We are told that long-term antipsychotic treatment reduces the risk of someone having a ‘relapse’ of schizophrenia or psychosis. What ‘relapse’ actually refers to in the studies that are supposed to establish this has not been examined though. Our recent study of relapse definitions, published in Schizophrenia Research, shows that there is no consistent or agreed definition of relapse in studies of long-term antipsychotic treatment, and that few of the definitions used can be confidently said to reflect a clinically significant psychotic episode (Moncrieff et al, 2019).
Antipsychotic drugs are prescribed to people who are diagnosed with schizophrenia and other psychotic disorders on the basis of trials that demonstrate a higher rate of ‘relapse’ in people who are withdrawn from these drugs compared to those who continue to take them (Leucht et al, 2012). Yet, incredibly, there is no consensus about what ‘relapse’ means in this situation. If you ask clinicians they generally agree that a relapse indicates the recurrence of a clinically significant episode, characterised by psychotic symptoms and a substantial decline in functioning or increase in risky behaviours (Burns et al, 2000).
Yet I know from working in mental health services that the term ‘relapse’ can be used in a variety of different ways, and sometimes it is applied loosely to situations in which someone has shown slight changes in symptoms or functioning, without evidence that they are experiencing a full-blown episode of psychosis. This often happens because people – the individual themselves, for example, or their family members or professionals – are anxious about the possibility of relapse and therefore highly vigilant to slight changes in the individual’s behaviour or demeanour. Slight changes in mood or behaviour, might, in some instances, be the precursor to a more significant deterioration, but this is not necessarily so, and they may instead, just be the regular ups and down of that person’s experience.
So ‘relapse’ can mean different things to different people in the real world, but you would think there was a consistent definition of relapse in research studies, or at least a small number of definitions with similar criteria. But it turns out this is not the case. As part of the RADAR (Research into Antipsychotic Discontinuation and Reduction) study, the research team and I looked at the definitions of relapse that are used in trials of long-term antipsychotic treatment. We wanted to know how it had been defined elsewhere to help us decide how to define it in the RADAR trial (a randomised trial comparing a supported programme of antipsychotic reduction and discontinuation with maintenance antipsychotic treatment in people diagnosed with psychotic disorders). We found that dozens of different definitions have been coined. Over the last three decades, there are almost as many definitions of relapse as there have been studies!
In older trials conducted before 1990, often just used the ‘clinical judgement’ of the investigator or treating psychiatrist to identify relapse, the need to increase or re-start antipsychotic medication or the need for other treatment or hospitalisation. Since the 1990s, trials have used increasingly complex combinations of alternative criteria, often including criteria based on changes in rating scales such as the Brief Psychiatric Rating Scale (BPRS) and the Positive And Negative Syndrome Scale (PANSS), alongside other criteria involving an increase in treatment or the presence of suicidal ideation, for example. There was no consistency in the way that rating scales were used to define relapse. Eighteen different PANSS-based criteria were used in the 23 trials that included a definition derived from the PANSS. The specified threshold for relapse varied between a 10 and a 30 point or 30% increase in the total score, for example, and in definitions that specified increases in individual item scores (such as those that concerned hallucinations or irritability) cut off scores varied from 3 (mild) to 6 (severe).
When we assessed whether definitions represented a clinically significant relapse, that is one involving the presence of positive psychotic symptoms and a deterioration in global condition, functioning or behaviour of at least a ‘moderate’ degree or involving hospitalisation, we found that only seven trials fulfilled such criteria. It is possible that some more of the older trials were also looking at a clinically significant change, but it was impossible to tell because there were so few details, or relapse was just defined by the clinical judgement of the investigator or treating psychiatrist.
We found other evidence that recent trials, at least, are often focused on slight deteriorations in people’s mental state or behaviour rather than what would usually be considered a full-blown ‘relapse’. In trials where the definitions included changes in rating scale scores, the majority of those who were rated as having relapsed did so because they met the rating scale based criteria. These scales were measured during routine appointments, but if you think of the practicalities of this, how is it possible to do a rating scale with someone who is experiencing a significant episode of psychosis? People have to have capacity to take part in research assessments, and they have to have the attention span to fill in questionnaires. The fact that relapses were picked up during routine assessments much of the time suggests they were not what would generally be considered a full-blown relapse. In fact some of the studies acknowledge this, and the text refers to ‘impending relapse’ or early signs of relapse, but nevertheless they are presented as studies of ‘relapse prevention’.
What relapse consists of in these studies of long-term antipsychotic treatment is important for a number of reasons. First, if we don’t know what ‘relapse’ refers to in studies of long-term antipsychotic treatment, this might change how we weigh up that treatment. Long-term treatment is promoted because relapse is considered to be something that should be avoided at all costs. This is because a full-blown psychotic episode can cause considerable disruption to someone’s life and may lead to hospitalisation and other unwanted consequences. But milder fluctuations in symptoms may not be so problematic, and the benefits of preventing them might not outweigh the negative effects of using antipsychotics on a long-term basis.
Second, if relapse is defined as an increase in non-specific symptoms, these might be a reflection of antipsychotic withdrawal, rather than the recurrence of the underlying problem (Moncrieff, 2013). Antipsychotic withdrawal symptoms include anxiety and irritability, for example (Dilsaver 1988), which are included in rating scales like the PANSS, and are particularly likely to occur after the rapid discontinuation that occurs in most antipsychotic maintenance studies. Antipsychotic withdrawal may also precipitate psychotic symptoms (Moncrieff, 2006; Whitaker, 2010), in which case ‘relapse’ of a prior condition may be difficult to distinguish from a withdrawal-induced episode.
This study of relapse definitions doesn’t necessarily show that discontinuing long-term antipsychotics only leads to a mild increase in symptoms, but it does show that we need more evidence about what it does do exactly. We cannot take the meaning of ‘relapse’ in these studies for granted.
In the RADAR trial we decided to use rehospitalisation as the marker of a serious relapse, but we are also using a panel of experts (including people with lived experience) to identify episodes of relapse from blinded summaries of clinical notes. They will identify relapse on the basis of agreed criteria, which include a recurrence or significant increase in psychotic symptoms and a substantial change in behaviour or functioning that is sustained for at least 7 days.
Moncrieff J, Crellin NE, Long MA, Cooper RE, Stockmann T (2019) Definitions of relapse in trials comparing antipsychotic maintenance with discontinuation or reduction for schizophrenia spectrum disorders: a systematic review. Schizophrenia Research, published online https://doi.org/10.1016/j.schres.2019.08.035
Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: A systematic review and meta-analysis. Lancet. 2012;379(9831):2063-2071. doi:10.1016/S0140-6736(12)60239-6.
Moncrieff J (2006) Does antipsychotic withdrawal provoke psychosis? Revoew of the literature on rapid-onset psychosis (super-sensitivity psychosis) and withdrawal-induced relapse. Acta Psychiatr Scand 114, 3-13