Showing papers in "Schizophrenia Bulletin in 2017"
TL;DR: It is suggested that multiple paths may exist between trauma and psychosis and may also be useful in mapping potential transdiagnostic processes.
Abstract: Childhood trauma (CT) has been identified as a potential risk factor for the onset of psychotic disorders. However, to date, there is limited consensus with respect to which symptoms may ensue after exposure to trauma in early life, and whether specific pathways may account for these associations. The aim of the present study was to use the novel network approach to investigate how different types of traumatic childhood experiences relate to specific symptoms of psychotic disorders and to identify pathways that may be involved in the relationship between CT and psychosis. We used data of patients diagnosed with a psychotic disorder (n = 552) from the longitudinal observational study Genetic Risk and Outcome of Psychosis Project and included the 5 scales of the Childhood Trauma Questionnaire-Short Form and all original symptom dimensions of the Positive and Negative Syndrome Scale. Our results show that all 5 types of CT and positive and negative symptoms of psychosis are connected through symptoms of general psychopathology. These findings are in line with the theory of an affective pathway to psychosis after exposure to CT, with anxiety as a main connective component, but they also point to several additional connective paths between trauma and psychosis: eg, through poor impulse control (connecting abuse to grandiosity, excitement, and hostility) and motor retardation (connecting neglect to most negative symptoms). The results of the current study suggest that multiple paths may exist between trauma and psychosis and may also be useful in mapping potential transdiagnostic processes.
273 citations
TL;DR: Overall, it is inadvisable to give weight to the presence of any featural properties alone in making a schizophrenia diagnosis, and it is more important to focus instead on the co-occurrence of other symptoms and the value of hallucinations as an indicator of vulnerability.
Abstract: Hallucinations constitute one of the 5 symptom domains of psychotic disorders in DSM-5, suggesting diagnostic significance for that group of disorders. Although specific featural properties of hallucinations (negative voices, talking in the third person, and location in external space) are no longer highlighted in DSM, there is likely a residual assumption that hallucinations in schizophrenia can be identified based on these candidate features. We investigated whether certain featural properties of hallucinations are specifically indicative of schizophrenia by conducting a systematic review of studies showing direct comparisons of the featural and clinical characteristics of (auditory and visual) hallucinations among 2 or more population groups (one of which included schizophrenia). A total of 43 articles were reviewed, which included hallucinations in 4 major groups (nonclinical groups, drug- and alcohol-related conditions, medical and neurological conditions, and psychiatric disorders). The results showed that no single hallucination feature or characteristic uniquely indicated a diagnosis of schizophrenia, with the sole exception of an age of onset in late adolescence. Among the 21 features of hallucinations in schizophrenia considered here, 95% were shared with other psychiatric disorders, 85% with medical/neurological conditions, 66% with drugs and alcohol conditions, and 52% with the nonclinical groups. Additional differences rendered the nonclinical groups somewhat distinctive from clinical disorders. Overall, when considering hallucinations, it is inadvisable to give weight to the presence of any featural properties alone in making a schizophrenia diagnosis. It is more important to focus instead on the co-occurrence of other symptoms and the value of hallucinations as an indicator of vulnerability.
204 citations
TL;DR: The neurodevelopment hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms.
Abstract: At its re-birth 30 years ago, the neurodevelopment hypothesis of schizophrenia focussed on aberrant genes and early neural hazards, but then it grew to include ideas concerning aberrant synaptic pruning in adolescence. The hypothesis had its own stormy development and it endured some difficult teenage years when a resurgence of interest in neurodegeneration threatened its survival. In early adult life, it over-reached itself with some reductionists claiming that schizophrenia was simply a neurodevelopmental disease. However, by age 30, the hypothesis has matured sufficiently to incorporated childhood and adult adversity, urban living and migration, as well as heavy cannabis use, as important risk factors. Thus, it morphed into the developmental risk factor model of psychosis and integrated new evidence concerning dysregulated striatal dopamine as the final step on the pathway linking risk factors to psychotic symptoms.
194 citations
TL;DR: Current knowledge on deconstructing the CHR-P paradigm across its 3 subgroups: genetic risk, attenuated psychotic symptoms, and short-lived and remitting psychotic episodes is advances.
Abstract: The Clinical High-Risk state for psychosis (CHR-P) paradigm was introduced about 2 decades ago. Over this period of time accumulating knowledge has been gained. Conceptual advancements involve new knowledge into risk enrichment and the impact of recruitment strategies, specificity for prediction of psychotic and nonpsychotic mental disorders and heterogeneity of psychosis risk among the different CHR-P subgroups. The current special issue advances current knowledge on deconstructing the CHR-P paradigm across its 3 subgroups: genetic risk, attenuated psychotic symptoms, and short-lived and remitting psychotic episodes. A conceptual revision of the paradigm (Version II) is suggested and supported by 3 original studies published in this special issue.
150 citations
TL;DR: Overall, KYNA levels are increased in patients with schizophrenia, specifically within the central nervous system, and an improved understanding of KYNA in Patients with schizophrenia may contribute to the development of novel diagnostic approaches and therapeutic strategies.
Abstract: Kynurenic acid (KYNA) is an endogenous antagonist of N-methyl-D-aspartate and α7 nicotinic acetylcholine receptors that is derived from astrocytes as part of the kynurenine pathway of tryptophan degradation. Evidence suggests that abnormal KYNA levels are involved in the pathophysiology of schizophrenia. However, this has never been assessed through a meta-analysis. A literature search was conducted through Ovid using Embase, Medline, and PsycINFO databases (last search: December 2016) with the search terms: (kynuren* or KYNA) and (schizophreni* or psychosis). English language studies measuring KYNA levels using any method in patients with schizophrenia and healthy controls (HCs) were identified. Standardized mean differences (SMDs) were calculated to determine differences in KYNA levels between groups. Subgroup analyses were separately performed for nonoverlapping participant samples, KYNA measurement techniques, and KYNA sample source. The influences of patients' age, antipsychotic status (%medicated), and sex (%male) on study SMDs were assessed through a meta-regression. Thirteen studies were deemed eligible for inclusion in the meta-analysis. In the main analysis, KYNA levels were elevated in the patient group. Subgroup analyses demonstrated that KYNA levels were increased in nonoverlapping participant samples, and centrally (cerebrospinal fluid and brain tissue) but not peripherally. Patients' age, %medicated, and %male were each positively associated with study SMDs. Overall, KYNA levels are increased in patients with schizophrenia, specifically within the central nervous system. An improved understanding of KYNA in patients with schizophrenia may contribute to the development of novel diagnostic approaches and therapeutic strategies.
142 citations
TL;DR: It was concluded thatnegative symptoms are relatively frequent across diagnostic categories, but individual disorders may differ in whether their negative symptoms are persistent/transient or primary/secondary.
Abstract: In the DSM5, negative symptoms are 1 of the 5 core dimensions of psychopathology evaluated for schizophrenia. However, negative symptoms are not pathognomonic-they are also part of the diagnostic criteria for other schizophrenia-spectrum disorders, disorders that sometimes have comorbid psychosis, diagnoses not in the schizophrenia-spectrum, and the general "nonclinical" population. Although etiological models of negative symptoms have been developed for chronic schizophrenia, there has been little attention given to whether these models have transdiagnostic applicability. In the current review, we examine areas of commonality and divergence in the clinical presentation and etiology of negative symptoms across diagnostic categories. It was concluded that negative symptoms are relatively frequent across diagnostic categories, but individual disorders may differ in whether their negative symptoms are persistent/transient or primary/secondary. Evidence for separate dimensions of volitional and expressive symptoms exists, and there may be multiple mechanistic pathways to the same symptom phenomenon among DSM-5 disorders within and outside the schizophrenia-spectrum (ie, equifinality). Evidence for a novel transdiagnostic etiological model is presented based on the Research Domain Criteria (RDoC) constructs, which proposes the existence of 2 such pathways-a hedonic pathway and a cognitive pathway-that can both lead to expressive or volitional symptoms. To facilitate treatment breakthroughs, future transdiagnostic studies on negative symptoms are warranted that explore mechanisms underlying volitional and expressive pathology.
133 citations
TL;DR: NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels, however, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement.
Abstract: Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.
113 citations
TL;DR: Altered functional connectivity suggests a specific intrinsic and tonic neural abnormality in the motor system in schizophrenia, and altered neural activity at rest was linked to motor abnormalities on the behavioral level.
Abstract: Motor abnormalities are frequently observed in schizophrenia and structural alterations of the motor system have been reported. The association of aberrant motor network function, however, has not been tested. We hypothesized that abnormal functional connectivity would be related to the degree of motor abnormalities in schizophrenia. In 90 subjects (46 patients) we obtained resting stated functional magnetic resonance imaging (fMRI) for 8 minutes 40 seconds at 3T. Participants further completed a motor battery on the scanning day. Regions of interest (ROI) were cortical motor areas, basal ganglia, thalamus and motor cerebellum. We computed ROI-to-ROI functional connectivity. Principal component analyses of motor behavioral data produced 4 factors (primary motor, catatonia and dyskinesia, coordination, and spontaneous motor activity). Motor factors were correlated with connectivity values. Schizophrenia was characterized by hyperconnectivity in 3 main areas: motor cortices to thalamus, motor cortices to cerebellum, and prefrontal cortex to the subthalamic nucleus. In patients, thalamocortical hyperconnectivity was linked to catatonia and dyskinesia, whereas aberrant connectivity between rostral anterior cingulate and caudate was linked to the primary motor factor. Likewise, connectivity between motor cortex and cerebellum correlated with spontaneous motor activity. Therefore, altered functional connectivity suggests a specific intrinsic and tonic neural abnormality in the motor system in schizophrenia. Furthermore, altered neural activity at rest was linked to motor abnormalities on the behavioral level. Thus, aberrant resting state connectivity may indicate a system out of balance, which produces characteristic behavioral alterations.
107 citations
TL;DR: Brief Limited Intermittent Psychotic Symptoms are most likely to fulfill the ATPD criteria, mainly acute schizophrenic subtypes and have an extreme high risk of psychosis.
Abstract: Background Brief Limited Intermittent Psychotic Symptoms (BLIPS) are key inclusion criteria to define individuals at ultra high risk for psychosis (UHR). Their diagnostic and prognostic significance is unclear. Objectives To address the baseline diagnostic relationship between BLIPS and the ICD-10 categories and examine the longitudinal prognostic impact of clinical and sociodemographic factors. Methods Prospective long-term study in UHR individuals meeting BLIPS criteria. Sociodemographic and clinical data, including ICD-10 diagnoses, were automatically drawn from electronic health records and analyzed using Kaplan-Meier failure function (1-survival), Cox regression models, bootstrapping methods, and Receiver Operating Characteristics (ROC) curve. Results Eighty BLIPS were included. At baseline, two-thirds (68%) of BLIPS met the diagnostic criteria for ICD-10 Acute and Transient Psychotic Disorder (ATPD), most featuring schizophrenic symptoms. The remaining individuals met ICD-10 diagnostic criteria for unspecified nonorganic psychosis (15%), mental and behavioral disorders due to use of cannabinoids (11%), and mania with psychotic symptoms (6%). The overall 5-year risk of psychosis was 0.54. Recurrent episodes of BLIPS were relatively rare (11%) but associated with a higher risk of psychosis (hazard ratio [HR] 3.98) than mono-episodic BLIPS at the univariate analysis. Multivariate analysis revealed that seriously disorganizing or dangerous features increased greatly (HR = 4.39) the risk of psychosis (0.89 at 5-year). Bootstrapping confirmed the robustness of this predictor (area under the ROC = 0.74). Conclusions BLIPS are most likely to fulfill the ATPD criteria, mainly acute schizophrenic subtypes. About half of BLIPS cases develops a psychotic disorder during follow-up. Recurrent BLIPS are relatively rare but tend to develop into psychosis. BLIPS with seriously disorganizing or dangerous features have an extreme high risk of psychosis.
106 citations
TL;DR: The findings suggest that the neurovascular decoupling in the brain may be a possible neuropathological mechanism of schizophrenia.
Abstract: Background Respective changes in resting-state cerebral blood flow (CBF) and functional connectivity in schizophrenia have been reported However, their coupling alterations in schizophrenia remain largely unknown Methods 89 schizophrenia patients and 90 sex- and age-matched healthy controls underwent resting-state functional MRI to calculate functional connectivity strength (FCS) and arterial spin labeling imaging to compute CBF The CBF-FCS coupling of the whole gray matter and the CBF/FCS ratio (the amount of blood supply per unit of connectivity strength) of each voxel were compared between the 2 groups Results Whole gray matter CBF-FCS coupling was decreased in schizophrenia patients relative to healthy controls In schizophrenia patients, the decreased CBF/FCS ratio was predominantly located in cognitive- and emotional-related brain regions, including the dorsolateral prefrontal cortex, insula, hippocampus and thalamus, whereas an increased CBF/FCS ratio was mainly identified in the sensorimotor regions, including the putamen, and sensorimotor, mid-cingulate and visual cortices Conclusion These findings suggest that the neurovascular decoupling in the brain may be a possible neuropathological mechanism of schizophrenia
101 citations
TL;DR: How research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-m motor behavior relationships, can elucidate the understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments is explained.
Abstract: Signs of motor dysfunction are evidenced across a range of psychiatric disorders including schizophrenia. Historically, these features have been neglected but emerging theoretical and methodological advancements have shed new light on the utility of considering movement abnormalities. Indeed, the National Institute of Mental Health Research Domain Criteria initiative has recently met to develop a Motor Systems Domain. This reflects a growing appreciation for the enhanced reliability and validity that can come along with evaluating disturbances relevant to psychiatric illnesses from multiple levels of analysis, and conceptualizing these domains with respect to the complexity of their role in a broader integrated system (ie, weighing contributions and interactions between the cognitive, affective, and motor domains). This article discusses motor behaviors and seeks to explain how research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-motor behavior relationships, can elucidate our understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments.
TL;DR: MAs appear to represent a true transdiagnostic domain putatively sharing neurobiological mechanisms of neurodevelopmental, functional or neurodegenerative origin.
Abstract: Background Motor abnormalities (MAs) of severe mental disorders have been traditionally neglected both in clinical practice and research, although they are an increasing focus of attention because of their clinical and neurobiological relevance. For historical reasons, most of the literature on MAs has been focused to a great extent on schizophrenia, and as a consequence their prevalence and featural properties in other psychiatric or neuropsychiatric disorders are poorly known. In this article, we evaluated the extent to which catatonic, extrapyramidal and neurological soft signs, and their associated clinical features, are present transdiagnostically. Methods We examined motor-related features in neurodevelopmental (schizophrenia, obsessive compulsive disorder, autism spectrum disorders), "functional" (nonschizophrenic nonaffective psychoses, mood disorders) and neurodegenerative (Alzheimer's disease) disorders. Examination of the literature revealed that there have been very few comparisons of motor-related features across diagnoses and we had to rely mainly in disorder-specific studies to compare it transdiagnostically. Results One or more motor domains had a substantial prevalence in all the diagnoses examined. In "functional" disorders, MAs, and particularly catatonic signs, appear to be markers of episode severity; in chronic disorders, although with different degree of strength or evidence, all motor domains are indicators of both disorder severity and poor outcome; lastly, in Alzheimer's disease they are also indicators of disorder progression. Conclusions MAs appear to represent a true transdiagnostic domain putatively sharing neurobiological mechanisms of neurodevelopmental, functional or neurodegenerative origin.
TL;DR: The overall conclusion is that insomnia has a causal role in the occurrence of certain psychotic experiences, and that a key route is via negative affect.
Abstract: Our view is that insomnia may be a causal factor in the occurrence of psychotic experiences such as paranoia and hallucinations. However, the causal relationship is not established. The aim of the study was to investigate the causal role of insomnia in psychotic experiences via a sleep restriction manipulation. The study was a within-subjects crossover design that included a planned mediation analysis. Sixty-eight nonclinical volunteers underwent a sleep loss condition (restricted to 4 h sleep for 3 nights) and a control condition (standard sleep) in randomized order in 2 consecutive weeks, with a weekend washout period. Psychotic experiences (paranoia, hallucinations, grandiosity, and cognitive disorganization) and candidate mediating variables (negative affect and related processes, working memory, decision making, and perceptual processing) were assessed before and after each condition. Actigraphy verified an average sleep duration of 5 h 15 min in the sleep loss condition, vs 6 h 58 min in the control condition. After the sleep loss condition, relative to the control condition, participants reported significant increases in paranoia, hallucinations, and cognitive disorganization, with no significant changes in grandiosity. The sleep loss condition was also associated with significant increases in negative affect, negative self and other cognitions, worry, and working memory impairment. Mediation analyses indicated that changes in psychotic experiences were mediated by changes in negative affect and related processes, but not memory impairment. The overall conclusion is that insomnia has a causal role in the occurrence of certain psychotic experiences, and that a key route is via negative affect.
TL;DR: A new study population: clairaudient psychics who receive daily auditory messages is introduced and it is found that this sample of non-help-seeking voice hearers were able to control the onset and offset of their voices, that they were less distressed by their voice-hearing experiences and that, the first time they admitted to voice- hearing, the reception by others was much more likely to be positive.
Abstract: Hearing voices that are not present is a prominent symptom of serious mental illness. However, these experiences may be common in the non-help-seeking population, leading some to propose the existence of a continuum of psychosis from health to disease. Thus far, research on this continuum has focused on what is impaired in help-seeking groups. Here we focus on protective factors in non-help-seeking voice-hearers. We introduce a new study population: clairaudient psychics who receive daily auditory messages. We conducted phenomenological interviews with these subjects, as well as with patients diagnosed with a psychotic disorder who hear voices, people with a diagnosis of a psychotic disorder who do not hear voices, and matched control subjects (without voices or a diagnosis). We found the hallucinatory experiences of psychic voice-hearers to be very similar to those of patients who were diagnosed. We employed techniques from forensic psychiatry to conclude that the psychics were not malingering. Critically, we found that this sample of non-help-seeking voice hearers were able to control the onset and offset of their voices, that they were less distressed by their voice-hearing experiences and that, the first time they admitted to voice-hearing, the reception by others was much more likely to be positive. Patients had much more negative voice-hearing experiences, were more likely to receive a negative reaction when sharing their voices with others for the first time, and this was subsequently more disruptive to their social relationships. We predict that this sub-population of healthy voice-hearers may have much to teach us about the neurobiology, cognitive psychology and ultimately the treatment of voices that are distressing.
TL;DR: Evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress is provided by a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ customers compared to both a matched FE BD patient group and a matchedhealthy control group.
Abstract: Balance between the redox pair of nicotinamide adenine dinucleotides (oxidized NAD+ and reduced NADH), reflects the oxidative state of cells and the ability of biological systems to carry out energy production. A growing body of evidence suggests that an "immuno-oxidative" pathway including oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response may contribute to disruptions in brain activity in schizophrenia (SZ). The aim of this study is to assess possible redox imbalance in SZ patients by using a novel in vivo 31P MRS technique. The participants included 40 healthy controls, 21 chronic SZ, 13 first-episode (FE) SZ, and 18 FE bipolar disorder (BD) patients (as a psychiatric control group). All participants initially underwent structural imaging at a 3 Tesla (3 T) and 31P MRS measurements were performed on a 4 T MR scanner. NAD+ and NADH components were determined by nonlinear least-square fitting of the model simulated spectra; these incorporated prior chemical shift and coupling constant information to in vivo resonances obtained from 31P MRS experiments. We found a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ patients compared to both a matched FE BD patient group and a matched healthy control group. These findings provide evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress.
TL;DR: While causality cannot be fully determined from cross-sectional data, DAGs indicate the relationships providing the best fit, and thereby advance investigation of the complex interactions seen in psychiatry, including the mechanisms underpinning psychiatric symptoms.
Abstract: Modern psychiatric epidemiology researches complex interactions between multiple variables in large datasets This creates difficulties for causal inference We argue for the use of probabilistic models represented by directed acyclic graphs (DAGs) These capture the dependence structure of multiple variables and, used appropriately, allow more robust conclusions about the direction of causation We analyzed British national survey data to assess putative mediators of the association between bullying victimization and persecutory ideation We compared results using DAGs and the Karlson-Holm-Breen (KHB) logistic regression commands in STATA We analyzed data from the 2007 English National Survey of Psychiatric Morbidity, using the equivalent 2000 survey in an instant replication Additional details of methods and results are provided in the supplementary material DAG analysis revealed a richer structure of relationships than could be inferred using the KHB logistic regression commands Thus, bullying had direct effects on worry, persecutory ideation, mood instability, and drug use Depression, sleep and anxiety lay downstream, and therefore did not mediate the link between bullying and persecutory ideation Mediation by worry and mood instability could not be definitively ascertained Bullying led to hallucinations indirectly, via persecutory ideation and depression DAG analysis of the 2000 dataset suggested the technique generates stable results While causality cannot be fully determined from cross-sectional data, DAGs indicate the relationships providing the best fit They thereby advance investigation of the complex interactions seen in psychiatry, including the mechanisms underpinning psychiatric symptoms It may consequently be used to optimize the choice of intervention targets
TL;DR: The great limitation is still the lack of studies comparing SZ and BD that include psychotic and nonpsychotic bipolar cases separately, and there are many cases, even in childhood/adolescent SZ, where no premorbid anomalies are found, and immunological disorders or other etiologies should be searched for.
Abstract: Ample evidence supports a neurodevelopmental origin in some cases of schizophrenia (SZ). More inconsistent information is available for bipolar disorder (BD). We herein review studies with a focus on premorbid (adjustment and functionality) and early developmental milestones that include both SZ and BD patients. A search was performed in the PubMed electronic database, retrieving 619 abstracts; 30 were ultimately included in this systematic review. Eight prospective cohorts, 15 retrospective studies, and 7 studies based on national registries. Psychomotor developmental deviations and general adjustment problems characterize the childhood of subjects later diagnosed with SZ or BD; they are more marked in those later diagnosed with SZ vs BD, earlier onset vs later onset, and psychotic vs nonpsychotic disorders. Cognitive impairment follows a linear risk trend for SZ and a U-shaped trend for BD. Social isolation and visuoperceptual/reading anomalies more frequently antecede SZ. Pervasive developmental disorders increase the risk for both SZ and BD, more so in cases with normal intelligence. The predictive risk of each isolated developmental marker is low, but a significant percentage of subjects with SZ and a minority of adults with BD showed signs of premorbid abnormalities in childhood. The great limitation is still the lack of studies comparing SZ and BD that include psychotic and nonpsychotic bipolar cases separately. There are many cases, even in childhood/adolescent SZ, where no premorbid anomalies are found, and immunological disorders or other etiologies should be searched for. At least in cases with clear neurodevelopmental markers, rare genetic variants should be investigated.
TL;DR: Test the prediction model of Cornblatt et al with a new sample of individuals with APS from the PREDICT study, and it was demonstrated that unusual thought content, disorganized communication, baseline social functioning, verbal fluency, and memory, processing speed and age were predictors of later transition to psychosis in thePREDICT sample.
Abstract: In the literature, there have been several attempts to develop prediction models for youth who are at clinical high risk (CHR) of developing psychosis Although there are no specific clinical or demographic variables that seem to consistently predict the later transition to psychosis in those CHR youth, in addition to attenuated psychotic symptoms, the most commonly occuring predictors tend to be poor social functioning and certain cognitive tasks Unfortunately, there has been little attempt to replicate alogorithms A recently published article by Cornblatt et al suggested that, for individuals with attentuated psychotic symptoms (APS), disorganized communication, suspiciousness, verbal memory, and a decline in social functioning were the best predictors of later transition to psychosis (the RAP model) The purpose of this article was to first test the prediction model of Cornblatt et al with a new sample of individuals with APS from the PREDICT study The RAP model was not the best fit for the PREDICT data However, using other variables from PREDICT, it was demonstrated that unusual thought content, disorganized communication, baseline social functioning, verbal fluency, and memory, processing speed and age were predictors of later transition to psychosis in the PREDICT sample Although the predictors were different in these 2 models, both supported that disorganized communication, poor social functioning, and verbal memory, were good candidates as predictors for later conversion to psychosis
TL;DR: The enrichment of transcriptional and epigenetic associations with schizophrenia during fetal life suggest that both genetic and environmental risk for schizophrenia have a particular molecular impact on early development, possibly because of genetic biases in environmental sensitivity.
Abstract: Since a proposal in 1986 that schizophrenia involved early neurodevelopmental deviations beginning in intrauterine life that showed varying expressivity as relevant neural systems matured, our understanding of the developmental components of the pathogenesis of schizophrenia has substantially evolved. This commentary highlights recent genetic and epigenetic evidence that prenatal development is a critical period for the expression of schizophrenia risk. Studies of gene expression have been fairly consistent in showing that genes implicated in schizophrenia show relatively greater expression during fetal than postnatal life. Consistent molecular evidence of early environmental perturbations contributing to risk has emerged from studies of epigenetic marks in the brain genome as potential environmental footprints and these also highlight the prenatal period. Analyses of gene expression in placenta dramatically identify the intrauterine environment as a direct point of impact of a component of schizophrenia genetic risk. Together, the enrichment of transcriptional and epigenetic associations with schizophrenia during fetal life suggest that both genetic and environmental risk for schizophrenia have a particular molecular impact on early development, possibly because of genetic biases in environmental sensitivity.
TL;DR: Recent evidence suggests these 2 symptom groups have different correlates and reflect the existence of 2 groups with in DS, and it may be useful in future research to determine whether findings in DS extend to patients with other neuropsychiatric disorders who also have negative symptoms.
Abstract: We previously proposed that people with schizophrenia who have primary, enduring negative symptoms have a disease-deficit schizophrenia (DS)-that is separate from that affecting people with schizophrenia without these features Additional evidence consistent with the separate disease hypothesis has accumulated in recent years White matter changes may be widespread in deficit compared to nondeficit patients and may relate to problems in early brain migration These 2 patient groups also appear to differ on metabolic measures prior to antipsychotic treatment Studies of reward and defeatist beliefs provide the basis for future treatment trials The 2 factors or groups within negative symptoms broadly defined (both primary and secondary) have also been found in DS, and recent evidence suggests these 2 symptom groups have different correlates and reflect the existence of 2 groups with in DS Negative symptoms are found in disorders other than schizophrenia, and excess summer birth, a deficit risk factor, has been found in a non-patient group with deficit-like features It may be useful in future research to determine whether findings in DS extend to patients with other neuropsychiatric disorders who also have negative symptoms
TL;DR: A whole-brain data-driven definition of network nodes and regularized partial correlations were used to evaluate and compare putatively direct brain network node interactions between groups, demonstrating robust reductions in functional connectivity in SZ spectrum disorders.
Abstract: Schizophrenia (SZ) is a severe mental illness with high heritability and complex etiology. Mounting evidence from neuroimaging has implicated disrupted brain network connectivity in the pathophysiology. However, previous findings are inconsistent, likely due to a combination of methodological and clinical variability and relatively small sample sizes. Few studies have used a data-driven approach for characterizing pathological interactions between regions in the whole brain and evaluated the generalizability across independent samples. To overcome this issue, we collected resting-state functional magnetic resonance imaging data from 3 independent samples (1 from Norway and 2 from Sweden) consisting of 182 persons with a SZ spectrum diagnosis and 348 healthy controls. We used a whole-brain data-driven definition of network nodes and regularized partial correlations to evaluate and compare putatively direct brain network node interactions between groups. The clinical utility of the functional connectivity features and the generalizability of effects across samples were evaluated by training and testing multivariate classifiers in the independent samples using machine learning. Univariate analyses revealed 14 network edges with consistent reductions in functional connectivity encompassing frontal, somatomotor, visual, auditory, and subcortical brain nodes in patients with SZ. We found a high overall accuracy in classifying patients and controls (up to 80%) using independent training and test samples, strongly supporting the generalizability of connectivity alterations across different scanners and heterogeneous samples. Overall, our findings demonstrate robust reductions in functional connectivity in SZ spectrum disorders, indicating disrupted information flow in sensory, subcortical, and frontal brain regions.
TL;DR: A systematic review of the research concerning overlap and differences in symptoms between schizophrenia spectrum and DDs found a large body of evidence showing the presence of symptoms of dissociation in SSDs.
Abstract: Schizophrenia spectrum disorders (SSDs) and dissociative disorders (DDs) are described in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) and tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) as 2 categorically distinct diagnostic categories. However, several studies indicate high levels of co-occurrence between these diagnostic groups, which might be explained by overlapping symptoms. The aim of this systematic review is to provide a comprehensive overview of the research concerning overlap and differences in symptoms between schizophrenia spectrum and DDs. For this purpose the PubMed, PsycINFO, and Web of Science databases were searched for relevant literature. The literature contained a large body of evidence showing the presence of symptoms of dissociation in SSDs. Although there are quantitative differences between diagnoses, overlapping symptoms are not limited to certain domains of dissociation, nor to nonpathological forms of dissociation. In addition, dissociation seems to be related to a history of trauma in SSDs, as is also seen in DDs. There is also evidence showing that positive and negative symptoms typically associated with schizophrenia may be present in DD. Implications of these results are discussed with regard to different models of psychopathology and clinical practice.
TL;DR: Light is shed on the development of childhood disorders into severe adult psychiatric disorders by optimally using longitudinal data across diagnoses in a multivariate meta-analysis and results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology.
Abstract: Background Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors. Methods Polygenic risk scores (PRS), reflecting an individual's genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders. Results Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25. Conclusion By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.
TL;DR: Elevated psychosis risk in several visible minority groups could not be explained by differences in postmigratory socioeconomic disadvantage, and patterns were observed across rural and urban areas of the catchment, suggesting that elevated psychosis risk for some ethnic minority groups is not a result of selection processes influencing rural–urban living.
Abstract: This work was supported by a Sir Henry Wellcome Research Fellowship from the Wellcome Trust (WT085540 to JBK), a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (101272/Z/13/Z to JBK) and by the National Institute of Health Research (RP-PG-0606-1335 to JP) Prof Peter Jones directs the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England
TL;DR: It is suggested that SZ patients simultaneously show over- and under-activation in TOM-related regions and less specialized brain activation in regions linked to TOM and increased activation in attention-related networks suggesting compensatory effects.
Abstract: Social cognition abilities are severely impaired in schizophrenia (SZ). The current meta-analysis used foci of 21 individual studies on functional abnormalities in the schizophrenic brain in order to identify regions that reveal convergent under- or over-activation during theory of mind (TOM) tasks. Studies were included in the analyses when contrasting tasks that require the processing of mental states with tasks which did not. Only studies that investigated patients with an ICD or DSM diagnosis were included. Quantitative voxel-based meta-analyses were done using Seed-based d Mapping software. Common TOM regions like medial-prefrontal cortex and temporo-parietal junction revealed abnormal activation in schizophrenic patients: Under-activation was identified in the medial prefrontal cortex, left orbito-frontal cortex, and in a small section of the left posterior temporo-parietal junction. Remarkably, robust over-activation was identified in a more dorsal, bilateral section of the temporo-parietal junction. Further abnormal activation was identified in medial occipito-parietal cortex, right premotor areas, left cingulate gyrus, and lingual gyrus. The findings of this study suggest that SZ patients simultaneously show over- and under-activation in TOM-related regions. Especially interesting, temporo-parietal junction reveals diverging activation patterns with an under-activating left posterior and an over-activating bilateral dorsal section. In conclusion, SZ patients show less specialized brain activation in regions linked to TOM and increased activation in attention-related networks suggesting compensatory effects.
TL;DR: The use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level.
Abstract: Treatment-resistant schizophrenia (TRS) affects around one-third of individuals with schizophrenia. Although a number of sociodemographic and clinical predictors of TRS have been identified, data on the genetic risk of TRS are sparse. We aimed to investigate the association between a polygenic risk score for schizophrenia and treatment resistance in patients with schizophrenia. We conducted a nationwide, population-based follow-up study among all Danish individuals born after 1981 and with an incident diagnosis of schizophrenia between 1999 and 2007. Based on genome-wide data polygenic risk scores for schizophrenia were calculated in 862 individuals with schizophrenia. TRS was defined as either clozapine initiation or at least 2 periods of different antipsychotic monotherapies and still being hospitalized. We estimated hazard rate ratios (HRs) for TRS in relation to the polygenic risk score while adjusting for population stratification, age, sex, geographical area at birth, clinical treatment setting, psychiatric comorbidity, and calendar year. Among the 862 individuals with schizophrenia, 181 (21.0%) met criteria for TRS during 4674 person-years of follow-up. We found no significant association between the polygenic risk score and TRS, adjusted HR = 1.13 (95% CI: 0.95-1.35). Based on these results, the use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level. Future research should include larger genetic samples in combination with non-genetic markers. Moreover, a TRS-specific developed polygenic risk score would be of great interest towards early prediction of TRS.
TL;DR: Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators do not substantially decrease heritability in schizophrenic samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits.
Abstract: Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%– 67%), Verbal Ability (43%–72%), Visuospatial Ability (20%–80%), and Attention/Processing Speed (28%–74%), while the lowest heritability was observed for Executive Function (20%–40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = −.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.
TL;DR: The embodiment perspective suggests novel treatment strategies through psychotherapy and body-oriented interventions, and may ultimately provide biomarkers for diagnosis of schizophrenia.
Abstract: In recent decades, embodiment has become an influential concept in psychology and cognitive neuroscience. Embodiment denotes the study of the reciprocal (causal) relationships between mind and body, with the mind not only affecting the body but also vice versa. Embodied cognition comes to the fore in sensorimotor coupling, predictive coding, and nonverbal behavior. Additionally, the embodiment of the mind constitutes the basis of social interaction and communication, as evident in research on nonverbal synchrony and mimicry. These theoretical and empirical developments portend a range of implications for schizophrenia research and treatment. Sensorimotor dysfunctions are closely associated with affective and psychotic psychopathology, leading to altered timing in the processing of stimuli and to disordered appraisals of the environment. Problems of social cognition may be newly viewed as disordered embodied communication. The embodiment perspective suggests novel treatment strategies through psychotherapy and body-oriented interventions, and may ultimately provide biomarkers for diagnosis.
TL;DR: This study showed that it is possible to map transdiagnostic experiences of psychopathology as a network and that important information can be derived from this approach in comparison to regular approaches.
Abstract: Our ability to accurately predict development and outcome of early expression of psychosis is limited. To elucidate the mechanisms underlying psychopathology, a broader, transdiagnostic approach that acknowledges the complexity of mental illness is required. The upcoming network paradigm may be fruitful here. In this study, we applied a transdiagnostic network approach to psychosis. Data pertain to the third wave (second follow-up) of a sample of adolescents originally recruited at age 7-8 years. At baseline, N = 347 children with auditory verbal hallucinations (AVH) and N = 347 control children were included. N = 293 of these N = 694 children participated in the second follow-up (mean age 18.9 years; 59% women). Participants completed the Community Assessment of Psychic Experiences (CAPE) and the Depression, Anxiety and Stress Scale (DASS-21). A specific type of network model, the Ising model, was applied to dichotomized CAPE and DASS items. Interconnections of experiences within the same domain were observed, as well as interconnections between experiences of multiple domains of psychopathology. Quantitative and qualitative differences in network architecture were found in networks of psychopathological experiences in individuals with or without AVH at age 7-8 years. Although adolescents with or without previous AVH did not differ in their current CAPE scores, differences in the interconnectedness of psychopathology items were still found, possibly mirroring a difference in psychosis liability. This study showed that it is possible to map transdiagnostic experiences of psychopathology as a network and that important information can be derived from this approach in comparison to regular approaches.
TL;DR: Findings suggest that the structural and functional integrity of fronto-limbic brain regions is consistently related to functional outcome in individuals with schizophrenia.
Abstract: Individuals with schizophrenia are burdened with impairments in functional outcome, despite existing interventions. The lack of understanding of the neurobiological correlates supporting adaptive function in the disorder is a significant barrier to developing more effective treatments. This research conducted a systematic and meta-analytic review of all peer-reviewed studies examining brain-functional outcome relationships in schizophrenia. A total of 53 (37 structural and 16 functional) brain imaging studies examining the neural correlates of functional outcome across 1631 individuals with schizophrenia were identified from literature searches in relevant databases occurring between January, 1968 and December, 2016. Study characteristics and results representing brain-functional outcome relationships were systematically extracted, reviewed, and meta-analyzed. Results indicated that better functional outcome was associated with greater fronto-limbic and whole brain volumes, smaller ventricles, and greater activation, especially during social cognitive processing. Thematic observations revealed that the dorsolateral prefrontal cortex, anterior cingulate, posterior cingulate, parahippocampal gyrus, superior temporal sulcus, and cerebellum may have role in functioning. The neural basis of functional outcome and disability is infrequently studied in schizophrenia. While existing evidence is limited and heterogeneous, these findings suggest that the structural and functional integrity of fronto-limbic brain regions is consistently related to functional outcome in individuals with schizophrenia. Further research is needed to understand the mechanisms and directionality of these relationships, and the potential for identifying neural targets to support functional improvement.