Clinical outcomes in individuals at clinical high risk of psychosis who do not transition to psychosis: a meta-analysis.

AIMS: The clinical outcomes of individuals at clinical high risk of psychosis (CHR-P) who do not transition to psychosis are heterogeneous and inconsistently reported. We aimed to comprehensively evaluate longitudinally a wide range of outcomes in CHR-P individuals not developing psychosis. METHODS: "Preferred Reporting Items for Systematic reviews and Meta-Analyses" and "Meta-analysis Of Observational Studies in Epidemiology"-compliant meta-analysis (PROSPERO: CRD42021229212) searching original CHR-P longitudinal studies in PubMed and Web of Science databases up to 01/11/2021. As primary analysis, we evaluated the following outcomes within CHR-P non-transitioning individuals: (a) change in the severity of attenuated psychotic symptoms (Hedge's g); (b) change in the severity of negative psychotic symptoms (Hedge's g); (c) change in the severity of depressive symptoms (Hedge's g); (d) change in the level of functioning (Hedge's g); (e) frequency of remission (at follow-up). As a secondary analysis, we compared these outcomes in those CHR-P individuals who did not transition vs. those who did transition to psychosis at follow-up. We conducted random-effects model meta-analyses, sensitivity analyses, heterogeneity analyses, meta-regressions and publication bias assessment. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS). RESULTS: Twenty-eight studies were included (2756 CHR-P individuals, mean age = 20.4, 45.5% females). The mean duration of follow-up of the included studies was of 30.7 months. Primary analysis: attenuated psychotic symptoms [Hedges' g = 1.410, 95% confidence interval (CI) 1.002-1.818]; negative psychotic symptoms (Hedges' g = 0.683, 95% CI 0.371-0.995); depressive symptoms (Hedges' g = 0.844, 95% CI 0.371-1.317); and functioning (Hedges' g = 0.776, 95% CI 0.463-1.089) improved in CHR-P non-transitioning individuals; 48.7% remitted at follow-up (95% CI 39.3-58.2%). Secondary analysis: attenuated psychotic symptoms (Hedges' g = 0.706, 95% CI 0.091-1.322) and functioning (Hedges' g = 0.623, 95% CI 0.375-0.871) improved in CHR-P individuals not-transitioning compared to those transitioning to psychosis, but there were no differences in negative or depressive symptoms or frequency of remission (p > 0.05). Older age was associated with higher improvements of attenuated psychotic symptoms (ß = 0.225, p = 0.012); publication years were associated with a higher improvement of functioning (ß = -0.124, p = 0.0026); a lower proportion of Brief Limited Intermittent Psychotic Symptoms was associated with higher frequencies of remission (ß = -0.054, p = 0.0085). There was no metaregression impact for study continent, the psychometric instrument used, the quality of the study or proportion of females. The NOS scores were 4.4 ± 0.9, ranging from 3 to 6, revealing the moderate quality of the included studies. CONCLUSIONS: Clinical outcomes improve in CHR-P individuals not transitioning to psychosis but only less than half remit over time. Sustained clinical attention should be provided in the longer term to monitor these outcomes.

Longitudinal outcome of attenuated positive symptoms, negative symptoms, functioning and remission in people at clinical high risk for psychosis: a meta-analysis.

BACKGROUND: Little is known about clinical outcomes other than transition to psychosis in people at Clinical High-Risk for psychosis (CHR-P). Our aim was to comprehensively meta-analytically evaluate for the first time a wide range of clinical and functional outcomes beyond transition to psychosis in CHR-P individuals. METHODS: PubMed and Web of Science were searched until November 2020 in this PRISMA compliant meta-analysis (PROSPERO:CRD42020206271). Individual longitudinal studies conducted in individuals at CHR-P providing data on at least one of our outcomes of interest were included. We carried out random-effects pairwise meta-analyses, meta-regressions, and assessed publication bias and study quality. Analyses were two-tailed with α=0.05. FINDINGS: 75 prospective studies were included (n=5,288, age=20.0 years, females=44.5%). Attenuated positive symptoms improved at 12 (Hedges' g=0.753, 95%CI=0.495-1.012) and 24 (Hedges' g=0.836, 95%CI=0.463-1.209), but not ≥36 months (Hedges' g=0.315. 95%CI=-0.176-0.806). Negative symptoms improved at 12 (Hedges' g=0.496, 95%CI=0.315-0.678), but not 24 (Hedges' g=0.499, 95%CI=-0.137-1.134) or ≥36 months (Hedges' g=0.033, 95%CI=-0.439-0.505). Depressive symptoms improved at 12 (Hedges' g=0.611, 95%CI=0.441-0.782) and 24 (Hedges' g=0.583, 95%CI=0.364-0.803), but not ≥36 months (Hedges' g=0.512 95%CI=-0.337-1.361). Functioning improved at 12 (Hedges' g=0.711, 95%CI=0.488-0.934), 24 (Hedges' g=0.930, 95%CI=0.553-1.306) and ≥36 months (Hedges' g=0.392, 95%CI=0.117-0.667). Remission from CHR-P status occurred in 33.4% (95%CI=22.6-44.1%) at 12 months, 41.4% (95%CI=32.3-50.5%) at 24 months and 42.4% (95%CI=23.4-61.3%) at ≥36 months. Heterogeneity across the included studies was significant and ranged from I2=53.6% to I2=96.9%. The quality of the included studies (mean±SD) was 4.6±1.1 (range=2-8). INTERPRETATION: CHR-P individuals improve on symptomatic and functional outcomes over time, but these improvements are not maintained in the longer term, and less than half fully remit. Prolonged duration of care may be needed for this patient population to optimize outcomes. FUNDING: None.

Examining service-user perspectives for the development of a good outcome checklist for individuals at clinical high risk for psychosis.

AIMS: Around 15% of patients at clinical high risk for psychosis (CHR-P) experience symptomatic remission and functional recovery at follow-up, yet the definition of a good outcome (GO) in this population requires further development. Outcomes are typically designed and rated by clinicians rather than patients, to measure adverse as opposed to GOs. Here we investigate how CHR-P subjects define a GO, with the aim of developing a checklist that could be used to measure GO in this clinical group. METHODS: A set of GO-focused questions were designed in collaboration with a service-user. CHR-P patients (n = 48) were asked to rate the importance of items that could indicate short-term (1 year) and long-term (5 years) GO. These items were then ranked using the relative importance index (RII). RESULTS: Patients rated improvement in subjective wellbeing (RII = 0.829) and non-specific presenting symptoms (RII = 0.817) amongst the factors most important for indicating GO in the short-term, and improved resilience (RII = 0.879) and negative symptoms (RII = 0.858) as key items for indicating long-term GO. Patients regarded building resilience (RII = 0.842) and having support from mental health services (RII = 0.833) as being protective for their mental health. These measures were included in a preliminary 12-item GO checklist (GO-12) for assessing GO in CHR-P subjects. CONCLUSIONS: Patient-defined measures of GO included items that are not incorporated into conventional measures of outcomes in CHR-P subjects, such as subjective wellbeing and resilience. Integrating patient-defined metrics of GO may improve the assessment of outcomes in the CHR-P population.

What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors.

Twenty percent of individuals at clinical high risk for psychosis (CHR-P) develop the disorder within 2 years. Extensive research has explored the factors that differentiate those who develop psychosis and those who do not, but the results are conflicting. The current systematic review and meta-analysis comprehensively addresses the consistency and magnitude of evidence for non-purely genetic risk and protective factors associated with the risk of developing psychosis in CHR-P individuals. Random effects meta-analyses, standardized mean difference (SMD) and odds ratio (OR) were used, in combination with an established stratification of evidence that assesses the association of each factor and the onset of psychotic disorders (from class I, convincing evidence to class IV weak evidence), while controlling for several types of biases. A total of 128 original controlled studies relating to 26 factors were retrieved. No factors showed class I-convincing evidence. Two further factors were associated with class II-highly suggestive evidence: attenuated positive psychotic symptoms (SMD = 0.348, 95% CI: 0.280, 0.415) and global functioning (SMD = -0.291, 95% CI: -0.370, -0.211). There was class III-suggestive evidence for negative psychotic symptoms (SMD = 0.393, 95% CI: 0.317, 0.469). There was either class IV-weak or no evidence for all other factors. Our findings suggest that despite the large number of putative risk factors investigated in the literature, only attenuated positive psychotic symptoms, global functioning, and negative psychotic symptoms show suggestive evidence or greater for association with transition to psychosis. The current findings may inform the refinement of clinical prediction models and precision medicine in this field.

Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis.

Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear. We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls. We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition. We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions. CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.

Towards a framework for good outcome in people at clinical high risk for psychosis: A Delphi consensus study.

BACKGROUND: Outcomes in people at clinical high risk for psychosis (CHRP) have usually been defined in terms of psychosis onset. However, within the subgroup of individuals who do not develop psychosis, some have persistent symptoms; while in others, symptoms resolve and functioning is restored. Currently, little is known about what predicts a good outcome (GO) in CHR-P individuals, partly because there is no consensus on how this should be defined. METHOD: The Delphi method was used to elicit the opinions of 46 experts to reach a consensus on factors that together could define GO in the CHR-P population. Three online surveys were implemented. The panel rated each survey item according to how important they thought it was as a measure of GO. Participants also answered open-ended questions on how GO should be determined, their responses were subject to content analysis. RESULTS: Ninety-eight items were endorsed by 80% of the panel as essential or important for a GO; these fell into 4 domains: Functioning; Symptoms; Distress/Suicidality; and Subjective Wellbeing. The individual item that was rated as the most important, was daily functioning. Themes emerged from the qualitative data, which corresponded to the Delphi domains, including 'functioning'; 'clinical factors; and 'user-defined outcomes'. CONCLUSIONS: A GO in CHR-P subjects can be defined by using a combination of measures from domains that reflect level of functioning; symptoms; distress/suicidality; and subjective wellbeing. These results provide a basis for a standardised definition of good outcome in people at clinical high risk of psychosis.

Poor medication adherence and risk of relapse associated with continued cannabis use in patients with first-episode psychosis: a prospective analysis.

BACKGROUND: Cannabis use following the onset of first-episode psychosis has been linked to both increased risk of relapse and non-adherence with antipsychotic medication. Whether poor outcome associated with cannabis use is mediated through an adverse effect of cannabis on medication adherence is unclear. METHODS: In a prospective analysis of data acquired from four different adult inpatient and outpatient units of the South London and Maudsley Mental Health National Health Service Foundation Trust in London, UK, 245 patients were followed up for 2 years from the onset of first-episode psychosis. Cannabis use after onset of psychosis was assessed by self-reports in face-to-face follow-up interviews. Relapse data were collected from clinical notes using the WHO Life Chart Schedule. This measure was also used to assess medication adherence on the basis of both face-to-face interviews and clinical notes. Patients were included if they had a diagnosis of first-episode non-organic or affective psychosis according to ICD-10 criteria, and were aged between 18 and 65 years when referred to local psychiatric services. We used structural equation modelling analysis to estimate whether medication adherence partly mediated the effects of continued cannabis use on risk of relapse. The primary outcome variable was relapse, defined as admission to a psychiatric inpatient unit after exacerbation of symptoms within 2 years of first presentation to psychiatric services. Information on cannabis use over the first 2 years after onset of psychosis was investigated as a predictor variable for relapse. Medication adherence was assessed as a mediator variable on the basis of clinical records and self-report data. Study researchers (TS, NP, EK, and EF) rated the adherence. FINDINGS: 397 patients who presented with their first episode of psychosis between April 12, 2002, and July 26, 2013 had a follow-up assessment until September, 2015. Of the 397 patients approached for followed up, 133 refused to take part in this study and 19 could not be included because of missing data. 91 (37%) of 245 patients with first-episode psychosis had a relapse over the 2 years of follow-up. Continued cannabis use predicted poor outcome, including risk of relapse, number of relapses, length of relapse, and care intensity at follow-up. In controlled structural equation modelling analyses, medication adherence partly mediated the effect of continued cannabis use on outcome, including risk of relapse (proportion mediated=26%, ßindirect effects=0·08, 95% CI 0·004 to 0·16), number of relapses (36%, ßindirect effects=0·07, 0·003 to 0·14), time until relapse (28%, ßindirect effects=-0·26, -0·53 to 0·001) and care intensity (20%, ßindirect effects=0·06, 0·004 to 0·11) but not length of relapse (6%, ßindirect effects=0·03, -0·03 to 0·09). The adjusted models explained moderate amounts of variance for outcomes defined as risk of relapse (R2=0·25), number of relapses (R2=0·21), length of relapse (R2=0·07), time until relapse (R2=0·08), and care intensity index (R2=0·15). INTERPRETATION: Between 20% and 36% of the adverse effects of continued cannabis use on outcome in psychosis might be mediated through the effects of cannabis use on medication adherence. Interventions directed at medication adherence could partly help mitigate the harm from cannabis use in psychosis. FUNDING: This study is funded by the National Institute of Health Research (NIHR) Clinician Scientist award.

Effect of continued cannabis use on medication adherence in the first two years following onset of psychosis.

Uncertainty exists whether the use of non-prescription psychoactive substances following onset of a first episode of psychosis (FEP), in particular cannabis use, affects medication adherence. Data from FEP patients (N=233) obtained through prospective assessments measured medication adherence and pattern of cannabis and other substance use in the first two years following onset of psychosis. Multiple logistic regression analyses were employed to compare the different substance use groups with regard to risk of medication non-adherence, while controlling for confounders. The proportion of non-adherent patients was higher in those who continued using high-potency forms of cannabis (skunk-like) following the onset (83%) when compared to never regular users (51%), corresponding to an Odds Ratio (OR) of 5.26[95% Confidence Interval (CI) 1.91-15.68]. No significant increases in risk were present in those who used cannabis more sporadically or used milder forms of cannabis (hash-like). Other substances did not make an independent contribution in this model, including cigarette use ([OR 0.88, 95% CI 0.41-1.89]), alcohol use ([OR 0.66, 95% CI 0.27-1.64]) or regular use of other illicit drugs ([OR 1.03, 95% CI 0.34-3.15]) following the onset. These results suggest that continued use of high-potency cannabis following the onset of psychosis may adversely affect medication adherence.

Association Between Continued Cannabis Use and Risk of Relapse in First-Episode Psychosis: A Quasi-Experimental Investigation Within an Observational Study.

IMPORTANCE: Cannabis use after first-episode psychosis is associated with poor outcomes, but the causal nature of this association is unclear. OBJECTIVE: To examine the precise nature of the association between continued cannabis use after the onset of psychosis and risk of relapse of psychosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services in South London, England, from April 12, 2002, to July 26, 2013, with first-episode psychosis. Longitudinal modeling (fixed-effects analysis, cross-lagged path analysis) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use, psychosis increasing the risk of cannabis use (reverse causation), or a causal effect of cannabis use on psychosis relapse. INTERVENTIONS: Exposure to cannabis within the first and second years after onset of psychosis. MAIN OUTCOMES AND MEASURES: The main outcome measure was relapse of psychosis, defined as subsequent hospitalization for psychosis. Effect of cannabis use status in the first year (Ct1) and second year (Ct2) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year (Rt1) and risk of relapse in the second year (Rt2) after psychosis onset. RESULTS: A total of 220 patients with first-episode psychosis were included in the analysis (mean [SD] age, 28.62 [8.58] years; age range, 18-65 years; 90 women [40.9%] and 130 men [59.1%]). Fixed-effects models that adjusted for time-variant (other illicit drug use, antipsychotic medication adherence) and time-invariant (eg, genetic or premorbid environment) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use (odds ratio, 1.13; 95% CI, 1.03-1.24). Change in the pattern of continuation significantly increased the risk (odds ratio, 1.07; 95% CI, 1.02-1.13), suggesting a dose-dependent association. Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse (Ct1→Rt2: ß = 0.44, P = .04) rather than an effect of relapse on subsequent cannabis use (Rt1→Ct2: ß = -0.29, P = .59). CONCLUSIONS AND RELEVANCE: These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding.

Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study.

BACKGROUND: Although cannabis use after a first episode of psychosis has been associated with relapse, little is known about the determinants of this most preventable risk factor for relapse of psychosis. Here we aimed to study whether the effects on outcome vary depending on the type of cannabis consumed and usage pattern. METHODS: In this observational study, we prospectively recruited and followed up patients aged 18-65 years who presented with their first episode of psychosis to psychiatric services in south London, London, UK. Relapse of psychosis within 2 years after onset of psychosis was defined as risk of subsequent admission to hospital. We classified patients into different patterns of cannabis use based on continuity of use after onset of psychosis, potency of cannabis consumed, and frequency of use after the onset of their illness. We used multiple regression analyses (logistic or binominal) to compare the different cannabis use groups and propensity score analysis to validate the results. FINDINGS: Between April 12, 2002, and July 26, 2013, 256 patients presented with a first episode of psychosis. We did follow-up assessments for these patients until September, 2015. Simple analyses showed that former regular users of cannabis who stopped after the onset of psychosis had the most favourable illness course with regards to relapse. In multiple analysis, continued high-frequency users (ie, daily use in all 24 months) of high-potency (skunk-like) cannabis had the worst outcome, indexed as an increased risk for a subsequent relapse (odds ratio [OR] 3·28; 95% CI 1·22-9·18), more relapses (incidence rate ratio 1·77; 95% CI 0·96-3·25), fewer months until a relapse occurred (b -0·22; 95% CI -0·40 to -0·04), and more intense psychiatric care (OR 3·16; 95% CI 1·26-8·09) after the onset of psychosis. INTERPRETATION: Adverse effects associated with continued use of cannabis after the onset of a first episode of psychosis depend on the specific patterns of use. Possible interventions could focus on persuading cannabis-using patients with psychosis to reduce use or shift to less potent forms of cannabis. FUNDING: National Institute for Health Research (NIHR).

Psychometric and neurobiological assessment of resilience in a non-clinical sample of adults.

BACKGROUND: Resilient individuals are capable of adjusting and coping successfully in the face of adversity. Efforts to assess resilience and its biomarkers have focused on individuals with a history of trauma and related disorders. OBJECTIVE: To psychologically assess resilience in a non-clinical community population through questionnaires, and analyse the associations between the psychological parameters and salivary cortisol and dehydroepiandrosterone sulphate (DHEA-S) as putative biomarkers of resilience. METHOD: An opportunistic sample (n=196) completed a cross-sectional survey assessing resilience, self-reported depressive symptoms and anxiety, and possible correlates. A sub-sample (n=32) selected in order to maximise variation of mental health, provided saliva samples for enzyme-linked immunoassay (ELISA) detection of cortisol and DHEA-S. RESULTS: Resilience correlated negatively with depressive symptoms, trait anxiety and early life stress, and positively with self-efficacy, optimism, social support and wellbeing (all r>0.40; all p-values ≤0.001 except for early life stress: r=-0.20; p≤0.05). Resilience and DHEA-S concentrations correlated significantly (r=0.35; p≤0.05); this relationship remained stable after adjustment for demographics. Gender differences were observed for DHEA-S and cortisol (p≤0.05). CONCLUSION: Resilience is associated with positive aspects of psychological health and salivary DHEA-S, suggesting the latter can be treated as a biomarker of resilience in a non-clinical sample of adults.