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.

A Dynamical Systems View of Psychiatric Disorders-Theory: A Review.

Importance: Psychiatric disorders may come and go with symptoms changing over a lifetime. This suggests the need for a paradigm shift in diagnosis and treatment. Here we present a fresh look inspired by dynamical systems theory. This theory is used widely to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. Observations: In the dynamical systems view, we propose the healthy state has a basin of attraction representing its resilience, while disorders are alternative attractors in which the system can become trapped. Rather than an immutable trait, resilience in this approach is a dynamical property. Recent work has demonstrated the universality of generic dynamical indicators of resilience that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforests and tipping elements of the climate system. Other dynamical systems tools are used in ecology and climate science to infer causality from time series. Moreover, experiences in ecological restoration confirm the theoretical prediction that under some conditions, short interventions may invoke long-term success when they flip the system into an alternative basin of attraction. All this implies practical applications for psychiatry, as are discussed in part 2 of this article. Conclusions and Relevance: Work in the field of dynamical systems points to novel ways of inferring causality and quantifying resilience from time series. Those approaches have now been tried and tested in a range of complex systems. The same tools may help monitoring and managing resilience of the healthy state as well as psychiatric disorders.

A Dynamical Systems View of Psychiatric Disorders-Practical Implications: A Review.

Importance: Dynamical systems theory is widely used to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. It has been suggested that the same theory may be used to explain the nature and dynamics of psychiatric disorders, which may come and go with symptoms changing over a lifetime. Here we review evidence for the practical applicability of this theory and its quantitative tools in psychiatry. Observations: Emerging results suggest that time series of mood and behavior may be used to monitor the resilience of patients using the same generic dynamical indicators that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforest and tipping elements of the climate system. Other dynamical systems tools used in ecology and climate science open ways to infer personalized webs of causality for patients that may be used to identify targets for intervention. Meanwhile, experiences in ecological restoration help make sense of the occasional long-term success of short interventions. Conclusions and Relevance: Those observations, while promising, evoke follow-up questions on how best to collect dynamic data, infer informative timescales, construct mechanistic models, and measure the effect of interventions on resilience. Done well, monitoring resilience to inform well-timed interventions may be integrated into approaches that give patients an active role in the lifelong challenge of managing their resilience and knowing when to seek professional help.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Functional Outcomes Among Young People With Trajectories of Persistent Childhood Psychopathology.

Importance: Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies. Objective: To investigate the odds of poor outcomes in emerging adulthood (ages 17 to 20 years) for children with different mental health trajectories at ages 9 to 13 years. Design, Setting, and Participants: Growing Up in Ireland is a longitudinal, nationally representative population-based cohort study. Data collection began in August 2007 and was repeated most recently in September 2018. All results were weighted to account for sampling bias and attrition and were adjusted for socioeconomic factors. Data analysis took place from October 2022 to April 2023. Exposure: Four latent classes captured variation in mental health in children aged 9 and 13 years, based on the parent-completed Strengths and Difficulties Questionnaire. Classes included no psychopathology, internalizing, externalizing, and high (comorbid) psychopathology. Those who remained in the same class from ages 9 to 13 years were included. Main Outcomes and Measures: Poor functional outcomes in emerging adulthood were measured at approximate ages 17 years (range, 16 to 18 years) and 20 years (range, 19 to 21 years). Outcomes included poor mental health, poor physical health, social isolation, heavy substance use, frequent health service use, poor subjective well-being, and adverse educational/economic outcomes. Results: Of 5141 included participants, 2618 (50.9%) were male. A total of 3726 (72.5%) were classed as having no childhood psychopathology, 1025 (19.9%) as having persistent externalizing psychopathology, 243 (4.7%) as having persistent internalizing psychopathology, and 147 (2.9%) as having persistent high psychopathology. Having any childhood psychopathology was associated with poorer functional outcomes in emerging adulthood. The internalizing group had elevated odds of most outcomes except for heavy substance use (range of odds ratios [ORs]: 1.38 [95% CI, 1.05-1.81] for frequent health service use to 3.08 [95% CI, 2.33-4.08] for poor mental health). The externalizing group had significantly elevated odds of all outcomes, albeit with relatively small effect sizes (range of ORs: 1.38 [95% CI, 1.19-1.60] for frequent health service use to 1.98 [95% CI, 1.67-2.35] for adverse educational/economic outcomes). The high psychopathology group had elevated odds of all outcomes (nonsignificantly for frequent health service use), though with wide confidence intervals (range of ORs: 1.53 [95% CI, 1.06-2.21] for poor physical health to 2.91 [95% CI, 2.05-4.12] for poor mental health). Female participants with any psychopathology had significantly higher odds of poor physical health and frequent health service use compared with male participants with any psychopathology. Conclusions and Relevance: In this longitudinal cohort study, childhood psychopathology was associated with a widespread pattern of functional impairment in emerging adulthood. Findings point to the need for a wider range of preventive interventions in child and adolescent mental health services.

The clinical and functional outcomes of a large naturalistic cohort of young people accessing national early psychosis services.

AIMS: Services for individuals with a first episode of psychosis or at ultra-high risk of psychosis have become a treatment model of choice in mental health care. The longitudinal changes in clinical and functional outcomes as a result of real-world treatment remain under-reported. METHODS: We analysed data from first episode of psychosis and ultra-high risk services delivered across Australian primary youth mental health care services known as headspace between 19 June 2017 and 30 September 2019. Outcome measures were completed and entered into a minimum dataset every 90 days a participant was receiving treatment and included psychiatric symptomatology (Brief Psychiatric Rating Scale and psychological distress, K10) and psychosocial functioning (Social and Occupational Functioning Assessment Scale and My Life Tracker). Linear mixed-effects models were used to evaluate changes in outcome over time. RESULTS: Outcome data from a total of 1252 young people were evaluated (643 first episode of psychosis, 609 ultra-high risk). Of those who entered ultra-high risk services, 11.8% transitioned to first episode of psychosis services. Overall, substantial improvement in clinical (Brief Psychiatric Rating Scale, K10) and functional (Social and Occupational Functioning Assessment Scale, My Life Tracker) outcomes were seen across groups and outcomes. Ultra-high risk patients showed a greater reduction in distress symptoms, while first episode of psychosis patients experienced a greater reduction in positive psychosis symptoms. Although clinical outcomes showed a plateau effect after approximately 3 months of care, improvement in functional outcomes (Social and Occupational Functioning Assessment Scale, My Life Tracker) continued later in treatment. CONCLUSION: These findings support the use of real-time, real-world and low-cost administrative data to rigorously evaluate symptomatic and functional outcomes in early psychosis treatment settings. Findings that functional outcomes improve past the remittance of clinical outcomes also support the functional recovery focus of early psychosis services and remaining high levels of distress suggest the need for ultra-high risk services to extend beyond 6 months of care.

The potential impact of COVID-19 on psychosis: A rapid review of contemporary epidemic and pandemic research.

The COVID-19 outbreak may profoundly impact population mental health because of exposure to substantial psychosocial stress. An increase in incident cases of psychosis may be predicted. Clinical advice on the management of psychosis during the outbreak needs to be based on the best available evidence. We undertook a rapid review of the impact of epidemic and pandemics on psychosis. Fourteen papers met inclusion criteria. Included studies reported incident cases of psychosis in people infected with a virus of a range of 0.9% to 4%. Psychosis diagnosis was associated with viral exposure, treatments used to manage the infection, and psychosocial stress. Clinical management of these patients, where adherence with infection control procedures is paramount, was challenging. Increased vigilance for psychosis symptoms in patients with COVID-19 is warranted. How to support adherence to physical distancing requirements and engagement with services in patients with existing psychosis requires careful consideration. Registration details: https://osf.io/29pm4.

Polyunsaturated fatty acids in emerging psychosis: a safer alternative?

AIM: A promising approach of indicated prevention in individuals at increased risk of psychosis was based on the finding of potential neuroprotective properties of omega-3 polyunsaturated fatty acids (PUFAs). Considering the rising interest in omega-3 PUFA supplementation as preventive treatment strategy in young people at risk of psychosis, the question of safety issues must be addressed. METHODS: For this systematic review, a literature search for studies on omega-3 PUFAs for emerging psychosis with a focus on the safety profile was undertaken. Because limited data are available, information regarding potential side effects of omega-3 PUFAs was additionally derived from currently available data in psychotic disorders at different stages of the illness. Furthermore, helpful evidence from somatic disorders and healthy controls was used. RESULTS: In terms of safety issues, evidence from the randomized controlled trial in ultra-high-risk individuals and a variety of studies in schizophrenia patients strongly suggests that omega-3 PUFAs are safe and well tolerated even when used in relatively high doses. Most commonly occurring but clinically rarely significant are mild gastrointestinal symptoms; similarly, the slight risk of prolonged bleeding time has not been shown to be clinically relevant. Differential effects on metabolic parameters, most of which appear beneficial, have been reported. CONCLUSIONS: Taken together, one promising aspect of omega-3 PUFAs is that there seem to be no reports of relevant deleterious side effects in humans, even at high doses. The differential effects on lipid parameters and bleeding time are noteworthy and need further clarification.

Primary care and youth mental health in Ireland: qualitative study in deprived urban areas.

BACKGROUND: Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15-24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people's unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals' experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16-25 years) in primary care in deprived urban settings in Ireland. METHODS: The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres. RESULTS: We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care's longitudinal nature as a key asset in promoting treatment engagement. CONCLUSIONS: Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people's experience and developing complex interventions that promote early intervention are priorities.

Polyunsaturated fatty acids in emerging psychosis.

The role of polyunsaturated fatty acids and their metabolites for the cause and treatment of psychotic disorders are widely discussed. The efficacy as an augmenting agent in chronic schizophrenia seems to be small or not present, however epidemiological data, as well as some recent controlled studies in emerging psychosis point towards possible preventive effects of long-chain polyunsaturated fatty acids in early and very early stages of psychotic disorders and some potential secondary or tertiary beneficial long-term effects in later, more chronic stages, in particular for metabolic or extra-pyramidal side effects. In this comprehensive review, we describe the physiology and metabolism of polyunsaturated fatty acids, phospholipases, epidemiological evidence and the effect of these fatty acids on the brain and neurodevelopment. Furthermore, we examine the available evidence in indicated prevention in emerging psychosis, monotherapy, add-on therapy and tolerability. The neuroprotective potential of n-3 LC-PUFAs for indicated prevention, i.e. delaying transition to psychosis in high-risk populations needs to be further explored.

Setting the stage: from prodrome to treatment resistance in bipolar disorder.

Bipolar disorder is common, and both difficult to detect and diagnose. Treatment is contingent on clinical needs, which differ according to phase and stage of the illness. A staging model could allow examination of the longitudinal course of the illness and the temporal impact of interventions and events. It could allow for a structured examination of the illness, which could set the stage for algorithms that are tailored to the individuals needs. A staging model could further provide as structure for assessment, gauging treatment and outcomes. The model incorporates prodromal stages and emphasizes early detection and algorithm appropriate intervention where possible. At the other end of the spectrum, the model attempts to operationalize treatment resistance. The utility of the model will need to be validated by empirical research.

Monitoring the safe use of clozapine: a consensus view from Victoria, Australia.

Clozapine is an important antipsychotic agent that has a unique profile of clinical benefits, but that has also been associated with several serious and potentially life-threatening safety concerns. In order to minimise the impact of haematological adverse events, health professionals treating patients with clozapine are currently required to register their patients on a centrally administered data network and to conform to strict protocols. The consensus statement documented in this article extends existing protocols by recommending monitoring of patients treated with clozapine for additional adverse effects during treatment. This consensus statement reflects the current practice at five major public psychiatric hospitals in Victoria, Australia, for the monitoring and management of clozapine-related adverse events, and has been implemented at these sites because of emerging safety concerns associating clozapine with cardiovascular and metabolic adverse effects.

Pharmacotherapy of first-episode psychosis.

Early intervention in psychosis has attracted more attention in the last few years. The treatment of this phase of the disorders requires a specific and adapted approach. The issue of engaging the patient is so critical that it influences not only the choice of medication, but also the context and the way in which it is administered. In the case of a first admission, patients should be observed for 24-48 h without any antipsychotic treatment, in order to clarify the diagnosis and exclude the possibility that symptoms are caused by acute intoxication with illicit substances, for example. The diagnosis is often difficult and unstable. A dimensional, rather than a categorical approach, is usually more likely to be adopted. In recent years, atypical antipsychotics have become the most frequently used first-line treatment. They are less likely to cause secondary negative symptoms, cognitive impairments and dysphoria. They also appear to influence the course of depression and hostility/aggression better than conventional neuroleptics, have possibly mood-stabilising properties and, subjectively, are often better accepted by patients. On the risk side, prevalence of acute extrapyramidal side effects and possibly tardive dyskinesia are lower, compared to the older neuroleptics. Although, the risk for short-term weight gain, cardiovascular, and especially hyperglycaemic complications are somewhat higher for some of these antipsychotics. Finally, the dose should be adapted as it has been shown that patients presenting a first psychotic episode respond to a lower dose of antipsychotic. This article focuses on the pharmacotherapy of first-episode psychosis, on the basis of a computerised and a manual search for articles dealing with antipsychotic treatment of these patients. Findings are discussed and combined in clinical guidelines for first-episode affective and non-affective psychosis, for patients with incomplete recovery or treatment resistance, for cases of emergency and for side effects associated with antipsychotic treatment.