Helping Youth at Ultra-High Risk for Psychosis

Over the last 2 decades, there has been an explosion of clinical and research interest in the early stages of the psychotic disorders. Careful studies by several research groups, including ours, have enabled the operationalization of criteria that allow the prospective identification of predominantly young, help-seeking patients who are at greatly increased risk of imminent transition to psychosis. A wave of interest in the possibility of preventing the onset of serious mental illness has developed, and research has led to advances in our understanding of the neurobiology of these illnesses and the specific therapeutic needs of those who are at high clinical risk.

My colleagues and I, and several other international research groups, have carried out a total of 10 intervention trials, with all of the available evidence suggesting that several different treatment strategies—including cognitive therapy, low-dose antipsychotic medication, and omega-3 fatty acids, either alone or in combination—are able to significantly reduce the risk of transition to psychosis over a 12-month period.¹ While promising, these early studies have not yet resolved the question of which interventions are the safest and most effective and what the appropriate sequence of interventions should be, and hence the field remains in clinical equipoise. Key issues, including the type and sequence of interventions, the timing and length of these interventions, and the risks and benefits associated with them are currently being explored.

Our latest study² sought to examine these latter issues. In a cohort of 115 young people who met criteria for being at ultra-high risk (UHR) of developing psychosis, we compared (1) low-dose risperidone plus cognitive-behavioral therapy (CBT), (2) cognitive therapy plus placebo, and (3) supportive therapy plus placebo. While lower-than-expected transition rates reduced the power of the study, meaning that no statistically significant differences in the rate of transition to psychosis could be found, all 3 groups showed significant clinical and functional improvements during the 12-month study, an important outcome in itself. These help-seeking, distressed, and functionally struggling patients do respond to interventions of several kinds. The take-home message is to offer the safer option of supportive care and monitoring first, since drug therapies are more likely to result in adverse events and should be reserved for those who fail to respond to simpler and safer interventions alone.

But what does the UHR state actually represent? The UHR concept has drawn controversy that does has not been attracted to similar medical concepts such as pre-diabetes, latent stage 1 cancer, or essential hypertension. Although those who meet UHR criteria show a greatly increased risk (up to 400-fold) of developing fully expressed psychotic illness, it is nevertheless only a minority who do ultimately transition to full-threshold psychosis. A recent meta-analysis calculated a mean rate of transition of 22% at 1 year of follow-up, 29% at 2 years, and 36% after 3 years.¹ The few existing longer-term outcome studies of those who do not transition to psychosis suggest that, while many do show symptom remission over time, the overwhelming majority remain significantly impaired, either through persistence of the subthreshold psychotic features or mood and anxiety disorders or the development of new episodes of anxiety and depression.^3,4 Apart from the attenuated positive symptoms and impaired functioning required by the UHR criteria, the majority of these young people present initially with at least one other Axis 1 diagnosis, with high levels of comorbid depression, anxiety, substance abuse, deliberate self-harm, and suicidal risk that merit treatment in their own right. Thus, while there is a strong risk for psychosis, it is not an exclusive link, and hence the UHR state cannot be considered as a highly specific “psychosis prodrome.” Rather, it is better thought of as a pluripotential risk state that captures a heterogenous group of individuals with a mixture of affective and psychotic symptoms, some of whom will have a true vulnerability to schizophrenia and related disorders, while others may either recover or develop more clearly defined mood disorders or mixed psychopathology.⁵ This concept of the UHR state is in keeping with the clinical staging model, which considers that specific syndromes slowly evolve from an initial state of mixed, nonspecific, subthreshold symptoms through stages of increasingly defined psychopathology that ultimately coalesces into diagnosable syndromes. Nevertheless, the UHR concept does have a stronger valence for later psychosis than for other diagnostic pathways and therefore has reasonably good predictive validity. There is disagreement as to whether this is good enough to justify entry into formal diagnostic nomenclature, but it clearly has had major heuristic value as a research tool.

What does all of this mean in terms of treatment? First, in the current absence of reliable recommendations for treatment strategies that specifically prevent or delay the onset of psychosis, and because the UHR state predicts such a broad range of outcomes, initial treatment approaches should be chosen on the basis of safety. The therapies of choice are supportive therapy and other psychological therapies, including CBT, and benign interventions (likely to be relatively nonspecific yet safe) such as omega-3 fatty acids. Antipsychotics should be explicitly reserved for those with severe and persistent symptoms that do not respond to these lower risk therapies. Second, because the appropriate treatment of this patient group may prevent a much broader range of poor outcomes, both psychotic and nonpsychotic, the public health relevance of stage-specific, appropriate treatment becomes much more significant, and careful and sequential choice of therapeutic strategy, guided by risk-benefit considerations, becomes even more important.

Financial disclosure:Dr McGorry has received honoraria for educational activities from AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, Roche, Lundbeck Institute, and Bristol-Myers Squibb and has received grant/research support from National Health and Medical Research Council of Australia, NARSAD, Colonial Foundation, AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, and Novartis.

References

1. Preti A, Cella M. Randomized-controlled trials in people at ultra high risk of psychosis: a review of treatment effectiveness. Schizophr Res. 2010;123(1):30–36. PubMed

2. McGorry PD, Nelson B, Phillips LJ, et al. Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome. J Clin Psychiatry. 2013;74(4):349–356. Abstract

3. Addington J, Cornblatt BA, Cadenhead KS, et al. At clinical high risk for psychosis: outcomes for nonconverters. Am J Psychiatry. 2011;168(8):800–805. PubMed

4. Simon AE, Velthorst E, Nieman DH, et al. Ultra high-risk state for psychosis and non-transition: a systematic review. Schizophr Res. 2011;132(1):8–17. PubMed

5. Fusar Poli P, Yung AR, McGorry PD, Van Os J. Lessons learned from the psychosis high-risk state: towards a general staging model of prodromal intervention [published online ahead of print February 18, 2013]. Psychol Med. PubMed