Francesco Barale

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.

GABAergic dysfunction in mood disorders

The authors review the available literature on the preclinical and clinical studies involving GABAergic neurotransmission in mood disorders. γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter present almost exclusively in the central nervous system (CNS), distributed across almost all brain regions, and expressed in interneurons modulating local circuits. The role of GABAergic dysfunction in mood disorders was first proposed 20 years ago. Preclinical studies have suggested that GABA levels may be decreased in animal models of depression, and clinical studies reported low plasma and CSF GABA levels in mood disorder patients. Also, antidepressants, mood stabilizers, electroconvulsive therapy, and GABA agonists have been shown to reverse the depression-like behavior in animal models and to be effective in unipolar and bipolar patients by increasing brain GABAergic activity. The hypothesis of reduced GABAergic activity in mood disorders may complement the monoaminergic and serotonergic theories, proposing that the balance between multiple neurotransmitter systems may be altered in these disorders. However, low GABAergic cortical function may probably be a feature of a subset of mood disorder patients, representing a genetic susceptibility. In this paper, we discuss the status of GABAergic hypothesis of mood disorders and suggest possible directions for future preclinical and clinical research in this area.

Brain anatomy and development in autism: review of structural MRI studies

Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.

Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis.

An understanding of the neurobiological correlates of vulnerability to psychosis is fundamental to research on schizophrenia. We systematically reviewed data from studies published from 1992 to 2006 on the neurocognitive correlates (as measured by fMRI) of increased vulnerability to psychosis. We also conducted a meta-analysis of abnormalities of activation in the prefrontal cortex (PFC) in high-risk and first episode subjects, and reviewed neuroimaging studies of high-risk subjects that used PET, SPECT and MRS. Twenty-four original fMRI papers were identified, most of which involved tasks that engaged the PFC. In fMRI studies, vulnerability to psychosis was associated with medium to large effect sizes when prefrontal activation was contrasted with that in controls. Relatives of patients affected with psychosis, the co-twins of patients and subjects with an At Risk Mental State (ARMS) appear to share similar neurocognitive abnormalities. Furthermore, these are qualitatively similar but less severe than those observed in the first episode of illness. These abnormalities have mainly been described in the prefrontal and anterior cingulated cortex, the basal ganglia, hippocampus and cerebellum.

Laterality effect on emotional faces processing: ALE meta-analysis of evidence

Recognizing emotion from facial expressions draws on diverse psychological processes implemented in a large array of neural structures. Two major theories of cerebral lateralization of emotional perception have been proposed: (i) the Right-Hemisphere Hypothesis (RHH) and (ii) the Valence-Specific Hypothesis (VSH). To test these lateralization models we conducted a large voxel-based meta-analysis of current functional magnetic resonance imaging (fMRI) studies employing emotional faces paradigms in healthy volunteers. Two independent researchers conducted separate comprehensive PUBMED (1990-May 2008) searches to find all functional magnetic resonance imaging studies using a variant of the emotional faces paradigm in healthy subjects. Out of the 551 originally identified studies, 105 studies met inclusion criteria. The overall database consisted of 1785 brain coordinates which yield an overall sample of 1600 healthy subjects. We found no support for the hypothesis of overall right-lateralization of emotional processing. Conversely, across all emotional conditions the parahippocampal gyrus and amygdala, fusiform gyrus, lingual gyrus, precuneus, inferior and middle occipital gyrus, posterior cingulated, middle temporal gyrus, inferior frontal and superior frontal gyri were activated bilaterally (p=0.001). There was a valence-specific lateralization of brain response during negative emotions processing in the left amygdala (p=0.001). Significant interactions between the approach and avoidance dimensions and prefrontal response were observed (p=0.001).

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

BackgroundSeveral antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.MethodWe examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.ResultsMean QTc intervals significantly increased in Group 2 (24 ± 21 ms) however this was not the case in Group 1 (-1 ± 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).ConclusionsNo significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.

Anatomical MRI findings in mood and anxiety disorders

OBJECTIVE In vivo structural magnetic resonance imaging (MRI) studies have evaluated the brain anatomy of various psychiatric disorders, allowing the investigation of putative abnormal brain circuits possibly involved in the patophysiology of psychiatric disorders. Here we reviewed the structural MRI literature in mood and anxiety disorders. METHODS All anatomical MRI studies evaluating mood and anxiety disorder patients were identified through a comprehensive Medline search conducted for the period from 1966 to January 2002, and a manual search of bibliographic cross-referencing complemented the Medline search. RESULTS Differential patterns of anatomical brain abnormalities appear to be involved in subtypes of mood disorders, with hippocampus and basal ganglia being abnormal in unipolar disorder, and amygdala and cerebellum in bipolar disorders, suggesting that these two mood disorders are biologically distinct. As for anxiety disorders, orbital frontal regions and basal ganglia have been reported to be anatomically abnormal in obsessive-compulsive disorder, temporal lobe was found to be abnormally reduced in panic disorder, and abnormal hippocampus shrinkage was shown in posttraumatic stress disorder. CONCLUSIONS The structural MRI findings reviewed here suggest abnormalities in specific brain regions participating in proposed neuroanatomic models possibly involved in the pathophysiology of mood disorders and anxiety disorders. Nonetheless, available MRI studies have suffered from limitations related to relatively small patient samples and involvement of medicated patients, and were largely cross-sectional investigations. Therefore, longitudinal MRI studies involving more sizeable samples of drug-free patients, patients at first episode of illness or at high risk for mood or anxiety disorders, associated to genetic studies, are likely to be extremely valuable to separate state from trait brain abnormalities and to characterize further the pathophysiology of these disorders.

Low-grade endotoxemia in patients with severe autism

The objective of this study was to examine whether levels of endotoxin and other markers of immuno-inflammatory activation are altered in adult patients with severe autism. We determined circulating serum endotoxin levels, its soluble receptor (sCD14), and markers of immuno-inflammatory activation (IL-1beta, IL-6, and IL-10) in 22 adult patients with severe autism and 28 age- and gender-matched healthy controls. Compared with healthy subjects, serum levels of endotoxin were significantly higher in autistic patients and inversely and independently correlated with Socialization scores on the Vineland Adaptive Behavior Scales (VABS) and ADI-R Domain A score (social). Whether increased endotoxin may contribute to the pathophysiology of inflammation and impaired reciprocal social interaction in autism should be further explored in future studies.

Ten years of "extended" life: quality of life among heart transplantation survivors.

Background: Long-term quality of life (QOL) outcome in heart transplant recipients still remains uncertain. This study evaluates the health status and QOL of survivors with associated predictors 10 years after heart transplantation. Patients and Methods: A total of 276 patients who underwent heart transplantation in the Department of Cardiac Surgery, University of Pavia, between 1985 and 1992 were included in a cross-sectional study. Patients still alive 10 years after transplantation (n=122) were asked to complete the SF36 questionnaire and then received a full clinical examination. All QOL instruments that were used had acceptable reliability and validity. Descriptive statistics, Kaplan-Meier estimate, correlation coefficients, and general linear regression were used to analyze the data. Results: Survival rates 1, 5, and 10 years after transplantation were 87%, 77%, and 57%, respectively, and the average life expectancy was 9.16 years. The mental QOL of patients 10 years after heart transplantation was similar to that among the general population. The physical QOL was worse among patients when compared with the QOL of the general population, with predictors including older age, being married, the presence of complications, and impaired renal function. Conclusions: Heart transplantation ensures a relatively high QOL even 10 years after surgery. Predictors of a poor QOL were determined, which may help to identify those patients for whom a poor outcome is likely so treatment can be tailored accordingly.

Dorsolateral prefrontal cortex and hippocampus sustain impulsivity and aggressiveness in borderline personality disorder

BACKGROUND Borderline Personality Disorder (BPD) patients are characterized by increased levels of aggressivity and reduction of impulse control, which are behavioural dimensions mainly sustained by hippocampus and dorsolateral prefrontal cortex (DLPFC). In this study we aimed at investigating whether hippocampus and DLPFC anatomy may sustain impulsive and aggressive behaviours in BPD. METHODS Fifteen DSM-IV BPD patients (11 females, 4 males) and fifteen 1:1 matched healthy controls (11 females, 4 males) were studied with a 1.5T magnetic resonance imaging (MRI) and underwent a psychopathological assessment in order to measure the severity of aggressive and impulsive traits. RESULTS Right hippocampal volumes were significantly reduced in BPD patients compared to healthy subjects (p=0.027), particularly in those with a history of childhood abuse (p=0.01). Moreover, in patients but not in controls, right hippocampal volumes significantly inversely correlated with aggressiveness and DLPFC grey matter volumes significantly inversely associated with impulsiveness (p<0.05). CONCLUSIONS Our results provide evidence that hippocampus and DLPFC play a separate and unique role in sustaining the control of impulse and aggressive behaviours in BPD patients.