Matthew J. Kempton

Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk.

CONTEXT A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. OBJECTIVE To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. DATA SOURCES The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. STUDY SELECTION Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. DATA EXTRACTION Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. CONCLUSIONS The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

Structural Neuroimaging Studies in Major Depressive Disorder: Meta-analysis and Comparison With Bipolar Disorder

CONTEXT Although differences in clinical characteristics exist between major depressive disorder (MDD) and bipolar disorder (BD), consistent structural brain abnormalities that distinguish the disorders have not been identified. OBJECTIVES To investigate structural brain changes in MDD using meta-analysis of primary studies; assess the effects of medication, demographic, and clinical variables; and compare the findings with those of a meta-analysis of studies on BD. DATA SOURCES The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1980, to February 2, 2010. STUDY SELECTION Two hundred twenty-five studies that used magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with MDD with that of controls were included in an online database, and 143 that measured common brain structures were selected for meta-analysis. DATA EXTRACTION Twenty-five variables, including demographic and clinical data, were extracted from each study, when available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and the proportion of patients and controls with an abnormality in brain structure was extracted for categorical variables. DATA SYNTHESIS Compared with the structure of a healthy brain, MDD was associated with lateral ventricle enlargement; larger cerebrospinal fluid volume; and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients during depressive episodes had significantly smaller hippocampal volume than patients during remission. Compared with BD patients, those with MDD had reduced rates of deep white matter hyperintensities, increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia. Both disorders were associated with increased lateral ventricle volume and increased rates of subcortical gray matter hyperintensities compared with healthy controls. CONCLUSIONS The meta-analyses revealed structural brain abnormalities in MDD that are distinct from those observed in BD. These findings may aid investigators attempting to discriminate mood disorders using structural magnetic resonance imaging data.

Meta-analysis, Database, and Meta-regression of 98 Structural Imaging Studies in Bipolar Disorder

CONTEXT Despite 25 years of structural imaging in bipolar disorder, brain regions affected in the disorder are ill defined. OBJECTIVES To use meta-analytical techniques to investigate structural brain changes in bipolar disorder and to assess the effect of medication use and demographic and clinical variables. DATA SOURCES The MEDLINE, EMBASE, and PsycINFO databases were searched from 1980-2007 for studies using magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with bipolar disorder and controls. STUDY SELECTION We identified 1471 unique publications from which 141 studies were included in a database and 98 were selected for meta-analysis. DATA EXTRACTION Twenty-six demographic and clinical variables were extracted from each study where available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and numbers of patients and controls with an abnormality were extracted for binary variables. DATA SYNTHESIS Bipolar disorder was associated with lateral ventricle enlargement (effect size = 0.39; 95% confidence interval, 0.24-0.55; P = 8 x 10(-7)) and increased rates of deep white matter hyperintensities (odds ratio = 2.49; 95% confidence interval, 1.64-3.79; P = 2 x 10(-5)) but not periventricular hyperintensities. Gray matter volume increased among patients when the proportion of patients using lithium increased (P = .004). Calculations from this meta-analysis show current imaging studies (which typically examine 8 regions) have a 34% chance of making a type I error. Type II errors are also appreciable (for example, 70% when measuring the lateral ventricular volume in a typical study involving 25 patients and 33 controls). CONCLUSIONS The meta-analyses revealed robust but regionally nonspecific changes of brain structure in bipolar disorder. Individual studies will remain underpowered unless sample size is increased or improvements in phenotypic selection and imaging methods are made to reduce within-study heterogeneity. The provision of online databases, as illustrated herein, may facilitate a more refined design and analysis of structural imaging data sets in bipolar disorder.

Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies

Context Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness. Objectives To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia. Data sources Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved. Study selection 30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria. Data extraction Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. Data synthesis The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity. Conclusions Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.

Neuroanatomy of vulnerability to psychosis: a voxel-based meta-analysis.

BACKGROUND Individual structural imaging studies in the pre-psychotic phases deliver contrasting findings and are unable to definitively characterize the neuroanatomical correlates of an increased liability to psychosis and to predict transition to psychosis. METHOD Ninenteen voxel-based morphometry (VBM) studies of subjects at enhanced risk for psychosis and healthy controls were included in an activation likelihood estimation (ALE) meta-analysis. RESULTS The overall sample consisted of 701 controls and 896 high risk subjects. Subjects at high risk for psychosis showed reduced gray matter (GM) volume as compared to controls in the right superior temporal gyrus, left precuneus, left medial frontal gyrus, right middle frontal gyrus, bilateral parahippocampal/hippocampal regions and bilateral anterior cingulate. High risk subjects who later developed a psychotic episode showed baseline GM volume reductions in the right inferior frontal gyrus and in the right superior temporal gyrus. CONCLUSIONS GM volume reductions in temporo-parietal, bilateral prefrontal and limbic cortex are neuroanatomical correlates of an enhanced vulnerability to psychosis. Baseline GM reductions in superior temporal and inferior frontal areas are associated with later transition to psychosis.

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.

Progressive lateral ventricular enlargement in schizophrenia: a meta-analysis of longitudinal MRI studies.

BACKGROUND Lateral ventricular enlargement is one of the most consistent findings in patients with schizophrenia; however whether progressive ventricular dilation occurs during the course of the illness has been controversial. To clarify this we conducted a meta-analysis of longitudinal studies measuring the lateral ventricles in patients with schizophrenia and a control group. METHODS The MEDLINE database was searched from 1980 to 2009 for longitudinal MRI studies of patients with schizophrenia. We identified 13 studies that measured the lateral ventricles in both patients and controls and these were included in a random effects meta-analysis. The effect of various clinical variables was investigated in a meta-regression analysis. RESULTS Patients showed evidence of progressive ventricular enlargement after illness onset greater than that seen in controls (effect size=0.45, 95%CI 0.19-0.71, p=0.0006). A sub-analysis of chronic patients with schizophrenia with a mean duration of illness of 7.6 years at baseline scan also showed progressive ventricular enlargement (p=0.002). The results were robust to inclusion criteria, and no significant effect of age of onset, duration of illness, or age at baseline scan, was found in the meta-regression analysis. CONCLUSIONS The meta-analysis shows progressive changes in ventricular volume a number of years after illness onset and challenges an exclusively neurodevelopmental model of schizophrenia.

Dehydration affects brain structure and function in healthy adolescents

It was recently observed that dehydration causes shrinkage of brain tissue and an associated increase in ventricular volume. Negative effects of dehydration on cognitive performance have been shown in some but not all studies, and it has also been reported that an increased perceived effort may be required following dehydration. However, the effects of dehydration on brain function are unknown. We investigated this question using functional magnetic resonance imaging (fMRI) in 10 healthy adolescents (mean age = 16.8, five females). Each subject completed a thermal exercise protocol and nonthermal exercise control condition in a cross‐over repeated measures design. Subjects lost more weight via perspiration in the thermal exercise versus the control condition (P < 0.0001), and lateral ventricle enlargement correlated with the reduction in body mass (r = 0.77, P = 0.01). Dehydration following the thermal exercise protocol led to a significantly stronger increase in fronto‐parietal blood‐oxygen‐level‐dependent (BOLD) response during an executive function task (Tower of London) than the control condition, whereas cerebral perfusion during rest was not affected. The increase in BOLD response after dehydration was not paralleled by a change in cognitive performance, suggesting an inefficient use of brain metabolic activity following dehydration. This pattern indicates that participants exerted a higher level of neuronal activity in order to achieve the same performance level. Given the limited availability of brain metabolic resources, these findings suggest that prolonged states of reduced water intake may adversely impact executive functions such as planning and visuo‐spatial processing. Hum Brain Mapp, 2010.

Dissociable Brain Structural Changes Associated with Predisposition, Resilience, and Disease Expression in Bipolar Disorder

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their first-degree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states.

Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly

OBJECTIVE Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. RESEARCH DESIGN AND METHODS Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume). RESULTS The HOMA-IR was negatively correlated with verbal fluency performance, brain size, and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses. CONCLUSIONS These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.