Beyond Attention-Deficit Hyperactivity Disorder: Exploring Psychiatric Comorbidities and Their Neuropsychological Consequences in Adults.

Objectives: This study aimed to identify the psychiatric comorbidity status of adult patients diagnosed with attention-deficit hyperactivity disorder (ADHD) and determine the impact of comorbidities on neuropsychological outcomes in ADHD. Methods: The study participants were 124 adult patients with ADHD. Clinical psychiatric assessments were performed by two boardcertified psychiatrists in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. All participants were assessed using the Mini-International Neuropsychiatric Interview Plus version 5.0.0 to evaluate comorbidities. After screening, neuropsychological outcomes were assessed using the Comprehensive Attention Test (CAT) and the Korean version of the Wechsler Adult Intelligence Scale, Fourth Edition (K-WAIS-IV). Results: Mood disorders (38.7%) were the most common comorbidity of ADHD, followed by anxiety (18.5%) and substance use disorders (13.7%). The ADHD with comorbidities group showed worse results on the Perceptual Organization Index and Working Memory Index sections of the K-WAIS than the ADHD-alone group (p=0.015 and p=0.024, respectively). In addition, the presence of comorbidities was associated with worse performance on simple visual commission errors in the CAT tests (p=0.024). Conclusion: These findings suggest that psychiatric comorbidities are associated with poor neuropsychological outcomes in adult patients with ADHD, highlighting the need to identify comorbidities in these patients.

Cognitive Developmental Trajectories in Adult ADHD Patients and Controls: A Comparative Study.

OBJECTIVE: There is an updated conceptualization of whole-lifespan attention-deficit hyperactivity disorder (ADHD), promoted by awareness of probable persistence of impairment into adulthood. We investigated cognition trajectories from adolescence to mid-adulthood in ADHD. METHOD: Data of 240 patients with ADHD and 244 healthy controls (HCs) were obtained; clinical symptoms and neuropsychological functions were assessed using the various tests. RESULTS: Compared to HCs, patients with ADHD except 35 to 44 age interval showed lower full scale intelligence quotient. They showed decreased verbal comprehensive scores except in the 35 to 44 age interval and working memory scores in all intervals. In the Comprehensive Attention Test, patients with ADHD showed increased working memory error frequencies except in the 15 to 17 age interval and divided attention omission error in all intervals. CONCLUSION: Adults with ADHD showed deficits not in simple attention but in complex attention, including divided attention and working memory.

Validity of the Korean Version of DIVA-5: A Semi-Structured Diagnostic Interview for Adult ADHD.

BACKGROUND: This study was to assess the validity of the Korean version of the semi-structured Diagnostic Interview for Adult ADHD, third edition (DIVA-5). The secondary aim was to compare sociodemographic and psychiatric comorbidities in adult patients with and without a diagnosis of ADHD. METHODS: A total of 279 participants were recruited from nine psychiatric outpatient clinics in Korea. All participants were administered the Mini-International Neuropsychiatric Interview (MINI) Plus v.5.0.0, the Adult ADHD Self-Report Scale v1.1 (ASRS-v1.1) Symptom Checklist, and DIVA-5. Diagnosis concordance between two board-certified psychiatrists and DIVA-5 were analysed. RESULTS: The DIVA-5 showed a diagnostic accuracy of 92%, a sensitivity of 91.30%, and a specificity of 93.62%. Significant clinical and demographic differences between ADHD and control groups were found. CONCLUSION: The Korean version of DIVA-5 is a reliable tool for assessing and diagnosing ADHD in adult Korean populations.

Development of the Korean Practice Parameter for Adult Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Adult attention-deficit/hyperactivity disorder (ADHD) is an important mental health problem that needs resolution, especially considering the high rates of ADHD continuation from childhood to adolescence/adulthood and the high prevalence of ADHD in adults. Adults with ADHD have lifelong negative impacts and require close monitoring with long-term follow-up. Hence, the establishment of a Korean practice parameter for adult ADHD is necessary to minimize discontinuation of treatment and enable information sharing among Korean mental health professionals. METHODS: The Korean practice parameter was developed using an evidence-based approach consisting of expert consensus survey coupled with literature review. RESULTS: According to the expert consensus survey, the most commonly used diagnostic methods were clinical psychiatric interview (20.66%) and self-report scales (19.25%) followed by attention (14.71%) and psychological tests (14.24%). Key evaluation instruments currently available in Korea are the World Health Organization Adult ADHD Self-Report Rating Scale, Korean Adult ADHD Rating Scale, Diagnostic Interview for ADHD in Adults, Barkley Deficits in Executive Functioning Scale for adults, Comprehensive Attention Test, Conners' Continuous Performance Test, and the subtests of Wechsler Adult Intelligence Scale, Digit Span and Letter-Number Sequencing. Although pharmacotherapy is recommended as the first-line of treatment for adult ADHD, we recommend that it be followed by a multimodal and multidisciplinary approach including psychoeducation, pharmacotherapy, cognitive behavior therapy and coaching. CONCLUSION: The Korean practice parameter introduces not only general information for the diagnosis and treatment of adult ADHD on a global scale, but also the process of diagnosis and treatment options tailored to the Korean population.

Developmental Trajectories of Attention in Normal Korean Population.

OBJECTIVES: This study aimed to investigate the trajectory of change of diverse attention and working memory in Koreans from 4 to 40 years of age. METHODS: The data of 912 subjects from 4 to 15 years of age obtained from a previous standardization study of the computerized comprehensive attention test were merged with the newly obtained data of 150 subjects aged 16 to 40 years from this study. We evaluated the various kinds of attention, in which each subtest had five indicators. Working memory, with parameters such as number of correct responses and span, was also measured. RESULTS: Our findings indicated that attention developed as age increased, and it decreased or was maintained after a certain age. Selective and sustained attention developed rapidly in children and adolescents, until mid-teens or 20 s when it ceased development. Divided attention, however, developed up to approximately age 20. In addition, working memory developed until mid-teens or 20 s. CONCLUSION: We presented the standardized data on diverse kinds of attention and working memory in children, adolescents, and adults in Korea. We could recognize any patterns of change in attention and working memory with increasing age.

Clinical Utility and Cut-Off Scores of the Korean Adult Attention-Deficit/Hyperactivity Disorder Rating Scale.

OBJECTIVES: This study was conducted to re-validate the clinical efficacy of the Korean Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale (K-AARS), which is a self-report scale for ADHD in adults, and to determine the clinical utility and cut-off scores of K-AARS. METHODS: The participants were 135 drug naïve adults with ADHD and 144 healthy controls. To diagnose ADHD based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, two board-certified pediatric psychiatrists interviewed the participants and completed the Mini International Neuropsychiatric Interview. K-AARS was applied to all participants. K-AARS comprises six clinical subscales, one impairment subscale, and one driving behavior subscale. The receiver operating characteristic analysis was conducted to calculate the cut-off scores of K-AARS. RESULTS: All subscale scores, including six clinical subscale, impairment subscale, and driving behavior subscale scores, were found to be significant in distinguishing adults with ADHD from healthy controls. The sensitivity and specificity of the six clinical subscales were 63.0-77.0% and 66.7-79.9%, respectively. The combined total score of the six clinical subscales, had a sensitivity of 80.0% and specificity of 79.9%. CONCLUSION: The discriminative power of K-AARS for the diagnosis of ADHD in adults was excellent, and K-AARS and the empirical diagnosis of adults can be useful in diagnosing ADHD in adulthood.

Comparison of Attention-Deficit/Hyperactivity Disorder Practice in Adults According to a Training Background in Child Psychiatry.

OBJECTIVES: Awareness of attention-deficit/hyperactivity disorder (ADHD) in adults has significantly increased; however, clinical data specific to the Korean population are insufficient. Clinical experience of ADHD may differ based on whether psychiatrists have received pediatric psychiatry-specific training. In order to prepare a practice parameter for adult ADHD patients in Korea, we examined questionnaire data to observe how pediatric psychiatry training could affect clinical practice for adults with ADHD. METHODS: A questionnaire about the diagnosis and treatment process was distributed to both general psychiatrists (GPsy) and child and adolescent psychiatrists (CAP) at the summer and winter workshop meetings of Korean Academy of Child and Adolescent Psychiatry. RESULTS: In total, 142 psychiatrists participated in the survey (86 GPsy, 56 CAP). GPsy and CAP preferred pharmacotherapy (GPsy 82.40%, CAP 64.30%) as the primary treatment option and answered that the clinical psychiatric interview is the most necessary step in diagnostic assessment (GPsy 22.16%, CAP 19.00%). The GPsy responded with an optimal and average treatment duration that was shorter than that reported by CAP. CONCLUSION: Identification of the initial presenting symptom as the correct diagnosis and the optimal duration of pharmacotherapy differed between GPsy and CAP in practice, whereas concepts in diagnosis and treatment of ADHD in adults were similar for both groups. These results suggest the urgent need for the Continuing Medical Education program for psychiatrists treating adults with ADHD.

Development of the Attention-Deficit Hyperactivity Disorder-After School Checklist.

OBJECTIVES: This study aimed to develop the attention-deficit hyperactivity disorder (ADHD)-After School Checklist (ASK) to evaluate the severity of ADHD symptoms and self-management ability in children and adolescents in South Korea. Additionally, we evaluated the reliability and validity of the scale. METHODS: We developed the ASK to evaluate the effect of ADHD psychopathologies on self-management and interpersonal impulsivity. We investigated the reliability and validity of the scale with 1349 parents (male 56.9%; 1202 parents of non-ADHD children, 147 parents of children with ADHD) in Seoul and Gyeonggi Province, Korea. RESULTS: According to the construct validity test using principal constant analysis with the varimax rotation method, two factors explained 60.7% of the cumulative variance in ASK scores. Cronbach's alpha for the whole scale was 0.71. There was no statistical difference between mean ASK scores at test and retest. Mean total ASK scores of the ADHD group were significantly higher than those of the non-ADHD group (p<0.001). CONCLUSION: The ASK can be used as a reliable and valid tool to evaluate not only self-management capability of children and adolescents with ADHD in their academic and everyday life, but also their impulsiveness in interpersonal relationships.

Cross Validation of Attention-Deficit/Hyperactivity Disorder-After School Checklist.

OBJECTIVES: This study aimed to evaluate the efficacy of the attention-deficit/hyperactivity disorder (ADHD)-After School Checklist (ASK) by comparing the results of the Comprehensive Attention Test (CAT) and Clinical Global Impression-Severity (CGI-S) Scale and then by calculating the area under the receiver operating characteristic (ROC) curve. METHODS: We performed correlation analyses on the ASK and CAT results and then the ASK and CGI-S results. We created a ROC curve and evaluated performance on the ASK as a diagnostic tool. We then analyzed the test results of 1348 subjects (male 56.8%), including 1201 subjects in the general population and 147 ADHD subjects, aged 6-15 years, from kindergarten to middle school in Seoul and Gyeonggi province, South Korea. RESULTS: According to the correlation analyses, ASK scores and the Attention Quotient (AQ) of CAT scores showed a significant correlation of -0.20--0.29 (p<0.05). The t-test between ADHD scores and CGI-S also showed a significant correlation (t=-2.55, p<0.05). The area under the ROC curve was calculated as 0.81, indicating good efficacy of the ASK, and the cut-off score was calculated as 15.5. CONCLUSION: The ASK can be used as a valid tool not only to evaluate functional impairment of ADHD children and adolescents but also to screen ADHD.

A multicenter, randomized, double-blind, placebo-controlled study of aripiprazole in children and adolescents with Tourette's disorder.

OBJECTIVE: To examine the short-term efficacy and tolerability of aripiprazole for children and adolescents with Tourette's disorder. METHOD: This 10-week multicenter, double-blind, randomized, placebo-controlled trial was conducted from August 2008 to April 2010. Children and adolescents (aged 6-18 years) with a DSM-IV diagnosis of Tourette's disorder and a Yale Global Tic Severity Scale total tic score of 22 or more were randomly assigned (1:1 ratio) to placebo or aripiprazole. The primary outcome measure was mean change from baseline in the total tic score on the Yale Global Tic Severity Scale (last observation carried forward). Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptoms, serum prolactin level, metabolic variables, and other laboratory evaluations. RESULTS: Of 61 subjects, 89% completed the study. Patients who received aripiprazole demonstrated a significant reduction from baseline to end of study on the mean (SD) total tic score of the Yale Global Tic Severity Scale compared to those who received placebo (-15.0 [8.4] and -9.6 [8.8], respectively, P=.0196). Response rate on the Tourette's Syndrome Clinical Global Impression-Improvement was 66% and 45% in the aripiprazole and placebo groups, respectively. Mean decrease in the Tourette's Syndrome Clinical Global Impression-Severity of Illness score was significantly different between the groups (P=.0321). In general, aripiprazole was well tolerated and there were no early discontinuations due to adverse events. The incidence of treatment-emergent adverse events between the groups was not significantly different (P=.7550). While aripiprazole decreased serum prolactin concentration (P<.0001), it increased mean body weight, body mass index, and waist circumference significantly (P=.0055, P=.0142, and P=.0270, respectively). CONCLUSIONS: In comparison with placebo, aripiprazole was efficacious, generally tolerated and safe in the short-term treatment of children and adolescents with Tourette's disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier:NCT00706589.

Methylphenidate-osmotic-controlled release oral delivery system treatment reduces parenting stress in parents of children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of the current study was to investigate the effect of methylphenidate-osmotic release oral delivery system (MPH-OROS) treatment on parenting stress in parents of children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: Four hundred and ninety-five children and adolescents (391 boys and 104 girls), aged 7 to 18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for ADHD, were recruited at 48 psychiatric outpatient clinics across South Korea. Children's symptoms, parenting stress, and parental depression were assessed at baseline, week 4, and week 8 of MPH-OROS treatment using the Korean version of the DuPaul's ADHD Rating Scale (ARS), the Beck's Depression Inventory (BDI), and the Parenting Stress Index, Short Form (PSI-SF). RESULTS: We found significantly decreased scores of ARS, parental BDI, and PSI-SF from baseline to week 4 and from week 4 to week 8. Also, there were positive correlations among baseline PSI-SF, ARS, and BDI scores. The changes in BDI and ARS scores were significantly associated with the PSI score changes, accounting for 20.1% and 10.0%, respectively. CONCLUSIONS: We suggest that the increased parenting stress and depression in parents of children and adolescents with ADHD can be improved following the treatment with MPH-OROS.

Neuropsychological status of children with newly diagnosed idiopathic childhood epilepsy.

We characterized the neuropsychological status of children with newly diagnosed idiopathic childhood epilepsy and measured differences in IQ between children with different types of epilepsy. The Korean Education Development Institute-Wechsler Intelligence Scale for Children (KEDI-WISC) was administered to 72 patients (35 males and 37 females), of mean age 8.7±2.6 years, with newly diagnosed idiopathic childhood epilepsy. Of these patients, 22 (30.6%) had generalized epilepsy, 48 (66.7%) localization-related epilepsy, and 2 (2.8%) mixed epilepsy. Children with generalized epilepsy and benign childhood epilepsy with centro-temporal spikes (BCECTS) were of similar verbal IQ and full-scale IQ, although performance IQ was significantly lower in patients with generalized epilepsy. Among children with BCECTS, those with unilateral spikes had higher full-scale and performance IQ scores than those with bilateral spikes. Follow-up studies on large numbers of patients are needed to determine the effects of epilepsy per se, and antiepileptic drugs, on intelligence.

Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders.

Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0 mg/d; maximum dose 20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (p < 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4 weeks after commencement of medication (p < 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients.

[Identification of a novel deletion region in 3q29 microdeletion syndrome by oligonucleotide array comparative genomic hybridization].

BACKGROUND: The 3q29 microdeletion syndrome is a genomic disorder characterized by mental retardation, developmental delay, microcephaly, and slight facial dysmorphism. In most cases, the microdeletion spans a 1.6-Mb region between low-copy repeats (LCRs). We identified a novel 4.0- Mb deletion using oligonucleotide array comparative genomic hybridization (array CGH) in monozygotic twin sisters. METHODS: G-banded chromosome analysis was performed in the twins and their parents. Highresolution oligonucleotide array CGH was performed using the human whole genome 244K CGH microarray (Agilent Technologies, USA) followed by validation using FISH, and the obtained results were analyzed using the genome database resources. RESULTS: G-banding revealed that the twins had de novo 46,XX,del(3)(q29) karyotype. Array CGH showed a 4.0-Mb interstitial deletion on 3q29, which contained 39 genes and no breakpoints flanked by LCRs. In addition to the typical characteristics of the 3q29 microdeletion syndrome, the twins had attention deficit-hyperactivity disorder, strabismus, congenital heart defect, and gray hair. Besides the p21-activated protein kinase (PAK2) and discs large homolog 1 (DLG1) genes, which are known to play a critical role in mental retardation, the hairy and enhancer of split 1 (HES1) and antigen p97 (melanoma associated; MFI2) genes might be possible candidate genes associated with strabismus, congenital heart defect, and gray hair. CONCLUSIONS: The novel 4.0-Mb 3q29 microdeletion found in the twins suggested the occurrence of genomic rearrangement mediated by mechanisms other than nonallelic homologous recombination. Molecular genetic and functional studies are required to elucidate the contribution of each gene to a specific phenotype.

Effect of methylphenidate on the quality of life in children with epilepsy and attention deficit hyperactivity disorder: and open-label study using an osmotic-controlled release oral delivery system.

This open study explored whether methylphenidate could be tolerated and effective in improving the quality of life (QOL) and attention deficit hyperactivity disorder (ADHD) symptoms of children with epilepsy and ADHD. Twenty-five subjects (aged 10.1 +/- 3.0 years) with ADHD and epilepsy were recruited at an outpatient clinic in Seoul, Korea. We used the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), ADHD rating scale (ARS) and clinical global impression (CGI) in this study. Osmotic-controlled release oral delivery system (OROS) methylphenidate, 1.0 +/- 0.4 mg/kg/day, was administered for 55.2 +/- 7.5 days. The QOL subscales including physical restriction (p = 0.005), self-esteem (p = 0.002), memory (p < 0.001), language (p = 0.005), other cognition (p < 0.001), social interaction (p = 0.002), behaviour (p < 0.001), general health (p = 0.002) and QOL (p < 0.001) were significantly increased and the ARS (p < 0.001) and CGI-Severity of illness scores (p < 0.001) were significantly reduced after medication. Although 60% of subjects had experienced adverse effects, most were tolerable and only two subjects withdrew from the study owing to unbearable adverse effects (anorexia and insomnia). Two subjects had seizure attacks during the study period without having to discontinue the trial drug. Despite limitations related to the small sample size and the open design of the present pilot study, our results suggest that OROS methylphenidate may be well tolerated and effective in reducing ADHD symptoms and improving QOL in this patient population.

Brain factor-7 extracted from Bombyx mori enhances cognition and attention in normal children.

It has been reported that brain factor-7 (BF-7) extracted from Bombyx mori improves cognitive functions in normal juveniles and adults as well as cognitively impaired patients. Clinical studies with normal children evaluated the role of BF-7 on brain function in these patients. The objective of this study was to improve cognitive functions of normal schoolchildren with BF-7. Forty-six normal healthy children were divided into two treatment groups: BF-7 (9.9 +/- 1.18 years old; 9 boys, 14 girls) and placebo (9.8 +/- 1.03 years old; 10 boys, 13 girls). The Color Trails Making Test was used to measure the efficacy of BF-7 on cognition and attention. Results showed that BF-7 reduced the response time by an average of 23% for the Color Trails Making Test. Moreover, BF-7 improved the accuracy of the task around twofold. The results reveal that BF-7 improves brain function for attention and cognitive flexibility in children.

Copy number variations associated with idiopathic autism identified by whole-genome microarray-based comparative genomic hybridization.

OBJECTIVES: Autism spectrum disorder (ASD) has been thought to have strong genetic background, but major contributing genes or associated molecular-genetic pathways are yet to be identified. To explore the idiopathic ASD-associated copy number variations (CNVs), we conducted case-control study using whole-genome copy number analysis. METHODS: Whole-genome microarray-based comparative genomic hybridization was carried out on 28 children (24 boys and four girls) diagnosed as ASD and 62 Korean adults (45 males and 17 females) without any signs of abnormalities and family history of genetic disorders as normal controls. Fluorescence in-situ hybridization and capillary electrophoresis-single-strand conformational polymorphism were used for quantitative verification of the ASD-associated CNVs. RESULTS: Thirty-eight CNVs were identified. Among them, the distributions of copy number loss CNVs on 8p23.1 (odds ratio: 5.1, 95% confidence interval: 1.7-14.5, P=0.003) and on 17p11.2 (odds ratio: uncalculable because of zero cell, P=0.008) were found to be significantly different between ASD and control groups. DEFENSIN family occurs in a cluster at 8p23.1 region. Fluorescence in-situ hybridization and capillary electrophoresis-single-strand conformational polymorphism coherently showed reduced copy number of DEFENSIN in cases with 8p23.1 copy number loss CNV, which validated microarray-based comparative genomic hybridization results; but there are no known coding genes in the CNV on 17p11.2. CONCLUSION: Our approach as well as results can help to elucidate the genetic mechanism of idiopathic ASD.

Microsatellite marker in gamma - aminobutyric acid - a receptor beta 3 subunit gene and autism spectrum disorders in Korean trios.

This study aimed to identify the association between gamma-aminobutyric acid-A (GABA-A) receptor subunit beta3 (GABRB3) gene and autism spectrum disorders (ASD) in Korea. Fifty-eight children with ASD [47 boys (81.0%), 5.5 +/- 4.1 years old], 46 family trios, and 86 healthy control subjects [71 males (82.6%), 33.6 +/- 9.3 years old] were recruited. Transmission disequilibrium test revealed that, 183 bp long allele in GABRB3 gene was preferentially transmitted in families with ASD (p = 0.025), whereas a population-based case-control study, however, showed no association between ASD and GABRB3 microsatellite polymorphism. Our data provide preliminary evidence that GABRB3 gene is associated with ASD in Korea.

New functional single nucleotide polymorphism (Ala72Ser) in the COMT gene is associated with aggressive behavior in male schizophrenia.

A new functional single nucleotide polymorphism (SNP) Ala72Ser in the COMT gene was discovered recently. The purpose of our study is to examine the association between Ala72Ser and Val158Met functional polymorphisms in COMT gene and homicidal behavior in schizophrenia. DNA was genotyped for the Ala72Ser and Val158Met SNPs of the COMT gene in a sample of 93 schizophrenic patients who committed homicide (H-SCZ) and 100 schizophrenic patients who had never committed homicide (NH-SCZ). A statistically significant difference was found in genotype distribution and allele frequencies in SNP Ala72Ser of COMT gene between H-SCZ and NH-SCZ group. In haplotype analysis, the frequency of the combination of high-high activity allele (Ala-Val) was lower in H-SCZ group than in NH-SCZ group (P = 0.000069). Our study showed a highly significant association between a COMT haplotype of two functional SNPs and aggressive behavior in schizophrenia.