Melissa J. Green

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=−0.458, 95% confidence interval=−0.770 to −0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia

BACKGROUND The large quantity of systematic reviews of magnetic resonance imaging studies in schizophrenia challenges their meaningful interpretation. This meta-review synthesises the available information from systematic reviews of structural alteration in both chronic and first-episode schizophrenia. METHODS Systematic reviews were identified using electronic databases. Review methodological quality was assessed according to the Assessment of Multiple Systematic Reviews checklist. Data were extracted in duplicate and quality assessed for consistency and precision, guided by Grading of Recommendations Assessment, Development and Evaluation recommendations. RESULTS Integration of volumetric and voxel-based estimates allowed critical assessment of the magnitude and location of anatomical differences. There is evidence for grey matter reductions of anterior cingulate, frontal (particularly medial and inferior) and temporal lobes, hippocampus/amygdala, thalamus, and insula that may be magnified over time. Other regional alterations appear specific to illness stage or medication status. CONCLUSIONS There is limited high quality evidence supporting grey or white matter changes in schizophrenia, which has previously been obscured by a large volume of conflicting lower quality evidence.

Schizoaffective disorder: diagnostic issues and future recommendations

OBJECTIVE Difficulties surrounding the classification of mixed psychotic and affective syndromes continue to plague psychiatric nosology. This paper addresses the controversy regarding the diagnostic validity of schizoaffective disorder (SAD), a diagnosis that is used in both DSM-IV and ICD-10 and one that encroaches on both schizophrenia (SCZ) and bipolar disorder (BD). METHODS A systematic synthesis of clinical and empirical literature, including evidence from cognitive, neurobiological, genetic, and epidemiological research, was undertaken with the aim of evaluating the utility of the SAD classification. RESULTS Distinctions between the diagnostic categories of SCZ, SAD and BD are not clearly demarcated by findings from neuropsychological, neuroimaging, molecular neurobiology, or genetic epidemiology studies. On the contrary, convergent evidence purports overlap across current diagnostic boundaries in the heritability and pathophysiology of psychotic and affective disorders. However, there are some disorder-specific findings. CONCLUSIONS Schizoaffective disorder is a prototypic boundary condition that epitomizes the pitfalls of the current categorical classification system. Future revisions to the DSM should consider the implementation of one of two alternative models to account for individuals presenting with mixed psychotic and affective symptoms. These include the views that (i) SAD is a comorbid set of symptoms that occur as a by-product of two separate disorders (SCZ and BD) or, that (ii) SAD exists as the mid-point on a continuum between SCZ and BD, such that the incorporation of these two disorders onto one dimension may be a suitable alternative. Hence the category SAD should be omitted in future revisions of DSM, allowing the development of meaningful nomenclature that rests upon further rigorous investigation of differences and similarities between disorders.

Social cognition, empathy and functional outcome in schizophrenia

Social and occupational functioning difficulties are a characteristic feature of schizophrenia, and a growing body of evidence suggests that deficits in social cognition contribute significantly to these functional impairments. The present study sought to investigate whether the association between social cognition and social functioning in schizophrenia would be mediated by self-reported levels of empathy. Thirty outpatients with a diagnosis of schizophrenia or schizoaffective disorder, and twenty-five healthy controls completed a well-validated facial affect processing task (Ekman 60-faces facial task from the Facial Expressions of Emotion - Stimuli and Tests; FEEST), The Awareness of Social Inference Test (TASIT; to assess emotion perception and complex social cognitive skills such as the detection of sarcasm and deceit, from realistic social exchanges), and measures of self-reported empathy and social functioning. Participants with schizophrenia performed more poorly than controls in identifying emotional states from both FEEST and TASIT stimuli, and were impaired in their ability to comprehend counterfactual information in social exchanges, including sarcasm and lies, on the TASIT. Impairment in the comprehension of sarcasm was associated with higher empathic personal distress, and lower recreational functioning. Impairment in the identification of the emotions of others was found to be associated with lower satisfaction and lower empathic fantasy. However, empathy could not be explored as a mediator of associations between social cognition and functional outcome, due to lack of common associations with functional outcome measures. These findings have implications for the remediation of specific social cognitive deficits with respect to improving functional outcomes in schizophrenia.

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia

Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

Emotion regulation in schizophrenia: Affective, social and clinical correlates of suppression and reappraisal

Individuals can exert considerable control over their experience and expression of emotion by applying different regulatory strategies such as reappraisal and suppression. However, although it has been suggested that blunted affect in schizophrenia, characterized by markedly reduced emotion expressivity alongside apparently normal emotion experience, may reflect overuse of suppression, no study to date has assessed self-reported use of these different emotion regulatory strategies in relation to this disorder. In the present study, 41 individuals with schizophrenia and 38 control participants completed a self-report measure that differentiated between use of suppression and reappraisal. Symptom severity and various aspects of cognitive and psychosocial functioning were also assessed. Relative to controls, individuals with schizophrenia did not differ with regard to their reported use of suppression and reappraisal, and reported use of both strategies was unrelated to clinical ratings of blunted affect. However, whereas (lower) use of reappraisal was associated with greater social function impairment for both groups, only for controls was (greater) use of suppression associated with reduced social functioning. Implications for understanding blunted affect and social dysfunction in schizophrenia are discussed.

Remediation of facial emotion perception in schizophrenia: Concomitant changes in visual attention

The study examined changes in visual attention in schizophrenia following training with a social-cognitive remediation package designed to improve facial emotion recognition (the Micro-Expression Training Tool; METT). Forty out-patients with schizophrenia were randomly allocated to active training (METT; n=26), or repeated exposure (RE; n=14); all completed an emotion recognition task with concurrent eye movement recording. Emotion recognition accuracy was significantly improved in the METT group, and this effect was maintained after one week. Immediately following training, the METT group directed more eye movements within feature areas of faces (i.e., eyes, nose, mouth) compared to the RE group. The number of fixations directed to feature areas of faces was positively associated with emotion recognition accuracy prior to training. After one week, the differences between METT and RE groups in viewing feature areas of faces were reduced to trends. However, within group analyses of the METT group revealed significantly increased number of fixations to, and dwell time within, feature areas following training which were maintained after one week. These results provide the first evidence that improvements in emotion recognition following METT training are associated with changes in visual attention to the feature areas of emotional faces. These findings support the contribution of visual attention abnormalities to emotion recognition impairment in schizophrenia, and suggest that one mechanism for improving emotion recognition involves re-directing visual attention to relevant features of emotional faces.

Processing of threat-related affect is delayed in delusion-prone individuals.

OBJECTIVES On the basis of previous reports of an attentional bias for threat-related emotional material in deluded schizophrenics (e.g. Bentall & Kaney, 1989), the present study examined the proposal that a similar bias would be demonstrated by delusion-prone individuals, reflected by longer response latencies for the task of processing threat-related facially displayed affects (e.g. anger, fear). DESIGN A non-randomized matched group design was employed to examine the performance of delusion-prone individuals in comparison with a control group. METHODS 50 psychiatrically healthy participants completed the Peters et al. Delusions Inventory (PDI) as an index of delusional ideation (Peters, Day, & Garety, 1996; Peters, Joseph, & Garety, 1999). Subjects were presented with a standard set of facial stimuli depicting happy, sad, neutral, fearful and angry emotion expressions (Mazurski & Bond, 1993). Reaction times for the task of identifying each type of affect were compared between groups of high and low scorers on the PDI. RESULTS Highly delusion-prone individuals displayed a significant delay in processing angry facial expressions in comparison with low scorers on the PDI. CONCLUSIONS The increased response latency for processing angry expressions was interpreted as evidence of attentional bias for material posing a threat to the self, supporting previous cognitive data in relation to deluded patients. Threatening facial expressions may be regarded with increased significance by delusion-prone individuals, and it is possible that this bias is involved in the formation of delusional beliefs.

Psychotic-like experiences in a community sample of 8000 children aged 9 to 11 years: an item response theory analysis

BACKGROUND Psychotic-like experiences (PLEs) in the general population are common, particularly in childhood, and may constitute part of a spectrum of normative development. Nevertheless, these experiences confer increased risk for later psychotic disorder, and are associated with poorer health and quality of life. METHOD This study used factor analytic methods to determine the latent structure underlying PLEs, problem behaviours and personal competencies in the general child population, and used item response theory (IRT) to assess the psychometric properties of nine PLE items to determine which items best represented a latent psychotic-like construct (PSY). A total of 7966 children aged 9-11 years, constituting 95% of eligible children, completed self-report questionnaires. RESULTS Almost two-thirds of the children endorsed at least one PLE item. Structural analyses identified a unidimensional construct representing psychotic-like severity in the population, the full range of which was well sampled by the nine items. This construct was discriminable from (though correlated with) latent dimensions representing internalizing and externalizing problems. Items assessing visual and auditory hallucination-like experiences provided the most information about PSY; delusion-like experiences identified children at more severe levels of the construct. CONCLUSIONS Assessing PLEs during middle childhood is feasible and supplements information concerning internalizing and externalizing problems presented by children. The hallucination-like experiences constitute appropriate items to screen the population to identify children who may require further clinical assessment or monitoring. Longitudinal follow-up of the children is required to determine sensitivity and specificity of the PLE items for later psychotic illness.

Schizotypy and creativity as effects of reduced cognitive inhibition

Abstract The present study was designed to test the hypothesis that enhanced creativity in highly schizotypal individuals may be explicable in terms of reduced cognitive inhibition. A total of 72 participants completed the STA measure of schizotypy ( Claridge and Broks, 1984 ), the instances and uses tests from the Wallach and Kogan (1965) divergent thinking battery and a negative priming task as a measure of cognitive inhibition. It was predicted that higher levels of schizotypy would be independently associated with higher creativity as reflected in greater divergent thinking, and with reduced cognitive inhibition. However, it was further hypothesised that the relationship between schizotypy and creativity would be partially mediated by the level of cognitive inhibition. A significant positive correlation was found between STA scores and the number of original (unique) responses generated for divergent thinking measures, but the previously reported association between reduced cognitive inhibition and schizotypy (e.g. Beech and Claridge, 1987 ) was not replicated. The contribution of schizotypy and cognitive mechanisms to creative thinking is discussed in terms of a broader theory which considers the interaction of these traits with other aspects of temperament.