Negative Psychosis Prevention Trials

Abstract

To the Editor In the wake of the recently published ω-3 polyunsaturated fatty acids multisite trial (NEURAPRO) by McGorry et al 1 in JAMA Psychiatry (n = 304), the 3 largest studies of preventive interventions in individuals at ultrahigh risk (UHR) for psychosis have turned out to be negative (Morrison et al, 2 n = 288; McFarlane et al, 3 n = 292), suggesting that it may not currently be possible to prevent psychosis. However, the actual risk for psychosis in these interventional studies was found to be extremely low, even in the control group (11.2% in the McGorry et al 1 study at 1 year, 9% at 2 years in the Morrison et al 2 study, and 2.3% at 2 years in the McFarlane et al 3 study), implying that these negative findings are likely to be secondary to small statistical power.On a conceptual level, these studies challenge the underlying assumption that it is acceptable to meet specific psychometric criteria at intake to be slotted into the UHR category. Actually, the predictive power of the UHR criteria is not fixed priority, but is dependent on the risk enrichment of the samples to which they are applied (ie, "pretest" risk). 4 This is owing to the psychometric characteristics of these UHR instruments: they are good to rule out psychosis but only moderately useful to rule in psychosis. 4 Therefore, most of the observed risk for psychosis is not gained through UHR assessment per se, but is obtained before the assessment (pretest phase) during the recruitment of these individuals. Pretest risk enrichment in those undergoing a UHR assessment remains substantial (15% at 38 months) and highly heterogeneous (9%-24% at 38 months). 4 Pretest risk enrichment is modulated by the type of recruitment strategies adopted to select individuals for UHR assessment. 4 For example, recruiting individuals who were already filtered by adult mental health services is associated with higher pretest risk enrichment, as compared with recruiting individuals through intensive community outreach. 5 Not surprisingly, the lowest transition risk was reported in the study by McFarlane et al, 3 which has adopted a "community outreach and education program targeted to teachers, school, and college counsellors." Owing to the heightened pressure to recruit participants into interventional studies, it is possible that a substantial proportion of these samples had been recruited through community outreach, diluting the transition risks.Therefore, it seems expedient to control the pretest risk enrichment of samples recruited into future interventional studies for psychosis prevention by using pretest risk stratification models that have been recently validated in this journal. 5

Lack of evidence to favor specific preventive interventions in psychosis: a network meta‐analysis

“…The current lack of evidence to support specific preventive treatments is also consistent with the fact that the three largest interventional studies in this field have all produced negative findings. Earlier studies that dominated the conclusions of some previous meta‐analyses (e.g., the omega‐3 trial) were likely false positives.…”

Efficacy and Acceptability of Interventions for Attenuated Positive Psychotic Symptoms in Individuals at Clinical High Risk of Psychosis: A Network Meta-Analysis

“…It is possible that the lack of evidence for effective treatments to reduce transition to psychosis may be secondary to low statistical power for testing this outcome. In turn, this can be caused by the recruitment strategies adopted by recent RCTs that have focused on individuals that were poorly risk enriched, causing a dilution of the final risk for psychosis ( 23 ). On the contrary, the lack of evidence for effects on attenuated positive psychotic symptoms cannot simply be attributed to low statistical power.…”

“…The key result of our analysis was that there is no evidence to favor any specific preventive treatment for CHR-P individuals over any others ( 22 ). This finding is not completely surprising, given that all of the most recent trials in this area were negative ( 23 – 31 ). Therefore, currently, there is no convincing evidence that indicated interventions implemented in CHR-P individuals can effectively prevent the onset of psychosis.…”

Why transition risk to psychosis is not declining at the OASIS ultra high risk service: The hidden role of stable pretest risk enrichment

“…The two-year risk of transition to psychosis from an initial UHR state has shifted from an early 30% (Fusar-Poli et al, 2012) to the current 20% (see Table 4 in (Fusar-Poli et al, 2016a)). Declining transition risk is concerning because it can undermine the clinical significance of preventative detection (Fusar-Poli, 2017c) and treatment, yielding negative findings (Fusar-Poli, 2017b).…”

“…Earlier studies had suggested that declining transition risk in UHR samples may be due to the fact that treatments were more effective (treatment effect). However, with the largest randomized controlled trials in UHR individuals yielding negative findings (Fusar-Poli, 2017b), there is no strong evidence indicating that the recommended preventative treatments are effective in preventing psychosis (Morrison et al, 2012). In fact, recent studies concluded that treatment effect (Nelson et al, 2016) cannot fully account for the observed decline in the transition risks.…”