A clinical trials agenda for testing interventions in earlier stages of psychotic disorders

To progress this more flexible model of clinical research and related health care, much better access to health care is required for young people with emerging mental health problems. Fortunately, a change has occurred that will allow a new level of mental health clinical research in Australia. With the establishment of 30 new youth mental health service centres across Australia, headspace (http://www.headspace.org.au), the federal government’s recent major funding initiative in youth mental health, has created a unique opportunity for longitudinal cohort studies and multicentre clinical trials focused on the earliest stages of emerging mental disorders. Although headspace is in its early stages of development, several thousand young people have already gained access to multidisciplinary care, many in the subset of services led by, or with close links to, clinical research centres. We expect this will allow the progressive creation of a firm evidence base for earlier diagnosis and treatment, and lead to a better understanding of a range of mental and substance-use disorders. Given the comorbidity and dimensionality that characterise the early stages of mental disorders in young people, a “wide-angle lens” is essential to allow a focus on those who are at greatest risk of persistent and disabling forms of mental disorder.

We propose a series of larger-scale cohort studies and multicentre effectiveness trials in young people with emerging mental and substance-use disorders (Box). Early interventions need to be simpler, safer and cheaper. In fact, with disorders of slow and diverse onset, there may be an optimal time to intervene — too early may be inefficient and trivialise the concept of what a disorder is, but delay may mean the disorder becomes refractory to intervention, either for biological or psychosocial reasons. Others have proposed that cost-effectiveness is superior to current severity or disability as a triage criterion.6,7 The notion of an optimal point for intervention represents a testable hypothesis that may vary across types of disorder.

Mounting large-scale multicentre studies with a sufficient overall sample size to rapidly test new therapies will require the use of practical trials that focus on effectiveness in real-world settings, rather than narrower efficacy trials.8 From a theoretical perspective, there is a clear need to increase statistical power to conduct valid preventive and early intervention trials. We can achieve this by setting the main research boundary at the level of indicated prevention, which in turn can be accomplished by focusing on groups with multiple risk factors and early clinical changes; defining outcomes broadly and using briefer and more robust measures, with multiple exit syndromes and/or poor functioning as the key outcome to be prevented; and progressively strengthening the effectiveness of specific interventions and programs.

EFAs, such as eicosapentaenoic acid and docosahexaenoic acid, may have an adjunctive therapeutic effect in first-episode psychosis14 and a primary therapeutic effect in prepsychotic or UHR states of psychosis.15 Imaging studies suggest these benefits of EFAs may be mediated by reducing oxidative stress through an effect on glutathione metabolism.16 Because EFAs have wider efficacy in a range of syndromes17,18 and are safe and well tolerated, they are excellent candidates for trials in earlier stages of mental disorders.

Lithium is a cornerstone in the treatment of mood disorders, and it has now become clear that it has potent neuroprotective properties.19,20 Lithium treatment is associated with short-term increases in grey matter,21 and has been shown to be dramatically effective in the treatment of degenerative neurological diseases, notably amyotrophic lateral sclerosis.22 We studied use of lithium in young people at UHR of psychosis and found it to be associated with symptomatic improvement.23 We also found that lithium was associated with positive central nervous system changes, as evidenced by significant reduction in T2 relaxometry and a trend for improvements in N-acetylaspartate–creatine ratios.23 Hence, lithium could be the focus of clinical trials, particularly for use in the UHR state and subsequently in early treatment resistance.

We conducted a series of studies examining potential dysregulation of the HPA axis in response to stress and trauma in early psychosis.24-27 We found evidence of relationships between HPA dysregulation and both clinical and neurobiological variables including changes in the volume of key brain structures, notably the pituitary and the hippocampus.24 Possible interventions to be tested in clinical trials in this area include tianeptine (a novel antidepressant that affects the HPA axis),28 glucocorticoid antagonists, and psychosocial interventions to reduce and moderate the effects of stress and trauma.

Recent studies have produced evidence that N-acetylcysteine, a neuroprotective treatment believed to act via the glutathione pathway and the reduction of oxidative stress, may be effective as an adjunctive therapy in established schizophrenia and bipolar disorder.29,30 Thus, there are logical grounds for moving it forward in terms of stage of illness to earlier stages of psychotic illness.