Early intervention in psychosis: p‐values, policy, and politics
Authors: Robert Rosenheck
Journal: World Psychiatry (2017)

Psychosis is among the most disabling, persistent and poorly understood medical conditions. The staging of psychotic illness outlined in Fusar-Poli et al's paper1 is innovative, but is only as useful as the magnitude of the effectiveness of available treatments at each stage and of the differences in effectiveness between stages. While some statistically significant experimental data support “stage 1” interventions targeting people at high risk but without manifest psychosis, and “stage 2” interventions for patients with recent-onset psychosis, there is no evidence to suggest that treatments are more effective at one stage than another and thus are stage-specific. The authors call for the global implementation of early intervention in psychosis, and of the staged approach more specifically, but p-values do not by themselves justify policies or suggest their political salience. It is sometimes mistakenly expected that statistically significant scientific findings have, by themselves, policy and political importance. Although there is a logical sequence leading from scientific findings to policy proposals and then to political action, there is no tight link between the three, because each represents only one of many inputs into the next. Good science does not always find a practical policy application, and rational policy is not assured of political success. The discovery of effective HIV treatment, by itself, generated neither a credible policy for making it available, nor political agreement about how to do so. Following the example of cancer research, long-term prospects for early intervention studies are based on the hope that incremental steps will eventually add up to major gains. Data from numerous rigorous studies show statistically significant positive outcomes of early intervention for symptoms, quality of life, employment and school participation, reduced hospitalization, substance use, depression and others. There is also evidence that potentially mediating indicators can be significantly improved such as delayed onset of psychosis, reduced duration of untreated psychosis, lowered family burden, and increased retention, trust and satisfaction. But we are also faced with sobering counter-observations1. Three trials of interventions at stage 1 had negative findings, possibly because of the difficulty of prospectively identifying patients who will develop psychosis, or low statistical power. Small trials in stage 2 showed “minimal beneficial effects or no effects at all on clinical outcomes”1, and in large trials benefits have rarely been shown to last beyond two years. Further, Fusar-Poli et al's systematic review of randomized controlled trials1 failed to show statistically significant benefits of early intervention on preventing relapse or re-hospitalization. The paper's section on antipsychotics suggests that these medications, while undoubtedly beneficial, may delay, but do not prevent, relapse. The presentation of both enthusiasm for positive results and candor about negative results, while jarring at times, ultimately reflects a high level of scientific integrity. In the end, the authors conclude that “to improve outcomes… it is necessary to globally adopt complex models integrating a clinical staging framework and coordinated specialty care programs”1. This conclusion, however, represents a leap from the realm of p-values to advocacy for a global initiative encompassing “national health care systems”, a bold proposal that would likely require a level of political commitment similar to that which has characterized the global fight against the HIV epidemic. Effective intervention in psychosis is, without doubt, desperately needed worldwide. The 2015 Global Burden of Disease Study estimates the disability-adjusted life years (DALYs) attributable to schizophrenia as 15,020,500 years, more than three times the 3,989,900 DALYs for HIV2. But the available data suggest that, in spite of this immense need, early intervention may not yet be a scientifically supportable or politically practical path. When we move from the realm of experimental outcome research to that of political action, we leave the realm of p-values (tests that show only that observed benefits in specific experimental studies are not simply due to chance) to a realm of policy analysis, in which large magnitude effects and grossly favourable balance sheets of benefits and costs may be needed to carry the day. For example, the RAISE Early Treatment Program, sponsored by the National Institute of Mental Health, perhaps the largest US study of intervention for early psychosis3, showed that the intervention was superior to usual care at p<0.05, but the effect size (Cohen's d) for quality of life gains was 0.31 and for symptom reduction was −0.29, reflecting small to moderate effects. At several points Fusar-Poli et al's paper assures readers that early intervention is cost-effective. However, of the three studies cited, one is a modelling effort based on judgments of clinical experts and selected publications4; a second is based on a “narrative review”5; and only the third is based a large randomized trial6. That study found increased benefits but also increased costs and concluded that the benefits, when converted to quality adjusted life years and then to dollars, were indeed greater than the costs. These three studies are not likely to be sufficiently robust to attract major national or international support and funding. The negative findings of the authors’ systematic review on relapse and re-hospitalization make it unlikely that savings can be realized that would be sufficient to pay for intensive early intervention. Taking the proposed initiative at face value, it may be informative to consider the process, beautifully described by H. Varmus7, that led President G.W. Bush to initiate the President's Emergency Plan For AIDS Relief (PEPFAR). By 2014 PEPFAR had provided antiretroviral treatment to over 7.7 million people, supported HIV testing for more than 57 million people, and seen commitments of $70 billion from Presidents Bush and Obama8. Could PEPFAR be a model for the proposed worldwide early intervention effort? At a minimum, it is a lesson on the political and scientific complexities involved in moving a global initiative into practice. According to Varmus, President Bush was highly skeptical about foreign aid, but impressed by the remarkable advances in HIV treatment, with life expectancy for an HIV positive 20-year old increasing from 39 years of age in 1996 to 73 by 20119. Bush further insisted on a high level of accountability and his support seems to have been won by the promise that changes in HIV mortality could be readily tracked. If the data reviewed here do not seem strong enough to support a “PEPFAR” for early intervention in psychosis, they may yet inspire more modest but exceptionally defensible, albeit challenging, objectives for stages 3 and 4 interventions. These objectives would include: a) making antipsychotic medication available with appropriate supervision to all who need it, worldwide, b) assuring respect for basic human rights of people with psychosis, and c) reducing stigma, an extraordinarily challenging goal that may, nevertheless, be the key to achieving objectives a) and b). The optimism engendered by early intervention studies has inspired wealthy countries such as Australia, the UK, Denmark, and recently the US, to publish recommendations for and funding to support early intervention programs. Even if not yet robustly justified by outcome or cost-effectiveness data, such initiatives provide humane, trust-engendering support to patients and families at a moment of heartbreak in their lives. By drawing attention to the unquestioned need for expanded intervention for psychosis across the globe, and to the hope for further advances in early intervention, Fusar-Poli et al's paper reminds us of the urgency of laying solid foundations for a much-needed “PEPFAR” for psychosis in the years to come. Robert Rosenheck Department of Psychiatry, Yale Medical School, New Haven, CT, USA; US Department of Veterans Affairs New England Mental Illness Research, Education and Clinical Center, West Haven, CT, USA