Euitae Kim

Social cognition and neurocognition as predictors of conversion to psychosis in individuals at ultra-high risk

BACKGROUND While deficits in cognitive functions are frequently reported in psychotic disorders, further longitudinal research is needed to confirm the specific risk factors for the development of psychosis. We examined longitudinally the social-cognitive and neurocognitive function of individuals at ultra-high risk for schizophrenia who developed psychosis later as predictive markers. METHOD The investigators studied 49 subjects at ultra-high risk (UHR) for psychosis and 45 healthy controls. The UHR subjects were followed for up 5.2 years (mean: 2.8 years) and 13 of these subjects developed psychosis. Theory of mind (ToM) tasks and neuropsychological tests were administered at baseline. Analyses compared the UHR patients who later developed psychosis, those who did not develop, and healthy controls. To examine the cognitive variables to predict transition to psychosis, Cox regression analyses were conducted. RESULTS At baseline, we found significant differences among the three groups in social cognition according to the False Belief and cartoon tasks and in neurocognition according to tasks measuring executive function, working memory, verbal memory, and visual memory. Our study showed that a model combining working memory, visual memory, executive function, and ToM tasks was significantly predictive of time to conversion to psychosis. CONCLUSION This study indicated that UHR patients who later converted to psychosis performed more poorly on tasks involving social cognition and neurocognition than did those who did not convert. We suggest that these deficits can serve as specific markers to predict the development of psychosis.

Cognitive functioning in obsessive-compulsive disorder: a meta-analysis

BACKGROUND Substantial empirical evidence has indicated impairment in the cognitive functioning of patients with obsessive-compulsive disorder (OCD) despite inconsistencies. Although several confounding factors have been investigated to explain the conflicting results, the findings remain mixed. This study aimed to investigate cognitive dysfunction in patients with OCD using a meta-analytic approach. METHOD The PubMed database was searched between 1980 and October 2012, and reference lists of review papers were examined. A total of 221 studies were identified, of which 88 studies met inclusion criteria. Neuropsychological performance and demographic and clinical variables were extracted from each study. RESULTS Patients with OCD were significantly impaired in tasks that measured visuospatial memory, executive function, verbal memory and verbal fluency, whereas auditory attention was preserved in these individuals. The largest effect size was found in the ability to recall complex visual stimuli. Overall effect estimates were in the small to medium ranges for executive function, verbal memory and verbal fluency. The effects of potentially confounding factors including educational level, symptom severity, medication status and co-morbid disorders were not significant. CONCLUSIONS Patients with OCD appear to have wide-ranging cognitive deficits, although their impairment is not so large in general. The different test forms and methods of testing may have influenced the performance of patients with OCD, indicating the need to select carefully the test forms and methods of testing used in future research. The effects of various confounding variables on cognitive functioning need to be investigated further and to be controlled before a definite conclusion can be made.

Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study

BackgroundIndividuals at ultra-high risk (UHR) for psychosis have self-disturbances and deficits in social cognition and functioning. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks. Thus, the neural substrates within the default mode network (DMN) have the potential to mediate self-referential and social cognitive information processing in UHR subjects.MethodsThis study utilized functional magnetic resonance imaging (fMRI) to investigate resting-state DMN and task-related network (TRN) functional connectivity in 19 UHR subjects and 20 matched healthy controls. The bilateral posterior cingulate cortex was selected as a seed region, and the intrinsic organization for all subjects was reconstructed on the basis of fMRI time series correlation.ResultsDefault mode areas included the posterior/anterior cingulate cortices, the medial prefrontal cortex, the lateral parietal cortex, and the inferior temporal region. Task-related network areas included the dorsolateral prefrontal cortex, supplementary motor area, the inferior parietal lobule, and middle temporal cortex. Compared to healthy controls, UHR subjects exhibit hyperconnectivity within the default network regions and reduced anti-correlations (or negative correlations nearer to zero) between the posterior cingulate cortex and task-related areas.ConclusionsThese findings suggest that abnormal resting-state network activity may be related with the clinical features of UHR subjects. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects.

Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole

We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene. In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n=14; A1A2+A2A2, n=76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured. Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups. The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole.

Modeling of brain D2 receptor occupancy-plasma concentration relationships with a novel antipsychotic, YKP1358, using serial PET scans in healthy volunteers

YKP1358 is a novel serotonin (5‐HT2A) and dopamine (D2) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D2 receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose‐escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [11C]raclopride. The D2 receptor occupancy of striatum was measured pre‐dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D2 receptor occupancy by YKP1358 increased to 53–83% at 2 h, and then decreased afterwards, ranging from 40–64% at 5 h to 20–51% at 10 h. The YKP1358 dose‐plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D2 receptor occupancy that was well predicted by a sigmoid Emax model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy.

Symptomatic and functional remission of subjects at clinical high risk for psychosis: A 2-year naturalistic observational study

BACKGROUND The aim of this study was to assess the frequency and predictors of symptomatic and functional remission in individuals at clinical high risk (CHR) for psychosis at 1-2 years of follow-up. METHODS Help-seeking CHR individuals with symptomatic (Scale of Prodromal Symptoms (SOPS) positive scores <3) and functional (Global Assessment of Functioning (GAF) score >60) (CHR-R) remission at 12-24 months were compared to non-remitted individuals (CHR-NR) regarding baseline and treatment characteristics, symptom changes and predictors. Time to full remission was compared with that of symptomatic remission only. RESULTS Of 73 individuals, 29 (39.7%) achieved full remission; 44 (60.3%) did not. Compared to CHR-NR individuals, CHR-R individuals had lower baseline SOPS positive symptoms (p=0.017), antipsychotic use (p=0.004), antipsychotic chlorpromazine dose equivalents (p=0.001) and anxiolytic use (p=0.004). In survival analyses, the estimated full remission rate was 48.3% (95% confidence interval (CI)=36.2-61.9) and symptomatic remission rate was 67.5% (CI95=55.4-79.2). Time to full remission was longer than time to symptomatic remission (p=0.017). Linear mixed-effect models revealed significantly greater improvements from 6 months onward in CHR-R subjects compared to CHR-NR subjects regarding SOPS positive symptoms (p=0.003), highest SOPS positive symptom (p<0.001) and GAF scores (p=0.004). Examining baseline predictors, time to full remission was significantly longer in patients with higher SOPS positive scores (p=0.017). CONCLUSIONS More stringent remission criteria that include functional status in addition to attenuated positive symptom severity should be applied to CHR subjects. Furthermore, more attention should be given to CHR individuals with highly positive prodromal symptoms at baseline.

A method for assessing the regional vibratory pattern of vocal folds by analysing the video recording of stroboscopy

Stroboscopy and kymography have been used to examine the motional abnormality of vocal folds and to visualise their regional vibratory pattern. In a previous study (Laryngoscope, 1999), we introduced the conceptual idea of videostrobokymography, in which we applied the concept of kymography on the prerecorded video images using stroboscopy, and showed its possible clinical application to various disorders in vocal folds. However, a more detailed description about the software and the mathematical formulation used in this system is needed for the reproduction of similar systems. The composition of hardwares, user-interface and detail procedures including mathematical equations in videostrobokymography software is presented in this study. As an initial clinical trial, videostrobokymography was applied to the preoperative and postoperative videostroboscopic images of 15 patients with Reinkes edema. On preoperative examination, videostrobokymograms showed irregular pattern of mucosal wave and, in some patients, a relatively constant glottic gap during phonation. After the operation, the voice quality of all patients was improved in acoustic and aerodynamic assessments, and videostrobokymography showed clearly improved mucosal waves (change in open quotient: mean±SD=0.11±0.05).

Disproportionate Alterations in the Anterior and Posterior Insular Cortices in Obsessive–Compulsive Disorder

Background Recent studies have reported that the insular cortex is involved in the pathophysiology of obsessive–compulsive disorder (OCD). However, specific morphometric abnormalities of the insular subregions remain unclear. In this study, we examined insular cortical volume to determine whether the volume of the anterior and posterior insular cortices of unmedicated OCD patients differed according to different symptom dimensions. Methods/Principal Findings Using magnetic resonance imaging, we measured the gray matter volumes of the insular cortex and its subregions (anterior and posterior divisions) in 41 patients with OCD (31 drug-naïve and 10 non-medicated) and 53 healthy controls. Volumetric measures of the insular cortex were compared according to different OC symptoms. Enlarged anterior and reduced posterior insular cortices were observed in OCD patients. The insular volumetric alterations were more significant in OCD patients with predominant checking rather than cleaning symptoms when compared with healthy controls. Conclusions/Significance Our results suggest the presence of unbalanced anterior and posterior insular volumetric abnormalities in unmedicated OCD patients and emphasize the distinct role of the insular cortex in different OC symptoms. We propose that the insular morphometric alterations may influence the modulation of interoceptive processing, the insular functional role, in OCD patients with different symptoms.

Pharmacotherapy and clinical characteristics of ultra-high-risk for psychosis according to conversion status: a naturalistic observational study

Aim: To explore the differences in pharmacotherapy and clinical characteristics of individuals at ultra‐high‐risk (UHR) for psychosis according to the conversion status, we analyzed the data for UHR patients seen at the Seoul Youth Clinic.

Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship.

Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic—PD (PK—PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration—occupancy relationship. To determine the effect of time on the concentration—occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [11C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK—PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration—occupancy relationship and the value of EC50 was different according to the analysis approach (EC50 derived from PD modeling alone = 11.1 ng/mL (95% confidence interval (CI) = 10.1 to 12.1); while that derived from combined PK—PD modeling = 8.63 ng/mL (95% CI = 7.75 to 9.51)). This finding suggests that PK—PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.