‘Prodromal’ diagnosis of psychosis: Ethical problems in research and clinical practice

Australian & New Zealand Journal of Psychiatry, 46(1) Ethical concerns surrounding the identification of an ‘at-risk’ state for psychosis are long-standing. Two major risks are the stigmatisation/ labelling of those identified as being at risk of progression to psychosis, and unnecessary anxiety and demoralisation about prognosis. False-positive diagnosis of ‘psychosis risk syndrome’ or ‘prodromal psychosis’ can have lifelong detrimental social and psychological consequences. An even more serious risk is unnecessary pre-emptive use of antipsychotics, with potentially serious side-effects, including weight gain, diabetes, metabolic syndrome (Foley and Morley, 2011), neurological symptoms, and brain shrinkage (Ho et al., 2011). Although weight gain emerges rapidly, many of these adverse effects only emerge in the longer term. Klosterkötter (2008) has suggested that a false-positive rate of 10% or less would be needed to justify any preventive intervention that had harmful side-effects. It is not possible to identify a genuine prodrome (as opposed to an at-risk state) prospectively. There are no reliable genetic markers for schizophrenia (Sebat et al., 2009), and the false-positive rate in high-risk groups using other markers (Stober et al., 2009) is nowhere near 10%. Consequently the use of potentially harmful preventive interventions cannot be justified. We argue that pre-emptive psychosis-related diagnoses cannot be justified either. McGorry (2011), among others, argues that the label ‘prodromal’ should not be used, but that ‘atrisk mental state’ and ‘ultra-high risk’ are appropriate. Jorm (2011), among others, argues that it is appropriate for a similar term, ‘psychosis risk syndrome’, to be used as a research diagnosis, but not as a clinical diagnosis. These cautions will reassure many. However, we argue that such diagnoses are also harmful in research, because of the consequences. The most likely studies to be undertaken are clinical trials of pre-emptive interventions, often antipsychotics with or without other treatment modalities. McGorry (2011) has acknowledged that 80% false-positive rates are common. This means that the majority of trial participants randomised to receive antipsychotics will be unnecessarily exposed to substantial risks. Furthermore, despite McGorry’s espousal of low-dose antipsychotics during first-episode psychosis (but not for the ‘at-risk’ state), he is a member of an international group that until recently was proposing to commence an industry-funded trial that would have allowed prescription of high doses (400 mg) of quetiapine (Australian New Zealand Clinical Trials Registry, 2011). Tellingly, the specified health condition in the trial – the NEURAPRO-Q (North America, EURope, Australia PROdrome) study – was ‘prodromal psychosis’. In addition, the specified follow-up period was only 6 months, the duration of the treatment. This is not long enough for some of the potential adverse effects to emerge and/or peak, nor for some cases of psychosis to emerge. Furthermore, because quetiapine reduces psychotic symptoms, it would have been symptom suppression rather than incidence of first episode psychosis – the stated primary outcome – that was measured, biasing the results in favour of quetiapine over placebo. Despite these problems, this trial was approved by an ethics committee. Such trials promote the acceptance of diagnoses such as psychosis risk syndrome. They are likely to escalate the inappropriate use of antipsychotics – in the longer term through the approval of antipsychotics for ‘treatment’ of psychosis risk, and in the shorter term through increasing off-label prescription for this purpose – with all the attendant harms and costs for both individuals and the community. Avoiding diagnoses such as ‘psychosis risk syndrome’ and ‘prodromal psychosis’ does not mean withholding treatment when it is required. However, whether in clinical practice or in research, such treatment should not be based on diagnoses that have significant social risks, increase the likelihood of potentially harmful drug prescribing, and are unsupported by evidence. ‘Prodromal’ diagnosis of psychosis: Ethical problems in research and clinical practice