Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Diagnostic biomarkers for obsessive-compulsive disorder: A reasonable quest or ignis fatuus?

Obsessive-compulsive disorder (OCD) has been associated with a wide range of biological and neurocognitive findings, which could assist in the search for biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses to assess and grade the strength of the evidence of the association between OCD and several potential diagnostic biomarkers while controlling for several potential biases. Twenty-four systematic reviews and meta-analyses were included, comprising 352 individual studies, more than 10,000 individuals with OCD, and covering 73 potential biomarkers. OCD was significantly associated with several neurocognitive biomarkers, with varying degrees of evidence, ranging from weak to convincing. A number of biochemical, neurophysiological, and neuroimaging biomarkers also showed statistically significant, albeit weak, associations with OCD. Analyses in unmedicated samples (123 studies) weakened the strength of the evidence for most biomarkers or rendered them non-significant. None of the biomarkers seem to have sufficient sensitivity and specificity to become a diagnostic biomarker. A more promising avenue for future biomarker research in OCD might be the prediction of clinical outcomes rather than diagnosis.

Acute oxytocin effects in inferring others' beliefs and social emotions in people at clinical high risk for psychosis.

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others' beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others' social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others' social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others' social emotions in those CHR-P subjects with low baseline social-emotional abilities.

Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis.

BACKGROUND: Prenatal and perinatal insults are implicated in the aetiopathogenesis of psychotic disorders but the consistency and magnitude of their associations with psychosis have not been updated for nearly two decades. The aim of this systematic review and meta-analysis was to provide a comprehensive and up-to-date synthesis of the evidence on the association between prenatal or perinatal risk and protective factors and psychotic disorders. METHODS: In this systematic review and meta-analysis, we searched the Web of Science database for articles published up to July 20, 2019. We identified cohort and case-control studies examining the association (odds ratio [OR]) between prenatal and perinatal factors and any International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) non-organic psychotic disorder with a healthy comparison group. Other inclusion criteria were enough data available to do the analyses, and non-overlapping datasets. We excluded reviews, meta-analyses, abstracts or conference proceedings, and articles with overlapping datasets. Data were extracted according to EQUATOR and PRISMA guidelines. Extracted variables included first author, publication year, study type, sample size, type of psychotic diagnosis (non-affective psychoses or schizophrenia-spectrum disorders, affective psychoses) and diagnostic instrument (DSM or ICD and version), the risk or protective factor, and measure of association (primary outcome). We did random-effects pairwise meta-analyses, Q statistics, I2 index, sensitivity analyses, meta-regressions, and assessed study quality and publication bias. The study protocol was registered at PROSPERO, CRD42017079261. FINDINGS: 152 studies relating to 98 risk or protective factors were eligible for analysis. Significant risk factors were: maternal age younger than 20 years (OR 1·17) and 30-34 years (OR 1·05); paternal age younger than 20 years (OR 1·31) and older than 35 years (OR 1·28); any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26); three or more pregnancies (OR 1·30); herpes simplex 2 (OR 1·35); maternal infections not otherwise specified (NOS; OR 1·27); suboptimal number of antenatal visits (OR 1·83); winter (OR 1·05) and winter to spring (OR 1·05) season of birth in the northern hemisphere; maternal stress NOS (OR 2·40); famine (OR 1·61); any famine or nutritional deficits in pregnancy (OR 1·40); maternal hypertension (OR 1·40); hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23); birth length less than 49 cm (OR 1·17); small for gestational age (OR 1·40); premature birth (OR 1·35), and congenital malformations (OR 2·35). Significant protective factors were maternal ages 20-24 years (OR 0·93) and 25-29 years (OR 0·92), nulliparity (OR 0·91), and birthweights 3500-3999 g (OR 0·90) or more than 4000 g (OR 0·86). The results were corrected for publication biases; sensitivity and meta-regression analyses confirmed the robustness of these findings for most factors. INTERPRETATION: Several prenatal and perinatal factors are associated with the later onset of psychosis. The updated knowledge emerging from this study could refine understanding of psychosis pathogenesis, enhance multivariable risk prediction, and inform preventive strategies. FUNDING: None.

Risk and protective factors for anxiety and obsessive-compulsive disorders: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: A multitude of risk/protective factors for anxiety and obsessive-compulsive disorders have been proposed. We conducted an umbrella review to summarize the evidence of the associations between risk/protective factors and each of the following disorders: specific phobia, social anxiety disorder, generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, and to assess the strength of this evidence whilst controlling for several biases. METHODS: Publication databases were searched for systematic reviews and meta-analyses examining associations between potential risk/protective factors and each of the disorders investigated. The evidence of the association between each factor and disorder was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of cases (>1000), random-effects p-values, 95% prediction intervals, confidence interval of the largest study, heterogeneity between studies, study effects, and excess of significance. RESULTS: Nineteen systematic reviews and meta-analyses were included, corresponding to 216 individual studies covering 427 potential risk/protective factors. Only one factor association (early physical trauma as a risk factor for social anxiety disorder, OR 2.59, 95% CI 2.17-3.1) met all the criteria for convincing evidence. When excluding the requirement for more than 1000 cases, five factor associations met the other criteria for convincing evidence and 22 met the remaining criteria for highly suggestive evidence. CONCLUSIONS: Although the amount and quality of the evidence for most risk/protective factors for anxiety and obsessive-compulsive disorders is limited, a number of factors significantly increase the risk for these disorders, may have potential prognostic ability and inform prevention.

Risk factors for posttraumatic stress disorder: An umbrella review of systematic reviews and meta-analyses.

Approximately one third of individuals who experience a severe traumatic event will develop posttraumatic stress disorder (PTSD). It is crucial to identify what factors may be associated with increased or decreased risk for PTSD. We conducted an umbrella review of systematic reviews and meta-analyses of risk/protective factors for PTSD and assessed and graded the evidence of the association between each factor and PTSD. Thirty-three systematic reviews and meta-analyses were included and 130 potential risk factors were identified. Of those, 57 showed a significant association with PTSD. Being female or being indigenous people of the Americas, among the sociodemographic factors; history of physical disease and family history of psychiatric disorder, among the pretrauma factors; and cumulative exposure to potentially traumatic experiences, trauma severity, and being trapped during an earthquake, among the peritrauma factors, showed convincing or highly suggestive evidence of an association with PTSD. Data from prospective studies were less conclusive. Our results have the potential of helping refine PTSD prediction models and contributing to the design of prevention strategies.

Neurochemical effects of oxytocin in people at clinical high risk for psychosis.

Alterations in neurochemical metabolites are thought to play a role in the pathophysiology of psychosis onset. Oxytocin, a neuropeptide with prosocial and anxiolytic properties, modulates glutamate neurotransmission in preclinical models but its neurochemical effects in people at high risk for psychosis are unknown. We used proton magnetic resonance spectroscopy (1H-MRS) to examine the effects of intranasal oxytocin on glutamate and other metabolites in people at Clinical High Risk for Psychosis (CHR-P) in a double-blind, placebo-controlled, crossover design. 30 CHR-P males were studied on two occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on the concentration of glutamate, glutamate+glutamine and other metabolites (choline, N-acetylaspartate, myo-inositol) scaled to creatine were examined in the left thalamus, anterior cingulate cortex (ACC) and left hippocampus, starting approximately 75, 84 and 93 min post-dosing, respectively. Relative to placebo, administration of oxytocin was associated with an increase in choline levels in the ACC (p=.008, Cohen's d = 0.54). There were no other significant effects on metabolite concentrations (all p>.05). Our findings suggest that, at ∼75-99 min post-dosing, a single dose of intranasal oxytocin does not alter levels of neurochemical metabolites in the thalamus, ACC, or hippocampus in those at CHR-P, aside from potential effects on choline in the ACC.

Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis.

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20-35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22-28 and at 30-36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

Semistructured Interview for Bipolar At Risk States (SIBARS).

The external prognostic accuracy of Bipolar At Risk (BAR) criteria is undetermined and no psychometric tools are available to measure them. We present here three studies that overcome these limitations. Study 1 and 2 investigated the prognostic accuracy (Harrell's C) of the original BAR and revised Bipolar At Risk States (BARS) criteria respectively for the prediction of bipolar disorders, using a retrospective cohort of individuals at Clinical High Risk for Psychosis (CHR-P). Study 3 validated externally the prognostic accuracy of a newly developed Semistructured Interview of At Risk Bipolar States (SIBARS) in an independent prospective CHR-P cohort. In study 1 (n = 205), those meeting BAR criteria had an increased risk of developing bipolar disorders (HR = 5.30) relative to those not meeting them, but the prognostic accuracy was poor (Harrell's C = 0.659). In study 2 (n = 205), those meeting the refined BARS criteria had a higher risk of developing bipolar disorders than those not meeting them (HR = 12.364), with an adequate prognostic accuracy (Harrell's C = 0.777). Study 3 (n = 71) confirmed that SIBARS criteria had an adequate prognostic accuracy (Harrell's C = 0.742) and clinical utility. Overall, these findings suggest that the SIBARS could be used for the detection of individuals at risk of developing bipolar disorders in CHR-P services.

What causes psychosis? An umbrella review of risk and protective factors.

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.

Diagnostic and Prognostic Significance of DSM-5 Attenuated Psychosis Syndrome in Services for Individuals at Ultra High Risk for Psychosis.

Background: The diagnostic and prognostic significance of the DSM-5-defined Attenuated Psychosis Syndrome (DSM-5-APS) in individuals undergoing an ultra high risk (UHR) clinical assessment for suspicion of psychosis risk is unknown. Methods: Prospective cohort study including all consecutive help-seeking individuals undergoing both a DSM-5-APS and a Comprehensive Assessment of At Risk Mental States (CAARMS 12/2006) assessment for psychosis risk at the Outreach and Support in South London (OASIS) UHR service (March 2013-April 2014). The diagnostic significance of DSM-5-APS was assessed with percent overall agreement, prevalence bias adjusted kappa, Bowker's test, Stuart-Maxwell test, residual analysis; the prognostic significance with Cox regression, Kaplan-Meier failure function, time-dependent area under the curve (AUC) and net benefits analysis. The impact of specific revisions of the DSM-5-APS was further tested. Result: In 203 help-seeking individuals undergoing UHR assessment, the agreement between the DSM-5-APS and the CAARMS 12/2006 was only moderate (kappa 0.59). Among 142 nonpsychotic cases, those meeting DSM-5-APS criteria had a 5-fold probability (HR = 5.379) of developing psychosis compared to those not meeting DSM-5-APS criteria, with a 21-month cumulative risk of psychosis of 28.17% vs 6.49%, respectively. The DSM-5-APS prognostic accuracy was acceptable (AUC 0.76 at 24 months) and similar to the CAARMS 12/2006. The DSM-5-APS designation may be clinically useful to guide the provision of indicated interventions within a 7%-35% (2-year) range of psychosis risk. The removal of the criterion E or C of the DSM-5-APS may improve its prognostic performance and transdiagnostic value. Conclusions: The DSM-5-APS designation may be clinically useful in individuals accessing clinical services for psychosis prevention.

Diagnostic and Prognostic Significance of Brief Limited Intermittent Psychotic Symptoms (BLIPS) in Individuals at Ultra High Risk.

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.

Deconstructing Pretest Risk Enrichment to Optimize Prediction of Psychosis in Individuals at Clinical High Risk.

IMPORTANCE: Pretest risk estimation is routinely used in clinical medicine to inform further diagnostic testing in individuals with suspected diseases. To our knowledge, the overall characteristics and specific determinants of pretest risk of psychosis onset in individuals undergoing clinical high risk (CHR) assessment are unknown. OBJECTIVES: To investigate the characteristics and determinants of pretest risk of psychosis onset in individuals undergoing CHR assessment and to develop and externally validate a pretest risk stratification model. DESIGN, SETTING, AND PARTICIPANTS: Clinical register-based cohort study. Individuals were drawn from electronic, real-world, real-time clinical records relating to routine mental health care of CHR services in South London and the Maudsley National Health Service Trust in London, United Kingdom. The study included nonpsychotic individuals referred on suspicion of psychosis risk and assessed by the Outreach and Support in South London CHR service from 2002 to 2015. Model development and validation was performed with machine-learning methods based on Least Absolute Shrinkage and Selection Operator for Cox proportional hazards model. MAIN OUTCOMES AND MEASURES: Pretest risk of psychosis onset in individuals undergoing CHR assessment. Predictors included age, sex, age × sex interaction, race/ethnicity, socioeconomic status, marital status, referral source, and referral year. RESULTS: A total of 710 nonpsychotic individuals undergoing CHR assessment were included. The mean age was 23 years. Three hundred ninety-nine individuals were men (56%), their race/ethnicity was heterogenous, and they were referred from a variety of sources. The cumulative 6-year pretest risk of psychosis was 14.55% (95% CI, 11.71% to 17.99%), confirming substantial pretest risk enrichment during the recruitment of individuals undergoing CHR assessment. Race/ethnicity and source of referral were associated with pretest risk enrichment. The predictive model based on these factors was externally validated, showing moderately good discrimination and sufficient calibration. It was used to stratify individuals undergoing CHR assessment into 4 classes of pretest risk (6-year): low, 3.39% (95% CI, 0.96% to 11.56%); moderately low, 11.58% (95% CI, 8.10% to 16.40%); moderately high, 23.69% (95% CI, 16.58% to 33.20%); and high, 53.65% (95% CI, 36.78% to 72.46%). CONCLUSIONS AND RELEVANCE: Significant risk enrichment occurs before individuals are assessed for a suspected CHR state. Race/ethnicity and source of referral are associated with pretest risk enrichment in individuals undergoing CHR assessment. A stratification model can identify individuals at differential pretest risk of psychosis. Identification of these subgroups may inform outreach campaigns and subsequent testing and eventually optimize psychosis prediction.

[The clinical, psychopathological and neurobiological features of salience]. / Salienza: clinica, psicopatologia e neurobiologia.

Salience is an integration process that allows to give attention to internal or external stimuli which grow in relevance becoming able to influence thoughts and behaviors. On the contrary, aberrant salience leads to the attribution of significance to innocuous or natural stimuli. Aberrant salience plays a basic role in the early phases of psychosis, mainly in the development of "revelation", but it also contributes to maintain the disorder. Nowadays, the current and specific instrument to assess this symptom is the Aberrant Salience Inventory (ASI) both in clinical and non-clinical samples. Furthermore, the documented interrelation between the dysregulation of the salience attribution and the dopamine system could explain the correlation between aberrant salience, substance abuse and development of psychotic symptoms. The assessment of aberrant salience in people with prodromal symptoms or at risk to develop them, could be a noteworthy clinical tool both for diagnostic and prognostic purposes. The aim of this review is to analyze the concept of salience: definition, historical and psychopathological background, neurobiological underpinnings, association with substance abuse, assessing instruments and clinical features.