You are to use the film either the film Heavenly Creatures a 1994 New Zealand film directed by Peter Jackson, or Darren Aronovskys Requiem for

Prevention of Psychosis Advances in Detection, Prognosis, and Intervention Paolo Fusar-Poli, MD, PhD; Gonzalo Salazar de Pablo, MD; Christoph U. Correll, MD; Andreas Meyer-Lindenberg, MD, PhD; Mark J. Millan, PhD; Stefan Borgwardt, MD, PhD; Silvana Galderisi, MD, PhD; Andreas Bechdolf, MD, PhD; Andrea Pfennig, MD, PhD; Lars Vedel Kessing, MD, DMSc; Therese van Amelsvoort, MD, PhD; Dorien H. Nieman, PhD; Katharina Domschke, MD, PhD; Marie-Odile Krebs, MD, PhD; Nikolaos Koutsouleris, MD; Philip McGuire, MD, PhD; Kim Q. Do, PhD; Celso Arango, MD, PhD

IMPORTANCE Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry.

OBJECTIVE To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations.

EVIDENCE REVIEW Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes.

FINDINGS In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered.

CONCLUSIONS AND RELEVANCE This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

JAMA Psychiatry. 2020;77(7):755-765. doi:10.1001/jamapsychiatry.2019.4779 Published online March 11, 2020.

Editorial page 672

Author Audio Interview

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Author Affiliations: Author affiliations are listed at the end of this article.

Corresponding Author: Paolo Fusar-Poli, MD, PhD, EPIC Lab, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, King’s College London, 16 De Crespigny Park, Fifth Floor, PO63, London SE5 8AF, United Kingdom ([email protected] kcl.ac.uk).

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D etection, assessment, and intervention before the onsetof a first episode of the disorder in individuals at clinicalhigh risk for psychosis (CHR-P) have the potential to maxi- mize the benefits of early interventions in psychosis.1,2 The CHR-P paradigm originated in Australia 25 years ago3 and has since gained enough traction to stimulate hundreds of research publications. These published studies have been summarized in evidence syn- thesis studies spanning different topics and have influenced sev- eral national4 and international5 clinical guidelines and diagnostic manuals (eg, DSM-56,7). Overall, CHR-P represents the most estab- lished preventive approach in clinical psychiatry; therefore, periodi- cally reviewing its progress and limitations is essential.

The rapid developments of detection, prognostic, and inter- vention-focused knowledge in the CHR-P field have not yet been in- tegrated into a comprehensive, evidence-based summary since a 2013 publication in JAMA Psychiatry.8 Produced by the European College of Neuropsychopharmacology Network on the Prevention of Mental Disorders and Mental Health Promotion,9 the present study aimed to provide the first umbrella review summarizing the most recent evidence in the CHR-P field. An additional objective was to provide evidence-based recommendations for the 3 core com- ponents that are necessary to implement the CHR-P paradigm in clini- cal practice: detection, prognosis, and intervention.10

Methods The protocol of this study was registered in PROSPERO (registra- tion No. CRD42019135880). This study was conducted in accor- dance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA) reporting guideline11 and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement12 (eTable 1 in the Supplement).

Search Strategy and Selection Criteria A multistep literature search was performed for articles published between January 1, 2013, and June 30, 2019 (eMethods 1 in the Supplement). Web of Science, Cochrane Central Register of Re- views, and Ovid/PsychINFO were searched for meta-analyses con- ducted in CHR-P individuals, and MEDLINE was used to search the reference lists of retrieved articles. The literature search, study se- lection, and data extraction were conducted independently by 2 of u s ( G . S.d . P. , P. F. – P. ) , a n d c o n s e n s u s wa s r e a c h e d t h r o u g h discussion.

Studies included were (1) meta-analyses (pairwise or network; aggregate or individual participant data) published as original in- vestigations, reviews, research letters, or gray literature without re- striction on the topic investigated13; (2) conducted in CHR-P indi- viduals (ie, individuals meeting ultra-high-risk and/or basic symptoms criteria) as established by validated psychometric instruments8

(eMethods 2 in the Supplement) without restriction on the type of comparison group; and (3) published in the past 6 years.

Studies excluded (1) were original studies, study protocols, sys- tematic reviews without quantitative analyses, and other non-meta- analy tical studies; (2) did not formally assess and selec ted participants with established CHR-P instruments; or (3) were ab- stracts and conference proceedings. Data obtained from each ar- ticle included first author, year of publication, topic investigated, type

of publication, study design and number, sample size of CHR-P popu- lation and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interven- tions, quality assessment (using AMSTAR [Assessing the Method- ological Quality of Systematic Reviews]), and key findings with their effect sizes.

To respect the hierarchy of the evidence (eMethods 3 in the Supplement), if 2 or more meta-analyses addressing the same topic were found, we gave preference to individual participant data meta- analyses over aggregate network meta-analyses and to network meta-analyses over pairwise meta-analyses. The most recent study was selected when the previous criteria did not apply. If, after ap- plying the hierarchical criteria, 2 studies were similar, both were included.

Outcome Measures, Data Extraction, and Timing and Effect Measures From each study, a predetermined set of outcome measures (eMethods 4 in the Supplement) was extracted. The results were then narratively reported in tables, clustered around 3 core do- mains: detection, prognosis, and intervention.

When feasible, effect size measures were estimated through Co- hen d. Other effect size measures were converted to Cohen d.13

In case of meta-analyses reporting time-dependent risks or rates or descriptive data only, proportions (95% CIs) or means (SDs) were summarized.

Quality Assessment The quality of the included meta-analyses was assessed with the AM- STAR tool.14 Details of the meta-analyses and items evaluated are found in eMethods 5 in the Supplement.

Standards for Guidelines Development To develop the recommendations, we followed the US Preventive Services Task Force (USPSTF) grading system15 (eTable 2 in the Supplement), which is suited explicitly for preventive approaches and has received extensive validation in articles published in sev- eral journals, including JAMA.16-21 Guideline development followed

Key Points Question What is the status of current clinical knowledge in the detection, prognosis, and interventions for individuals at risk of psychosis?

Findings In this review of 42 meta-analyses encompassing 81 outcomes, detecting individuals at risk for psychosis required knowledge of their specific sociodemographic, clinical, functional, cognitive, and neurobiological characteristics, and predicting outcomes was achieved with good accuracy provided that assessment tools were used in clinical samples. Evidence for specific effective interventions for this patient population is currently insufficient.

Meaning Findings of this review suggest that, although clinical research knowledge for psychosis prevention is substantial and detecting and formulating a prognosis in individuals at risk for psychosis are possible, further research is needed to identify specific effective interventions in individuals with sufficient risk enrichment.

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the JAMA Clinical Guidelines Synopsis, reaching consensus across the multidisciplinary European College of Neuropsychopharmacol- ogy Network on the Prevention of Mental Disorders and Mental Health Promotion.9 The rationale for the recommendations was pro- vided. Conflicts of interest were fully detailed.

Results The literature search yielded 886 citations, which were screened for eligibility, and 55 of them were considered. After checking the in- clusion and exclusion criteria, we included 42 meta-analyses en- compassing 81 outcomes in the final analysis (Figure 1; eTables 3 to 11 in the Supplement).

Detection Characteristics No meta-analysis focused on the basic symptoms criteria. Overall, 85% (95% CI, 79%-90%) of CHR-P individuals met the attenuated psychosis symptoms (APS) criteria,22 10% (95% CI, 6%-14%) met the brief limited intermittent psychotic symptoms (BLIPS) criteria,22

and 5% (95% CI, 3%-7%) met the genetic risk and deterioration (GRD) syndrome criteria.22 The mean (SD) age of CHR-P individu- als across the included studies was 20.6 (3.2) years, with a range of 12 to 49 years.5,22-52 These individuals were predominantly male (58%)22-29,31,33,35-43,46-50,53,54 and had attenuated psychotic symp- toms lasting for more than 1 year before their presentation to spe- c i a l i z e d s e r v i c e s . S e v e r a l s t u d i e s i n c l u d e d u n d e r a g e patients.5,22-30,32-35,39-50,52,55,56 No differences were observed across the APS, BLIPS, and GRD subgroups.22 However, the mean (SD) du- ration of untreated attenuated psychotic symptoms tended to be shorter in the BLIPS group (435.8 [456.4] days) compared with the GRD group (783.5 [798.6] days) and APS group (709.5 [518.5] days) (eTable 3 in the Supplement).

Genetic and Environmental Risk and Protective Factors Individuals who met CHR-P criteria, compared with those who did not, were more likely to have olfactory dysfunction (Cohen d = 0.71),57 be physically inactive (Cohen d = 0.7), have obstetric complications (Cohen d = 0.62), be unemployed (Cohen d = 0.57), be single (Cohen d = 0.27), have a low educational level (Cohen d = 0.21), and be male (Cohen d = 0.18).55 Trauma, which encom- passed childhood emotional abuse (Cohen d = 0.98),55 high per- ceived stress (Cohen d = 0.85),55 childhood physical neglect (Co- hen d = 0.62),55 and being bullied (Cohen d = 0.62)56 (eTable 4 in the Supplement; Figure 2), was also more frequent (87% for over- all trauma)23 and severe (Cohen d = 1.38)56 in CHR-P individuals com- pared with the control groups. No meta-analysis addressed the as- sociation between genetic factors and the CHR-P state.

Substance Use A statistically significant association was found between the CHR-P state and tobacco use (Cohen d = 0.61).55 Altogether, 33% of CHR-P individuals smoked tobacco compared with 14% in the control groups.58 Those in the CHR-P group were also more likely to be cur- rent cannabis users than control participants (27% vs 17%).53 Cur- rent cannabis use disorder was associated with an increased risk of psychosis (Cohen d = 0.31), whereas lifetime cannabis use was not.24

Higher levels of unusual thought content (Cohen d = 0.27) and sus- piciousness (Cohen d = 0.21) were found in CHR-P individuals who were cannabis users compared with non–cannabis users,53 but at- tenuated positive or negative psychotic symptoms did not differ be- tween these 2 groups53 (eTable 5 in the Supplement).

Clinical Comorbidity Depressive (41%) and anxiety (15%) disorders were frequent in the CHR-P state.25 Most CHR-P individuals presented with suicidal ide- ation (66%).26 The prevalence of self-harm was 49% and of sui- cide attempts was 18% in CHR-P individuals26 (eTable 6 in the Supplement).

Functioning and Quality of Life CHR-P individuals had lower levels of adolescence (Cohen d = 0.96- 1.03) and childhood (Cohen d = 1.0) functioning compared with con- trol participants.55 Functional impairments in CHR-P individuals were as severe as impairments in other mental disorders and were more severe than in control participants (Cohen d = 3.01)27 but were less severe than in established psychosis (Cohen d = 0.34). The CHR-P status was also associated with significant social deficits (Cohen d = 1.25).55 Quality of life was worse in CHR-P individuals than in con- trol individuals (Cohen d = 1.75),27 whereas no differences from in- d i v i d u a l s w i t h p syc h o s i s 2 7 we r e r e p o r t e d ( e Ta b l e 7 i n t h e Supplement).

Cognition Visual learning (Cohen d = 0.27), processing speed (Cohen d = 0.42), and verbal learning (Cohen d = 0.42)54 were impaired in CHR-P in- dividuals compared with control participants. CHR-P individuals who later developed psychosis showed poorer cognitive functioning (Cohen d = 0.24-0.54)54 compared with those who did not de- velop psychosis. However, no evidence of cognitive decline was

Figure 1. PRISMA Flowchart of Study Selection Process

846 Records identified through database search

886 Titles and abstracts screened for eligibility

166 Full-text articles assessed for eligibility

55 Studies considered

42 Studies included and extracted

40 Additional records identified through other sources

720 Records excluded during screening

111 Full-text articles excluded 58 Did not have desired

design 53 Did not have desired

population

13 Full-text articles excluded 10 Had overlapping topic 3 Were abstract or

conference proceedings

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