Laura Pina-Camacho

Pro-/Anti-inflammatory Dysregulation in Patients With First Episode of Psychosis: Toward an Integrative Inflammatory Hypothesis of Schizophrenia

BACKGROUND Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention. METHODS Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011. RESULTS Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors. DISCUSSION Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.

The Human Cerebral Cortex Flattens during Adolescence

The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11–17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex (“exposed”) part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter.

Autism Spectrum Disorder: Does Neuroimaging Support the DSM-5 Proposal for a Symptom Dyad? A Systematic Review of Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging Studies

A systematic review of 208 studies comprising functional magnetic resonance imaging and diffusion tensor imaging data in patients with ‘autism spectrum disorder’ (ASD) was conducted, in order to determine whether these data support the forthcoming DSM-5 proposal of a social communication and behavioral symptom dyad. Studies consistently reported abnormal function and structure of fronto-temporal and limbic networks with social and pragmatic language deficits, of temporo-parieto-occipital networks with syntactic–semantic language deficits, and of fronto-striato-cerebellar networks with repetitive behaviors and restricted interests in ASD patients. Therefore, this review partially supports the DSM-5 proposal for the ASD dyad.

Predictors of outcome in early-onset psychosis: a systematic review

Given the global burden of psychotic disorders, the identification of patients with early-onset psychosis (EOP; that is, onset before the age of 18) at higher risk of adverse outcome should be a priority. A systematic search of Pubmed, Embase, and PsycInfo (1980 through August 2014) was performed to identify longitudinal observational studies assessing correlates and/or predictors of clinical, functional, cognitive, and biological outcomes in EOP. Seventy-five studies were included in the review. Using multivariate models, the most replicated predictors of worse clinical, functional, cognitive, and biological outcomes in EOP were premorbid difficulties and symptom severity (especially of negative symptoms) at baseline. Longer duration of untreated psychosis (DUP) predicted worse clinical, functional, and cognitive outcomes. Higher risk of attempting suicide was predicted by greater severity of psychotic illness and of depressive symptoms at the first episode of psychosis. Age at onset and sex were not found to be relevant predictors of outcome in most multivariate models, whereas studies using bivariate analyses yielded inconsistent results. Lower intelligence quotient at baseline predicted lower insight at follow-up, worse functional outcomes, and a diagnostic outcome of schizophrenia. Biological predictors of outcome in EOP have been little studied and have not been replicated. Lower levels of antioxidants at baseline predicted greater brain volume changes and worse cognitive functioning at follow-up, whereas neuroimaging markers such as regional cortical thickness and gray matter volume at baseline predicted remission and better insight at follow-up, respectively. EOP patients with poorer premorbid adjustment and prominent negative symptoms at initial presentation are at risk of poor outcome. They should therefore be the target of careful monitoring and more intensive interventions to address whether the disease course can be modified in this especially severely affected group. Early intervention strategies to reduce DUP may also improve outcome in EOP.

Cortical morphology of adolescents with bipolar disorder and with schizophrenia

INTRODUCTION Recent evidence points to overlapping decreases in cortical thickness and gyrification in the frontal lobe of patients with adult-onset schizophrenia and bipolar disorder with psychotic symptoms, but it is not clear if these findings generalize to patients with a disease onset during adolescence and what may be the mechanisms underlying a decrease in gyrification. METHOD This study analyzed cortical morphology using surface-based morphometry in 92 subjects (age range 11-18 years, 52 healthy controls and 40 adolescents with early-onset first-episode psychosis diagnosed with schizophrenia (n=20) or bipolar disorder with psychotic symptoms (n=20) based on a two year clinical follow up). Average lobar cortical thickness, surface area, gyrification index (GI) and sulcal width were compared between groups, and the relationship between the GI and sulcal width was assessed in the patient group. RESULTS Both patients groups showed decreased cortical thickness and increased sulcal width in the frontal cortex when compared to healthy controls. The schizophrenia subgroup also had increased sulcal width in all other lobes. In the frontal cortex of the combined patient group sulcal width was negatively correlated (r=-0.58, p<0.001) with the GI. CONCLUSIONS In adolescents with schizophrenia and bipolar disorder with psychotic symptoms there is cortical thinning, decreased GI and increased sulcal width of the frontal cortex present at the time of the first psychotic episode. Decreased frontal GI is associated with the widening of the frontal sulci which may reduce sulcal surface area. These results suggest that abnormal growth (or more pronounced shrinkage during adolescence) of the frontal cortex represents a shared endophenotype for psychosis.

A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis

BACKGROUND The relationship between duration of untreated psychosis (DUP) and executive function (EF) in patients with first-episode psychosis (FEP) is controversial. We aim to assess the influence of DUP on changes in EF over a 2-year period in subjects with early-onset FEP (first psychotic symptom before age 18) and less than 6 months of positive symptoms. METHODS A total of 66 subjects were included in the study (19 females [28.8%], mean age 16.2 ± 1.6 years). The influence of DUP on changes in EF over the 2-year follow-up (expressed as a composite score of 5 cognitive abilities: attention, working memory, cognitive flexibility, response inhibition, and problem solving) was estimated using a multivariate linear regression model after removing the effect of intelligence quotient and controlling for age, gender, diagnosis, premorbid adjustment, severity of positive and negative symptoms at baseline, global functioning at baseline, and mean daily antipsychotic dosage during follow-up. RESULTS Mean DUP was 65.0 ± 6.9 days (95% confidence interval [CI], 51.2, 78.8). Median DUP was 47.5 days (range 2-180 days). Negative symptoms at baseline was the only variable significantly associated with EF at baseline (10.9% of explained variance [e.v. 10.9%], p=0.007). Only shorter DUP (e.v. 8.7%, p=0.013) and greater severity of baseline negative symptoms (e.v. 10.0%, p=0.008) were significantly associated with greater improvement in EF. CONCLUSIONS In early-onset FEP, shorter DUP was associated with greater improvement in EF over a 2-year follow-up period.

Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12-35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15-20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18-20 y). The AFP group also had age-constant (12-35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis.

Reduced Gyrification Is Related to Reduced Interhemispheric Connectivity in Autism Spectrum Disorders.

OBJECTIVE Autism spectrum disorders (ASD) have been associated with atypical cortical gray and subcortical white matter development. Neurodevelopmental theories postulate that a relation between cortical maturation and structural brain connectivity may exist. We therefore investigated the development of gyrification and white matter connectivity and their relationship in individuals with ASD and their typically developing peers. METHOD T1- and diffusion-weighted images were acquired from a representative sample of 30 children and adolescents with ASD (aged 8-18 years), and 29 typically developing children matched for age, sex, hand preference, and socioeconomic status. The FreeSurfer suite was used to calculate cortical volume, surface area, and gyrification index. Measures of structural connectivity were estimated using probabilistic tractography and tract-based spatial statistics (TBSS). RESULTS Left prefrontal and parietal cortex showed a relative, age-dependent decrease in gyrification index in children and adolescents with ASD compared to typically developing controls. This result was replicated in an age-and IQ-matched sample provided by the Autism Brain Imaging Data Exchange (ABIDE) initiative. Furthermore, tractography and TBSS showed a complementary pattern in which left prefrontal gyrification was negatively related to radial diffusivity in the forceps minor in participants with ASD. CONCLUSION The present study builds on earlier findings of abnormal gyrification and structural connectivity in the prefrontal cortex in ASD. It provides a more comprehensive neurodevelopmental characterization of ASD, involving interdependent changes in microstructural white and cortical gray matter. The findings of related abnormal patterns of gyrification and white matter connectivity support the notion of the intertwined development of 2 major morphometric domains in ASD.

Predictors of Functional and Clinical Outcome in Early-Onset First-Episode Psychosis: The Child and Adolescent First Episode of Psychosis (CAFEPS) Study

OBJECTIVE The objective of this study was to study baseline clinical and biological predictors of 2-year outcome in a cohort of children and adolescents with a first episode of psychosis. METHOD Standard instruments were used to evaluate symptoms and functioning in 110 children and adolescents (mean age = 15.47 years) with first episode of psychosis at admission (between 2003 and 2005) and after 2-year follow-up. Clinical assessments included diagnostic assessment to yield DSM-IV diagnosis, developmental, premorbid, and past-year data, together with structural neuroimaging and other biological parameters (genetics and oxidative stress). Eighty-three subjects had assessments at baseline (including the Strauss-Carpenter Outcome Scale [SCOS]) and at 2-year follow-up. Association and multistep regression analyses were conducted to show correlates and predictors of primary outcome measures: functional outcome (Childrens Global Assessment Scale [CGAS]), improvement (CGAS change), and primary negative symptoms (Proxy for the Deficit Syndrome Scale). RESULTS The SCOS predicted 27.46% (P < .001) of the variance in CGAS score at 2 years. Baseline severity (measured by CGAS) predicted 30.9% (P < .001) of CGAS improvement after 2 years, and SCOS total score predicted an added 24.1% (P < .001). A diagnosis of nonaffective psychosis, primary negative symptoms, and less white matter at baseline predicted more primary negative symptoms at follow-up. The prediction of functional outcome was not increased by genetic, oxidative stress, or neurostructural markers. CONCLUSIONS Baseline clinical assessments have a better predictive value than biological assessments for 2-year follow-up functioning of children and adolescents with a first episode of psychosis. Patients with primary negative symptoms at baseline continue to have negative symptoms 2 years later, and neurostructural markers predict these. Clinicians must still rely on clinical variables to judge the functional prognosis of early-onset first psychotic episodes.

Estudio farmacogenético del tratamiento a largo plazo con antipsicóticos de segunda generación y sus efectos adversos metabólicos (Estudio SLiM): justificación, objetivos, diseño y descripción de la muestra

AIM Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs. MATERIALS AND METHODS The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited. RESULTS This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline. CONCLUSIONS Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment.