Mononitrate Isosorbide as an Adjunctive Therapy in Schizophrenia: A Randomized Controlled Crossover Trial.

BACKGROUND: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia. METHODS: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns. RESULTS: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology. CONCLUSIONS: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning.

Clinical validity and intrarater and test-retest reliability of the Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV).

AIM: The Structured Clinical Interview for the DSM is one of the most used diagnostic instruments in clinical research worldwide. The current Clinician Version of the instrument (SCID-5-CV) has not yet been assessed in respect to its psychometric qualities. We aimed to assess the clinical validity and different reliability indicators (interrater test-retest, joint interview, face-to-face vs telephone application) of the SCID-5-CV in a large sample of 180 non-prototypical and psychiatric patients based on interviews conducted by raters with different levels of clinical experience. METHODS: The SCID-5-CV was administered face-to-face and by telephone by 12 psychiatrists/psychologists who took turns as raters and observers. Clinical diagnoses were established according to DSM-5 criteria and the longitudinal, expert, all data (LEAD) procedure. We calculated the percentage of agreement, diagnostic sensitivity and specificity, and the level of agreement (kappa) for diagnostic categories and specific diagnoses. RESULTS: The percentage of positive agreement between the interview and clinical diagnoses ranged between 73% and 97% and the diagnostic sensitivity/specificity were >0.70. In the joint interview, the levels of positive agreement were high (>75%) and kappa levels were >0.70 for most diagnoses. The values were less expressive, but still adequate, for interrater test-retest interviews. CONCLUSION: The SCID-5-CV presented excellent reliability and high specificity as assessed with different methods. The clinical validity of the instrument was also confirmed, which supports its use in daily clinical practice. We highlight the adequacy of the instrument to be used via telephone and the need for careful use by professionals with little experience in psychiatric clinical practice.

Paliperidone palmitate for refractory and clozapine-resistant schizophrenia.

This is a report on two cases of refractory schizophrenia and two cases of clozapine-resistant schizophrenia successful treated with paliperidone palmitate. To the authors' knowledge, this is the first report of the successful use of paliperidone palmitate in such patients.

Validation and internal consistency of Patient Health Questionnaire-9 for major depression in Parkinson's disease.

BACKGROUND: depression is common in Parkinson's disease (PD), although frequently under-recognised. Among the scales used to investigate depressive features in PD, the Patient Health Questionnaire-9 (PHQ-9) has been largely used, but no specific cut-off scores for depression have been established thus far, which hinders the use of the PHQ-9 in clinical and research settings. OBJECTIVE: we assessed the discriminant validity of the PHQ-9 in order to establish the best cut-off score for the diagnosis of major depression in PD patients. METHOD: one hundred and ten patients with a diagnosis of PD without dementia were evaluated with the Structured Clinical Interview for DSM-IV (SCID), considered as the gold standard for the diagnosis of major depression. Eighty-four PD patients completed the PHQ-9, the 15-item Geriatric Depression Scale (GDS-15) and the Zung Self-rating Depression Scale (SDS). RESULTS: the prevalence of current depression in the sample of PD patients was 25.5%. Maximal discrimination between depressed and non-depressed patients was reached with a cut-off score of 9 in the PHQ-9 (sensitivity of 100% and specificity of 83.1%). The internal consistency of the scale was 0.83 and, when used as a diagnostic instrument, the PHQ-9 had a sensitivity of 52.6% and specificity of 95.4%. The correlation coefficient between the PHQ-9 and the other two scales was 0.63. CONCLUSIONS: the PHQ-9 is an adequate instrument for the screening-but not diagnosis-of depression in PD patients, with optimal sensitivity and specificity attained with a cut-off score of 9.

Sodium nitroprusside as an adjunctive treatment for schizophrenia reduces the Ndel1 oligopeptidase activity.

OBJECTIVE: Schizophrenia (SCZ) is a disabling disorder that continues to defy clinicians and researchers. We investigated the effects of sodium nitroprusside (sNP) in an animal model of SCZ and as an add-on therapy in patients and the relationship between treatment with sNP and activity of the nDel1 enzyme, whose involvement in the pathophysiology of the disorder has been suggested earlier. METHODS: Ndel1 activity was measured following sNP infusions in spontaneously hypertensive rats (SHR; 2.5 or 5.0 mg/kg) and in a double-blind trial with SCZ patients (0.5 µg/kg/min). RESULTS: Ndel1 activity was significantly reduced after sNP infusion in blood of SHR compared to controls, and in patients receiving sNP (t = 7.756, df = 97, p < 0.0001, dcohen = 1.44) compared to placebo. Reduced Ndel1 activity between baseline and the end of the infusion was only seen in patients after treatment with sNP. CONCLUSION: Our findings suggest that SCZ patients may benefit from adjunctive therapy with sNP and that the Ndel1 enzyme is a candidate biomarker of psychopathology in the disorder. Future research should look into the role of Ndel1 in SCZ and the potential effects of sNP and drugs with similar profiles of action in both animals and patients.

Late-onset social anxiety disorder following traumatic brain injury.

BACKGROUND: Neuropsychiatric sequelae are the predominant long-term disability after traumatic brain injury (TBI). This study reports a case of late-onset social anxiety disorder (SAD) following TBI. CASE REPORT: A patient that was spontaneous and extroverted up to 18-years-old started to exhibit significant social anxiety symptoms. These symptoms became progressively worse and he sought treatment at age 21. He had a previous history of traumatic brain injury (TBI) at age 17. Neuroimaging investigations (CT, SPECT and MRI) showed a bony protuberance on the left frontal bone, with mass effect on the left frontal lobe. He had no neurological signs or symptoms. The patient underwent neurosurgery with gross total resection of the lesion and the pathological examination was compatible with intradiploic haematoma. CONCLUSIONS: Psychiatric symptoms may be the only findings in the initial manifestation of slowly growing extra-axial space-occupying lesions that compress the frontal lobe from the outside. Focal neurological symptoms may occur only when the lesion becomes large. This case report underscores the need for careful exclusion of general medical conditions and TBI history in cases of late-onset SAD and may also contribute to the elucidation of the neurobiology of this disorder.

The fast alcohol screening test (FAST) is as good as the AUDIT to screen alcohol use disorders.

This study was aimed at assessing the psychometric qualities of the fast alcohol screening test (FAST), and at comparing these qualities to those of the alcohol use disorders identification test (AUDIT) in three samples of Brazilian adults: (i) subjects attended at an emergency department (530); (ii) patients from a psychosocial care center (40); and (iii) university students (429). The structured clinical interview for diagnosis (SCID)-IV was used as gold standard. The FAST demonstrated high test-retest and interrater reliability coefficients, as well as high predictive and concurrent validity values. The results attest the validity and reliability of the Brazilian version of the FAST for the screening of indicators of alcohol abuse and dependence.

Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD).

OBJECTIVE: The last decade has seen increasing evidence of dysfunctions in the endogenous cannabinoid system in schizophrenia and of its relationship with the typical cognitive impairment of the disorder. Studies in animal models, healthy volunteers, and psychotic patients clearly suggest an antipsychotic-like effect of cannabidiol. This study investigated the effects of cannabidiol on selective attention in 28 schizophrenic patients using the Stroop Color Word Test and on these patients' electrodermal responsiveness to auditive stimuli. METHOD: The subjects attended two experimental sessions, the first one without the administration of drugs. In the second session the subjects were divided into three groups that received either a single dose of cannabidiol 300 mg or cannabidiol 600 mg or placebo. RESULTS: The three groups did not differ significantly with respect to electrodermal measures in the two experimental sessions. When the first and second sessions were compared improved performance was found in all three groups, with patients who received placebo and cannabidiol 300 mg performing better than those who received cannabidiol 600 mg. CONCLUSION: The single, acute administration of cannabidiol seems to have no beneficial effects on the performance of schizophrenic patients in the Stroop Color Word Test, although the hypothesis that chronic administration may lead to improvement cannot be disregarded.

Proneness, urbanicity, trauma, and cannabis triggering psychotic states in large urban centers.

PURPOSE OF REVIEW: The two past decades have seen the production of a vast amount of evidence about the genetic and nongenetic factors that contribute to the onset of psychosis from various fields of research. The present article reviews recent evidence from four of these fields that were shown to be strongly associated with psychosis: proneness, urbanicity, trauma, and cannabis use. RECENT FINDINGS: The evidence reviewed shows that all four sets of factors investigated here are implicated in the occurrence of psychosis. The specificity and complexity of these associations, however, are not yet clear and recent findings show that the directions of the associations described may be different than we first thought. SUMMARY: It is clear that psychosis is strongly affected by a number of environmental determinants that act in concert with genetic determinants to cause psychotic disorders; however, these influences are complex and their actual impact may be difficult to establish because of poor definitions and specificity. Urbanicity in special is a poorly defined concept that seems to encompass different sets of factors in each study, which hinders discussions and conclusions regarding its impact.

Cross-cultural adaptation of the Internet Gaming Disorder Scale - Short Form (IGDS9-SF) to the Brazilian context.

INTRODUCTION: The Internet Gaming Disorder Scale - Short Form (IGDS9-SF) assesses the severity, harmful effects and/or consequences of excessive online and offline gaming. Its conciseness and theoretical foundations on current diagnostic criteria of gaming disorders make it a useful resource for clinical and screening settings. OBJECTIVE: To describe the process of cross-cultural adaptation of the IGDS9-SF to the Brazilian context. METHODS: The cross-cultural adaptation involved the steps of independent translation of the instrument, synthesis version, back-translation, pre-test and elaboration of the final version. Content validity assessment was conducted by a multidisciplinary committee of experts and consisted of both a quantitative analysis (calculation of content validity coefficients - CVC) and a qualitative analysis (assessment of the experts' comments and suggestions). The pre-test sample consisted of 30 gamers with variable sociodemographic characteristics. RESULTS: The cross-cultural adaptation of the scale followed the proposed protocol, and the CVC was satisfactory (≥ 0.83) for all the structures and equivalences assessed. Most of the suggestions made by the experts were accepted (mainly adjustments and language standardization). The gamers who participated in the pre-test judged the scale easy to understand and did not suggest changes. DISCUSSION: The Brazilian version of the IGDS9-SF showed adequate content validity and is available for researchers and clinicians, as well as for the investigation of additional psychometric characteristics.

Adverse childhood experiences and chronic lung diseases in adulthood: a systematic review and meta-analysis.

Background: Adverse childhood experiences (ACE) affect physical and mental health and may appear as risk factors for the development of different conditions in adult life. Objective: To perform a literature review and meta-analysis on risk indicators for the development of chronic lung diseases in adulthood associated with ACE. Method: We conducted a systematic literature review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the online databases PubMed, PsycINFO, and Web of Science. Quantitative studies involving male and female adults were included. Fixed- and random-effect models were used in the estimation of meta-analytical measures. The heterogeneity between studies was assessed using I2 statistics and Cochran's Q test. Results: A total of 19 studies were selected for the meta-analysis. The analyses showed statistically significant associations between ACE and lung diseases in general (OR = 1.41; CI 95%: 1.28-1.54), besides specific associations with asthma (OR = 1.32; CI 95%: 1.13-1.50) and COPD (OR = 1.44; CI 95%: 1.13-1.76). When the mediating effect of smoking was assessed separately we found a significant - although not quite expressive - association (OR = 1.06; CI 95%: 1.02 to 1.10), which weakens the hypothesis that a direct relationship exists between childhood trauma and the occurrence of lung diseases. Conclusions: ACE are an important risk factor for the development of lung diseases in adulthood, whether through direct or indirect contribution to this outcome, which highlights the relevance of increasing the awareness of health staff for the early detection and intervention in situations of vulnerability or risk in childhood as an important preventative measure.

Antecedentes: Experiencias infantiles adversas (ACE) afectan la salud física y mental y pueden aparecer como factores de riesgo para el desarrollo de diferentes afecciones en la vida adulta.Objetivo: realizar una revisión de la literatura y un metanálisis sobre indicadores de riesgo para el desarrollo de enfermedades pulmonares crónicas en la edad adulta asociadas con ACE.Método: Realizamos una revisión sistemática de la literatura de acuerdo con las pautas PRISMA (Elementos de Referencia para Revisiones Sistemáticas y Metaanálisis) utilizando las bases de datos en línea PubMed, PsycINFO y Web of Science. Se incluyeron estudios cuantitativos con hombres y mujeres adultos. Se utilizaron modelos de efectos fijos y aleatorios en la estimación de medidas meta-analíticas. La heterogeneidad entre los estudios se evaluó mediante estadísticas I 2 y la prueba Q de Cochran.Resultados: Se seleccionaron un total de 19 estudios para el metanálisis. Los análisis mostraron asociaciones estadísticamente significativas entre el ACE y las enfermedades pulmonares en general (OR = 1.41; IC 95%: 1.28­1.54), además de asociaciones específicas con el asma (OR = 1.32; IC 95%: 1.13 ­ 1.50) y EPOC (OR = 1,44; IC 95%: 1,13­1,76). Cuando el efecto mediador del tabaquismo se evaluó por separado, encontramos una asociación significativa (aunque no del todo clara) (OR = 1.06; IC 95%: 1.02 a 1.10), lo que debilita la hipótesis de que existe una relación directa entre el trauma infantil y la ocurrencia de enfermedades pulmonares.Conclusiónes: las experiencias ACE son un factor de riesgo importante para el desarrollo de enfermedades pulmonares en la edad adulta, ya sea a través de una contribución directa o indirecta, lo que resalta la relevancia de aumentar la conciencia del personal de salud para la detección temprana y la intervención en situaciones de vulnerabilidad o riesgo en la infancia como una medida preventiva importante.

Brain functional and perfusional alterations in schizophrenia: an arterial spin labeling study.

Schizophrenia is a severe mental disorder that affects the anatomy and function of the brain, with an impact on one's thoughts, feelings, and behavior. The purpose of the study was to investigate cerebral blood flow (CBF) and brain connectivity in a group of patients with schizophrenia. Pseudo-continuous arterial spin labeling (pCASL) images were acquired from 28 patients in treatment and 28 age-matched healthy controls. Mean CBF and connectivity patterns were assessed. Schizophrenia patients had decreased CBF in the bilateral frontal pole and superior frontal gyrus, right medial frontal gyrus, triangular and opercular parts of the inferior frontal gyrus, posterior division of the left supramarginal gyrus, superior and inferior divisions of the left lateral occipital cortex, and bilateral occipital pole. Moreover, through different methods to assess connectivity, our results showed abnormal connectivity patterns in regions involved in motor, sensorial, and cognitive functions. Using pCASL, a non-invasive technique, we found CBF deficits and altered functional organization of the brain in schizophrenia patients that are associated with the symptoms and characteristics of the disorder.

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia.

The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.

Neuroimaging of major depression in Parkinson's disease: Cortical thickness, cortical and subcortical volume, and spectroscopy findings.

Depression is the most common psychiatric disorder in Parkinson's disease (PD). The aim of this study was to compare PD patients with current Major Depressive Disorder (MDD), lifetime MDD, and no MDD using three neuroimaging techniques. A total of 43 PD patients were selected and divided into three groups: (i) current MDD (n = 15), (ii) previous MDD without current MDD (n = 10); and (iii) control group (no current or lifetime MDD; n = 18). All participants underwent magnetic resonance imaging to evaluate cortical thickness, cortical and subcortical volume, and spectroscopy in the bilateral putamen and cingulate cortex. Volumetric analysis showed volume decreases in frontal and temporal areas, bilateral amygdala, and left cerebellar white matter in the lifetime MDD group compared to the control group. Furthermore, the volumes of the anterior cingulate cortex, right amygdala, and left cerebellar white matter were smaller in the group with current MDD compared to the control group. Regarding cortical thickness, the left rostral anterior cingulate gyrus of the group with previous MDD was thinner compared to the control group. There was a weak negative correlation between the NAA/Cre ratio in the right putamen and depressive symptoms. The results suggested current and lifetime MDD have a negative impact on the neurodegenerative process of PD, with decreased volume and/or reduction of cortical thickness in temporal and frontal areas, anterior cingulate cortex, amygdala, and cerebellar white matter.

Nitric Oxide's Involvement in the Spectrum of Psychotic Disorders.

BACKGROUND: Recent findings suggest that dopaminergic abnormalities found in psychotic disorders may be secondary to nitric oxide dysfunctions. Nitric oxide seems to influence glutamatergic and dopaminergic neurotransmission, both of which have been associated with psychosis. OBJECTIVE: To search and review published works which examined the influence of nitric oxide in psychotic disorders subjects. METHODS: The research was executed in the on-line collections of Pubmed and ISI Web of Science. The key aspects utilized were "Psychotic Disorders AND Nitric Oxide", "Psychosis AND Nitric Oxide","Schizotypal Personality Disorder AND Nitric Oxide", "Delusional Disorder AND Nitric Oxide", "Brief Psychotic Disorder AND Nitric Oxide", "Schizophreniform Disorder AND Nitric Oxide", "Schizoaffective Disorder AND Nitric Oxide", and "Schizophrenia AND Nitric Oxide". Empirical works utilizing human subjects, published in the last 10 years, in English language were included. RESULTS: Initially, the search yielded a total of 95 studies. Then, 39 were elected according to the inclusion requirements. The selected articles were divided into five groups: biochemical studies (n=15; 38.5%), genetic studies (n=11; 28.2%), postmortem studies (n=6; 15.4%), clinical trials (n=6; 15.4%), and case reports (n=1; 2.5%). The studies evaluated only schizophrenic or schizoaffective disorder subjects. The great majority of them found evidence of nitric oxide dysfunctions in psychosis. CONCLUSIONS: The results of the review strengthen the idea that nitric oxide has a key participation in psychotic disorders and deserves deeper investigation as a target for future pharmacological intervention.

An Overview on the Search for Schizophrenia Biomarkers.

UNLABELLED: Schizophrenia is a severe psychiatric disorder with a complex presentation comprising positive symptoms (e.g.: hallucinations and delusions), negative symptoms (e.g.: social withdrawal, blunted affect) and pervasive cognitive deficits that have been associated with functional decline. The pathophysiology of the disorder is equally complex, with abnormalities known to occur in the molecular, cellular, neurophysiological, and neuroanatomical domains. Despite significant progress in the comprehension of the various manifestations of schizophrenia, the full picture of its etiology remains unknown. As a result, currently available pharmacological treatments have limited efficacy and little has improved since the discovery of the first antipsychotics back in the 1950s. In addition, these medications have significant adverse effects. Differently from other medical areas, the diagnosis of schizophrenia is essentially clinical and dependent on subjective elements. In an attempt to change this, efforts have been directed to find biomarkers of the disorder that could improve diagnostic accuracy and validity, predict treatment response, enable the early identification of individuals at risk of developing schizophrenia and indicate new targets for the development of drugs with better selective, safety, and efficacy profiles. In this article we describe the main potential schizophrenia markers currently under study and suggest avenues for future research in the field. KEY POINTS: - No reliable markers exist for schizophrenia to date. - The identification of schizophrenia markers could increase diagnostic accuracy and treatment efficacy. - The main research lines in the current search for biomarkers are described.

Cognition in at-risk mental states for psychosis.

RATIONALE: The devastating nature of schizophrenia and treatment limitations have triggered a search for early detection methods to enable interventions to be implemented as soon as the first signs and symptoms appear. In this effort, several studies have investigated the cognitive functions in individuals regarded as being in at-risk mental states (ARMS) for psychosis. OBJECTIVE: Our aim was to make a systematic review of the literature regarding basic and social cognition in individuals in ARMS following the guidelines of the PRISMA statement. RESULTS: In general, the results of the 49 articles included in the review show that individuals in ARMS have pervasive cognitive deficits that seem to be greater in individuals who later convert to psychosis. CONCLUSIONS: Cognitive impairment can be detected in individuals considered to be in ARMS according to current classifications and may serve as a risk marker for psychotic conversion; however, the lack of standardized criteria to define ARMS and of homogeneous cognitive assessment methods hamper the generalization of findings from different studies.

Oxytocin does not improve performance of patients with schizophrenia and healthy volunteers in a facial emotion matching task.

The neuropeptide oxytocin improves the performance in facial emotion recognition tests in healthy volunteers and in individuals with schizophrenia. Different paradigms are used in emotion recognition tasks, engaging different neurobiological bases. To date, the effects of oxytocin in facial emotion matching tasks have not been studied. The objective of this study was to evaluate the effects of intranasal oxytocin in a facial emotion matching task in patients with schizophrenia and healthy volunteers. Twenty patients and 20 healthy volunteers received 48 IU intranasal oxytocin and placebo in a double-blind, randomized, placebo-controlled, within subjects design. Fifty minutes after treatment, subjects completed a facial emotion matching task and three control tests. Oxytocin failed to improve facial affect processing, in contrast with previous results. Possible explanations are the fact that we used a facial emotion matching paradigm instead of emotion labeling tasks and a higher dose of oxytocin than the one used in most similar studies.

Increased amygdalar and hippocampal volumes in young adults with social anxiety.

BACKGROUND: Functional neuroimaging studies have consistently shown abnormal limbic activation patterns in socially anxious individuals, but structural data on the amygdala and hippocampus of these patients are scarce. This study explored the existence of structural differences in the whole brain, amygdala, and hippocampus of subjects with clinical and subthreshold social anxiety compared to healthy controls. We hypothesized that there would be volumetric differences across groups, without predicting their direction (i.e. enlargement or reduction). METHODS: Subjects classified as having social anxiety disorder (n = 12), subthreshold social anxiety (n = 12) and healthy controls (n = 14) underwent structural magnetic resonance imaging scans. The amygdala and hippocampus were defined a priori as regions of interest and volumes were calculated by manual tracing. Whole brain volume was calculated using voxel-based morphometry. RESULTS: The bilateral amygdala and left hippocampus were enlarged in socially anxious individuals relative to controls. The volume of the right hippocampus was enlarged in subthreshold social anxiety participants relative to controls. No differences were found across groups in respect to total brain volume. CONCLUSIONS: Our results show amygdalar and hippocampal volume alterations in social anxiety, possibly associated with symptom severity. The time course of such alterations and the cellular and molecular bases of limbic plasticity in social anxiety should be further investigated.