological intervention on neurobiological properties at different hierarchical levels, we explored long-term changes in neurobiological parameters of an N-methyl-D-aspartate canonical microcircuit model (CMM-NMDA) in the default mode network (DMN) and auditory hallucination network (AHN) using dynamic causal modeling of longitudinal EEG in clozapine-treated patients with schizophrenia. The neurobiological properties of the CMM-NMDA model associated with symptom improvement in schizophrenia were found across hierarchical levels, from a reduced membrane capacity of the deep pyramidal cell and intrinsic connectivity with the inhibitory population in DMN and intrinsic and extrinsic connectivity in AHN. The medication duration mainly affects the intrinsic connectivity and NMDA time constant in DMN. Virtual perturbation analysis specified the contribution of each parameter to the cross-spectral density (CSD) of the EEG, particularly intrinsic connectivity and membrane capacitances for CSD frequency shifts and progression. It further reveals that excitatory and inhibitory connectivity complements frequency-specific CSD changes, notably the alpha frequency band in DMN. Positive and negative synergistic interactions exist between neurobiological properties primarily within the same region in patients treated with clozapine. The current study shows how computational neuropharmacology helps explore the multiscale link between neurobiological properties and clinical observations and understand the long-term mechanism of neuropharmacological intervention reflected in clinical EEG.

Association between level of suicide risk, characteristics of suicide attempts, and mental disorders among suicide attempters.

BACKGROUND: Past attempted suicide is a strong predictor of future suicide risk, but the risk varies among suicide attempters. Hence, it is important to clarify distinguishing features of lifetime attempters with a high level of current suicide risk for efficient preventive management. METHODS: We compared characteristics of suicide attempts and clinical characteristics among high-, moderate-, and low-risk attempters. Among the total of 6022 participants in the Korean Epidemiologic Catchment Area study, 193 reported a suicide attempt in their lifetime, 36 of which had high, 126 moderate, and 30 low levels of current suicide risk (1 incomplete response). RESULTS: High-risk suicide attempters had more past attempts compared with moderate- and low-risk suicide attempters. Suicide attempts were closely linked to a wide range of psychiatric comorbidities regardless of degree of current level of suicide risk, but the relative risk for having at least one mental disorder was the highest in high-risk attempters. Specifically, the relative risks for depressive disorder, anxiety disorders including obsessive-compulsive disorder and post-traumatic stress disorder, and substance use disorders were higher in high-risk attempters, and relative risk for somatoform disorder was higher in low-risk attempters than others. CONCLUSIONS: Our findings indicated that special attention is required for suicide attempters with a history of repeated attempts and current mental disorders, particularly anxiety disorders.

Long-term clinical efficacy of maintenance electroconvulsive therapy in patients with treatment-resistant schizophrenia on clozapine.

Electroconvulsive therapy (ECT) has been suggested as a treatment for augmenting the response to clozapine in patients that do not respond well to clozapine alone and maintenance ECT (M-ECT) had also been recommended to sustain improvement. This retrospective study of up to 2 years of observation was conducted to explore whether M-ECT is beneficial for long-term maintenance of the symptom remission elicited by acute ECT. Positive and Negative Syndrome Scale (PANSS) were plotted for each patient and compared using a linear mixed-effect model. A total of thirty-eight patients were followed and classified into three groups: (1) clozapine alone (CZP, n = 15), (2) acute ECT only (A-ECT, n = 11), and (3) acute ECT with M-ECT (M-ECT, n = 12). The mean number and interval of ECT sessions during the maintenance period in the M-ECT group were 39.0 ±â€¯26.7 and 15.6 ±â€¯8.4 days, respectively. The slope of the M-ECT group eventually declined, but that of the A-ECT group gradually increased back to the pre-ECT level. No persistent or serious adverse effects were observed. In conclusion, A-ECT augmented the effect of clozapine, but M-ECT was required for sustaining symptom improvement.

Initial Seizure Threshold in Brief-Pulse Bilateral Electroconvulsive Therapy in Patients with Schizophrenia or Schizoaffective Disorder.

OBJECTIVE: The present study aimed to report the initial seizure threshold (IST) of a brief-pulse bilateral electroconvulsive therapy (BP-BL ECT) in Korean patients with schizophrenia/schizoaffective disorder and to identify IST predictors. METHODS: Among 67 patients who received ECT and diagnosed with schizophrenia/schizoaffective disorder based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, we included 56 patients who received 1-millisecond BP-BL ECT after anesthesia with sodium thiopental between March 2012 and June 2018. Demographic and clinical information was gathered from electronic medical records, and a multiple regression analysis was conducted to identify predictors of the IST. RESULTS: The mean age of the patients was 36.9±12.0 years and 30 (53.6%) patients were male. The mean and median IST were 105.9±54.5 and 96 millicoulombs (mC), respectively. The IST was predicted by age, gender, and dose (mg/kg) of sodium thiopental. Other physical and clinical variables were not associated with the IST. CONCLUSION: The present study demonstrated that the IST of 1-ms BP-BL ECT following sodium thiopental anesthesia in Korean patients was comparable to those reported in previous literature. The IST was associated with age, gender, and dose of sodium thiopental.

Long-Term Changes in Self-Report Auditory Verbal Hallucinations in Patients with Schizophrenia Using Clozapine.

This study explored long-term changes in self-report auditory verbal hallucinations (AVHs) among patients with schizophrenia taking clozapine. Forty-four patients who were evaluated more than twice and were above the mild severity category on the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) were enrolled. The mean observation period was 492.5±350.1 days (median, 452 days). The mean total, physical, and emotional factor scores on the HPSVQ were significantly reduced from baseline to the final observations except for one item "interference with life," which was not significantly reduced. Regarding the time-dependent longitudinal changes modeled using linear mixed-effect regression, the total and physical factor scores showed significant changes during the first year, but the emotional factor score did not satisfy a more stringent level of significance. Female gender was negatively associated with the reduction in total and physical factor scores. The duration of treatment with clozapine also had a negative relationship with the reductions in all three scores.

Association between electroencephalogram changes and plasma clozapine levels in clozapine-treated patients.

This retrospective observational study was performed to investigate electroencephalogram abnormalities in clozapine-treated patients with refractory schizophrenia or bipolar disorder. The electroencephalogram and plasma clozapine and norclozapine levels in 71 patients were measured on the same day. Fifty-nine patients (85.9%) had a diagnosis of schizophrenia, and 12 patients (14.1%) had a diagnosis of bipolar disorder. The mean daily clozapine dose was 242.9 ± 105.5 mg (range 25-500 mg), and the mean plasma clozapine and norclozapine levels were 429.4 ± 264.1 and 197.8 ± 132.6 ng/ml, respectively. Twenty-five patients (35.2%) were taking valproate in combination with clozapine. electroencephalogram abnormalities were found in 51 (71.8%) patients. No patient reported clinical seizures. Plasma clozapine level was significantly associated with electroencephalogram abnormalities and was identified as a significant predictor of electroencephalogram abnormalities in a logistic regression analysis. The plasma norclozapine levels of patients taking both clozapine and valproic acid were significantly lower than those of patients treated with clozapine alone. These results demonstrate that electroencephalogram abnormalities are closely correlated with plasma clozapine levels. Valproate reduced plasma norclozapine levels. Simultaneous monitoring of electroencephalogram and plasma clozapine levels was useful for adjusting clozapine doses, improving clinical efficacy, and preventing the side effects of clozapine treatment.

Different hemispheric specializations for pitch and audioverbal working memory.

Critical times of involvement of areas important to working memory were examined both with pitch and audioverbal N-back tasks using single-pulse transcranial magnetic stimulation (TMS). TMS was administered to 12 healthy participants over dorsolateral prefrontal and inferior parietal regions in each hemisphere at four different times after stimulus onset (250, 450, 650, and 850 ms). For the pitch N-back task, interference with working memory, as evidenced by a significant increase in reaction time, was observed with TMS over the right hemisphere regions. In contrast, for the audioverbal N-back task, TMS resulted in significantly increased reaction time only for left inferior parietal TMS delivered 450 ms after stimulus onset. These results imply different hemispheric specializations for pitch and audioverbal working memory.

Factors potentiating the risk of mirtazapine-associated restless legs syndrome.

OBJECTIVE: Mirtazapine is known to often provoke restless legs syndrome (RLS). In this retrospective chart review study, we evaluated the socio-demographic and clinical factors related to mirtazapine-associated RLS. METHODS: Computerized medical records of 181 patients treated with mirtazapine from May 2004 to October 2007 were reviewed. RLS was identified using the diagnostic criteria of the International RLS Study Group. Socio-demographic and clinical characteristics were gathered, including comorbid physical illness and concomitant medications. RESULTS: Mirtazapine-associated RLS was observed in 14 patients (8%), and most cases had developed within a few days after starting mirtazapine. Concomitant medication with tramadol, non-opioid analgesics, antihistamine, and dopamine-blocking agents was more frequently prescribed in subjects developing mirtazapine-associated RLS. In logistic regression analysis, concomitant medication with tramadol (odds ratio: 8.61, 95% confidence interval: 1.71-43.49) and dopamine-blocking agents (odds ratio: 4.67, 95% confidence interval: 1.31-16.70) enhanced the risk of mirtazapine-associated RLS. CONCLUSION: The combined use of mirtazapine with tramadol or dopamine-blocking agents could potentiate the risk of RLS. Clinician should watch carefully for the development of RLS when mirtazapine is administered to patients who are taking tramadol or dopamine-blocking agents.

Effect of organizational strategy on visual memory in patients with schizophrenia.

AIMS: The aim of the present study was to examine how copy organization mediated immediate recall among patients with schizophrenia using the Rey-Osterrieth Complex Figure Test (ROCF). METHODS: The Boston Qualitative Scoring System (BQSS) was applied for qualitative and quantitative analyses of ROCF performances. Subjects included 20 patients with schizophrenia and 20 age- and gender-matched healthy controls. RESULTS: During the copy condition, the schizophrenia group and the control group differed in fragmentation; during the immediate recall condition, the two groups differed in configural presence and planning; and during the delayed recall condition, they differed in several qualitative measurements, including configural presence, cluster presence/placement, detail presence/placement, fragmentation, planning, and neatness. The two groups also differed in several quantitative measurements, including immediate presence and accuracy, immediate retention, delayed retention, and organization. Although organizational strategies used during the copy condition mediated the difference between the two groups during the immediate recall condition, group also had a significant direct effect on immediate recall. CONCLUSION: Schizophrenia patients are deficient in visual memory, and a piecemeal approach to the figure and organizational deficit seem to be related to the visual memory deficit. But schizophrenia patients also appeared to have some memory problems, including retention and/or retrieval deficits.

Combination of Electroconvulsive Therapy and Clozapine in Treatment-Resistant Schizophrenia.

OBJECTIVE: This study aimed to investigate the effectiveness and tolerability of the combination of electroconvulsive therapy (ECT) in patients with clozapine-treated schizophrenia. METHODS: Patients with clozapine-treated schizophrenia during five years of pre-determined period were recruited from Electronic Medical Record. Clinical effects of acute ECT on psychotic symptoms were investigated. We also tried to identify predictive variables requiring maintenance treatment of ECT. RESULTS: Fourteen patients received ECT and clozapine and sixteen were treated with clozapine alone. In the ECT group, which could be refined as clozapine-resistance, PANSS total score was significantly reduced by 19.0±9.9 points, corresponding to a reduction rate of 18.5±8.3%. The clinical remission defined as 20% PANSS reduction criteria was achieved at 42.9%. The subscale factors were significantly reduced, among which the negative symptom was the least. There was no difference in demographic and clinical information between patients receiving and not receiving maintenance ECT, and not all patients seemed to need maintenance ECT if clozapine is continued. CONCLUSION: Combination of ECT and clozapine in patients with clozapine-resistant schizophrenia resulted in a rapid and substantial reduction of psychotic symptoms. Further studies are needed to improve the effectiveness and tolerability of ECT.

Long-Term Evolution of Metabolic Status in Patients with Schizophrenia Stably Maintained on Second-Generation Antipsychotics.

OBJECTIVE: Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Despite the risk of MetS, SGAs may have to be continued with change in some patients. The aim of this study was to trace the evolution of MetS in these patients. METHODS: Patients with schizophrenia who had been maintained on a fixed SGA regimen for more than a year were followed-up without changing the regimen. Metabolic indicators were evaluated at baseline and at follow-up. Prevalence, incidence and spontaneous normalization rate of MetS were estimated. Risk factors that might have influenced the evolution were scrutinized. RESULTS: A total of 151 subjects were included. During the mean observation period of 389.9±162.4 days, the prevalence of MetS was increased from 35.1 to 45.0%. The incidence rate was 29.6%, while the normalization rate was 26.4%, risk factors affecting incidence were age (OR=1.09, 95% CI: 1.03-1.17), baseline continuous values of metabolic syndrome risk scores (cMetS, OR=1.77, 95% CI:1.29-2.55) and baseline body weight (OR=1.06, 95% CI: 1.01-1.13). Normalization was influenced by age (OR=0.74, 95% CI: 0.57-0.89) and baseline body weight (OR=0.85, 95% CI: 0.72-0.95). CONCLUSION: The prevalence of MetS steadily increased with the continuous use of SGAs. However, individual difference was extensive and about a quarter of the patients were able to recover naturally without specific measurements.

Comparison of clinician-rated and self-report insight in Korean patients with schizophrenia using VAGUS insight scale.

This study was aimed to explore self-report auditory verbal hallucinations to provide unique and valuable information in addition to clinician-rated assessment in patients with schizophrenia. The VAGUS (http://www.vagusonline.com) is a recently developed insight scale that includes both clinician-rated (CR) and self-report (SR) versions. Insight measures obtained by the two versions of the VAGUS from the clinicians and the patients, respectively, in forty-one patients diagnosed with schizophrenia by DSM-IV-TR criteria were compared. Correlation coefficients for inter-scale convergence and 3-D biplots for multivariate relationship were derived from the subscales of the VAGUS. For external validation, correlation analyses with abridged version of Scale to Assess Unawareness in Mental Disorder (SUMD-A) and PANSS G12 item were conducted. Total scores of VAGUS-CR and -SR were 5.2 ± 2.6 and 4.9 ± 2.2, respectively. There was a strong correlation between them along with moderate pairwise correlations among the subscales. The 3-D biplots demonstrated that most subscales were clustered as a single factor apart from self-report Symptom Attribution separated as an independent factor. The VAGUS-CR, not -SR correlated significantly with the SUMD-A and PANSS G12. The utility of the VAGUS in reaching more overall understanding of the elusive phenomenon of insight in patients with schizophrenia is discussed.

Effectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia.

OBJECTIVE: This retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review. METHODS: Clozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo-resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT. RESULTS: The average number of ECT sessions was 13.4 (±4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (±12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (±14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects. CONCLUSION: This study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy.

Functional imaging evidence of the relationship between recurrent psychotic episodes and neurodegenerative course in schizophrenia.

It remains controversial as to what determines the neurodegenerative course in schizophrenia. This study administered a modified version of the Stroop task and investigated the relationship between functional magnetic resonance imaging (fMRI) signal changes in dysfunctioned task-related regions and clinical course variables. Functional MRI data during task performance were acquired from 10 right-handed schizophrenic patients (mean+/-SD age=29.2+/-10.3 years, range of illness duration=0.8-14 years, number of episodes=1-5) and 10 healthy controls (mean+/-SD age=30.3+/-6.4). Imaging data were investigated on a voxel-by-voxel basis for single group analysis and for between-group analysis according to the random effect model using Statistical Parametric Mapping (SPM 99b). Correlation analysis with age as a covariate identified those brain regions whose fMRI signal changes were significantly related to clinical course variables in schizophrenia. The number of psychotic episodes was negatively correlated with the fMRI signal change in the right inferior frontal and the right frontal precentral gyri among the activated regions during the Stroop task in schizophrenia, whereas the length of illness was not so correlated. The number of psychotic episodes was also negatively correlated with the fMRI signal change in the left paracingulate in which functional activity was diminished in the patients relative to the controls. Our results indicate that recurrent psychotic episodes are related to the neurodegenerative course in some dysfunctional brain regions in schizophrenia.

Decreased caudal anterior cingulate gyrus volume and positive symptoms in schizophrenia.

The anterior cingulate gyrus is a heterogeneous region that has specialized subdivisions with respect to its cytoarchitecture, function and connectivity. The aim of this study was to examine the morphological changes of the caudal subdivision of the anterior cingulate gyrus in the context of the cortico-striatal-thalamo-cortical circuitry of schizophrenia and their relationship to clinical symptoms. Accordingly, we measured the volumes of the caudal and rostral anterior cingulate gyrus, the orbitofrontal cortex, the caudate and the thalamus by magnetic resonance imaging in age- and sex-matched groups, which consisted of 22 patients with schizophrenia and 22 normal volunteers. The clinical symptoms of schizophrenia patients were obtained using the Positive and Negative Syndrome Scale. Volumetric reduction of the right caudal anterior cingulate gyrus was observed in patients with schizophrenia as compared with the normal controls. Furthermore, a smaller volume of the caudal anterior cingulate gyrus was significantly correlated with more severe positive symptoms of schizophrenia. Thus, these findings suggest that a volumetric abnormality of the caudal anterior cingulate gyrus in schizophrenia may be related to positive symptoms and possibly involved in the pathophysiology of schizophrenia.

Functional disconnection between the prefrontal and parietal cortices during working memory processing in schizophrenia: a[15(O)]H2O PET study.

OBJECTIVE: The prefrontal-parietal circuits have been reported to play an important role in working memory. The purpose of this study was to use direct neuroimaging to address whether interregional correlation in the prefrontal-parietal circuits is impaired in schizophrenia. METHOD: [(15)O]H(2)O positron emission tomography was used to compare regional blood flow changes in 12 schizophrenic and 12 healthy comparison subjects during the n-back sequential-picture working memory task. Interregional correlation was assessed by correlating the regional activation of the lateral prefrontal area with that of other activated areas in each subject group. RESULTS: Dorsolateral prefrontal activation was observed around the right superior frontal sulcus in the healthy subjects, and ventrolateral prefrontal activation below the right inferior frontal sulcus was observed in the schizophrenic patients. Activation in the right lateral prefrontal cortex was significantly correlated with activation in the bilateral inferior parietal region in the healthy subjects but was not correlated with any regional activation in the patients. CONCLUSIONS: The findings suggest prefrontal-parietal functional disconnection, particularly prefrontal dissociation and abnormal prefrontal-parietal interaction, during working memory processing in schizophrenia.

Altered hemispheric asymmetry and positive symptoms in schizophrenia: equivalent current dipole of auditory mismatch negativity.

The abnormality of mismatch negativity (MMN) in schizophrenia is thought to be associated with perceptional disturbance and cognitive dysfunction. The purpose of the present study was to investigate the change of the normal functional hemispheric lateralization in schizophrenia by employing the equivalent current dipole (ECD) model of auditory MMN with individual MRI and high-density electroencephalography (EEG). The MMNs resulting from auditory stimuli with passive oddball paradigm in a group of schizophrenics (n = 15), and also a group of age-, sex-, and handedness-matched normal controls, were recorded by 128 channel EEG. The location and power of ECD sources at the peak point were calculated. Individual 3-D brain magnetic resonance images (MRI) were used for realistic head modeling and for source localization. For both groups, the MMN source was determined to be located in the superior temporal gyrus (STG). However, the normal functional hemispheric asymmetry of ECD power was significantly altered in the schizophrenics (chi(2) test = 16.13, p < 0.001). Left MMN ECD power and the asymmetry coefficient (AC) were negatively correlated with the positive scores from Positive and Negative Syndrome Scale (PANSS) (r = -0.673, p = 0.008), especially with the hallucinatory behavior subscale (r = -0.677, p = 0.008). These findings support the deficits in preattentive automatic processing of auditory stimuli, especially in the left hemisphere, and indicate the correlation between positive symptoms, especially auditory hallucination, and left temporal lobe dysfunction in schizophrenia.

Morphometric abnormality of the insula in schizophrenia: a comparison with obsessive-compulsive disorder and normal control using MRI.

The insula is increasingly the subject of great interest in psychiatric disorders of neurodevelopmental origin because of its anatomical location, wide interconnectivity, and variety of functions. This study explores the possible morphometric change of the insula in schizophrenia and obsessive-compulsive disorder (OCD), and its potential relationship to clinical symptoms. The insula was traced on all coronal slices of magnetic resonance images of three age- and sex-matched diagnostic groups, which consisted of 21 patients with schizophrenia, 21 patients with OCD and 21 normal volunteers. The volumetric measures of the insula were compared among the three groups, and their relationships to the symptom severity were investigated. Volumetric reduction of the left insula was observed in the schizophrenia group, but not in the OCD group. These results confirm the involvement of deficient insular function in the pathophysiology of schizophrenia.

Left anterior subregion of orbitofrontal cortex volume reduction and impaired organizational strategies in obsessive-compulsive disorder.

The orbitofrontal cortex (OFC) may be involved in the clinical and cognitive expressions of obsessive-compulsive disorder (OCD) and is a heterogenous region with respect to its cytoarchitecture, function and connectivity. This study was designed to examine the morphological abnormality of the anterior subregion of OFC and its relationship to clinical symptoms and cognitive performance in patients with OCD. We divided the OFC into anterior and posterior subregions using an external landmark and measured the gray matter volumes of each by three-dimensional magnetic resonance imaging in age- and sex-matched groups, which consisted of 34 OCD and 34 normal volunteers. Clinical and cognitive evaluations were completed using Yale-Brown Obsessive Compulsive Scale (YBOCS) and four sets of neuropsychological tests that assessed executive functions and visual memory. Volume reduction of the left anterior OFC was observed in patients with OCD versus normal controls. Also, a significant positive correlation was found between left anterior OFC gray matter volume and the copy score of the Rey-Osterrieth Complex Figure Test in patients with OCD. These results suggest that left anterior subregion volume reduction of the OFC may be related to impaired organizational strategies in patients with OCD.

N-methyl-D-aspartate receptor in working memory impairments in schizophrenia: event-related potential study of late stage of working memory process.

Working memory (WM) deficit in schizophrenic patients has been well established. Still, underlying biological substrate of the impairment is not clear. Among neurotransmitter hypotheses of schizophrenia, N-methyl-D-aspartate (NMDA) receptor model is mostly supported, considering that NMDA receptor antagonist can elicit both psychosis and cognitive impairment observed in schizophrenic patients. In current study, to test the neuropsychological and the electrophysiological effects of NMDA receptor in WM, event-related potentials (ERPs) of Sternberg's short-term memory scanning task (SMST) were analyzed in 10 healthy subjects under intravenous administration of a subanesthetic dose of ketamine (0.65 mg/kg/h) or placebo (normal saline). Late positive component (LPC) of ERP was hypothesized to reflect later stage of WM. Brief Psychiatric Rating Scale score was significantly increased (t=-5.75, df=9, P<.001) and correct response rate was significantly decreased (t=2.21, df=9, P=.054) after ketamine administration. Neither reaction time nor LPC latency, which reflect memory scanning time, was changed. Amplitude of LPC was significantly reduced after ketamine administration (z=-2.31, number of observations=120, P=.021). In conclusion, NMDA receptor antagonist administration elicited WM deficit both in behavioral and electrophysiological level. Electrophysiological component reflecting later stage of WM was impaired by NMDA antagonist.