Review
Preventive interventions for individuals at ultra high risk for psychosis: An updated and extended meta-analysis

https://doi.org/10.1016/j.cpr.2021.102005Get rights and content

Highlights

  • This meta-analysis of 26 randomized controlled trials (N = 2351) examined the efficacy of interventions for ultra-high risk for psychosis.

  • Psychological interventions pooled, and cognitive behavioral, reduced transition to psychosis at 12-months and up to 4 years follow-up.

  • Treatments also had a small effect on attenuated positive psychotic symptoms at 12-months.

  • It is feasible to prevent or delay the onset of psychotic disorders through preventive interventions that are safe and effective.

  • A broad range of head-to-head treatment studies that target the full spectrum of clinical and functional outcomes is needed.

Abstract

Intervention at the earliest illness stage, in ultra or clinical high-risk individuals, or indicated prevention, currently represents the most promising strategy to ameliorate, delay or prevent psychosis. We review the current state of evidence and conduct a broad-spectrum meta-analysis of various outcomes: transition to psychosis, attenuated positive and negative psychotic symptoms, mania, depression, anxiety, general psychopathology, symptom-related distress, functioning, quality of life, and treatment acceptability. 26 randomized controlled trials were included. Meta-analytically pooled interventions reduced transition rate (risk ratio [RR] = 0.57, 95%CI 0.41–0.81) and attenuated positive psychotic symptoms at 12-months (standardized mean difference = −0.15, 95%CI = -0.28–-0.01). When stratified by intervention type (pharmacological, psychological), only the pooled effect of psychological interventions on transition rate was significant. Cognitive behavioral therapy (CBT) was associated with a reduction in incidence at 12-months (RR = 0.52, 95%CI = 0.33–0.82) and 18–48-months (RR = 0.60, 95%CI = 0.42–0.84), but not 6-months. Findings at 12-months and 18–48-months were robust in sensitivity and subgroup analyses. All other outcomes were non-significant. To date, effects of trialed treatments are specific to transition and, a lesser extent, attenuated positive symptoms, highlighting the future need to target other symptom domains and functional outcomes. Sound evidence supports CBT in reducing transition and the value of intervening at this illness stage.

Study registration

Research Registry ID: reviewregistry907.

Introduction

The development of the ultra-high risk (UHR) criteria, as part of a new early intervention approach to psychosis in the early 1990s, to detect individuals at high and imminent risk of developing first episode psychosis (FEP) (Yung et al., 1996) was a major advance in the potential for indicated prevention of psychosis. In fact, indicated prevention in psychosis is really a form of early intervention, given that these patients are already highly symptomatic, help-seeking and functionally impaired. True primary prevention (universal and selective) is, of course, not yet achievable. Since the first studies of this early stage of illness were conducted over two decades ago, rates of transition to psychosis in UHR samples have declined from an initial level of 40% (Yung et al., 2003), and it is currently estimated that 22% of UHR cases develop a psychotic disorder over the medium term (Fusar-Poli, Salazar de Pablo, et al., 2020). This decline has not been adequately explained (Hartmann et al., 2016; Nelson et al., 2016; Yung et al., 2007) but it could represent true incidence reduction due to the positive impact of improved clinical interventions (Nelson, Amminger, Thompson, et al., 2020). However, even those individuals who do not develop sustained psychosis remain at risk of a range of other adverse outcomes, including persistent attenuated positive psychotic symptoms (in 28–71% of cases), persistent negative psychotic symptoms (6–19%), persistent or incident non-psychotic disorders, notably anxiety and depression (70%), and impaired psychosocial functioning (~50%) (Beck et al., 2019; Devoe, Lu, et al., 2020; Lin et al., 2015; Yung, Nelson, McGorry, Wood, & Lin, 2019).

Although preventing the worsening of psychotic symptoms and transition to sustained psychosis is a core target of treatment, the heterogenous clinical trajectories and risk factors for psychosis (Fusar-Poli, Salazar de Pablo, et al., 2020; Polari et al., 2018) have led to the increasing recognition that treatment targets during the UHR stage should be broadened to address the range of clinical and functional needs (McGorry, Hartmann, Spooner, & Nelson, 2018; van der Gaag, van den Berg, & Ising, 2019; Yung, Nelson, Thompson, & Wood, 2010). The persistence of attenuated psychotic symptoms has been associated with a significantly worse clinical profile (compared to remitted cases) characterized by lower levels of functioning and more severe negative, anxiety and depressive symptoms (Cropley et al., 2016), while persistent negative symptoms have been associated with poor long-term social functioning and quality of life (Yung et al., 2019). In addition to consistent evidence indicating that UHR status is a marker of poor prognosis transdiagnostically (Addington, Cornblatt, et al., 2011; Hazan et al., 2020; Lin et al., 2015), recent evidence suggests that co-morbid depression reduces the probability of remitting from UHR status (Kline et al., 2018). Even when remission is achieved, functional levels often remain significantly impaired (de Wit et al., 2014), in line with evidence that functional impairment is not solely dependent on positive symptoms and psychosis onset (Carrión et al., 2013). Impairments in functioning often remain stable (Cornblatt et al., 2012), with nearly a quarter of UHR patients experiencing consistent levels of severe impairment (in addition to severe symptom severity) over a 2-year period (Allswede et al., 2019).

It was recognized very early on that UHR patients, while being in the early stages of a mental illness, were distressed, impaired and manifesting a clear-cut “need for care”, despite not meeting traditional thresholds for a psychotic diagnosis (Fusar-Poli et al., 2015). This recognition justified sustained efforts to improve the outcomes of UHR patients, and to examine the effectiveness of a range of preventive or proactive interventions in randomized controlled trials (RCTs). Initial meta-analyses confirmed that receiving any trial intervention (e.g., cognitive behavioral therapy [CBT], omega-3 fatty acids, antipsychotic medication) reduced transition to psychosis by 54% at 12-months (van der Gaag et al., 2013). The effects of psychological and pharmacological treatments on functioning, positive and negative symptoms, depression, mania, symptom-related distress and quality of life were not as promising (Hutton & Taylor, 2014; Stafford, Jackson, Mayo-Wilson, Morrison, & Kendall, 2013), although CBT was associated with a small effect on overall symptoms at 12-months (Hutton & Taylor, 2014). However, the lack of significant treatment effects on these outcomes may have been due in part to a lack of power, reflecting the limited number of trials available that examined non-transition outcomes. At present, only CBT has shown demonstrable effectiveness in UHR samples across several pairwise meta-analyses (Bosnjak Kuharic, Kekin, Hew, Rojnic Kuzman, & Puljak, 2019; Hutton & Taylor, 2014; Stafford et al., 2013; van der Gaag et al., 2013). In earlier meta-analyses, the pooled risk ratio (RR) for CBT varied from 0.47 (Stafford et al., 2013) to 0.54 (Hutton & Taylor, 2014), indicating that the risk of psychosis was reduced by 53% and 46%, respectively. The quality of evidence was moderate in Stafford et al. (2013), and Hutton and Taylor (2014) reported that all studies were at least concealed with random allocation. Recent pairwise meta-analytic evidence confirmed the efficacy of CBT on reducing transition (Devoe, Farris, Townes, & Addington, 2020), with trend-level reductions in attenuated psychotic symptoms (Devoe, Farris, Townes, & Addington, 2019a). This research has shown that it is possible to “bend the curve” on incidence and early course of psychotic illness to a certain extent.

Network meta-analyses (NMAs) have indicated that no treatment is currently superior to other treatments during the UHR stage of illness (Davies, Cipriani, et al., 2018; Davies, Radua, et al., 2018; Devoe et al., 2019a; Devoe, Farris, et al., 2020). This fact had been already recognized by earlier authors (Preti & Cella, 2010; van der Gaag et al., 2013). The absence of superiority does not mean that all interventions have been proven effective or ineffective. If we inspect efficacy in pairwise meta-analyses, then the effectiveness of CBT is statistically significant. Other interventions may be effective too, but just lack sufficient evidence to reach statistical power at the moment. In depression for instance, several different interventions, such as CBT, interpersonal therapy and problem-solving therapy, have comparable benefits without one intervention being superior to the other interventions (Barth et al., 2013).

Compared to pairwise meta-analysis, NMA does have the advantage of making optimal use of all available evidence by combining multiple comparisons in one analysis and by using direct and indirect evidence (i.e., the relative effectiveness of intervention A versus B is deduced by triangulation with intervention C). NMAs consequently produce more precise estimates of the differences between treatments, have greater statistical power, and can present consolidated comparisons among alternative treatments (Mavridis, Giannatsi, Cipriani, & Salanti, 2015). Heterogeneity is an issue in pairwise and network meta-analyses and is caused, among other factors, by variation within the same treatment modality (e.g., treatment dose), gender ratios, baseline symptom severity, therapist experience, and blind ratings. Transitivity (the assumption that potential effect modifiers are similarly distributed across comparisons) is an additional prerequisite for NMAs but is often violated as an assumption as patients could never have been randomized across multiple studies: patients can only be randomized over conditions within one study. Study samples can differ considerably despite meeting the same intake criteria, reflecting local circumstances. Multiple effect moderators may cause inconsistency between direct and indirect evidence. Although there is a statistical check on consistency, confidence intervals become very large if too many head-to-head comparisons are missing and have to be estimated indirectly. Meta-analysis attempts to gain statistical power to detect pooled effects, but NMAs may in fact lose power if too much evidence is estimated indirectly.

This is the likely scenario in two recent NMAs. The first found a trend-level effect for CBT on attenuated psychotic symptoms at 12-months in a pairwise meta-analysis and no significant effects in the NMA (Devoe et al., 2019a). The authors concluded that a lack of direct comparisons and a limited number of trials may have increased the chances of type 2 error. In another NMA, no effects on transition rates were found, but “many nodes were not well connected, with the corollary of limited ability to check for inconsistency, more imprecise estimates and wide 95% CIs…– suggesting that true effects may be substantially different from the estimates” (Davies, Cipriani, et al., 2018). This is an understatement. Of the 55 comparisons at 6-months, 54 were estimated indirectly and only one comparison was based on direct evidence. This indicates that the use of NMAs in the field of UHR for psychosis may well be premature. More direct comparisons between interventions are needed, so that findings can be interpreted with greater confidence. Another approach, based on clinical staging, is the use of sequential multiple assignment randomized trial (SMART) methodologies, where a stepwise intervention approach is offered, which mirrors the way clinicians work, guided by safety and choice considerations (Nelson et al., 2018).

A further issue of recent meta-analyses is that the bar or target for improvement has been set too high. A living meta-analysis (i.e., a meta-analysis that is continually updated) on CBT for preventing psychosis set the target at a minimum 50% transition reduction with a power of 0.90 (Fusar-Poli et al., 2019). The argument for such a high risk ratio is based on the fact that trials to date have not been powered to detect smaller effect sizes. CBT in fact produces a risk reduction rate of ~45% and a number needed to treat (NNT) of ~13 (van der Gaag et al., 2013), indicating that 13 patients would need to be treated to prevent transition in one additional patient. CBT therefore failed the arbitrary threshold set by the authors. The bar should be set at the level of an agreed clinically important benefit. In another recent pairwise meta-analysis of the range of UHR interventions trialed, the significant findings for CBT on transition to psychosis at 12-months (RR = 0.47, 95% CI 0.29–0.76; NNT = 13) were minimized (Bosnjak Kuharic et al., 2019). Setting such an inappropriately high bar in order to regard an intervention as being of value would not be accepted in other medical disciplines such as type 1 diabetes (Dayan, Korah, Tatovic, Bundy, & Herold, 2019) and cardiovascular disease (Chou et al., 2016; Saglietto et al., 2020). Atrial fibrillation catheter ablation has a 3.5 year hazard ratio (HR) of 0.64 (NNT = 33) to prevent heart failure/hospitalization; a HR of 0.63 (NNT = 59) to prevent stroke; and a HR of 0.62 (NNT = 28) to prevent mortality (Saglietto et al., 2020). Cholesterol reduction by statin has a RR of 0.70 (NNT = 72) to prevent composite cardiovascular outcomes; a RR of 0.64 (NNT = 123) to prevent myocardial infarction; a RR of 0.71 (NNT = 263) to prevent stroke; and a RR of 0.82 (NNT = 500) to prevent cardiovascular mortality (Chou et al., 2016). Both treatments are well accepted and used globally.

There is concern that the findings, and especially their interpretation, from recent network meta-analyses of non-superiority have created the perception that current interventions are not effective (McGorry et al., 2020; McGorry, Mei, Hartmann, Yung, & Nelson, 2021; McGorry & Nelson, 2020; Nelson et al., 2020; Nelson, Amminger, & McGorry, 2018; Nelson, Amminger, Thompson, et al., 2020). Although superiority over other therapeutic options has not been demonstrated via NMA, which is not unexpected, pairwise meta-analyses have shown clear benefits in favor of CBT. At a clinical level, differences in interpretation of the evidence pose challenges for frontline clinicians in ensuring that all patients are provided with evidence-based care. Since the publication of the recent meta-analyses, five new RCTs have been published, which includes a trial of integrated social- and neurocognitive remediation that reported medium sized effects on social functioning (Friedman-Yakoobian, Parrish, Eack, & Keshavan, 2021), an area that has been resistant to treatment in previous trials (Devoe, Farris, Townes, & Addington, 2019b). For these reasons, we believe a new pairwise meta-analysis with a wider focus and more careful interpretation is needed.

The present meta-analysis addresses a further issue. Transition rates have declined over the years (Formica et al., 2020), potentially due to increased attention to the early stages of psychosis onset, resulting in earlier detection and intervention (Nelson, Amminger, Thompson, et al., 2020). Consequently, intervention trials with lower transition rates lose statistical power. Our analysis has compared studies with low and high transition rates.

In the current work, we conducted pairwise meta-analyses with the updated database (searched until March 2020; most recent study published in September 2020) of all preventive interventions. We included reports with participants who fulfilled criteria of UHR or At Risk Mental State, who received any preventive treatment, compared against any control, in an RCT. Recognizing the need to broaden treatment outcomes for this population, the current work extended our previous 2013 meta-analysis of 10 studies with 1150 participants focused specifically on transition to psychosis (van der Gaag et al., 2013) to 26 studies with 2351 participants focused on 12 outcomes, which included the primary outcome of transition to psychosis and secondary outcomes encompassing symptomatology, functioning, quality of life and treatment acceptability.

Section snippets

Methods

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher, Liberati, Tetzlaff, Altman, & The Prisma Group, 2009) and was registered with Research Registry (ID: reviewregistry907).

Study selection

5095 unique records were identified from the searches (Fig. 1). Of the 162 full-text articles retrieved for further eligibility screening, 39 met criteria for inclusion, comprising 26 independent RCTs (23 published, the most recent in September 2020, and 3 unpublished). The PREVENT trial (Bechdolf et al., 2011) was excluded on advice from the study's corresponding author as it was in the process of publication. Two conference abstracts described the results from this trial, but did not contain

Main findings

In this comprehensive meta-analysis, we examined the effectiveness of interventions across 12 key outcomes, based on 26 independent trials involving 2351 UHR participants. Our main findings are that (1) receiving any type of trial intervention (pharmacological or psychological) significantly reduced the risk of transition to psychosis at 12-months by 43% compared to control conditions, (2) CBT has been trialed the most and there is robust evidence in support of its use in reducing rates of

Conclusions

Results from this meta-analysis demonstrate the real and proven benefit of UHR interventions, specifically on the outcomes of transition to psychosis and, to a lesser extent, attenuated positive psychotic symptoms. CBT was associated with a relatively durable reduction in transition rates at 12-months and over the medium-term that was robust to sensitivity and subgroup analyses. CBT is not only effective but also cost-effective and potentially cost-saving (Ising et al., 2015; Ising et al., 2017

Role of funding sources

PDM is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (1155508). BN is supported by an NHMRC Senior Research Fellowship (1137687). The funding source had no role in the study design, data collection, analysis and interpretation, writing of the manuscript, and in the decision to submit the article for publication.

Contributors

Authors MG, FS and BN outlined the meta-analysis. Authors CM, MB and MK conducted literature searches and provided summaries of previous research studies. Authors MG, FS and HPY conducted the statistical analysis. Authors PDM, MG, FS, BN and CM wrote the first draft of the manuscript and all authors contributed to and have approved the final manuscript.

Declaration of competing interest

PDM has received past unrestricted grant funding from Janssen-Cilag, Astra Zeneca, Eli Lilly, Novartis, and Pfizer, and honoraria for consultancy and teaching from Janssen-Cilag, Eli Lilly, Pfizer, Astra Zeneca, Roche, Bristol-Meyers Squibb, and Lundbeck. He has received grant funding from the Colonial Foundation, the National Health and Medical Research Council of Australia, NARSAD, the Stanley Foundation, NIH, Wellcome Trust, and the Australian and Victorian governments. PM and PA have been

Acknowledgements

We thank the authors who responded to requests concerning unpublished data.

Cristina Mei is a research academic at Orygen and The University of Melbourne. Her research has covered a range of topics, including early psychosis, youth mental health, and speech and language disorders.

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  • Cited by (0)

    Cristina Mei is a research academic at Orygen and The University of Melbourne. Her research has covered a range of topics, including early psychosis, youth mental health, and speech and language disorders.

    Mark van der Gaag is a clinical psychologist and Professor of Clinical Psychology at the Vrije Universiteit at Amsterdam, The Netherlands. He is a honorary member of the Dutch Association of Cognitive and Behavioral therapy as a recognition of his effort to develop and implement CBT for psychosis in the Netherlands. His research was in CBT for psychosis, PTSD treatment in people with florid psychosis and the last decade on the prevention of first episode of psychosis in help-seeking people with an at risk mental state. He published over 200 peer-reviewed papers in the field of psychosis.

    Barnaby Nelson is professor at the University of Melbourne and Head of Ultra High Risk for Psychosis Research at The Centre for Youth Mental Health. He is a clinical psychologist with particular interest in psychotic disorders. Professor Nelson's work focuses on early identification strategies and prediction of outcome and treatments for young people in the early stages of psychotic disorders. He has a particular interest in psychopathology and phenomenology; psychotherapy for psychotic disorders; and integrating neuroscience with phenomenology and clinical characteristics.

    Filip Smit is Professor of evidence-based public mental health at Amsterdam Public Health research institute, VU medical centre. In addition, he is Chief Scientist of Trimbos Institute, the Netherlands Institute of Mental Health and Addiction. He published over 200 peer-reviewed papers mainly in the field of preventive intervention in mental disorders.

    Hok Pan Yuen is a Senior Research Fellow at Orygen. He has a PhD and a MSc degree in Statistics. He is a highly experienced statistician with 30 years' experience having been the statistician and a chief investigator in numerous research projects and has played an important role in all relevant statistical aspects. Dr. Yuen is an author of more than 90 scientific publications in peer-reviewed journals, has acted as a reviewer for a number of journals and has been an assessor for research grant applications. He is currently the supervisor of a team of three database developers in the development and maintenance of a research project management system.

    Maximus Berger is a Research Fellow at Orygen and at the Centre for Youth Mental Health at the University of Melbourne. His main research interests are novel interventions for young people with emerging mental disorders, and understanding the role of peripheral biomarkers in predicting treatment response and outcome. Prior to joining Orygen in May 2018, he completed a medical degree at the University of Vienna, and a PhD at James Cook University.

    Marija Krcmar is a Project Manager at Orygen specialising in ultra-high risk for psychosis research. She coordinates study activities involved in the set-up, recruitment, assessment and follow up phases for a number of successful studies with a focus on early identification strategies, and prediction of outcome for young people identified as being at ultra-high risk for psychotic disorder.

    Paul French is Professor at the School of Health Sciences of the University of Manchester, United Kingdom and currently the Clinical Lead for Early Intervention in Psychosis services across Greater Manchester and Honorary Professor at Liverpool University. His research interests are on the development of novel interventions for people with psychosis and preventative interventions for young people with emerging mental health conditions. He continues to look for ways to embed research into practice and ensure that services deliver evidence-based interventions. Paul French is currently contributing to a number of National Institute of Health Research funded clinical trials.

    G. Paul Amminger is Head of Neuroprotective Biotherapies Research at Orygen, and Professor of Neurobiology and Neuroprotection in Emerging Mental Disorders at the Centre of Youth Mental Health, University of Melbourne. His research is devoted to testing neuroprotective agents to promote mental health in young people. He has been involved in 14 investigator initiated clinical trials and has >200 peer-reviewed publications.

    Andreas Bechdolf is Professor of Psychiatry and Psychotherapy at the University of Cologne and Chief Psychiatrist at the Vivantes Hospital am Urban and he Vivantes Hospital Friedrichshain Berlin/Charite Medicine, Berlin, Germany. He conducted several intervention trials in people with schizophrenia and in people at-risk of psychosis. His main research interests lay in early detection and intervention as well as in psychosocial interventions in people with severe mental disorders.

    Pim Cuijpers is Professor of Clinical Psychology at the Vrije Universiteit Amsterdam (The Netherlands), and Head of the Department of Clinical, Neuro and Developmental Psychology. Pim Cuijpers is specialised in conducting randomized controlled trials and meta-analyses on prevention and psychological treatments of common mental disorders. Much of his work is aimed at prevention of mental disorders, psychological treatments of depression and anxiety disorders, and Internet-delivered treatments. He has also published on a broad range of subjects in the field of clinical psychology, including psychoeducational treatment and early interventions, psychotic disorders, caregivers of dementia patients and bibliotherapy. Pim Cuijpers has published more than 900 peer-reviewed papers, chapters, reports and professional publications, including more than 700 papers in international peer-reviewed scientific journals (more than 150 as first author). According to Clarivate Analytics, he is one of the “most influential scientific minds” and is listed since 2014 in the “top 1% cited scientists in the area of psychiatry and psychology.

    Alison R. Yung is a Principal Research Fellow, Consultant Psychiatrist and Professor at the Centre for Youth Mental Health and Orygen, University of Melbourne and Professor of Psychiatry at the University of Manchester. She is acknowledged internationally as an authority in early psychosis. Her research has resulted in reform in the delivery of mental health services for young people thought to be at high risk of psychotic disorders (the Ultra High Risk group).

    Patrick D. McGorry is the Executive Director of Orygen, Professor of Youth Mental Health at The University of Melbourne, and a Founding Director of the National Youth Mental Health Foundation (headspace). He is a world‑leading clinician, researcher and reformer in early psychosis, early intervention and youth mental health. His work has played a critical role in the development of safe and effective treatments for, and innovative research into the needs of, young people with emerging mental disorders, notably psychotic and severe mood disorders. He has also played a major part in the transformational reform of mental health services to better serve the needs of young people with mental ill-health. He is Editor-in- Chief of Early Intervention in Psychiatry, and is a Fellow of the Australian Academy of Science, the Academy of the Social Sciences in Australia, and the Australian Academy of Health and Medical Sciences.

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    Authors contributed equally.

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