Emre Bora

Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives

BACKGROUND Our aim was to delineate neuropsychological deficits related to genetic susceptibility, illness process and iatrogenic factors in bipolar disorder (BD). METHODS Following an extensive publication search on several databases, meta-analyses were conducted for 18 cognitive variables in studies that compared performances of euthymic BD patients (45 studies; 1423 subjects) or first-degree relatives of BD patients (17 studies; 443 subjects) with healthy controls. The effect of demographic variables and confounding factors like age of onset, duration of illness and medication status were analysed using the method of meta-regression. RESULTS While response inhibition, set shifting, executive function, verbal memory and sustained attention deficits were common features for both patient (medium to large effect sizes) and relative groups (small to medium effect sizes), processing speed, visual memory and verbal fluency deficits were only observed in patients. Medication effects contributed to psychomotor slowing in BD patients. Earlier age of onset was associated with verbal memory impairment and psychomotor slowing. LIMITATION Data related to some confounding variables was not reported in a substantial number of extracted studies. CONCLUSIONS Response inhibition deficit, a potential marker of ventral prefrontal dysfunction, seems to be the most prominent endophenotype of BD. The cognitive endophenotype of BD also appears to involve fronto-temporal and fronto-limbic related cognitive impairments. Processing speed impairment is related, at least partly, to medication effects indicating the influence of confounding factors rather than genetic susceptibility. Patterns of sustained attention and processing speed impairments differ from schizophrenia. Future work in this area should differentiate cognitive deficits associated with disease genotype from impairments related to other confounding factors.

Neuroanatomical abnormalities in schizophrenia: A multimodal voxelwise meta-analysis and meta-regression analysis

Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion-weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis.

Evidence for theory of mind deficits in euthymic patients with bipolar disorder

Objective:  i) To investigate the subtle ToM (theory of mind) deficits in euthymic patients with bipolar disorder. ii) To investigate the impact of non‐ToM cognitive deficits on ToM abilities.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.

Cognitive functioning in schizophrenia, schizoaffective disorder and affective psychoses: meta-analytic study

BACKGROUND Cognitive functioning in affective psychosis and schizoaffective disorder is much less studied compared with schizophrenia. AIMS To quantitatively undertake a meta-analysis of the available data that directly compares cognitive functioning across schizophrenia, schizoaffective disorder and affective psychosis. METHOD Following a thorough literature review, 31 studies that compared the performances of people with schizophrenia (1979 participants) with that of those with affective psychosis or schizoaffective disorder (1314 participants) were included. To determine the effect of demographic and clinical confounders, meta-regression and subgroup analyses were conducted. RESULTS In 6 of 12 cognitive domains, people with schizophrenia performed worse than people with schizoaffective disorder or affective psychosis. However, the between-group differences were small and the distribution of effect sizes showed substantial heterogeneity. The between-group differences were driven by a higher percentage of males, more severe negative symptoms and younger age at onset of illness in the schizophrenia samples. CONCLUSIONS Neuropsychological data do not provide evidence for categorical differences between schizophrenia and other groups. However, a subgroup of individuals with schizophrenia who have more severe negative symptoms may be cognitively more impaired than those with affective psychosis/schizoaffective disorder.

Cognitive impairment in euthymic major depressive disorder: a meta-analysis

BACKGROUND There is evidence to suggest that cognitive deficits might persist beyond the acute stages of illness in major depressive disorder (MDD). However, the findings are somewhat inconsistent across the individual studies conducted to date. Our aim was to conduct a systematic review and meta-analysis of existing studies that have examined cognition in euthymic MDD patients. METHOD Following a systematic search across several publication databases, meta-analyses were conducted for 27 empirical studies that compared euthymic adult MDD patients (895 participants) and healthy controls (997 participants) across a range of cognitive domains. The influence of demographic variables and confounding factors, including age of onset and recurrent episodes, was examined. RESULTS Compared with healthy controls, euthymic MDD patients were characterized by significantly poorer cognitive functions. However, the magnitude of observed deficits, with the exception of inhibitory control, were generally modest when late-onset cases were excuded. Late-onset cases demonstrated significantly more pronounced deficits in verbal memory, speed of information processing and some executive functions. CONCLUSIONS Cognitive deficits, especially poor response inhibition, are likely to be persistent features, at least of some forms, of adult-onset MDD. More studies are necessary to examine cognitive dysfunction in remitted psychotic, melancholic and bipolar spectrum MDD. Cognitive deficits overall appear to be more common among patients with late-onset depression, supporting the theories suggesting that possible vascular and neurodegenerative factors play a role in a substantial number of these patients.

Meta-analysis of Cognitive Deficits in Ultra-high Risk to Psychosis and First-Episode Psychosis: Do the Cognitive Deficits Progress Over, or After, the Onset of Psychosis?

Cognitive dysfunction is a well-established feature of schizophrenia, and there is evidence suggesting that cognitive deficits are secondary to abnormal neurodevelopment leading to problems in acquiring such abilities. However, it is not clear whether there is also a decline in cognitive performance over, or after, the onset of psychosis. Our objective was to quantitatively examine the longitudinal changes in cognitive function in patients who presented with first-episode psychosis (FEP), ultra-high risk (UHR) for psychosis, and controls. Electronic databases were searched for the studies published between January 1987 and February 2013. All studies reporting longitudinal cognitive data in FEP and UHR subjects were retrieved. We conducted meta-analyses of 25 studies including 905 patients with FEP, 560 patients at UHR, and 405 healthy controls. The cognitive performances of FEP, UHR, and healthy controls all significantly improved over time. There was no publication bias, and distributions of effect sizes were very homogenous. In FEP, the degree of improvement in verbal working memory and executive functions was significantly associated with reduction in negative symptoms. There was no evidence of cognitive decline in patients with UHR and FEP. In contrast, the cognitive performances of both groups improved at follow-up. These findings suggest that cognitive deficits are already established before the prodromal phases of psychosis. These data support the neurodevelopmental model rather than neurodegenerative and related staging models of schizophrenia.

Theory of mind impairments in first-episode psychosis, individuals at ultra-high risk for psychosis and in first-degree relatives of schizophrenia: Systematic review and meta-analysis

Theory of mind (ToM) deficit is a well-established feature of schizophrenia and has been suggested as a vulnerability marker of this disorder. However, as most of this evidence is based on studies in chronic patients, it is less clear whether ToM is impaired prior to or following the onset of a first-episode and whether it is evident in unaffected relatives of patients. In this meta-analysis, ToM performance of 3005 individuals with first-episode psychosis (FEP), individuals at ultra-high risk for psychosis (UHR) and unaffected relatives were compared with 1351 healthy controls. ToM was substantially impaired in first-episode psychosis (Cohen d=1.0) and this deficit was comparable to findings in chronic patients. ToM was also impaired in unaffected relatives (d=0.37) and UHR subjects (d=0.45) and performances of these groups were intermediate between FES and healthy controls. Severity of ToM deficits in unaffected relatives and UHR subjects was similar to other cognitive deficits observed in these groups. Longitudinal studies of clinical and genetic high-risk subjects are necessary to investigate the trajectory of development of ToM deficits in schizophrenia.

Neurodevelopmental origin of cognitive impairment in schizophrenia

Cognitive impairment is a common feature of schizophrenia; however, its origin remains controversial. Neurodevelopmental abnormalities clearly play a role in pre-morbid cognitive dysfunction in schizophrenia, yet many authors believe that schizophrenia is characterized by illness-related cognitive decline before and after onset of the psychosis that can be the result of neurodegenerative changes. The main reasons behinds such arguments include, first, the evidence showing that effect sizes of the cognitive deficits in subjects who develop adult schizophrenia gradually increase in the first two decades of life and, second, the fact that there is functional decline in many patients with schizophrenia over the years. In this Editorial, I argue that current evidence suggests that illness-related cognitive impairment is neurodevelopmental in origin and characterized by slower gain (developmental lag) but not cognitive decline continuing throughout the first two decades of life. I introduce a model suggesting that neurodevelopmental abnormality can in fact explain the course of cognitive dysfunction and variations in the trajectory of functional decline throughout the life in individuals with schizophrenia. In this model, the severity of underlying neurodevelopmental abnormality determines the age that cognitive deficits first become apparent and contributes to the cognitive reserve of the individual. Interaction of neurodevelopmental abnormality with clinical symptoms, especially negative symptoms and aging, vascular changes, psychological and iatrogenic factors contributes to the heterogeneity of the functional trajectory observed in this disorder.

Theory of mind impairment: a distinct trait-marker for schizophrenia spectrum disorders and bipolar disorder?

Objective:  The aim of this study was to critically review the literature in order to determine if Theory of Mind (ToM) impairment can be considered a trait‐marker for schizophrenia spectrum disorders and bipolar disorder (BD).