Staging 2.0: refining transdiagnostic clinical staging frameworks to enhance reliability and utility for youth mental health.

Globally, 75% of depressive, bipolar, and psychotic disorders emerge by age 25 years. However, these disorders are often preceded by non-specific symptoms or attenuated clinical syndromes. Difficulties in determining optimal treatment interventions for these emerging mental disorders, and uncertainties about accounting for co-occurring psychopathology and illness trajectories, have led many youth mental health services to adopt transdiagnostic clinical staging frameworks. In this Health Policy paper, an international working group highlights ongoing challenges in applying transdiagnostic staging frameworks in clinical research and practice, and proposes refinements to the transdiagnostic model to enhance its reliability, consistent recording, and clinical utility. We introduce the concept of within-stage heterogeneity and describe the advantages of defining stage in terms of clinical psychopathology and stage modifiers. Using examples from medicine, we discuss the utility of categorising stage modifiers into factors associated with progression (ie, potential predictors of stage transition) and extension (ie, factors associated with the current presentation that add complexity to treatment selection). Lastly, we suggest how it is possible to revise the currently used transdiagnostic staging approach to incorporate these key concepts, and how the revised framework could be applied in clinical and research practice.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Baseline Antipsychotic Dose and Transition to Psychosis in Individuals at Clinical High Risk: A Systematic Review and Meta-Analysis.

Importance: Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics is associated with an increased risk of transitioning to psychosis in individuals at clinical high-risk for psychosis (CHR-P) and that such effect is not a result of pretest risk enrichment. However, to maximize its translational utility for prognostic stratification in clinical practice, testing for the potential presence of a dose-response association is crucial. Objective: To test whether the negative prognostic effect of baseline antipsychotic exposure in individuals at CHR-P follows a dose-effect pattern, as indicated by mean chlorpromazine equivalent doses (CPZ-ED). Data Sources: MEDLINE and Cochrane Library, performed up to August 31, 2023, searching for English-language studies on individuals at CHR-P reporting data on exposure to antipsychotics at baseline and detailed information on dosage by transition status. Study Selection: Studies that provided information on antipsychotic exposure at baseline and included detailed dosage data categorized by transition status. Data Extraction and Synthesis: Eligible studies were identified following PRISMA guidelines and evaluated independently by 2 reviewers with the Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. Main Outcomes and Measures: The primary outcome was transition to psychosis in individuals at CHR-P who were receiving antipsychotic treatment at baseline, measured by baseline mean CPZ-ED in individuals at CHR-P who transitioned to psychosis compared to those who did not. Results: Eight studies were included in the systematic review and meta-analysis. Among 290 individuals at CHR-P (mean [SD] age, 19.4 [2.6] years) who were exposed to antipsychotics at baseline and remained in contact up to the completion of the study, 66 converted to psychosis and 224 did not. The mean CPZ-ED ranged 60 to 395 mg/d in those who converted and 13 to 224 mg/d in those who did not. Those who converted to psychosis had higher CPZ-ED than those who did not in both the common-effects model (Hedges g, 0.41; 95% CI, 0.12-0.70; z, 2.78; P = .005) and in the random-effects model (Hedges g, 0.41; 95% CI, 0.15-0.67; z, 3.69; P = .008; τ2, 0.0). There was no relevant heterogeneity (Cochran Q, 3.99; df, 7; P = .78; I2, 0.0%; 95% CI, 0.0-68.0). The radial plot indicated a good fit of the model. Conclusions and Relevance: In individuals at CHR-P who were exposed to antipsychotics at baseline, those receiving higher antipsychotic doses demonstrated an increased likelihood of transitioning to psychosis. This meta-analytic evidence of putative dose-effect association confirms that baseline antipsychotic exposure and the corresponding dosage carry salient prognostic information that could improve current CHR-P criteria-based risk stratification at inception.

Baseline antipsychotic prescription and short-term outcome indicators in individuals at clinical high-risk for psychosis: Findings from the Parma At-Risk Mental States (PARMS) program.

AIM: The prognostic prediction of outcomes in individuals at clinical high-risk for psychosis (CHR-P) is still a significant clinical challenge. Among multiple baseline variables of risk calculator models, the role of ongoing pharmacological medications has been partially neglected, despite meta-analytical evidence of higher risk of psychosis transition associated with baseline prescription exposure to antipsychotics (AP) in CHR-P individuals. The main aim of the current study was to test the hypothesis that ongoing AP need at baseline indexes a subgroup of CHR-P individuals with more severe psychopathology and worse prognostic trajectories along a 1-year follow-up period. METHODS: This research was settled within the 'Parma At-Risk Mental States' program. Baseline and 1-year follow-up assessment included the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). CHR-P individuals who were taking AP medications at entry were included in the CHR-P-AP+ subgroup. The remaining participants were grouped as CHR-P-AP-. RESULTS: Hundred and seventy-eight CHR-P individuals (aged 12-25 years) were enrolled (91 CHR-P-AP+, 87 CHR-P-AP-). Compared to CHR-P AP-, CHR-P AP+ individuals had older age, greater baseline PANSS 'Positive Symptoms' and 'Negative Symptoms' factor subscores and a lower GAF score. At the end of our follow-up, CHR-P-AP+ subjects showed higher rates of psychosis transition, new hospitalizations and urgent/non-planned visits compared to CHRP- AP- individuals. CONCLUSIONS: In agreement with increasing empirical evidence, also the results of the current study suggest that AP need is a significant prognostic variable in cohorts of CHR-P individuals and should be included in risk calculators.

Debate: The prevention of psychosis in child and adolescent mental health services.

Psychopathological conditions in adolescence and young adulthood often result from an altered neurodevelopment already phenotypically expressed in childhood. Child and adolescent mental health services are ideally placed to intercept in the developmental trajectories of younger adolescents and contribute to the early detection of a risk for psychosis, as proposed by Salazar de Pablo and Arango (2023, Child and Adolescent Mental Health), opening a debate to which we contribute. The early detection of a specific risk for psychosis and of a broader risk for severe mental illness requires an understanding of the clinical staging of psychosis, neurodevelopmental antecedents of severe mental illness and of heterotypic trajectories between childhood phenotypes and adult disorders.

Baseline benzodiazepine exposure is associated with greater risk of transition in clinical high-risk for psychosis (CHR-P): a meta-analysis.

BACKGROUND: Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics and to antidepressants in individuals at clinical high-risk for psychosis (CHR-P) have opposite prognostic effects as regards imminent transition to psychosis, with antipsychotics associated with higher risk and antidepressants associated with a lower risk in comparison to not-exposed individuals. Despite their common use, baseline exposure to benzodiazepines (BDZ) in CHR-P has surprisingly received poor attention as a potential risk modulator for transition to psychosis. The current systematic review and meta-analysis were performed to fix such a knowledge gap. METHODS: Systematic scrutiny of Medline and Cochrane library, performed up to 31 December 2022, searching for English-language studies on CHR-P reporting numeric data about the sample, the transition outcome at a predefined follow-up time and raw data on BDZ baseline exposure in relation to such outcome. RESULTS: Of 1893 identified records, five studies were included in the systematic review and meta-analysis. The proportion of participants with exposure to BDZ at baseline ranged from 5.5% (one study) to 46.2%, with an average of 16.8%. At the end of the period of observation, i.e., the follow-up as reported in the study, 28.4% [95% confidence interval (CI) 19.7-39.1%] participants developed psychosis among the BDZ-exposed against 9.3% (7.3 to 11.9%) among the controls. CHR-P participants who were already under BDZ treatment at baseline had more than double chance of transition to psychosis than CHR-P participants who were BDZ-naïve. The risk ratio (RR) was 2.42 (95% CI 1.38-4.23) in the common effects model (z = 3.09; p = 0.002), and 2.40 (1.53 to 3.77) in the random-effects model (z = 5.40; p = 0.006; tau-squared = 0.0). There was no relevant heterogeneity: Cochran's Q = 1.49; df = 4; p = 0.828; I2 = 0.0% (95% CI 0.0-79%). Quality was good in four studies. CONCLUSIONS: Ongoing BDZ exposure at inception in CHR-P is associated with a higher risk of transition to psychosis at follow up. This meta-analytic association, which echoes a similar effect of baseline antipsychotic exposure, plausibly indicates that the clinicians' prescription of pharmacological intervention captures some form of prognostically-relevant information (e.g. an anxiety permeated mental state requiring BDZ prescription) that are not adequately encompassed by current CHR-P categorical criteria.

The temporal dynamics of transition to psychosis in individuals at clinical high-risk (CHR-P) shows negative prognostic effects of baseline antipsychotic exposure: a meta-analysis.

Meta-analytic evidence indicates that baseline exposure to antipsychotics (AP) in individuals at clinical high-risk for psychosis (CHR-P) is associated with an even higher risk of transition to psychosis. However, the temporal dynamics of such prognostic effect have not been clarified yet. This study was therefore designed to address this knowledge gap. We performed a systematic review and meta-analysis of all longitudinal studies published up to 31 December 2021 on CHR-P individuals identified according to a validated diagnostic procedure and reporting numeric data of transition to psychosis according to baseline antipsychotic exposure. 28 studies covering a total of 2405 CHR-P were included. 554 (23.0%) were exposed to AP at baseline, whereas 1851 (77.0%) were not. At follow-up (12 to 72 months), 182 individuals among AP-exposed (32.9%; 95% CI: 29.4% to 37.8%) and 382 among AP-naive CHR-P (20.6%; 18.8% to 22.8%) developed psychosis. Transition rates increased over time, with the best-fit for an ascending curve peaking at 24 months and reaching then a plateau, with a further increase at 48 months. Baseline AP-exposed CHR-P had higher transition risk at 12 months and then again at 36 and 48 months, with an overall higher risk of transition (fixed-effect model: risk ratio = 1.56 [95% CI: 1.32-1.85]; z = 5.32; p < 0.0001; Random-effect model: risk ratio = 1.56 [95% CI: 1.07-2.26]; z = 2.54; p = 0.0196). In conclusion, the temporal dynamics of transition to psychosis differ in AP-exposed vs. AP-naive CHR-P. Baseline AP exposure in CHR-P is associated with a persistently higher risk of transition at follow up, supporting the rationale for more stringent clinical monitoring in AP-exposed CHR-P. The insufficiency of more granular information in available primary literature (e.g., temporal and quantitative details of AP exposure as well as psychopathological dimensions in CHR-P) did not allow the testing of causal hypotheses on this negative prognostic association.

Anhedonia and suicidal ideation in young people with early psychosis: Further findings from the 2-year follow-up of the ReARMS program.

Hedonic deficits have been extensively studied in schizophrenia, but little is known about their association with suicidal ideation in early psychosis. The aim of this research was to examine the relationship between anhedonia and suicidal thoughts across a 2-year follow-up period in people with First Episode Psychosis (FEP) and at Ultra High Risk (UHR) of psychosis. Ninty-six UHR and 146 FEP, aged 13-35 years, completed the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Beck Depression Inventory-II (BDI-II). The BDI-II "Anhedonia" subscale score to assess anhedonia and the CAARMS "Depression" item 7.2 subscore to measure depression were used across the 2 years of follow-up. Hierarchical regression analyses were performed. No difference in anhedonia scores between FEP and UHR individuals was found. In the FEP group, a significant enduring association between anhedonia and suicidal ideation was found at baseline and across the follow-up, independent of clinical depression. In the UHR subgroup, the enduring relationship between anhedonia and suicidal thoughts were not completely independent from depression severity. Anhedonia is relevant in predicting suicidal ideation in early psychosis. Specific pharmacological and/or psychosocial interventions on anhedonia within specialized EIP program could reduce suicide risk overtime.

Obsessive-compulsive symptoms in the schizophrenia-spectrum: current developments in psychopathology research.

PURPOSE OF REVIEW: Schizophrenia-spectrum disorders (SSD) frequently involve symptoms that usually are ascribed to nonpsychotic disorder spectra, such as obsessive-compulsive symptoms (OCS). These symptoms can cause differential diagnostic challenges, particularly in early illness stages, and must be considered in treatment planning. In this review, we provide an overview of recent literature within the field of OCS in SSD, with a focus on psychopathology research. RECENT FINDINGS: OCS are seen in approximately a quarter of patients with SSD or at-risk mental state of psychosis. They are associated with more severe clinical features and specific temporal patterns of OCS may be linked with different clinical trajectories. However, the current definitions of OCS have been criticized for their overinclusive nature, which is a limiting step for differential diagnosis and more precise prognostic stratification. Specific phenomenological features, including a link with experiential anomalies (disorders of basic self), have been suggested to provide clinically relevant distinctions. SUMMARY: The presence of OCS in SSD is associated with more severe clinical features and invites a higher clinical attention and perspectival monitoring. Some findings suggest that more fine-grained psychopathological distinctions might be a viable clinical and research strategy to advance the field in the direction of precision psychiatry.

Pathology of imagination in an adolescent at clinical high-risk for psychosis.

We report a pathological imagination process in an adolescent at clinical high-risk for psychosis, associated with the presence of self-disorders. The subjective experience associated with pathological imagination helped in distinguishing such mental activity from intrusive thoughts of obsessive-compulsive patients; moreover, such anomalous imagination focused on other people may be an adaptive process triggered by negative emotionality against others that appear difficult or impossible to relationally grasp and attune with. In conclusion, anomalies of imaginations may occur within the schizophrenic spectrum since adolescent prodromal stages, associated with self-disorders.

Do antidepressants prevent transition to psychosis in individuals at clinical high-risk (CHR-P)? Systematic review and meta-analysis.

BACKGROUND: Emerging meta-analytical evidence indicates that baseline exposure to antipsychotics in individuals at clinical high-risk for psychosis (CHR-P) is associated with a higher risk of an imminent transition to psychosis. Despite their tolerability profile and potential beneficial effects, baseline exposure to antidepressants (AD) in CHR-P has surprisingly received far less attention as a potential risk modulator for transition to psychosis. The current systematic review and meta-analysis were performed to fix such a knowledge gap. METHODS: Systematic scrutiny of Medline and Cochrane library, performed up to 1 August 2021, searching for English-language studies on CHR-P reporting numeric data about the sample, the transition outcome at a predefined follow-up time and raw data on AD baseline exposure in relation to such outcome. RESULTS: Of 1942 identified records, 16 studies were included in the systematic review and meta-analysis. 26% of the participants were already exposed to AD at baseline; at the end of the follow-up 13.5% (95% CI 10.2-17.1%) of them (n = 448) transitioned to psychosis against 21.0% (18.9 to 23.3%) of non-AD exposed CHR-P (n = 1371). CHR-P participants who were already under AD treatment at baseline had a lower risk of transition than non-AD exposed CHR-P. The RR was 0.71 (95% CI 0.56-0.90) in the fixed-effects model (z = -2.79; p = 0.005), and 0.78 (0.58-1.05) in the random-effects model (z = -1.77; p = 0.096; tau-squared = 0.059). There was no relevant heterogeneity (Cochran's Q = 18.45; df = 15; p = 0.239; I2 = 18.7%). CONCLUSIONS: Ongoing AD exposure at inception in CHR-P is associated to a reduced risk of transition to psychosis at follow up.