Comparing interventions for early psychosis: a systematic review and component network meta-analysis.

Background: 'Early Intervention in Psychosis' (EIP) services have been associated with improved outcomes for early psychosis. However, these services are heterogeneous and many provide different components of treatment. The impact of this variation on the sustained treatment effects is unknown. Methods: We performed a systematic review and component network meta-analysis (cNMA) of randomised controlled trials (RCTs) that compared specialised intervention services for early psychosis. We searched CENTRAL (published and unpublished), EMBASE, MEDLINE, CINAHL, PsycINFO and Web of Science from inception to February 2023. Primary outcomes were negative and positive psychotic symptoms at 3-month and 1-year follow-up and treatment dropouts. Secondary outcomes were depressive symptoms and social functioning at 1-year follow-up. We registered a protocol for our study in PROSPERO (CRD42017057420). Findings: We identified 37 RCTs including 4599 participants. Participants' mean age was 25.8 years (SD 6.0) and 64.0% were men. We found evidence that psychological interventions (this component grouped all psychological treatment intended to treat, or ameliorate the consequences of, psychotic symptoms) are beneficial for reducing negative symptoms (iSMD -0.24, 95% CI -0.44 to -0.05, p = 0.014) at 3-month follow-up and may be associated with clinically relevant benefits in improving social functioning scores at 1-year follow-up (iSMD -0.52, 95% CI -1.05 to 0.01, p = 0.052). The addition of case management has a beneficial effect on reducing negative symptoms (iSMD -1.17, 95% CI -2.24 to -0.11, p = 0.030) and positive symptoms (iSMD -1.05, 95% CI -2.02 to -0.08, p = 0.033) at 1-year follow-up. Pharmacotherapy was present in all trial arms, meaning it was not possible to examine the specific effects of this component. Interpretation: Our findings suggest psychological interventions and case management in addition to pharmacotherapy as the core components of services for early psychosis to achieve sustained clinical benefits. Our conclusions are limited by the small number of studies and sparsely connected networks. Funding: National Institute for Health and Care Research.

The Translational Future of Stress Neurobiology and Psychosis Vulnerability: A Review of the Evidence.

Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise highrisk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, largescale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.

Psycho-Pharmacomicrobiomics: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we first explored whether psychotropics modify the gut microbiome; second, we investigated whether the gut microbiome affects the efficacy and tolerability of psychotropics. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched (November 2022) for longitudinal and cross-sectional studies that investigated the effect of psychotropics on the gut microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies) and in medicated compared with unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics included standardized mean difference and Higgins I2 for alpha diversity metrics and F and R values for beta diversity metrics. RESULTS: Nineteen studies were included in our synthesis; 12 investigated antipsychotics and 7 investigated antidepressants. Results showed significant changes in alpha (4 studies; standard mean difference: 0.12; 95% CI: 0.01-0.23; p = .04; I2: 14%) and beta (F = 15.59; R2 = 0.05; p < .001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; standard mean difference: 2.45; 95% CI: 0.50-4.40; p < .001, I2: 0%). CONCLUSIONS: Treatment with psychotropic medications is associated with altered gut microbiome composition, and the gut microbiome may in turn influence the efficacy and tolerability of these medications.

The role of mild stressors in children's cognition and inflammation: positive and negative impacts depend on timing of exposure.

Although the impact of stressful life events (SLEs) on mental health is well-established, the research on the impact of such stressors on cognitive outcomes has produced mixed results. Arguably, the timing and severity of exposure may play a key role. In this study, we shed light on the relationship between timing of exposure to relatively minor SLEs and cognitive ability in children, while taking into account the role of a plausible biological mediator: inflammation. Using data from the Avon Longitudinal Study of Parents and Children, a general population birth cohort, we explored the role of relatively minor SLEs, experienced during two crucial developmental stages: up to transition to school (1-4.5 years) and up to transition to puberty (5.5-8.5 years). We then tested if they may impact differently on inflammatory markers (serum C-reactive protein [CRP] and interleukin 6 [IL-6]) at age 9 and general intelligence, measured with the Wechsler Abbreviated Scale of Intelligence at age 15. Data (n = 4,525) were analyzed using path analysis while controlling for covariates. We found that when relatively minor stressful events were experienced up to transition to school they were significantly associated with higher IQ at age 15, whereas when experienced up to transition to puberty they were significantly associated with higher levels of IL-6 at age 9. Results were robust to adjustment for relevant covariates, including IQ at age 8. Mild stressors in childhood may result in positive (i.e., improved cognition) or negative (i.e., inflammation) outcomes depending on the timing of exposure.

Suicide-Related Knowledge among Italian Early Career Psychiatrists and Trainees: Results from a Cross-Sectional Survey.

The training of mental health professionals is an important component of suicide-prevention programs. A cross-sectional survey was conducted in different Italian regions to evaluate knowledge of, and attitudes toward, suicide as well as the experience of a patient's suicide or a suicide attempt in early career psychiatrists (ECPs) and trainees (N = 338). The Suicide Knowledge and Skills Questionnaire and the Impact of a Patient's Suicide on Professional and Personal Lives scale were administered. Furthermore, symptoms of intrusion, avoidance, and arousal were examined through the Impact of Event Scale in ECPs and trainees who had experienced the suicide of a patient or a suicide attempt. Participants with training were more confident in the clinical management of suicide-risk patients. The group with experience of a patient's suicide reported more suicide skills except for support and supervision. Finally, the participants who reported a patient's suicide presented a more conservative patient selection, difficulties in relationships, loss of self-esteem, dreams linked to suicide, intrusive thoughts of suicide, guilt, and anger. Our results show that knowledge of, and attitudes toward, suicide are essential in the management of suicide-risk patients.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.

Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

Investigating the pro-cognitive and anti-depressant efficacy of metformin: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The preclinical and clinical data regarding the efficacy of metformin as a pro-cognitive and anti-depressant therapy is mixed. We conducted a systematic review and meta-analysis of randomised controlled trials investigating the effects of metformin on cognition and depressive symptoms. METHODS: The study was conducted in accordance with PRISMA guidelines (PROSPERO identifier: CRD42020184547). PubMed and Web of Science were searched (inception through to May 6, 2020) for trials which measured the effects (change from baseline to end-of-treatment) of metformin on cognition and depressive symptoms, compared to either placebo or other oral antidiabetic therapies. When feasible, pooled meta-analytic estimates were provided using a random-effects model. RESULTS: Eight studies met the inclusion criteria: four assessed only cognition, three assessed only depressive symptoms, and one study assessed both cognition and depressive symptoms. Results suggested that metformin was significantly superior to placebo in improving cognitive function in patients suffering with clinical conditions associated with cognitive impairment (SMD: 0.80; 95%CI: 0.46 to 1.15; p < 0.001; N = 2 studies; I2 = 0.0%). One study reported an association between improved cognition and depressive symptoms in a cohort of patients with type 2 diabetes mellitus and depression. Two studies investigating metformin versus pioglitazone showed a superior, but not significant, effect of pioglitazone on depressive symptoms (SMD: 1.56; 95%CI: -0.52 to 3.56; p = 0.13;I2 = 94.9%; N = 2 studies). LIMITATIONS: Assessment of risk of bias identified two studies as having "some concerns". CONCLUSIONS: Our findings suggest that metformin might be re-purposed for the treatment of cognitive deficits in select clinical conditions.

Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis.

Reduced gut-microbial diversity ("gut dysbiosis") has been associated with an anhedonic/amotivational syndrome ("sickness behavior") that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10-1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27-1.70; P < 0.01, I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16-0.81; P < 0.01, I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25-1.48; P < 0.01; I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57-1.88; P < 0.01, I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.

ITAlian partnership for psychosis prevention (ITAPP): Improving the mental health of young people.

BACKGROUND: The European impact of the clinical high risk for psychosis (CHR-P) paradigm is constrained by the lack of critical mass (detection) to power prognostic and preventive interventions. METHODS: An ITAlian partnership for psychosis prevention (ITAPP) was created across CHR-P centers, which were surveyed to describe: (a) service, catchment area, and outreach; (b) service users; and (c) interventions and outcomes. Descriptive statistics and Kaplan-Meier failure function complemented the analyses. RESULTS: The ITAPP included five CHR-P clinical academic centers established from 2007 to 2018, serving about 13 million inhabitants, with a recruitment capacity of 277 CHR-P individuals (mean age: 18.7 years, SD: 4.8, range: 12-39 years; 53.1% females; 85.7% meeting attenuated psychotic symptoms; 85.8% without any substance abuse). All centers were multidisciplinary and included adolescents and young adults (transitional) primarily recruited through healthcare services. The comprehensive assessment of at-risk mental state was the most widely used instrument, while the duration of follow-up, type of outreach, and preventive interventions were heterogeneous. Across 205 CHR-P individuals with follow up (663.7 days ± 551.7), the cumulative risk of psychosis increased from 8.7% (95% CI 5.3-14.1) at 1 year to 15.9% (95% CI 10.6-23.3) at 2 years, 21.8% (95% CI 14.9-31.3) at 3 years, 34.8% (95% CI 24.5-47.9) at 4 years, and 51.9% (95% CI 36.3-69.6) at 5 years. CONCLUSIONS: The ITAPP is one of the few CHR-P clinical research partnerships in Europe for fostering detection, prognosis, and preventive care, as well as for translating research innovations into practice.

Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case-control study at 7 T.

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.

Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (ß = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (ß = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (ß = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (ß = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

The gut-microbiome as a target for the treatment of schizophrenia: A systematic review and meta-analysis of randomised controlled trials of add-on strategies.

The gut-microbiome has been hypothesised as a novel potential target for intervention for schizophrenia. We tested this hypothesis with a systematic review and meta-analysis of studies investigating the efficacy and acceptability of add-on strategies known to affect the gut-microbiome for the treatment of schizophrenia. Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobials, pre/probiotics, and faecal transplant in schizophrenia. Primary outcomes were severity of negative symptoms and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. We identified 28 eligible trials: 21 investigated antibiotics, 4 antimicrobials (Artemisinin, Artemether, and Sodium Benzoate), 3 pre/probiotics, none faecal transplant. Results showed no effect of D-Cycloserine (10 studies; SMD, -0.16; 95% CI -0.40, 0.08; P = .20; I2: 28.2%), Minocycline (7 studies; SMD: -0.35; 95% CI -0.70, 0.00; P = .05, I2:77.7%), other antibiotics (2 studies), probiotics alone (1 study), and Artemisinin (1 study) on negative symptoms of schizophrenia when compared to placebo. Limited evidence suggests efficacy on negative symptoms for Sodium benzoate (2 studies; SMD, -0.63; 95%CI -1.03, -0.23; P < .001; I2:0%), Artemether (1 study), and probiotics combined with Vitamin D (1 study) when compared to placebo. Acceptability of intervention was similar to placebo. Negative findings were mainly led by antibiotics trials, with paucity of evidence available on pre/probiotics. There is a need of expanding our knowledge on the clinical relevance of gut-microbiome-host interaction in psychosis before engaging in further trials.

Reprint of: Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood.

Psychotic-like experiences (PLEs) are part of a continuum of psychosis. Previous longitudinal studies highlighted a relationship between peripheral inflammation during childhood and onset of PLEs in adulthood. In this study, we tested if this association is mediated by internalising and externalising symptoms experienced during childhood and adolescence. To test this hypothesis, we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We investigated a subsample of 4525 individuals from this cohort with data on interleukin 6 (IL-6) and C-reactive protein (CRP) in childhood (age 9 years). We measured PLEs at age 18 years, and we used latent growth curve modelling to estimate longitudinal trajectories of internalising and externalising symptoms from ages 9 to 16 years. The individual predicted values of the intercept (set at baseline, 9 years) and the slope (rate of annual change) were then used in the mediation analysis. There was evidence for full mediation by the intercept of internalising symptoms. Our findings suggest that inflammation during childhood may be relevant for the future onset of PLEs via its association with a high level of internalising symptoms. These findings, although obtained from a non-clinical population, provide an additional step in advancing knowledge on the relationship between inflammation and symptoms of the psychosis continuum.

Specialised early intervention teams (extended time) for recent-onset psychosis.

BACKGROUND: Psychosis is an illness characterised by the presence of hallucinations and delusions that can cause distress or a marked change in an individual's behaviour (e.g. social withdrawal, flat or blunted effect). A first episode of psychosis (FEP) is the first time someone experiences these symptoms that can occur at any age, but the condition is most common in late adolescence and early adulthood. This review is concerned with FEP and the early stages of a psychosis, referred to throughout this review as 'recent-onset psychosis.' Specialised early intervention (SEI) teams are community mental health teams that specifically treat people who are experiencing, or have experienced, a recent-onset psychosis. SEI teams provide a range of treatments including medication, psychotherapy, psychoeducation, educational and employment support, augmented by assertive contact with the service user and small caseloads. Treatment is time limited, usually offered for two to three years, after which service users are either discharged to primary care or transferred to a standard adult community mental health team. Evidence suggests that once SEI treatment ends, improvements may not be sustained, bringing uncertainty about the optimal duration of SEI to ensure the best long-term outcomes. Extending SEI has been proposed as a way of providing continued intensive treatment and continuity of care, of usually up to five years, in order to a) sustain the positive initial outcomes of SEI; and b) improve the long-term trajectory of the illness. OBJECTIVES: To compare extended SEI teams with treatment as usual (TAU) for people with recent-onset psychosis. To compare extended SEI teams with standard SEI teams followed by TAU (standard SEI + TAU) for people with recent-onset psychosis. SEARCH METHODS: On 3 October 2018 and 22 October 2019, we searched Cochrane Schizophrenia's study-based register of trials, including registries of clinical trials. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) comparing extended SEI with TAU for people with recent-onset psychosis and all RCTs comparing extended SEI with standard SEI + TAU for people with recent-onset psychosis. We entered trials meeting these criteria and reporting usable data as included studies. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected studies, extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and their 95% CIs, or if assessment measures differed for the same construct, we calculated the standardised mean difference (SMD) with 95% CIs. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We included three RCTs, with a total 780 participants, aged 16 to 35 years. All participants met the criteria for schizophrenia spectrum disorders or affective psychoses. No trials compared extended SEI with TAU. All three trials randomly allocated people approximately two years into standard SEI to either extended SEI or standard SEI + TAU. The certainty of evidence for outcomes varied from low to very low. Our primary outcomes were recovery and disengagement from mental health services. No trials reported on recovery, and we used remission as a proxy. Three trials reported on remission, with the point estimate suggesting a 13% increase in remission in favour of extended SEI, but this included wide confidence intervals (CIs) and a very uncertain estimate of no benefit (RR 1.13, 95% CI 0.97 to 1.31; 3 trials, 780 participants; very low-certainty evidence). Two trials provided data on disengagement from services with evidence that extended SEI care may result in fewer disengagements from mental health treatment (15%) in comparison to standard SEI + TAU (34%) (RR 0.45, 95% CI 0.27 to 0.75; 2 trials, 380 participants; low-certainty evidence). There may be no evidence of a difference in rates of psychiatric hospital admission (RR 1.55, 95% CI 0.68 to 3.52; 1 trial, 160 participants; low-certainty evidence), or the number of days spent in a psychiatric hospital (MD -2.70, 95% CI -8.30 to 2.90; 1 trial, 400 participants; low-certainty evidence). One trial found uncertain evidence regarding lower global psychotic symptoms in extended SEI in comparison to standard SEI + TAU (MD -1.90, 95% CI -3.28 to -0.52; 1 trial, 156 participants; very low-certainty evidence). It was uncertain whether the use of extended SEI over standard SEI + TAU resulted in fewer deaths due to all-cause mortality, as so few deaths were recorded in trials (RR 0.38, 95% CI 0.09 to 1.64; 3 trials, 780 participants; low-certainty evidence). Very uncertain evidence suggests that using extended SEI instead of standard SEI + TAU may not improve global functioning (SMD 0.23, 95% CI -0.29 to 0.76; 2 trials, 560 participants; very low-certainty evidence). There was low risk of bias in all three trials for random sequence generation, allocation concealment and other biases. All three trials had high risk of bias for blinding of participants and personnel due to the nature of the intervention. For the risk of bias for blinding of outcome assessments and incomplete outcome data there was at least one trial with high or unclear risk of bias. AUTHORS' CONCLUSIONS: There may be preliminary evidence of benefit from extending SEI team care for treating people experiencing psychosis, with fewer people disengaging from mental health services. Evidence regarding other outcomes was uncertain. The certainty of evidence for the measured outcomes was low or very low. Further, suitably powered studies that use a consistent approach to outcome selection are needed, but with only one further ongoing trial, there is unlikely to be any definitive conclusion for the effectiveness of extended SEI for at least the next few years.

Specialised early intervention teams for recent-onset psychosis.

BACKGROUND: Psychosis is an illness characterised by the presence of hallucinations and delusions that can cause distress or a marked change in an individual's behaviour (e.g. social withdrawal, flat or blunted effect). A first episode of psychosis (FEP) is the first time someone experiences these symptoms that can occur at any age, but the condition is most common in late adolescence and early adulthood. This review is concerned with first episode psychosis (FEP) and the early stages of a psychosis, referred to throughout this review as 'recent-onset psychosis.' Specialised early intervention (SEI) teams are community mental health teams that specifically treat people who are experiencing, or have experienced a recent-onset psychosis. The purpose of SEI teams is to intensively treat people with psychosis early in the course of the illness with the goal of increasing the likelihood of recovery and reducing the need for longer-term mental health treatment. SEI teams provide a range of treatments including medication, psychotherapy, psychoeducation, and occupational, educational and employment support, augmented by assertive contact with the service user and small caseloads. Treatment is time limited, usually offered for two to three years, after which service users are either discharged to primary care or transferred to a standard adult community mental health team. A previous Cochrane Review of SEI found preliminary evidence that SEI may be superior to standard community mental health care (described as 'treatment as usual (TAU)' in this review) but these recommendations were based on data from only one trial. This review updates the evidence for the use of SEI services. OBJECTIVES: To compare specialised early intervention (SEI) teams to treatment as usual (TAU) for people with recent-onset psychosis. SEARCH METHODS: On 3 October 2018 and 22 October 2019, we searched Cochrane Schizophrenia's study-based register of trials, including registries of clinical trials. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) comparing SEI with TAU for people with recent-onset psychosis. We entered trials meeting these criteria and reporting useable data as included studies. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected studies, extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and their 95% CIs, or if assessment measures differed for the same construct, we calculated the standardised mean difference (SMD) with 95% CIs. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We included three RCTs and one cluster-RCT with a total of 1145 participants. The mean age in the trials was between 23.1 years (RAISE) and 26.6 years (OPUS). The included participants were 405 females (35.4%) and 740 males (64.6%). All trials took place in community mental healthcare settings. Two trials reported on recovery from psychosis at the end of treatment, with evidence that SEI team care may result in more participants in recovery than TAU at the end of treatment (73% versus 52%; RR 1.41, 95% CI 1.01 to 1.97; 2 studies, 194 participants; low-certainty evidence). Three trials provided data on disengagement from services at the end of treatment, with fewer participants probably being disengaged from mental health services in SEI (8%) in comparison to TAU (15%) (RR 0.50, 95% CI 0.31 to 0.79; 3 studies, 630 participants; moderate-certainty evidence). There was low-certainty evidence that SEI may result in fewer admissions to psychiatric hospital than TAU at the end of treatment (52% versus 57%; RR 0.91, 95% CI 0.82 to 1.00; 4 studies, 1145 participants) and low-certainty evidence that SEI may result in fewer psychiatric hospital days (MD -27.00 days, 95% CI -53.68 to -0.32; 1 study, 547 participants). Two trials reported on general psychotic symptoms at the end of treatment, with no evidence of a difference between SEI and TAU, although this evidence is very uncertain (SMD -0.41, 95% CI -4.58 to 3.75; 2 studies, 304 participants; very low-certainty evidence). A different pattern was observed in assessment of general functioning with an end of trial difference that may favour SEI (SMD 0.37, 95% CI 0.07 to 0.66; 2 studies, 467 participants; low-certainty evidence). It was uncertain whether the use of SEI resulted in fewer deaths due to all-cause mortality at end of treatment (RR 0.21, 95% CI 0.04 to 1.20; 3 studies, 741 participants; low-certainty evidence). There was low risk of bias for random sequence generation and allocation concealment in three of the four included trials; the remaining trial had unclear risk of bias. Due to the nature of the intervention, we considered all trials at high risk of bias for blinding of participants and personnel. Two trials had low risk of bias and two trials had high risk of bias for blinding of outcomes assessments. Three trials had low risk of bias for incomplete outcome data, while one trial had high risk of bias. Two trials had low risk of bias, one trial had high risk of bias, and one had unclear risk of bias for selective reporting. AUTHORS' CONCLUSIONS: There is evidence that SEI may provide benefits to service users during treatment compared to TAU. These benefits probably include fewer disengagements from mental health services (moderate-certainty evidence), and may include small reductions in psychiatric hospitalisation (low-certainty evidence), and a small increase in global functioning (low-certainty evidence) and increased service satisfaction (moderate-certainty evidence). The evidence regarding the effect of SEI over TAU after treatment has ended is uncertain. Further evidence investigating the longer-term outcomes of SEI is needed. Furthermore, all the eligible trials included in this review were conducted in high-income countries, and it is unclear whether these findings would translate to low- and middle-income countries, where both the intervention and the comparison conditions may be different.

Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood.

Psychotic-like experiences (PLEs) are part of a continuum of psychosis. Previous longitudinal studies highlighted a relationship between peripheral inflammation during childhood and onset of PLEs in adulthood. In this study, we tested if this association is mediated by internalising and externalising symptoms experienced during childhood and adolescence. To test this hypothesis, we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We investigated a subsample of 4525 individuals from this cohort with data on interleukin 6 (IL-6) and C-reactive protein (CRP) in childhood (age 9 years). We measured PLEs at age 18 years, and we used latent growth curve modelling to estimate longitudinal trajectories of internalising and externalising symptoms from ages 9 to 16 years. The individual predicted values of the intercept (set at baseline, 9 years) and the slope (rate of annual change) were then used in the mediation analysis. There was evidence for full mediation by the intercept of internalising symptoms. Our findings suggest that inflammation during childhood may be relevant for the future onset of PLEs via its association with a high level of internalising symptoms. These findings, although obtained from a non-clinical population, provide an additional step in advancing knowledge on the relationship between inflammation and symptoms of the psychosis continuum.

Measuring Disturbance of the Endocannabinoid System in Psychosis: A Systematic Review and Meta-analysis.

Importance: The endocannabinoid system (ECS) is a lipid-based endogenous signaling system. Its relevance to psychosis is through the association between cannabis use and the onset and course of illness and through the antipsychotic properties of cannabidiol, a potential ECS enhancer. Objective: To conduct a systematic review and meta-analysis of the blood and cerebrospinal fluid (CSF) measures of the ECS in psychotic disorders. Data Sources: Web of Science and PubMed were searched from inception through June 13, 2018. The articles identified were reviewed, as were citations to previous publications and the reference lists of retrieved articles. Study Selection: Original articles were included that reported blood or CSF measures of ECS activity in patients with psychotic illnesses and in healthy controls. Data Extraction and Synthesis: PRISMA guidelines, independent extraction by multiple observers, and random-effects meta-analysis were used. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Main Outcomes and Measures: The clinical relevance of ECS modifications in psychotic disorders was investigated by (1) a quantitative synthesis of the differences in blood and CSF markers of the ECS between patients and healthy controls, and (2) a qualitative synthesis of the association of these markers with symptom severity, stage of illness, and response to treatment. Results: A total of 18 studies were included. Three individual meta-analyses were performed to identify the differences in ECS markers between people with schizophrenia and healthy controls. Five studies, including 226 patients and 385 controls, reported significantly higher concentrations of anandamide in the CSF of patients than controls (standardized mean difference [SMD], 0.97; 95% CI, 0.67-1.26; P < .001; I2 = 54.8%). In 9 studies, with 344 patients and 411 controls, significantly higher anandamide levels in blood were found in patients, compared with controls (SMD, 0.55; 95% CI, 0.05-1.04; P = .03; I2 = 89.6%). In 3 studies, involving 88 patients and 179 controls, a significantly higher expression of type 1 cannabinoid receptors on peripheral immune cells was reported in patients compared with controls (SMD, 0.57; 95% CI, 0.31-0.84; P < .001; I2 = 0%). Higher ECS tone was found at an early stage of illness in individuals who were antipsychotic naïve or free, and it had an inverse association with symptom severity and was normalized after successful treatment. Moderate to high level of heterogeneity in methods was found between studies. Conclusions and Relevance: Testing clinically relevant markers of the ECS in the blood and CSF of people with psychotic illness appears possible, and these markers provide useful biomarkers for the psychotic disorder; however, not all studies accounted for important variables, such as cannabis use. Trial Registration: PROSPERO identifier: CRD42018099863.

Unmet needs in patients with brief psychotic disorders: Too ill for clinical high risk services and not ill enough for first episode services.

BACKGROUND: Patients with acute and transient psychotic disorders (ATPDs) are by definition remitting, but have a high risk of developing persistent psychoses, resembling a subgroup of individuals at Clinical High Risk for Psychosis (CHR-P). Their pathways to care, treatment offered and long-term clinical outcomes beyond risk to psychosis are unexplored. We conducted an electronic health record-based retrospective cohort study including patients with ATPDs within the SLaM NHS Trust and followed-up to 8 years. METHODS: A total of 2561 ATPDs were included in the study. A minority were detected (8%) and treated (18%) by Early Intervention services (EIS) and none by CHR-P services. Patients were offered a clinical follow-up of 350.40 ± 589.90 days. The cumulative incidence of discharges was 40% at 3 months, 60% at 1 year, 69% at 2 years, 77% at 4 years, and 82% at 8 years. Treatment was heterogeneous: the majority of patients received antipsychotics (up to 52%), only a tiny minority psychotherapy (up to 8%). RESULTS: Over follow-up, 32.88% and 28.54% of ATPDS received at least one mental health hospitalization or one compulsory hospital admission under the Mental Health Act, respectively. The mean number of days spent in psychiatric hospital was 66.39 ± 239.44 days. CONCLUSIONS: The majority of ATPDs are not detected/treated by EIS or CHR-P services, receive heterogeneous treatments and short-term clinical follow-up. ATPDs have a high risk of developing severe clinical outcomes beyond persistent psychotic disorders and unmet clinical needs that are not targeted by current mental health services.

Personality features and vulnerability to stress: a case study on hyperhidrosis.

By using the Rorschach test, self-reports, and psychophysiological measures, we investigated thoroughly the psychological functioning in a hyperhidrotic case. Erica, a young female with hyperhidrosis, was assessed in three times at one-week distance. First, specific tools assessing potential psychological and affective distress, and the Rorschach test were administered. About one week later, Electrodermal Activity was recorded during the exposure to a mild laboratory stress-inducing task. Finally, a magnetic resonance imaging exam was performed in order to exclude medical conditions/neurological alterations for potential physiological anomalies. Erica tends to avoid living in the moment and prefers to experience close relationships in her inner world where she can rehearse the future and imagine different contexts and social situations without risks and embarrassment. She reports high capacities to perform goaldirected behaviors and clarity of emotions only in absence of stressful situations. The study has the merit to be the first to combine Rorschach data with physiological data in order to investigate the psychological functioning in a hyperhidrotic case.