Recent-onset Psychotic Disorder Research Articles

Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders – An individual patient data meta-analysis

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorderś(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI −0.55–0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05–0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17–0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptomś severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Levels of cytokines in the cerebrospinal fluid of patients with psychotic disorders compared to individually matched healthy controls

BackgroundIncreased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders. MethodsPatients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22–29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria’s except for the psychiatric diagnoses. All participants were aged 18–50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8. ResultsWe included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84–1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93–1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04–1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99–1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74–0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ). ConclusionsWe found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders.

73.4 Developing Sustainable Funding to Enable Implementation of Coordinated Specialty Care for Recent-Onset Psychotic Disorders

73.4 Developing Sustainable Funding to Enable Implementation of Coordinated Specialty Care for Recent-Onset Psychotic Disorders

Antineuronal antibodies in cerebrospinal fluid and serum of 104 patients with psychotic disorders compared to 104 individually matched healthy controls

BackgroundAntineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse. MethodsWe included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody. ResultsNo antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA. ConclusionsWe found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.

Cerebrospinal Fluid and Blood Biomarkers of Neuroinflammation and Blood-Brain Barrier in Psychotic Disorders and Individually Matched Healthy Controls.

Neuroinflammation and blood-brain barrier (BBB) dysfunction have been observed in patients with psychotic disorders. However, previous studies have mainly focused on selected patients and broad screenings of cerebrospinal fluid (CSF) of patients with recent onset psychosis compared to healthy controls are lacking. We included 104 patients with recent onset psychotic disorder and 104 individually matched healthy controls. CSF and blood were analyzed for readily available markers assessing neuroinflammation and BBB dysfunction. Primary outcomes were CSF white blood cell count (WBC), total protein, IgG Index, and CSF/serum albumin ratio. Secondary outcomes included additional markers of inflammation and BBB, and analyses of association with clinical variables. CSF/serum albumin ratio (Relative Mean Difference (MD): 1.11; 95%CI: 1.00-1.23; P = .044) and CSF/serum IgG ratio (MD: 1.17; 95%CI: 1.01-1.36; P = .036) was increased in patients compared to controls. A higher number of patients than controls had CSF WBC >3 cells/µl (seven vs. one, OR: 7.73, 95%CI: 1.33-146.49, P = .020), while WBC>5 cells/µl was found in two patients (1.9%) and no controls. Inpatients had higher serum WBC and neutrophil/lymphocyte ratio (all p-values for effect heterogeneity < .011). Mean CSF WBC (MD: 1.10; 95%CI: 0.97-1.26), protein (MD: 1.06; 95%CI: 0.98-1.15) and IgG index (MD: 1.05; 95%CI: 0.96-1.15) were not significantly elevated. When comparing a broad group of patients with psychotic disorders with healthy controls, patients had increased BBB permeability, more patients had high CSF WBC levels, and inpatients had increased peripheral inflammation, consistent with the hypothesis of a subgroup of patients with increased activation of the immune system.

The association between clinical symptoms and later subjective quality of life in individuals with ultra-high risk for psychosis and recent-onset psychotic disorder: A longitudinal investigation.

Subjective quality of life is a clinically relevant outcome that is strongly associated with the severity of clinical symptoms in individuals with ultra-high risk for psychosis and patients with recent-onset psychotic disorder. Our objective was to examine whether longitudinal changes in clinical symptoms are associated with quality of life in ultra-high risk individuals and patients with recent-onset psychotic disorder. Individuals with ultra-high risk and patients with recent-onset psychosis disorder were recruited in the same clinical settings at baseline and were followed up with more than 6 months and less than 5 years later. We assessed five factors of clinical symptoms using the positive and negative syndrome scale, and quality of life using the World Health Organization quality of life questionnaire-short form. We used multiple regression to examine the relationships between clinical symptoms and quality of life while controlling for diagnosis, follow-up period, age, and sex. Data were collected from 22 individuals with ultra-high risk and 27 patients with recent-onset psychosis disorder. The multiple regression analysis results indicated that the more severe anxiety/depression was at baseline, the poorer the quality of life at follow-up. Further, improvement of anxiety/depression and disorganized thoughts were associated with improvement in quality of life. The difference in diagnosis did not affect the association between clinical symptoms and quality of life. These findings suggest that the improvement of anxiety/depression and disorganized thoughts is important in the early stages of psychosis before it becomes severe, affecting the quality of life.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BackgroundThough many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls.MethodsWe will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME).DiscussionThis study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options.Trial registrationThe study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth.

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL.

Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: a trial design

BackgroundThe symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia.Methods/designIn total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted.DiscussionIt is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo.Trial registrationClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

M95. DSM-5 CLINICIAN-RATED DIMENSIONS OF PSYCHOSIS SYMPTOM SEVERITY: PSYCHOMETRIC PROPERTIES

BackgroundIn DSM-5, a number of “emerging measures” are included for further research and clinical evaluation. These patient assessment measures were developed to be administered at the initial patient interview and to monitor treatment progress. One of these instruments is the Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). Using this instrument, a clinician can rate the severity of eight symptom dimensions of psychotic disorders. The psychometric properties and the applicability of the instrument in clinical practice have not yet been investigated. The current study aims to investigate the internal consistency, factor structure and external validity with other assessment instruments.MethodsThe CRDPSS measures eight symptom dimensions, namely Hallucinations, Delusions, Disorganized speech, Abnormal psychomotor behavior, Negative Symptoms, Impaired Cognition, Depression and Mania. Items are scored on a five-point scale ranging from “Not present” to “Present and Severe”. This interview has been applied in the Psychosis Recent Onset GRoningen Survey (PROGR-S), a diagnostic protocol for patients with a suspected recent-onset psychotic disorder (n = 164 in the current analysis). Besides the CRDPSS, scores on the Positive and Negative Syndrome Scale (PANSS), Health of Nations Outcome Measure (HoNOS), the Mongomery Asberg Depression Rating Scale (MADRS), Cambridge Cambridge Neuropsychological Test Automated Battery (CANTAB) and mini-Structural Clinical Assessment in Neuropsychiatry (mini-SCAN) were used for current analyses. The Crohnbach Alpha was calculated to investigate internal consistency, exploratory factor analysis was applied, and the convergent validity was investigated by calculating non-parametric correlations of the CRDPSS with similar items or subscales of the other instruments.ResultsThe Cronbach’s alpha of the CRDPSS was 0.36, indicating low internal consistency. Factor analysis resulted in three Factors: 1. Delusions/Mania, 2. Abnormal psychomotor behavior/Negative Symptoms/Impaired cognition, 3. Hallucinations/Depression. For hallucinations, Delusions, and Depression a Kendall’s tau of 0.35 – 0.45 was observed with the other instrument scores and for Impaired cognition tau = 0.6, indicating a weak to moderate association. Negative symptoms resulted in tau < 0.2 and for the other instruments tau < 0.1, but in these cases the measure of the other instruments was of questionable quality.DiscussionThe internal consistency of the CRDPSS was poor and factor analysis resulted in factors that differed to some extent from previous findings. Moreover, the convergent validity with other instruments was poor to moderate. In conclusion, based on first analyses the reliability and clinical applicability of the CRDPSS appears limited. Future studies should investigate inter-rater reliability, test-retest reliability, use more optimal measures to investigate convergent validity and use larger samples.

Racial-Ethnic Differences in Service Use Patterns Among Young, Commercially Insured Individuals With Recent-Onset Psychosis.

The aim of this study was to investigate racial-ethnic differences in use of mental health services and antipsychotic medication in the year following the recent onset of a psychotic disorder and to examine the role of household income as a proxy for socioeconomic status. Deidentified administrative claims data from the OptumLabs Data Warehouse were used to identify 8,021 commercially insured individuals ages 14 through 30 with a recent-onset psychotic disorder (January 1, 2011, through December 31, 2015). The authors compared mental health service use among African-American (11.5%), Hispanic (11.0%), and non-Hispanic white (77.4%) individuals during the year following an index diagnosis and adjusted these analyses for household income. The probability of any use of outpatient mental health services was lower among African-American (67.4%±1.4%) and Hispanic individuals (66.5%±1.5%) compared with non-Hispanic white patients (72.3%±0.6%; p<0.05 for each comparison). Among those who used services, African-American and Hispanic individuals had fewer mean outpatient mental health visits per year compared with non-Hispanic whites (9.7±0.7 and 10.2±0.7 versus 14.3±0.5, respectively, p<0.001 for each comparison). These racial-ethnic differences in service use remained after adjustment for household income. Among young, commercially insured individuals using outpatient services following an index diagnosis of psychotic disorder, African Americans and Hispanics received less intensive outpatient mental health care than their non-Hispanic white counterparts. Amid the upsurge of early intervention programs, special attention should be paid to increasing access to mental health services for racial-ethnic minority groups.

Expressive deficits and amotivation as mediators of the associations between cognitive problems and functional outcomes: Results from two independent cohorts

Many individuals with severe mental disorders have difficulties in vocational and social functioning, which are regarded the most important outcomes, together with clinical symptoms. To understand the underlying mechanisms, research is increasingly focused on factors influencing functional outcomes. One established association has been shown between cognition and community functioning with negative symptoms as a possible mediator. Although it has been shown that negative symptoms consist of two subdomains, thus far negative symptoms have been assessed as one unitary construct. This study considers for the first time subdomains of negative symptoms as putative mediators (expressive deficits, amotivation) of the association between cognition (neuro- and social cognition) and functional outcome (living situation, occupation, social functioning). We expected that specific subdomains of negative symptoms (e.g. amotivation) would mediate the effect of cognition on specific functional outcomes (e.g. social functioning) independently from illness duration. To assess this, we included two independent cohorts, consisting of participants with different illness duration.These two independent cohorts consisted of patients with a recent-onset psychotic disorder: PROGR-S (first time treated; N = 1129) and GROUP (illness duration preferably <5 years; N = 1200). Using linear regression, mediation analyses were performed with two cognition domains (neurocognition and social cognition) as predictors, negative symptoms (Expressive deficits and Amotivation as indexed with items from the Positive and Negative Syndrome Scale) as mediators and three measures of functional outcomes (living situation, occupation and social functioning) as outcome measures. The analyses were repeated with the same outcome measures three years later.Three main results were obtained. I) Both in the cross-sectional and longitudinal analyses, the associations of neurocognition (both cohorts) and social cognition (GROUP) with social functioning were mediated by amotivation. II) The association between cognition and living situation was mediated by Expressive deficits in one cohort (GROUP) but not in the cohort assessing first-episode psychosis (PROGR-S). III) The association between cognition and occupation was mediated by Amotivation in PROGR-S and by Expressive deficits in GROUP. ConclusionThe current results show a less robust mediating role for specific negative symptom domains regarding the associations of cognition with occupation and living situation that may depend on the duration of psychotic illness. However, Amotivation, mediates the association between cognition and social functioning, which holds true for patients experiencing a first-onset and patients with a longer illness duration alike. The results may have implications for the development of therapeutic approaches focusing on amotivation to improve social functioning. General scientific summaryThis study stresses the importance of distinguishing subdomains of negative symptoms, cognition and functioning. Our results show that specific negative symptom dimensions mediate the effects of cognition on specific functional outcomes.

Baseline Frontoparietal Task-Related BOLD Activity as a Predictor of Improvement in Clinical Symptoms at 1-Year Follow-Up in Recent-Onset Psychosis.

The early course of illness in psychotic disorders is highly variable, and predictive biomarkers of treatment response have been lacking. Trial and error remains the basis for care in early psychosis, and poor outcomes are common. Early prediction of nonimprovement in response to treatment could help identify those who would benefit from alternative and/or supplemental interventions. The goal of this study was to evaluate the ability of functional MRI (fMRI) measures of cognitive control-related brain circuitry collected at baseline to predict symptomatic response in patients after 1 year. Patients with recent-onset (<2 years) psychotic disorders (N=82) in early psychosis specialty care were classified as improvers (>20% improvement in total score on the Brief Psychiatric Rating Scale [BPRS] at 1-year follow-up compared with baseline) or as nonimprovers. Behavioral (d' context) and fMRI (proactive control-associated activation in a priori frontoparietal regions of interest) measures of cognitive control were then evaluated on their ability to predict BPRS improvement using linear and logistic regression. Cognitive control-associated measures significantly predicted BPRS improvement and improver status, with 70% positive predictive value, 60% negative predictive value, and 66% accuracy. Only the fMRI-based measure (and not the behavioral measure) significantly predicted status. These results suggest that frontoparietal activation during cognitive control performance at baseline significantly predicts subsequent symptomatic improvement during early psychosis specialty care. Potential implications for fMRI-based personalized patient treatment are discussed.

Self-esteem moderates affective and psychotic responses to social stress in psychosis: A virtual reality study

BackgroundHigher liability to psychosis is associated with low self-esteem and increased sensitivity to social stress. Recently, we reported a positive relation between liability to psychosis and affective and psychotic responses to social stress. This study investigated how self-esteem moderates paranoia, peak subjective distress and stress reactivity of people with different psychosis liability in response to social stressors in virtual reality. MethodsNinety-four individuals with lower (41 siblings and 53 controls) and 75 persons with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) explored five times a virtual café with various social stressors (crowdedness, ethnic minority status, and hostility). They rated momentary paranoia (State Social Paranoia Scale) after each experiment and subjective distress on a visual analogue scale before and after the experiments. Positive and negative self-esteem were assessed with the Self-Esteem Rating Scale. ResultsMomentary paranoia, peak subjective distress, and reactivity to social stressors were associated with negative self-esteem, but not positive self-esteem. Effects of both positive and negative self-esteem on psychotic and affective stress responses, but not stress reactivity, became significantly stronger when individuals were exposed to more stressful environments. Effects of self-esteem on momentary paranoia and peak subjective distress did not differ between the high liability and low liability group. Persons with lower psychosis liability had a stronger effect of negative self-esteem on stress reactivity than persons with higher liability. ConclusionsPositive and negative self-esteem may play an important role in affective and psychotic responses to social stress.

High psychosis liability is associated with altered autonomic balance during exposure to Virtual Reality social stressors

BackgroundSocial stressors are associated with an increased risk of psychosis. Stress sensitisation is thought to be an underlying mechanism and may be reflected in an altered autonomic stress response. Using an experimental Virtual Reality design, the autonomic stress response to social stressors was examined in participants with different liability to psychosis. MethodFifty-five patients with recent onset psychotic disorder, 20 patients at ultra-high risk for psychosis, 42 siblings of patients with psychosis and 53 controls were exposed to social stressors (crowdedness, ethnic minority status and hostility) in a Virtual Reality environment. Heart rate variability parameters and skin conductance levels were measured at baseline and during Virtual Reality experiments. ResultsHigh psychosis liability groups had significantly increased heart rate and decreased heart rate variability compared to low liability groups both at baseline and during Virtual Reality experiments. Both low frequency (LF) and high frequency (HF) power were reduced, while the LF/HF ratio was similar between groups. The number of virtual social stressors significantly affected heart rate, HF, LF/HF and skin conductance level. There was no interaction between psychosis liability and amount of virtual social stress. ConclusionHigh liability to psychosis is associated with decreased parasympathetic activity in virtual social environments, which reflects generally high levels of arousal, rather than increased autonomic reactivity to social stressors.

Long-acting injectable antipsychotics for the prevention of relapse in patients with recent-onset psychotic disorders: A systematic review and meta-analysis of randomized controlled trials.

This meta-analysis of randomized controlled trials (RCTs) investigated the advantages of long-acting injectable antipsychotics (LAI-APs) over oral antipsychotics (OAPs) with regard to efficacy and safety for patients with recent-onset psychotic disorders. Effect sizes and 95% confidence intervals (95%CIs) were calculated. We identified five RCTs (1022 patients, mean study duration=18±7.59 months) that compared LAI-APs (paliperidone or risperidone) with OAPs. Pooled LAI-APs did not outperform OAPs in terms of the preventing of relapse (N=3, n=875). However, there was significant heterogeneity (I2=76%), with one study showing no superiority of LAI-APs over OAPs [Malla 2013: risk ratio (RR)=1.83, 95%CI=0.70-4.77, n=77] and the other two studies showing LAI-APs to be superior [Schreiner 2015: [RR=0.71, 95%CI=0.51-0.97, number needed to treat (NNT)=-17, n=715, Subotnik 2015: RR=0.15, 95%CI=0.04-0.63, NNT=-4, n=83]. Pooling the studies, there were no significant differences between LAI-APs and OAPs in the improvement of Positive and Negative Syndrome Scale scores or in discontinuation due to all-cause, adverse events (AEs), and death, but LAI-APs outperformed OAPs in terms of discontinuation due to inefficacy (RR=0.34, NNT=-50) and nonadherence (RR=0.30, NNT=-33). However, the LAI-APs were associated with a higher incidence of at least one AE (RR=1.13) and tremor (RR=2.38) compared with OAPs.

Childhood trauma, psychosis liability and social stress reactivity: a virtual reality study.

Childhood trauma is associated with higher risk for mental disorders, including psychosis. Heightened sensitivity to social stress may be a mechanism. This virtual reality study tested the effect of childhood trauma on level of paranoid ideations and distress in response to social stress, in interaction with psychosis liability and level of social stress exposure. Seventy-five individuals with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) and 95 individuals with lower psychosis liability (42 siblings and 53 controls) were exposed to a virtual café in five experiments with 0-3 social stressors (crowded, other ethnicity and hostility). Paranoid ideation was measured after each experiment. Subjective distress was self-rated before and after experiments. Multilevel random regression analyses were used to test main effects of childhood trauma and interaction effects. Childhood trauma was more prevalent in individuals with higher psychosis liability, and was associated with higher level of (subclinical) psychotic and affective symptoms. Individuals with a history of childhood trauma responded with more subjective distress to virtual social stress exposures. The effects of childhood trauma on paranoia and subjective distress were significantly stronger when the number of virtual environmental stressors increased. Higher psychosis liability increased the effect of childhood trauma on peak subjective distress and stress reactivity during experiments. Childhood trauma is associated with heightened social stress sensitivity and may contribute to psychotic and affective dysregulation later in life, through a sensitized paranoid and stress response to social stressors.

Environmental Social Stress, Paranoia and Psychosis Liability: A Virtual Reality Study.

The impact of social environments on mental states is difficult to assess, limiting the understanding of which aspects of the social environment contribute to the onset of psychotic symptoms and how individual characteristics moderate this outcome. This study aimed to test sensitivity to environmental social stress as a mechanism of psychosis using Virtual Reality (VR) experiments. Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra high risk for psychosis, 42 siblings of patients with psychosis, and 53 controls walked 5 times in a virtual bar with different levels of environmental social stress. Virtual social stressors were population density, ethnic density and hostility. Paranoia about virtual humans and subjective distress in response to virtual social stress exposures were measured with State Social Paranoia Scale (SSPS) and self-rated momentary subjective distress (SUD), respectively. Pre-existing (subclinical) symptoms were assessed with the Community Assessment of Psychic Experiences (CAPE), Green Paranoid Thoughts Scale (GPTS) and the Social Interaction Anxiety Scale (SIAS). Paranoia and subjective distress increased with degree of social stress in the environment. Psychosis liability and pre-existing symptoms, in particular negative affect, positively impacted the level of paranoia and distress in response to social stress. These results provide experimental evidence that heightened sensitivity to environmental social stress may play an important role in the onset and course of psychosis.

Prefrontal NAA and Glx Levels in Different Stages of Psychotic Disorders: a 3T 1H-MRS Study.

H-Magnetic Resonance Spectroscopy (1H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A 1H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness, and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate.

Symptom assessment in early psychosis: The use of well-established rating scales in clinical high-risk and recent-onset populations

Symptom assessment in early psychosis research typically relies on scales validated in chronic schizophrenia samples. Our goal was to inform investigators who are selecting symptom scales for early psychosis research. We described measure characteristics, baseline scores, and scale inter-relationships in clinical-high-risk (CHR) and recent-onset psychotic disorder (RO) samples using the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms; for the CHR group only, we included the Scale of Prodromal Symptoms. For investigators selecting symptom measures in intervention or longitudinal studies, we also examined the relationship of symptom scales with psychosocial functioning. In both samples, symptom subscales in the same domain, across measures, were moderately to highly intercorrelated. Within all measures, positive symptoms were not correlated with negative symptoms, but disorganized symptoms overlapped with both positive and negative symptoms. Functioning was significantly related to negative and disorganized, but not positive, symptoms in both samples on most measures. Findings suggest strong overlap in symptom severity ratings among the most common scales. In recent-onset samples, each has strengths and weaknesses. In CHR samples, they appear to add little information above and beyond the SOPS.