Predictors of schizophrenia spectrum disorders in early-onset first episodes of psychosis: a support vector machine model.

Identifying early-onset schizophrenia spectrum disorders (SSD) at a very early stage remains challenging. To assess the diagnostic predictive value of multiple types of data at the emergence of early-onset first-episode psychosis (FEP), various support vector machine (SVM) classifiers were developed. The data were from a 2-year, prospective, longitudinal study of 81 patients (age 9-17 years) with early-onset FEP and a stable diagnosis during follow-up and 42 age- and sex-matched healthy controls (HC). The input was different combinations of baseline clinical, neuropsychological, magnetic resonance imaging brain volumetric and biochemical data, and the output was the diagnosis at follow-up (SSD vs. non-SSD, SSD vs. HC, and non-SSD vs. HC). Enhanced recursive feature elimination was performed for the SSD vs. non-SSD classifier to select and rank the input variables with the highest predictive value for a diagnostic outcome of SSD. After validation with a test set and considering all baseline variables together, the SSD vs. non-SSD, SSD vs. HC and non-SSD vs. HC classifiers achieved an accuracy of 0.81, 0.99 and 0.99, respectively. Regarding the SSD vs. non-SSD classifier, a combination of baseline clinical variables (severity of negative, disorganized symptoms and hallucinations or poor insight) and neuropsychological variables (impaired attention, motor coordination, and global cognition) showed the highest predictive value for a diagnostic outcome of SSD. Neuroimaging and biochemical variables at baseline did not add to the predictive value. Thus, comprehensive clinical/cognitive assessment remains the most reliable approach for differential diagnosis during early-onset FEP. SVMs may constitute promising multivariate tools in the search for predictors of diagnostic outcome in FEP.

Functional impairment as a defining feature of: amnestic MCI cognitive, emotional, and demographic correlates.

BACKGROUND: Early definitions of mild cognitive impairment (MCI) excluded the presence of functional impairment, with preservation of a person's ability to perform activities of daily living (ADL) as a diagnostic criterion. However, recent studies have reported varying degrees of functional impairment associated with MCI. Hence, we aimed to test the potential functional impairment associated with MCI and its predictors. METHODS: Sixty-nine healthy elderly subjects, 115 amnestic single-domain MCI subjects (a-MCI), and 111 amnestic multi-domain MCI subjects (md-MCI) were assessed using a battery of neuropsychological tests including measures of attention, memory, working memory, executive functions, language, and depression. Additionally, functional ability was assessed by both qualitative (WHO-DAS II) and quantitative (CHART) instruments. Cognitive and functional performance was compared between groups, and regression analyses were performed to identify predictors of functional ability. RESULTS: The md-MCI group was more impaired than the a-MCI group, and both were more impaired than healthy subjects in all cognitive measures, in total CHART score, CHART cognitive and mobility subscores, and WHO-DAS II communication and participation subscales. For the rest of the functional measures, the md-MCI group was more impaired than healthy controls. Prediction of functional ability by cognitive measures was limited to md-MCI subjects and was higher for the CHART than for the WHO-DAS II. The WHO-DAS II was largely influenced by depressive symptoms. CONCLUSIONS: Functional impairment is a defining feature of MCI and is partially dependent on the degree of cognitive impairment. Quantitative measures of functional ability seem more sensitive to functional impairment in MCI than qualitative measures, which seem to be more related to depression.

Participation Predicts Cognitive Functioning in Older Adults Using the PART-O Transformed Scores Systems.

Participation has been shown to be a protective factor for cognition in older adults, but instruments to assess it are limited. The main objective was to determine the validity of two scoring systems (direct vs transformed) for the Participation Assessment with Recombined Tools-Objective (PART-O) by applying structural equation modeling to the relationship between the subscales and the cognitive functions, in a sample of 245 people over 60 years of age. The transformed scores model showed stronger relationships and larger explained variance in overall participation (55.4% vs 37.4%), especially in the Social Relations subscale (31.4% vs 14.6%). Participation was a direct predictor of cognitive functions in both models. Age and depression inversely influenced participation in the transformed scores model. The proposed score transformation for the PART-O provides a more appropriate measurement of the older adults' participation. Participation has a mediating role in the relationship between cognition and both age and depression.

Dysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis.

Dysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring.

Fronto-Parietal Gray Matter Volume Loss Is Associated with Decreased Working Memory Performance in Adolescents with a First Episode of Psychosis.

Cognitive maturation during adolescence is modulated by brain maturation. However, it is unknown how these processes intertwine in early onset psychosis (EOP). Studies examining longitudinal brain changes and cognitive performance in psychosis lend support for an altered development of high-order cognitive functions, which parallels progressive gray matter (GM) loss over time, particularly in fronto-parietal brain regions. We aimed to assess this relationship in a subsample of 33 adolescents with first-episode EOP and 47 matched controls over 2 years. Backwards stepwise regression analyses were conducted to determine the association and predictive value of longitudinal brain changes over cognitive performance within each group. Fronto-parietal GM volume loss was positively associated with decreased working memory in adolescents with psychosis (frontal left (B = 0.096, p = 0.008); right (B = 0.089, p = 0.015); parietal left (B = 0.119, p = 0.007), right (B = 0.125, p = 0.015)) as a function of age. A particular decrease in frontal left GM volume best predicted a significant amount (22.28%) of the variance of decreased working memory performance over time, accounting for variance in age (14.9%). No such association was found in controls. Our results suggest that during adolescence, EOP individuals seem to follow an abnormal neurodevelopmental trajectory, in which fronto-parietal GM volume reduction is associated with the differential age-related working memory dysfunction in this group.

Neuropsychological functioning in early-onset first-episode psychosis: comparison of diagnostic subgroups.

The aims of this study were to examine the nature and extent of cognitive impairment in first-episode early-onset psychosis (FE-EOP) soon after their stabilisation and to search for potential differences according to specific diagnostic sub-groups of patients. As part of a Spanish multicentre longitudinal study, 107 FE-EOP patients and 98 healthy controls were assessed on the following cognitive domains: attention, working memory, executive functioning, and verbal learning and memory. Three diagnostic categories were established in the patient sample: schizophrenia (n = 36), bipolar disorder (n = 19), and other psychosis (n = 52). Patients performed significantly worse than controls in all cognitive domains. The three diagnostic sub-groups did not differ in terms of impaired/preserved cognitive functions or degree of impairment. FE-EOP patients show significant cognitive impairment that, during this early phase, seems to be non-specific to differential diagnosis.

Cognitive functioning in children and adolescents in their first episode of psychosis: differences between previous cannabis users and nonusers.

To investigate the relationship between cognition and prior cannabis use in children and adolescents presenting a first episode of psychosis. A total of 107 patients with first episode of psychosis and 96 healthy controls, aged 9 to 17 years, were interviewed about their previous substance use and to assess their cognitive functions. Patients were assessed while not using cannabis by means of a comprehensive neuropsychological battery. They were divided into 2 groups depending on the history of prior cannabis use: cannabis users (CU) and cannabis nonusers (CNU). Significant differences were found in all areas evaluated between the 3 groups. Both CU and CNU patients obtained lower scores than controls on verbal learning and memory and working memory. Patients with prior cannabis use performed better on some tests of attention (Continuous performance test (CPT) number of correct responses, p = 0.002; CPT average reaction time, p < 0.001) and executive functions (Trail Making Test, part B (TMT-B) number of mistakes, p < 0.001; Wisconsin Card Sorting Test (WCST) number of categories completed, p < 0.001) than CNU patients. CU patients performed better than CNU subjects on some cognitive measures. This may indicate lower individual vulnerability for psychosis in CU patients in whom cannabis use can be a precipitating factor of psychotic episodes.

Brain morphology and neurological soft signs in adolescents with first-episode psychosis.

BACKGROUND: Adolescents with first-episode psychosis have increased severity of neurological soft signs when compared with controls, but it is unclear whether increased severity of neurological soft signs is an expression of specific structural brain deficits. AIMS: To examine whether increased severity of neurological soft signs was associated with decreased brain volumes in adolescents with first-episode psychosis. METHOD: Brain scans were obtained for 70 adolescents (less than 18 years of age) with first-episode psychosis (duration of positive symptoms less than 6 months). Volumes were assessed using voxel-based morphometry and through segmentation of anatomical structures. RESULTS: Increased severity of sensory integration neurological soft signs correlated with smaller right and left thalamus volume, whereas increased severity of sequencing of complex motor acts neurological soft signs correlated with smaller right caudate volume. CONCLUSIONS: Neurological soft signs may be an easy-to-assess marker of region-specific structural brain deficits in adolescents with first-episode psychosis.

Olanzapine compared to quetiapine in adolescents with a first psychotic episode.

OBJECTIVE: To compare the efficacy, safety, and tolerability of olanzapine and quetiapine in adolescents with first episode psychosis. METHOD: Fifty adolescents (age 16 +/- 1.25) with a first episode of psychosis were randomized to quetiapine or olanzapine in a 6-month open label study. Efficacy and side effect scales, as well as vital signs and laboratory data were recorded at baseline, 7, 15, 30, 90, and 180 days (end of study). RESULTS: Out of the total sample included in the study, 32 patients completed the trial (quetiapine n = 16, olanzapine n = 16). Patients in both treatment groups had a significant reduction in all clinical scales with the exception of the negative scale of the Positive and Negative Symptom Scale (PANSS) for olanzapine and the general psychopathology scale of the PANSS for quetiapine. The only difference between treatment arms on the clinical scales was observed on the patients' strength and difficulties questionnaire (SDQ) scale, with greater improvement for olanzapine. Patients on olanzapine gained 15.5 kg and patients on quetiapine gained 5.5 kg. CONCLUSION: Olanzapine and quetiapine reduced psychotic symptoms in this adolescent sample. Patients on olanzapine gained significantly more weight. Side effects with both drugs seemed to be more prevalent than those reported in adult studies.

Association study between obsessive-compulsive disorder and serotonergic candidate genes.

BACKGROUND: To date, research examining the relationship between serotonergic genes and obsessive-compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. METHODS: 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS: All groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls (chi(2) (1)=7.21, corrected p=0.021; OR=3.38, 95% CI=1.32-8.62) and non-OCD psychiatric patients (chi(2) (1)=6.70, corrected p=0.030; OR=3.24, 95% CI=1.27-8.26). However, no differences were found between non-OCD patients and healthy controls (chi(2) (1)=0.05, corrected p>1; OR=1.04, 95% CI=0.72-1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. CONCLUSIONS: Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.

Neurological soft signs in adolescents with first episode psychosis: two-year followup.

Neurological soft signs were assessed in 24 first episodes of early onset psychosis and 30 healthy adolescents over a 2-year period. Patients presented more neurological soft signs than controls and showed a significant decrease in some Neurological Evaluation Scale scores over the followup period. This decrease in the patient group was influenced by changes in symptomatology.

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first-episode psychosis adolescents.

Catechol-O-methyltransferase (COMT) and dopamine receptors 2 (DRD2) and 3 (DRD3) have been associated with a higher risk of developing psychosis and with dopaminergic system (DAS) regulation. Frontal cognitive functioning has been proven to be a useful endophenotype for psychosis and it is partially controlled by the DAS. Val158Met (rs4680, COMT), Taq IA (rs1800497, DRD2) and Ser9Gly (rs6280; DRD3) polymorphisms were analyzed in a sample of 84 adolescent Caucasian patients with first-episode psychosis (ages 11-17) and 85 healthy Caucasian controls (ages 10-17). A comprehensive neuropsychological battery, assessing attention, working memory, memory, and executive functions, was administered to the entire sample. The relationship between neuropsychological scores and genotype was determined. Subjects with the DRD3 Gly/Gly genotype showed significantly poorer performance than Ser/Ser subjects in executive functioning tasks (P = 0.002; adjusted R(2) = 0.031), with no significant differences in the other cognitive paradigms. Neither COMT nor DRD2 polymorphisms significantly contributed to variance in cognition in our adolescent sample. The DRD3 Ser9Gly polymorphism seems to be involved with prefrontal cognition. This effect seems to be heterogeneous in terms of cognitive paradigms. The lack of association between COMT and DRD2 genotypes and cognition in our sample may be partially explained by the young age of the sample and the clinical heterogeneity of the patients.

Significance and meaning of neurological signs in schizophrenia: two decades later.

OBJECTIVE: Patients with schizophrenia are characterized by neurological abnormalities, which can be assessed by bedside clinical examination. These abnormalities have been argued to represent core features of the illness. We review studies published since our last review in 1988 that address the validity of neurological signs as a trait feature of schizophrenia. METHODS: We conducted a literature search in the following computer databases: MEDLINE, PSYCHLIT, EMBASE, and COCHRANE. The search was limited to articles published from January 1988 to May 2005. RESULTS: Neurological signs occur in the majority of patients with schizophrenia. Their occurrence is independent of demographic and most medication variables. Neurological signs are strongly associated with negative symptoms and cognitive impairments. There is also evidence to suggest that their occurrence is under genetic control. CONCLUSIONS: There is compelling evidence to suggest the hypothesis that neurological signs represent a trait feature of schizophrenia.

Premorbid adjustment and clinical correlates of cognitive impairment in first-episode psychosis. The PEPsCog Study.

BACKGROUND: The extent to which socio-demographic, clinical, and premorbid adjustment variables contribute to cognitive deficits in first-episode schizophrenia spectrum disorders remains to be ascertained. AIMS: To examine the pattern and magnitude of cognitive impairment in first-episode psychosis patients, the profile of impairment across psychosis subtypes and the associations with premorbid adjustment. METHODS: 226 first-episode psychosis patients and 225 healthy controls were assessed in the PEPsCog study, as part of the PEPs study. RESULTS: Patients showed slight to moderate cognitive impairment, verbal memory being the domain most impaired compared to controls. Broad affective spectrum patients had better premorbid IQ and outperformed the schizophrenia and other psychosis groups in executive function, and had better global cognitive function than the schizophrenia group. Adolescent premorbid adjustment together with age, gender, parental socio-economic status, and mean daily antipsychotic doses were the factors that best explained patients' cognitive performance. General and adolescent premorbid adjustment, age and parental socio-economic status were the best predictors of cognitive performance in controls. CONCLUSIONS: Poorer premorbid adjustment together with socio-demographic factors and higher daily antipsychotic doses were related to a generalized cognitive impairment and to a lower premorbid intellectual reserve, suggesting that neurodevelopmental impairment was present before illness onset.

Cognitive reserve as a predictor of two year neuropsychological performance in early onset first-episode schizophrenia.

INTRODUCTION: The concept of cognitive reserve (CR) has been defined as individual differences in the efficient utilization of brain networks which allow some people to cope better than others with brain pathology. CR has been developed mainly in the field of aging and dementia after it was observed that there appears to be no direct relationship between the degree of brain pathology and the severity of clinical manifestations of this damage. The present study applies the concept of CR to a sample of children and adolescents with a first episode of schizophrenia, aiming to assess the possible influence of CR on neuropsychological performance after two year follow-up, controlling for the influence of clinical psychopathology. METHODS: 35 patients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder (SSD) and 98 healthy controls (HC) matched for age and gender were included. CR was assessed at baseline, taking into account premorbid IQ, educational-occupational level and leisure activities. Clinical and neuropsychological assessments were completed by all patients at two year follow-up. RESULTS: The CR proxy was able to predict working memory and attention at two year follow-up. Verbal memory and cognitive flexibility were not predicted by any of the variables included in the regression model. The SSD group obtained lower scores than HC on CR. CR measures correctly classified 79.8% of the sample as being SSD or HC. CONCLUSIONS: Lower scores on CR were observed in SSD than in HC and the CR measure correctly classified a high percentage of the sample into the two groups. CR may predict SSD performance on working memory and attention tasks.

Cognitive efficacy of quetiapine and olanzapine in early-onset first-episode psychosis.

The primary purpose of this study was to compare changes in cognition in early-onset psychosis after 6-months treatment with quetiapine or olanzapine. This is a randomized, single-blind, 6-month study in 50 adolescents with a diagnosis of early-onset psychosis. Patients were randomized to quetiapine (n = 24) or olanzapine (n =26). A thorough neuropsychological battery was administered at baseline and after 6-month treatment. Out of the total sample included in the study, 32 patients completed at least 6-months treatment with the assigned medication (quetiapine, n =16; olanzapine, n = 16). No changes were observed in cognitive performance after 6-month treatment with quetiapine or olanzapine. Although some trends toward cognitive improvement were observed for the olanzapine group after 6-month treatment, neither group showed statistically significant gains. Furthermore, there was no evidence of any differential efficacy of olanzapine or quetiapine on cognitive improvement in this sample of adolescents with psychosis.

Predominance of symptoms over time in early-onset psychosis: a principal component factor analysis of the Positive and Negative Syndrome Scale.

BACKGROUND: Early-onset psychosis is a symptomatically nonspecific and heterogeneous entity composed of several diagnoses. This study examined the dimensional structure of symptoms and the temporal stability of this structure during a 6-month follow-up. METHOD: A principal component factor analysis of the Positive and Negative Syndrome Scale was conducted at baseline, 4 weeks, and 6 months in a sample of 99 first-episode psychotic patients (mean age = 15.5 years). RESULTS: The factor analysis produced a 5-dimension solution (Positive, Negative, Depression, Cognitive, Hostility) that explained 62.4% of the variance at baseline, 63.4% at 4 weeks, and 65.1% at 6 months. Negative dimension was the most consistent and stable over time and was predominant at baseline (23.9%) and at 4 weeks (25.7%). Depression was predominant at 6 months (31.1%). CONCLUSIONS: There is a stable 5-dimension structure of symptoms in early-onset psychosis with varying predominance of symptoms over time. Negative symptoms are a core feature of psychosis and are thus important diagnostic criteria.