Kyung Sue Hong

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.

Reduced prefrontal functional connectivity in the default mode network is related to greater psychopathology in subjects with high genetic loading for schizophrenia

OBJECTIVE Neuroimaging studies in subjects at genetic high risk (GHR) of schizophrenia can provide clues to the causes for the development of schizophrenia. Little is known about genetic influence on functional connectivity status, although studies on schizophrenia have reported an abnormal default mode network (DMN). We sought to identify putative genetic vulnerability markers by examining whether aberrant DMN connectivity was present in GHR subjects with high genetic loading. METHOD Sixteen GHR subjects who had at least two relatives with schizophrenia and 16 age- and sex-matched controls were included and scanned using resting-state functional magnetic resonance imaging. A posterior cingulate cortex (PCC) seed region connectivity analysis was used to identify the DMN. Correlations between severity of psychopathology, level of genetic loading and DMN connectivity were calculated. RESULTS The DMN network in GHR subjects showed reduced functional connectivity in the prefrontal areas, PCC, and precuneus. In addition, this reduced connectivity in the prefrontal cortices correlated with total and general scores on the Positive and Negative Syndrome Scale. GHR subjects having two first-degree relatives with schizophrenia showed a trend toward greater reduction in DMN connectivity in the precuneus and anterior cingulate cortex. CONCLUSION This study suggests significant abnormalities in the DMN of subjects at GHR of schizophrenia. Alterations of DMN connectivity in the prefrontal cortex may reflect psychopathologies such as an inability to allocate resources properly between internal thoughts and external stimuli. Dysfunction of the anterior cingulate cortex and precuneus might be related to genetic risk for schizophrenia.

Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics-Induced Obsessive-compulsive Symptoms

CONTEXT Several studies have indicated that atypical antipsychotics (AAP) induce obsessive-compulsive (OC) symptoms. Research exploring the mechanism of this phenomenon, however, has been extremely limited. Considering the indirect evidence of genetic control and difficulties in developing animal models and performing gene expression studies, genetic association studies could be an important approach to understanding the molecular mechanism of AAP-induced OC symptoms. The glutamate transporter gene SLC1A1, which was recently reported to be associated with obsessive-compulsive disorder (OCD), is a promising candidate gene for susceptibility to AAP-induced OC symptoms. OBJECTIVE To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia. DESIGN A pharmacogenetic case-control association study. SETTING Outpatient schizophrenia clinics. PATIENTS Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms. MAIN OUTCOME MEASURES Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates. RESULTS Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model). CONCLUSIONS These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.

759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment

5-HT2C receptor gene is viewed as an important candidate gene in pharmacogenetic studies of antipsychotic drug-induced weight gain. However, inconsistent results have been obtained in different populations. We investigated the association between the -759C/T polymorphism of the 5-HT2C receptor gene with early phase (after 4 weeks of treatment) weight gain induced by antipsychotic treatment in Korean schizophrenia patients. The study subjects were eighty-four in-patients receiving monotherapy with one of six antipsychotic drugs. Patients with the variant allele (-759T) were found to be less likely to have substantial (> 5%) weight gain (Fishers exact test, p=0.030), and this association (t=1.91, df=75, p=0.030) was supported by the repeated measures analysis after controlling for possible confounding effects, i.e., age, sex, baseline BMI, and the type of antipsychotic medicine administered. The variant allele also appeared to have a protective effect against weight gain in a subgroup of patients receiving risperidone. These results support the involvement of the -759C/T polymorphism of the 5-HT2C receptor gene in antipsychotics-induced weight gain in the Korean population.

Phase-Specific Brain Change of Spatial Working Memory Processing in Genetic and Ultra-High Risk Groups of Schizophrenia

Spatial working memory (WM) processing has 3 distinct phases: encoding, maintenance, and retrieval and its dysfunction is a core feature in schizophrenia. We examined phase-specific brain activations associated with spatial WM in first-degree relatives of schizophrenia (genetic high risk, GHR), ultra-high risk (UHR) subjects, patients with schizophrenia, and healthy controls. We used an event-related functional magnetic resonance imaging in 17 GHR subjects, 21 UHR subjects, 15 clinically stable patients with schizophrenia and 16 healthy controls, while subjects were performing a spatial delayed-response task. During the encoding phase, the GHR group showed increased activation in the fronto-parietal regions, whereas the UHR and schizophrenia groups showed significantly less activation in these regions than did the healthy control group. Especially, frontal activation was strongest in GHR subjects, followed by healthy controls, and occurred to a lesser degree in the UHR group, with the least activation occurring in the schizophrenia group. During the maintenance phase, the thalamus showed a differential activation, similar to frontal activation pattern during the encoding phase. During the retrieval phase, no prominent differential activations were found. Increased activations were observed in the superior temporal gyrus during the encoding and maintenance phases in the GHR, UHR, and schizophrenia groups relative to healthy controls. Our findings suggest that functional deficits associated with spatial WM processing emerge in the UHR before the onset of schizophrenia and compensatory neural processes exist in the GHR with genetic liability to schizophrenia.

Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response.

Objective Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. Methods Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. Results Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. Conclusions We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy.

Association of seasonality and premenstrual symptoms in Bipolar I and Bipolar II disorders

BACKGROUND Although seasonal affective disorder and premenstrual syndrome (PMS) are frequently observed in mood disorders, little is known as to whether lifetime traits of seasonality and premenstrual distress are related to bipolar disorder independent of mood episodes. This study aimed at investigating these two cyclic traits with respect to bipolar I and II disorders as well as evaluating the association between them. METHODS Subjects included 61 female patients with bipolar I or II disorders and 122 healthy women. Seasonality and premenstrual symptoms were measured retrospectively on a lifetime basis using the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Premenstrual Symptoms Screening Tool (PSST). RESULTS Patients showed higher global seasonality scores on the SPAQ compared to the normal controls. Further, the patient-control difference was more prominent in cases of bipolar II disorder (p<0.0001) than in bipolar I disorder (p=0.001). The prevalence of moderate to severe PMS as indicated on the PSST was also significantly higher in bipolar II disorder patients (51.6%) as compared to controls (19.7%). A significant association between seasonality and PMS was observed in both patient and control groups. CONCLUSIONS The results suggested that female patients with bipolar disorder experience seasonal and premenstrual changes in mood and behavior regardless of their mood episodes, and traits of seasonality and PMS are associated with each other. A common biological mechanism of these two cyclic conditions may be involved in the development of the cyclicity of bipolar disorder.

Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population

Chromosome 8p21‐12 has been reported to be a susceptibility locus for schizophrenia based on genome‐wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21‐12 were genotyped for 40 families with schizophrenia, and a non‐parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5′ end of the first exon of NRG1 for two (“narrow” and “narrow with auditory hallucination (AH)”) of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness.

Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms.

Adverse effects of atypical antipsychotics (AAP) can include obsessive–compulsive (OC) symptoms. Based on biological evidence of the relationship between the glutamatergic system and both OC disorder and AAP, this study aimed to determine whether DLGAP3, coding a post‐synaptic scaffolding protein of glutamatergic synapses, is associated with AAP‐induced OC symptoms. Furthermore, we explored the interactions between DLGAP3 and a previously reported susceptibility gene, the glutamate transporter gene SLC1A1, regarding this phenotype. Subjects were clinically stable schizophrenia patients receiving AAP treatment (n = 94), and they comprised an OC group (n = 40) and a non‐OC group (n = 54) (patients with and without AAP‐induced OC symptoms, respectively). We performed allelic/genotypic/haplotype association analyses for seven tag single‐nucleotide polymorphisms of DLGAP3 and gene–gene interaction analyses with rs2228622 of SLC1A1, observing a nominally significant association between AAP‐induced OC symptoms and rs7525948 in both simple chi‐square tests and the regression analyses (nominal P < 0.05). In the logistic regression analysis of gene–gene interaction, we found a significant interaction effect of rs7525948 of DLGAP3 and rs2228622 of SLC1A1 (permutation P = 0.036) on AAP‐induced OC symptoms, with a 30.2 times higher odds for individuals carrying risk genotypes at both loci in comparison with the reference group, which had no risk genotypes. This study provides suggestive evidence that DLGAP3 and its interactive effect with SLC1A1 might be involved in susceptibility to developing OC symptoms in schizophrenia patients receiving AAP treatment.

Diagnostic stability of first-episode psychosis and predictors of diagnostic shift from non-affective psychosis to bipolar disorder: A retrospective evaluation after recurrence☆

Diagnostic changes during follow-up are not uncommon with a first-episode psychosis (FEP). This study aimed to evaluate the diagnostic stability of the FEP and to identify factors associated with a diagnostic shift from non-affective psychosis to bipolar disorder. Considering that the diagnosis of FEP is frequently more definite after recurrence in many clinical settings, a retrospective evaluation after recurrence was preformed. Subjects were 150 patients with psychotic disorders who had been admitted to a psychiatric ward both for first episode and recurrence of their psychosis. Consensus diagnosis was made for each episode through a review of hospital records. Patients diagnosed with non-affective psychoses at the first episode were included in the analysis of predictive factors of a diagnostic shift to bipolar disorder. First-episode diagnoses were revised upon recurrence in 20.7% of patients. The most common change was to bipolar disorder accounting for more than half of all diagnostic changes. Schizophrenia exhibited the highest prospective and retrospective diagnostic consistencies. Female gender, short duration of untreated psychosis, high level of premorbid functioning, and several symptoms including lability, mood elation, hyperactivity, and delusions with religious or grandiose nature were identified as predictive factors for a diagnostic shift from non-affective psychosis to bipolar disorder. Clinical features of psychoses seem to evolve during the disease course resulting in diagnostic changes upon recurrence in a significant portion of FEP. Special consideration on a diagnostic shift to bipolar disorder is required in patients exhibiting the predictive factors identified in the current study.