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Randomized Controlled Trial
. 2023 Sep 1;80(9):875-885.
doi: 10.1001/jamapsychiatry.2023.1947.

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis: The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial

Patrick D McGorry  1   2 , Cristina Mei  1   2 , G Paul Amminger  1   2 , Hok Pan Yuen  1   2 , Melissa Kerr  1   2 , Jessica Spark  1   2 , Nicky Wallis  1   2 , Andrea Polari  1   2   3 , Shelley Baird  1   2 , Kate Buccilli  1   2 , Sarah-Jane A Dempsey  1   2 , Natalie Ferguson  1   2 , Melanie Formica  1   2 , Marija Krcmar  1   2 , Amelia L Quinn  1   2 , Yohannes Mebrahtu  1   2 , Arlan Ruslins  1   2 , Rebekah Street  1   2 , Cassandra Wannan  1   2 , Lisa Dixon  4 , Cameron Carter  5 , Rachel Loewy  6 , Tara A Niendam  5 , Martha Shumway  6 , Barnaby Nelson  1   2
Affiliations
Randomized Controlled Trial

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis: The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial

Patrick D McGorry et al. JAMA Psychiatry. .

Abstract

Importance: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis.

Objective: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis.

Design, setting, and participants: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited.

Interventions: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months.

Main outcomes and measures: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates.

Results: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission).

Conclusions and relevance: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments.

Trial registration: ClinicalTrials.gov Identifier: NCT02751632.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McGorry reported grants from the National Institute of Mental Health during the conduct of the study; in addition, Dr McGorry had a patent for AU 2015203289 issued, a patent for US 9884034 issued, a patent for US 15/844444 issued, and a patent for CA 2773031 issued; and he has received past unrestricted grant funding from Janssen-Cilag, AstraZeneca, Eli Lilly, Novartis, and Pfizer, and honoraria for consultancy and teaching from Janssen-Cilag, Eli Lilly, Pfizer, AstraZeneca, Roche, Bristol Meyers Squibb, and Lundbeck. He has received grant funding from the Colonial Foundation, the National Health and Medical Research Council of Australia, Australian Research Council, NARSAD, the Stanley Foundation, NIH, the Wellcome Trust, and the Australian and Victorian governments. Dr Yuen reported grants from National Institutes of Health during the conduct of the study. Dr Spark reported grants from National Institute of Health during the conduct of the study. Dr Buccilli reported grants from National Institute of Health (NIH) during the conduct of the study. Dr Krcmar reported grants from National Institute of Mental Health during the conduct of the study. Dr Ruslins reported grants from NIMH during the conduct of the study. Dr Niendam reported grants from National Institute of Health during the conduct of the study; and owning shares in and being a founder and board member of Safari Health, Inc, outside the submitted work. Dr Shumway reported grants from NIH during the conduct of the study. Dr Nelson reported grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Figure 2.
Figure 2.. Changes in Mean Symptom and Functioning Scores From Baseline to the End of Step 3
Circles represent individual participant data. Fluoxetine or placebo commenced at 6 months (start of step 3). AQoL indicates assessment of quality of life; BPRS, Brief Psychiatric Rating Scale; CBCM, cognitive-behavioral case management; DACOBS, Davos Assessment of Cognitive Biases Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; SANS, Scale for the Assessment of Negative Symptoms; SOFAS, Social and Occupational Functioning Assessment Scale.
See this image and copyright information in PMC

References

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