Discussion
STAR*D, Depression, psychosis
SECONDARY, REMISSION
This is the first SMART trial to be conducted in the ultrahigh risk population. The primary outcome of functioning at the end of step 2 was selected for sample size and power calculations; however, results should be considered as a whole, spanning all steps. For the primary outcome, there was no difference between CBCM and SPS. While the sample overall showed modest functional and symptomatic improvement over 12 months, remission rates were lower than expected, the transition rate was slightly higher than anticipated, and there was no significant difference between groups on the secondary outcomes. Even when remission was achieved, it was difficult to maintain, and continuing supportive therapy did not reduce relapse rates compared to monitoring. While the monitoring group showed greater improvement in 6-month SOFAS scores than SPS, this was likely due to 4 outliers in the SPS group whose 6-month SOFAS outcomes were worse than the other individuals who remitted at step 1. The findings suggest that enhancing the intensity of treatment with psychological interventions (CBCM) or antidepressant medication in real-world youth mental health services does not produce benefit over continuing simpler care for a longer period. However, some caution is needed given the following caveats.First, the bar for remission was high, although appropriately so, requiring sustained symptomatic and functional improvement. If remission had been based on symptomatic improvement only, the overall remission rate would have increased to 41.2% (compared to 27.2%).Second, the rate of treatment discontinuation was substantial (18% at step 1, 48% at step 2, and 38% at step 3). However, this rate was comparable to that of the seminal Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial,Third, adherence to psychological therapy and medication and fidelity to CBCM were suboptimal. These challenges are common in psychotherapy trials.A positive note is that transition to psychosis was significantly lower among participants who remitted (3.3%) than those who did not (17.4%). While this may indicate that trials with transition as the primary outcome may enroll an enriched sample by filtering out those with early remission, relapse to ultrahigh risk positive status was common. Although all treatment arms showed a trend of symptomatic and functional improvement by the end of steps 2 and 3, improvement was typically modest, slow to emerge, and somewhat fragile. The lack of a no-treatment comparison group makes firm conclusions difficult.While some caution is warranted, and needs-based care should continue to be provided to all patients at ultrahigh risk, the findings indicate the need for further sequential randomized trials examining existing treatments with improved adherence and fidelity and for the development of innovative, more effective treatments and enhanced modes of delivery. This could include virtual reality; neurofeedback; higher-fidelity CBT; individual placement and support; biotherapies (eg, cannabidiol,