Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.

BACKGROUND: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown. PATIENTS AND METHODS: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes . RESULTS: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002]. CONCLUSION: Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.

Study of the inferior colliculus in patients with schizophrenia by magnetic resonance spectroscopy.

INTRODUCTION. Previous studies have suggested morphometric and functional abnormalities in the inferior colliculus in patients with schizophrenia. Auditory hallucinations are one of the central symptoms in schizophrenia. In this complex and multidimensional event both attention and emotion are thought to play a key role. AIM. To study metabolic changes in the inferior colliculus, a nucleus integrated in the auditory pathway, in patients with schizophrenia and the possible relationship with auditory hallucinations. SUBJECTS AND METHODS. Magnetic resonance spectroscopic imaging studies were performed in 30 right-handed patients with chronic schizophrenia (19 of them with auditory hallucinations) and 28 controls. A magnetic resonance spectroscopic imaging 2D slice was acquired and the voxels representative of both inferior colliculi were selected. N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) peak areas were measured. RESULTS. The patients with schizophrenia showed a NAA/Cr significant reduction in the right inferior colliculus compared to the control subjects. The metabolic data in the right inferior colliculus were correlated with emotional auditory hallucinations items. CONCLUSIONS. The contribution of the inferior colliculus on neural underpinnings of auditory hallucinations is particularly relevant for the right inferior colliculus and is centered on attention-emotional component of this symptom.

TITLE: Estudio del coliculo inferior de pacientes con esquizofrenia mediante espectroscopia de resonancia magnetica.Introduccion. Algunos estudios anteriores en pacientes con esquizofrenia han sugerido alteraciones morfometricas y funcionales en el coliculo inferior. Las alucinaciones auditivas son uno de los sintomas centrales en la esquizofrenia. Se piensa que en este evento complejo y multidisciplinar, tanto la atencion como la emocion desempeñan un papel clave. Objetivo. Estudiar los cambios metabolicos en el coliculo inferior, un nucleo integrado en la via auditiva, en pacientes con esquizofrenia y su posible relacion con las alucinaciones auditivas. Sujetos y metodos. Se llevaron a cabo estudios de espectroscopia de resonancia magnetica en 30 pacientes diestros con esquizofrenia cronica (19 de ellos con alucinaciones auditivas) y 28 controles. Se adquirio una secuencia 2D de espectroscopia de resonancia magnetica y se seleccionaron los voxeles representativos de ambos coliculos inferiores. Se calculo el area de los picos de N-acetilaspartato (NAA), creatina (Cr) y colina (Co). Resultados. Los pacientes con esquizofrenia mostraron una reduccion significativa de NAA/Cr en el coliculo inferior derecho comparados con los sujetos control. Los datos metabolicos en el coliculo inferior derecho se correlacionaron con los items emocionales de las alucinaciones auditivas. Conclusiones. La contribucion del coliculo inferior a las bases neuronales de las alucinaciones auditivas es particularmente relevante para el coliculo inferior derecho y se centra en el componente atencional-emocional de este sintoma.

[Magnetic resonance imaging postprocessing techniques in the study of brain connectivity]. / Técnicas de análisis de posproceso en resonancia magnetica para el estudio de la conectividad cerebral.

Brain connectivity is a key concept for understanding brain function. Current methods to detect and quantify different types of connectivity with neuroimaging techniques are fundamental for understanding the pathophysiology of many neurologic and psychiatric disorders. This article aims to present a critical review of the magnetic resonance imaging techniques used to measure brain connectivity within the context of the Human Connectome Project. We review techniques used to measure: a) structural connectivity b) functional connectivity (main component analysis, independent component analysis, seed voxel, meta-analysis), and c) effective connectivity (psychophysiological interactions, causal dynamic models, multivariate autoregressive models, and structural equation models). These three approaches make it possible to combine and use different statistical techniques to elaborate mathematical models in the attempt to understand the functioning of the brain. The findings obtained with these techniques must be validated by other techniques for analyzing structural and functional connectivity. This information is integrated in the Human Connectome Project where all these approaches converge to provide a representation of all the different models of connectivity.

Spectroscopic metabolomic abnormalities in the thalamus related to auditory hallucinations in patients with schizophrenia.

OBJECTIVE: Previous studies have found neurochemical abnormalities in thalamic nuclei in patients with schizophrenia. These abnormalities have been associated with information processing deficiencies and symptom formation. There are no metabolic spectroscopy studies in patients with schizophrenia attending to auditory hallucinations. The aim of the present study is to explore metabolic Magnetic Resonance Spectroscopy (MRS) ratio differences in the thalamus between schizophrenic patients with and without auditory hallucinations and control subjects. METHODS: MRS studies (MRI 1.5 T unit) were performed in 49 patients with schizophrenia (30 with auditory hallucinations and 19 without auditory hallucinations) and 37 controls. (1)H MRS imaging was used to acquire 2 transverse slices (TR/TE 2700/272 ms, region of interest 110 x 100 x 23 mm). In the quantitative analysis four elements of volume (9.2 x 9.2 x 23 x 4 mm), added into one spectrum representative of each thalamus, were chosen in the slice passing through the main body of the thalamus. The areas of metabolites were integrated with the jMRUI program. RESULTS: The patients with schizophrenia had significantly lower bilateral NAA/Cho ratios when compared with healthy subjects. There was also a lower NAA/Cho ratio in the right thalamus in patients with auditory hallucinations compared to patients without auditory hallucinations and control subjects. Significant correlations were found between metabolic ratios and BPRS, PANSS and PSYRATS scores, age of onset of auditory hallucinations, and age of subjects. CONCLUSIONS: Choline and NAA ratio abnormalities determined by thalamic spectroscopy may be related to the pathogenesis of auditory hallucinations in patients with schizophrenia.

Left orbitofrontal and superior temporal gyrus structural changes associated to suicidal behavior in patients with schizophrenia.

Suicidal attempts are relatively frequent and clinically relevant in patients with schizophrenia. Recent studies have found gray matter differences in suicidal and non-suicidal depressive patients. However, no previous neuroimaging study has investigated possible structural abnormalities associated to suicidal behaviors in patients with schizophrenia. A whole-brain magnetic resonance voxel-based morphometric examination was performed on 37 male patients meeting the DSM-IV criteria for schizophrenia. Thirteen (35.14%) patients had attempted suicide. A non-parametric permutation test was computed to perform the comparability between groups. An analysis of covariance (AnCova) model was constructed with a statistical threshold of p<0.05 corrected for multiple comparisons. After controlling for age and severity of illness, results showed significant gray matter density reduction in left superior temporal lobe (p=0.03) and left orbitofrontal cortex (p=0.04) in patients who had attempted suicide when comparing with non-suicidal patients. Although sample size limitations and potential clinical heterogeneity preclude definitive conclusions, these data point to structural differences in key cerebral areas. Neuroimaging studies are necessary to expand our knowledge of biological mechanisms underlying suicide in schizophrenia.

Persistent auditory hallucinations.

BACKGROUND: There is still a significant proportion of psychotic patients who suffer from persistent auditory hallucinations (PAH) in spite of treatment. The objective of our study was to analyze those clinical dimensions that characterize persistent hallucinators in comparison with episodic hallucinators. SAMPLING AND METHODS: Ninety-one outpatients with AH were assessed through semistructured interviews. The interviews included the Psychotic Symptom Rating Scales for AH and the Krawiecka scale. They elicited descriptions about the persistence of AH, existence of pleasurable hallucinations and other types of hallucinations. RESULTS: Forty-five patients fulfilled criteria for reported PAH. Persistent hallucinators showed greater scores in frequency and duration of hallucinations, Krawiecka total score and incoherence of speech. Moreover, pleasurable experiences were more frequent in this group of patients. Logistic regression analysis rendered a model with the following variables: duration of voices, degree of control and pleasurable hallucinations. CONCLUSION: Specific dimensions of AH can predict the possibility of treatment resistance.

Emotional auditory paradigm in neuroimaging: a base for the study of psychosis.

INTRODUCTION: Since the arrival of neuroimaging numerous studies have tried to analyze the differences between emotional and non-emotional response. The majority of these studies use visual approach (faces) and begin with data in normal subjects. The present study introduces a new paradigm for the study of emotional response based on auditory approach and designed specifically for the study of psychoses. METHOD: The most frequent words heard by psychotic patients with auditory hallucinations were analyzed. They were classified according to five categories which were compared with 13 other words with the same structure but with a neutral emotional valency. This paradigm was applied to see the cerebral activation with functional magnetic resonance imaging (fMRI) in 10 right handed healthy males. RESULTS: In the preliminary analysis a clear differentiation is observed depending on the type of stimulus applied (emotional or non-emotional), both in the intensity of activation (right and left temporal cortex) as in the activation of specific areas (right precentral and supramarginal gyrus) only with the emotional stimulus. CONCLUSIONS: The present paradigm allows the observation of a differentiation in the cerebral activation to emotional auditory stimulus and could be of utility in the study of psychotic patients.

Pleasurable auditory hallucinations.

OBJECTIVE: The focus in auditory hallucination (AH) research is usually on the negative impact of the experience itself. There are practically no studies on whether voices can be perceived as pleasurable. The aim of the present study was to assess the frequency of voices as a pleasurable experience in a psychotic patient population. METHOD: A total of 160 patients with AHs (89 schizophrenia and 17 other psychoses) were assessed with the psychotic symptom rating scale (PSYRATS) for AHs, including an added item on whether the experience was pleasurable. RESULTS: Twenty-eight patients (26%) reported the voices as a pleasurable experience and 10 of them did so frequently. Pleasurable hallucinations showed negative associations with amount and intensity of distress, degree of negative content and loudness. Positive associations were apparent with chronicity and perceived control over the voices. CONCLUSION: Pleasurable hallucinations can be detected in a substantial proportion of patients, and cross validated with existing instruments.

A psychopathological study of a group of schizophrenic patients after attempting suicide. Are there two different clinical subtypes?

Fifty-six schizophrenic patients at the moment of their suicidal attempt were compared to a control group of 60 patients. Schizophrenic suicidal attempters showed an identifiable clinical profile at the acute phase. Two main groups could be differentiated in regard to their reasons (depressive or psychotic) for attempting suicide.

Hopelessness and first-episode psychosis: a longitudinal study.

Hopelessness has not been adequately studied in first-episode psychotic patients, although it is already present at the early stages, especially in schizophrenic patients. We have studied 96 neuroleptic-naive psychotic patients (49 schizophrenic patients and 47 other non-affective psychotic patients) over a period of 12 months after their first admission. The total score on the Hopelessness Scale (HS) at first admission was higher in the schizophrenic patients, and correlated with younger age and with negative symptoms. High HS scores at baseline predicted poor short-term outcome in schizophrenic patients, as evidenced by worse global functioning at the 12-month follow-up. These correlations were not observed in the other psychoses group. Our results suggest that young, severely affected schizophrenic patients who experience hopelessness might be at higher risk of poor outcome.

Predictors of acute dystonia in first-episode psychotic patients.

Sixty-two first-episode psychotic patients who were neuroleptic-naive were studied to examine predictors of acute dystonia after treatment with haloperidol. Twenty-three patients developed dystonia, two of them despite being treated with biperiden. Biperiden significantly prevented dystonic reactions. Dystonia development was significantly related to younger age, severity of illness, and negative symptoms at baseline and showed a trend to be related to positive symptoms as well. No significant effect of gender or diagnosis was found. The authors suggest that young, severely ill patients in their first psychotic episode who have never been treated with neuroleptics might be at higher risk to develop dystonia.

[Bullous eruption in systemic lupus erythematosus]. / Erupcão bolhosa em lupus eritematoso sistêmico.

A 39 years old black woman with systemic lupus erythematosus developed tense bullae on erythematous bases on the flexor surfaces of the forearms and oral cavity. Some blisters healed with atrophy and pruritus was a striking feature. The diagnosis of systemic lupus erythematosus was based upon the following criteria: the typical blush in the butterfly area, alopecia, a painful macular papular eruption on the palms and fingers, fever, arthralgia, anemia, leukopenia, elevation of erythrocyte sedimentation rate and positive ANA. Histologic examination showed a subepidermal bulla formation and perivascular inflammatory infiltrate containing lymphocytes and eosinophils. By indirect immunofluorescence no autoantibodies were detected. Direct immunofluorescence showed deposition of linear IgG. High doses of prednisone brought about clinical remission but there was no response to sulfone. The patient is on maintenance dose. The authors discuss the differences between the three diseases and conclude that the bullous eruption cannot be classified.