Emmanuel Stip

Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review

BACKGROUND Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence. METHODS Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers. RESULTS Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines. CONCLUSIONS These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

The functional neuroanatomy of major depression: an fmri study using an emotional activation paradigm

AN important issue regarding the neural basis of major depression is whether the functional brain changes associated with the affect disturbance seen in this syndrome are similar to those that accompany transient sadness in normal subjects. To address this question, we carried out an fMRI study using an emotional activation paradigm. Brain activity associated with passive viewing of an emotionally laden film clip aimed at inducing a transient state of sadness was contrasted with that associated with passive viewing of an emotionally neutral film clip in patients suffering from unipolar depression and in normal control subjects. Results showed that transient sadness produced significant activation in the medial and inferior prefrontal cortices, the middle temporal cortex, the cerebellum and the caudate in both depressed and normal subjects. They also revealed that passive viewing of the emotionally laden film clip produced a significantly greater activation in the left medial prefrontal cortex and in the right cingulate gyrus in depressed patients than in normal control subjects. These findings suggest that these two cortical regions might be part of a neural network implicated in the pathophysiology of major depression. Taken together, these results strongly support the view that activation paradigms represent an extremely useful and powerful way of delineating the functional anatomy of the various symptoms that characterize major depression.

Cognitive predictors of psychosocial functioning outcome in schizophrenia: A follow-up study of subjects participating in a rehabilitation program

The aims of this prospective study were to explore in subjects with psychosis participating in a rehabilitation program whether cognitive performances at baseline predicted (i) psychosocial functioning over a 15-16 month follow-up; (ii) improvement in psychosocial functioning over the rehabilitation program. Visuo-spatial tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered to assess cognitive performance in 55 subjects with schizophrenia spectrum disorders who completed a rehabilitation program. The Multnomah Community Ability Scale (MCAS) was used to measure dimensions of community functioning. One subscale of the Clients Assessment of Strengths, Interests, and Goals (CASIG) provided a measure of subjective quality of life (QoL). Improvement was defined as a 15% or more increase in psychosocial scores between baseline and follow-up. Worse baseline sustained attention predicted better self-rated quality of life, and better baseline visual memory predicted better community functioning over the rehabilitation follow-up period, in particular, higher autonomy in activities of daily living, and less physical and psychiatric symptoms that could interfere with rehabilitation. Baseline cognitive performances predicted community functioning improvement during the follow-up period: visual memory predicted improvement in daily living autonomy and in social competence; sustained attention predicted improvement in behavioral problems (such as medication compliance, collaboration with treatment providers or impulse control) and social competence; planning performances predicted improvement in social competence. These cognitive functions could be specifically targeted in a rehabilitation program aimed at enhancing functioning in those particular dimensions.

Assessment of executive dysfunction during activities of daily living in schizophrenia

Many neuropsychological studies have described deficits of memory and executive functions in patients with schizophrenia, and the severity of these deficits seems to be determinant in predicting the community outcome of these patients [Schizophr. Bull. 26 (2000) 119]. However, neuropsychological evaluation does not provide valuable information about how the cognitive deficits directly affect daily living, that is, which cognitive deficit affects which behavior. The present study aimed at determining whether executive dysfunction in schizophrenia could be directly measured by analyzing three activities of daily living (ADL), in addition to assessing the ecological validity of commonly used neuropsychological tests. Within specific ADL (choosing a menu, shopping the ingredients, cooking a meal), the sequences of behaviors that have been performed by 27 control subjects and 27 patients with schizophrenia were both analyzed by using a preset optimal sequence of behavior. When compared with control subjects, patients with schizophrenia showed more omissions when choosing the menu, more sequencing and repetitions errors during the shopping task, and more planning, sequencing, repetition and omission errors during the cooking task. These behavioral errors correlated significantly with negative, but not with positive symptoms of the patients. Furthermore, they also correlated with the poor performances on executive neuropsychological tests, especially those sensitive to shifting and sequencing abilities, but not with memory tests. These results suggest that executive deficits in schizophrenia may specifically affect ADL and that such deficits can be quantitatively assessed with a behavioral scale of action sequences.

Exploring cognitive complaints in schizophrenia: the subjective scale to investigate cognition in schizophrenia☆

While it has become commonplace to test the various components of memory in schizophrenia with paper-and-pencil or in-lab tasks, very little data exist on the subjective complaints of patients regarding their memory. Few instruments have been designed to collect systematically the complaints of patients with schizophrenia. We present a work in progress on the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), a 21-item, Likert-type scale that is simple and easy to use. It allows a quantitative approach to the subjective and cognitive dimensions of schizophrenia. Stip constructed the scale based on a questionnaire covering several cognitive domains: memory (working memory, explicit long-term memory), attention (divided, distractibility, alertness, sustained), language, and praxia. We evaluated the psychometric properties of the SSTICS in a population of 114 French-speaking patients in Montreal. Patients were recruited in the community and assessed with the Structured Clinical Interview for DSM-III-R (SCID), the Positive and Negative Syndrome Scale (PANSS), and the Extrapyramidal Symptoms Rating Scale (ESRS). Cognition was measured using the Rey Auditory Verbal Learning Test (RAVLT) (long-term memory), Controlled Oral Word Association Test (verbal fluency), and Trails A and B. Preliminary analyses showed very good internal consistency for the global score (alpha=0.88), and alphas varying from 0.57 to 0.72 for the subscales. Stability over time was very good. The principal components analysis accounted for a multiple structure. Correlations between subjective scores and objective cognitive assessment were significant for several domains. Validation of the SSTICS needs to be completed through further exploration of the factorial structure and testing of the English version.

Sleep architecture and its clinical correlates in first episode and neuroleptic-naive patients with schizophrenia

The goal of the present study was to characterize sleep organization in first episode and neuroleptic-naive patients with schizophrenia and to evaluate relationships between those sleep parameters and clinical symptoms. Eleven patients with acute schizophrenia never treated with neuroleptics were compared to 11 healthy controls. Sleep stages and phasic events (sleep spindles and rapid-eye-movements during REM sleep (REMs) were visually identified. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Compared to controls, patients with schizophrenia had difficulty initiating sleep, decreased stage 4 duration, reduced rapid eye movement (REM) sleep latency, and normal sleep spindles and REMs densities. Positive symptoms correlated negatively with REM sleep latency. The BPRS total score correlated negatively with REM sleep duration and REMs density. The present results indicate that first episode and neuroleptic-naive patients with schizophrenia have difficulties initiating, but not maintaining, sleep. These results also confirm that the duration of stage 4 and REM sleep latency are reduced in first episode and neuroleptic-naive patients with schizophrenia. The fact that measures of REM sleep correlate with clinical scales of schizophrenia suggests that REM sleep physiology shares common substrates with symptoms of this disease.

Contradictory cognitive capacities among substance-abusing patients with schizophrenia: a meta-analysis.

Although a substance use disorder (SUD) is traditionally associated with psycho-bio-social impairments, recent investigations among persons with schizophrenia (Sz) generated divergent results. Certain persons with Sz+SUD might in fact present better social and cognitive functioning than persons with Sz without SUD. This meta-analysis was conducted to verify this counterintuitive possibility and to determine whether factors such as substance type, severity or nature of psychotic symptoms and age of the patients help discriminate these subgroups. Twenty-three studies met the inclusion criteria and data from 1807 persons with schizophrenia, with or without comorbid SUD, were available for analyses. As a group, persons with Sz+SUD did not obtain significantly higher scores at a Global Cognitive Index than persons with Sz without SUD, although they were better at the Trail Making Task and the speed processing domain. Secondary analyses showed the importance of considering intermediate factors, particularly the preferred substance used and the mean age. While consumption of alcohol was associated with a global cognitive scores similar to that of persons with Sz without an SUD and lower working memory capacities, preferential use of cannabis was instead associated with higher scores for problem solving and reasoning and visual memory. Age was inversely related to the size of the effects. It is concluded that previous mixed results obtained with cognitive evaluations of persons with Sz+SUD might reflect the heterogeneity of participants and that subgroups of patients might be defined on the basis of intermediate factors.

Are metabolic indices different between drug-naïve first-episode psychosis patients and healthy controls?

OBJECTIVE To compare glucose and lipid metabolism parameters between drug-naïve first-episode psychosis (FEP) patients with a diagnosis of schizophrenia spectrum disorder and healthy controls matched for age, ethnicity, and gender. METHOD Baseline evaluations of fasting glucose and lipid metabolism parameters and the oral glucose tolerance test were performed with FEP patients (n=38), having no more than 10 days of cumulative exposure to antipsychotic medication, and normal community controls (n=36). Analysis of variance (ANOVA) was conducted to examine between group differences. RESULTS FEP patients did not show a higher prevalence of the precursors to diabetes (impaired fasting glucose, impaired glucose tolerance, insulin resistance), and no significant difference in beta-cell function or lipid profile measures, compared to healthy controls. FEP patients showed a higher waist to hip ratio compared to controls. CONCLUSIONS FEP patients having a schizophrenia spectrum disorder do not differ from healthy controls, in their baseline measures of glucose and lipid metabolites, nor in the prevalence of diabetes or its precursors, before (or close to) the onset of antipsychotic treatment.

Predictors of quality of life in schizophrenia.

The objective of this study was to clarify the relationships between socio-demographics, clinical characteristics, stressors, coping strategies, social support and quality of life (QOL) in 143 patients with a diagnosis of either schizophrenia or schizoaffective disorders. The research design is cross-sectional with repeated measures on the same subjects after a 6-month interval. A regression analysis generated a model that accounts for 50% of the variance in QOL at Time 1 and 43% at Time 2. The best predictors of QOL were two components of social support: attachment and reassurance of worth. Severity of daily hassles, the coping strategy of changing the situation, level of education and life-time hospitalization length were also related to QOL.

Self-assessed cognitive dysfunction and objective performance in outpatients with schizophrenia participating in a rehabilitation program

OBJECTIVE To explore the pattern of associations between self-assessed and objective neuropsychological performance in a sample of outpatients with schizophrenia participating in a rehabilitation program. METHOD The Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) [Compr. Psychiatry 44 (2003) 331] was used to assess cognitive complaints in 73 subjects with schizophrenia. Visuo-spatial tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) [Cogn. Neuropsychiatry 3 (1998) 45] were administered as objective measures. RESULTS Cognitive complaints in several cognitive domains were mainly correlated with a true difficulty in memory. Higher SSTICS attention scores, i.e. increased complaints, were associated with poorer CANTAB explicit visual memory and planning performances. Higher SSTICS executive functioning scores were associated with poorer CANTAB explicit visual memory scores. CONCLUSION These findings suggest that outpatients with schizophrenia express some cognitive difficulties. However, the cognitive nature of these subjective complaints does not strictly correspond with objective performances. These results also suggest that theoretical constructs of cognitive functions do not always have ecological validity. Thus, subjective cognitive complaints should be taken into account in assessment of patient well-being, but cannot be used as a substitute to objective cognitive measures. The simultaneous use of subjective and objective measures of cognitive dysfunction may provide a more complete picture of individual rehabilitation targets in patients with schizophrenia.