Margriet M. Sitskoorn

Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis.

BACKGROUND Schizophrenia is characterized by a generalized cognitive impairment with pronounced deficits in the domains of verbal memory, executive functioning and attention. AIM To investigate whether cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. METHOD A meta-analytic review of the published literature on cognitive performance between relatives of schizophrenic patients and healthy controls. RESULTS The meta-analyses yielded nine weighted effect sizes from 37 studies comprising 1639 relatives of schizophrenia patients and 1380 control subjects. The largest differences were found on verbal memory recall (d=0.54, 95% CI=0.43-0.66) and executive functioning (d=0.51, 0.36-0.67). Attentional functioning showed smaller effect sizes (d=0.28, 0.06-0.50). These effect sizes are in the moderate range. CONCLUSION Cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. This finding is consistent with the idea that certain cognitive deficiencies in relatives are caused by familial predisposition to schizophrenia and that these deficiencies might be putative endophenotypes for schizophrenia. However, our results do not address genetic causes directly. Further work is needed to determine whether certain cognitive traits are familial and whether there is co-inheritance of these traits with schizophrenia within families.

Long-Term Neurocognitive Effects of Olanzapine or Low-Dose Haloperidol in First-Episode Psychosis

BACKGROUND Neurocognitive deficits are severe in first-episode psychosis. METHODS Patients (N = 263) with first-episode psychosis (schizophrenia, schizoaffective, or schizophreniform disorders) were randomly assigned to double-blind treatment with olanzapine (mean 11.30 mg/day) or haloperidol (mean 4.87 mg/day) for 104 weeks. A neurocognitive battery was administered at baseline (n = 246) and 12 (n = 167), 24 (n = 126), 52 (n = 89), and 104 (n = 46) weeks during treatment. Weighted principal component and unweighted composite scores were derived from individual tests. RESULTS Both treatment groups demonstrated significant improvement on both composite scores. On the basis of the weighted composite score, olanzapine had greater improvement than haloperidol only at 12 (p = .014) and 24 (p = .029) weeks. For the unweighted composite, olanzapine had significantly better improvement compared with haloperidol only at week 12 (p = .044). At week 12 only, olanzapine improved performance on the Digit Symbol and Continuous Performance Test significantly more than haloperidol. CONCLUSIONS Both antipsychotic agents appeared to improve neurocognitive functioning among first-episode psychosis patients with schizophrenia. A significantly greater benefit in terms of neurocognitive improvement was found with olanzapine than with haloperidol at weeks 12 and 24.

Does the Schizotypal Personality Questionnaire reflect the biological–genetic vulnerability to schizophrenia?

We investigated whether the Schizotypal Personality Questionnaire (SPQ) [Schizophr. Bull. 17 (1991) 555.] could be an indicator of the biological-genetic vulnerability to schizophrenia. We hypothesized that the mean scores on three dimensions of the SPQ of different groups of relatives of patients with schizophrenia would parallel their risk for developing schizophrenia. The SPQ was administered to 51 first-episode schizophrenia patients, 63 parents of schizophrenia patients, 42 siblings of schizophrenia patients and 12 children of schizophrenia patients. Patients differed from the relatives on all three dimensions. Siblings and children scored significantly higher than parents on Positive Schizotypy, and the insignificant difference between the siblings and children was in the expected direction. The results could not be explained by the differences in age, sex, IQ or substance abuse. No differences were found for Disorganization Schizotypy between the relatives. Children scored higher than parents on Negative Schizotypy. The current study offers support to the hypothesis that the positive dimension of SPQ reflects the genetic vulnerability to schizophrenia.

Brain volumes as predictor of outcome in recent-onset schizophrenia: a multi-center MRI study

Gray matter brain volume decreases have been found in patients with schizophrenia as compared to healthy control subjects measured by using Magnetic Resonance Imaging (MRI). An association has been suggested between decreased gray matter volume and poor outcome in chronically ill patients with schizophrenia. The present longitudinal multi-center study investigated whether gray matter volume at illness onset can predict poor outcome in recent-onset schizophrenia after a follow-up of approximately 2 years. An MRI calibration study was performed since scans of patients with recent-onset psychosis were conducted at three sites with 1.5 T MR scanners from two different manufacturers. Applying a linear scaling procedure on the histogram improved comparability between volume measurements acquired from images from the different scanners. Brain scans were obtained from 109 patients with recent-onset schizophrenia. Volumes of intracranium, total brain, cerebral gray and white matter, third and lateral ventricles, and cerebellum were measured. After a mean follow-up period of approximately 2 years, measurements of symptoms, functioning, need for care, and illness history variables were assessed. No significant correlations were found between the brain volume measures and any of these measures. Gray matter volume at illness onset does not predict outcome after 2 years in recent-onset schizophrenia.

Long-term memory deficits in schizophrenia: Primary or secondary dysfunction?

Long-term memory impairment is often found in schizophrenia. The question remains whether this is caused by other cognitive deficits. One hundred eighteen first-episode patients were compared with 45 control participants on several memory tasks. The role of processing speed and central executive functions on memory performance was examined with regression analysis for all participants and for patients separately. Deficits were found in general verbal learning performance and retrieval in episodic memory and semantic memory. Processing speed reduced disease-related variance in all memory variables. Coordination, organization of information, and speed of processing were the best predictors for long-term memory deficits in patients. The amount of explained variance, however, is small, especially in general verbal learning performance.

Attention and cognition in patients with obsessive–compulsive disorder

Abstract  Although a dysfunctional prefrontal‐striatal system is presupposed in obsessive–compulsive disorder (OCD), this is not sustained by neuropsychological studies. The aim of this study was twofold: (i) to investigate the cognitive deficits in patients with OCD compared to matched healthy controls; and (ii) to relate cognitive performance to clinical characteristics in patients with OCD. In this study, 39 patients with primary OCD according to Diagnostic and Statistical Manual, fourth edition criteria were compared to 26 healthy control subjects on a battery measuring verbal memory and executive functioning. Patients with OCD showed slowed learning on the verbal memory task and made more errors on the Wisconsin Card Sorting Test. Errors were failures to maintain set, which were related to severity of OCD symptomatology. The results show that patients with OCD have cognitive deficits. The authors hypothesize that these deficits may be interpreted by attentional deficits caused by a dysfunctional anterior cingulate cortex.

Effects of recurrent major depressive disorder on behavior and cognitive function in female depressed patients

Little is known about the effects of recurring depressive episodes on cognition and behavior. The objective of the study was to compare cognitive function and depression-related behavior between healthy female subjects and female outpatients with early-onset DSM-IV recurrent major depressive disorder and to investigate the effect of cumulative depressive duration. Neuropsychological tests and scales for apathy, anhedonia and psychomotor retardation were assessed in 23 female patients and 60 healthy age-matched female controls. Significantly higher levels of apathy, anhedonia and psychomotor retardation, and worse performance on tests of executive function were found in the patient group compared with the healthy controls. In the patient group, cumulative depression duration was not significantly correlated with cognitive function, apathy, anhedonia or psychomotor retardation. The deficits in executive function were not related to the actual level of depression. Mild executive dysfunction may be the effect of the illness process underlying recurrent depressive disorder. Repeated or extensive depressive episodes do not seem to additionally affect cognitive deficits or behavior in depressed patients.

Finding Suitable Phenotypes for Genetic Studies of Schizophrenia: Heritability and Segregation Analysis

BACKGROUND Schizophrenia is a highly heritable and complex disorder. Multiple genes are likely to be involved, complicating genetic research into the etiology of this disorder. Intermediate phenotypes or endophenotypes may facilitate genetic research if they display a simpler mode of transmission than schizophrenia itself, i.e., if they reflect more closely the underlying genetic effects. METHODS Twenty-five multigenerational families with multiple members affected with schizophrenia (180 subjects) were administered an extensive neuropsychological, psychophysiological, and personality test battery. Familial correlations were calculated to select heritable traits. Subsequent heritability analysis followed by commingling and segregation analysis were performed to unravel the pattern of transmission and to estimate heritability. RESULTS Five traits, including sensorimotor gating, openness, verbal fluency, early visual perception, and spatial working memory, showed moderate familial correlations. Heritability estimates for these traits ranged from 37% to 54%. A major gene model resembling dominant transmission was found for both sensorimotor gating and openness. Verbal fluency, early visual perception, and spatial working memory may be accounted for by polygenic, multifactorial, or environmental effects. CONCLUSIONS Only 2 of 13 candidate endophenotypes showed a simple mode of transmission useful for successful application in molecular genetic research: sensorimotor gating and openness. To our knowledge, this is the first study to investigate the pattern of transmission for these traits.

Differentiating between low and high susceptibility to schizophrenia in twins: the significance of dermatoglyphic indices in relation to other determinants of brain development

Both the skin and the brain develop from the same ectoderm and it is thought, therefore, that dermatoglyphics are informative for early disturbances in brain development in schizophrenia. This study was aimed at investigating the differences in both digital and palmar dermatoglyphic indices between twins discordant for schizophrenia and control twins. Furthermore, the significance of dermatoglyphic indices in relation to other determinants of brain development with regard to the susceptibility to schizophrenia was investigated. Data on dermatoglyphic indices of the hand and the palm were obtained from 21 same-sex discordant and 37 same-sex control twins. For 19 discordant and 25 control twins, there was also data available on brain volumes. Non-genetic intra-uterine circumstances early in pregnancy (10-13 weeks of gestation) are associated with a susceptibility to schizophrenia, since both the twins with schizophrenia and the unaffected co-twins showed more fluctuating asymmetry of the finger ridges (P<0.01), and marginally higher absolute finger ridge counts (P=0.06) than control twin pairs. Fluctuating asymmetry of the finger ridges was as important as whole brain and left hippocampal volumes in differentiating twins with a high susceptibility to schizophrenia from those with a low susceptibility.

Genetic overlap among intelligence and other candidate endophenotypes for schizophrenia

BACKGROUND A strategy to improve genetic studies of schizophrenia involves the use of endophenotypes. Information on overlapping genetic contributions among endophenotypes may provide additional power, reveal biological pathways, and have practical implications for genetic research. Several cognitive endophenotypes, including intelligence, are likely to be modulated by overlapping genetic influences. METHODS We quantified potential genetic and environmental correlations among endophenotypes for schizophrenia, including sensorimotor gating, openness, verbal fluency, early visual perception, spatial working memory, and intelligence, using variance component models in 35 patients and 145 relatives from 25 multigenerational Dutch families multiply affected with schizophrenia. RESULTS Significant correlations were found between spatial working memory and intelligence (.45), verbal fluency and intelligence (.36), verbal fluency and spatial working memory (.20), and early visual perception and spatial working memory (.19). A strong genetic correlation (.75) accounted for 76% of the variance shared between spatial working memory and intelligence. Significant environmental correlations were found between verbal fluency and openness (.50) and between verbal fluency and spatial working memory (.58). Sensorimotor gating and openness showed few genetic or environmental correlations with other endophenotypes. CONCLUSIONS Our results suggest that intelligence strongly overlaps genetically with a known cognitive endophenotype for schizophrenia. Intelligence may thus be a promising endophenotype for genetic research in schizophrenia, even though the underlying genetic mechanism may still be complex. In contrast, sensorimotor gating and openness appear to represent separate genetic entities with simpler inheritance patterns and may therefore augment the detection of separate genetic pathways contributing to schizophrenia.