Imagining schizophrenia without relapses

In a recent edition of the Journal, Drs Catts and O’Toole outline their concerns that patients with schizophrenia are not realizing the best possible outcomes from their illness as a result of a number of unresolved controversies in the field (Catts and O’Toole, 2016). They contend that this ongoing uncertainty has limited the strength of recommendations made in the recently published revisions of the Clinical Practice Guidelines (CPGs) for the Management of Schizophrenia and Related Disorders from the Royal Australian and New Zealand College of Psychiatrists (RANZCP). They highlight six clinical issues for which ongoing controversy has led to inconsistencies on different sets of CPGs. They systematically address these issues and propose a ‘radical re-engineering’ of treatment for patients with a first-episode psychosis (FEP) predicated on achieving the goal of eliminating all relapses in those patients with a diagnosis of schizophrenia.

Drs Catts and O’Toole should be commended for their bold proposal. Their approach appropriately challenges two key tenets of the early intervention (EI) for psychosis movement: (1) keeping diagnoses generic in the early years of treatment, and (2) maintaining openness about the possibility of medication discontinuation. Their proposal for re-engineering the early management of schizophrenia could have substantial impact on the outcomes achieved and deserves very serious consideration.

Their argument would be strengthened by eliminating those premises that invoke progressive brain changes in schizophrenia and their mitigation by antipsychotic medication. Whether progressive brain changes occur over the course of schizophrenia and their association with psychotic relapse and antipsychotic medication remain matters of ongoing debate. Essentially, their argument can then be distilled down to the following: (1) psychotic relapses contribute substantially to the poor long-term outcomes associated with schizophrenia; (2) once the diagnosis of schizophrenia is established, maintenance antipsychotic medications should be continued indefinitely to prevent relapses; and (3) long-acting injectable antipsychotic medications (LAIs) are more effective in preventing relapses and should be considered as a best practice for the maintenance treatment of those diagnosed with a first episode of schizophrenia.

There is an important distinction that needs to be made between considering schizophrenia as an illness that is by nature progressive versus one in which outcomes sometimes worsen over time. My own view is not, as attributed to me by Drs Catts and O’Toole, that antipsychotic medications cause progressive brain changes in patients with schizophrenia. Rather, I am of the opinion that once the effects of antipsychotic medications and other factors that can influence measures of magnetic resonance imaging (MRI) volumes are taken into account, there is little evidence to suggest that schizophrenia itself leads to progressive changes in brain structure over the course of the illness (Zipursky et al., 2013). Weinberger and Radulescu (2016) have also cautioned that we do not know whether the MRI changes observed over time as a result of antipsychotic medications and other factors common in patients with schizophrenia are ‘neurobiologically meaningful’ and might be better understood as being ‘artefact or epiphenomenon of uncertain value’. What is important is that we not assume that the clinical deterioration that may be observed over time reflects the biological progression of the illness.

The notion that untreated psychosis is somehow toxic to the brain either prior to or following treatment of the first episode has been advanced as a particularly compelling argument for EI programmes despite minimal supporting evidence. We do not know whether the longitudinal changes reported with MRI are reversible, whether they are of functional significance and what the direction of causality is in the reported associations between these changes and clinical outcomes. Drs Catts and O’Toole contend that clinicians should have confidence that the longitudinal changes observed in grey matter volumes early in the course of illness in treated patients are disease-related and that antipsychotics protect against these volume changes. Neither of these assertions has been established (Weinberger and Radulescu, 2016; Zipursky et al., 2013) and, as a result, should not be part of any argument for changing clinical practice. To be clear, this in no way invalidates the importance of EI in reducing the terrible suffering involved in experiencing psychosis and the detrimental impact of relapses on long-term outcomes.

Drs Catts and O’Toole state that ‘schizophrenia goes from being a relatively treatment-responsive disorder at first episode to one that is treatment resistant in almost all multi-episode patients’ This is not consistent with our current understanding of treatment resistance. Many multi-episode patients continue to respond robustly to antipsychotic medication. We know that 20–30% of patients respond poorly to antipsychotic treatment for their first episode, and these individuals probably make up the majority of patients with treatment resistance (Lally et al., 2016). Patients with more severe, enduring and less responsive symptoms are likely to be greatly over-represented in specialized clinical settings, so psychiatrists may well experience the illusion that almost all multi-episode patients are treatment resistant (Zipursky et al., 2013). There are some patients who respond less completely after relapsing, a tragic occurrence that does add substantial weight to the argument that relapses ought to be avoided.

The authors assert that there should be no doubt that LAIs are best practice as a first-line treatment in all patients as soon as the diagnosis of schizophrenia is made. While they have rightly outlined the limitations of the randomized controlled trial (RCT) data that have not found any advantage of LAIs, this body of work might reasonably be interpreted as suggesting that there are some patients who are unlikely to have additional benefit from LAIs. There has been understandable ambivalence about recommending LAIs for patients early in the illness which is reflected in the new CPGs developed by the RANZCP: LAIs are recommended for first-episode patients if they prefer them, have a history of poor adherence or have failed to respond to oral medication. However, these guidelines pre-dated the important publication by Subotnik et al. (2015). In this study, patients who were randomized to LAI risperidone after responding to treatment for a first episode of schizophrenia, schizoaffective disorder (depressed type) or schizophreniform disorder had an 85% reduction in their likelihood of recurrence or relapse compared to those who received oral risperidone.

While it seems counterintuitive that patients with a first episode of schizophrenia stand to benefit most from LAIs, there are a number of characteristics of these patients that likely contribute to this observation. FEP patients are very often robust responders, which also means that they are likely at high risk of relapse without antipsychotic medication. They also have very high rates of discontinuation from oral medications as it is often very challenging for young patients to continue medications when their symptoms have resolved, and doubt about the need for maintenance medication lingers. While the study by Subotnik et al. requires replication, it does appear that it would indeed be the best clinical practice to recommend LAIs as among the first-line treatments for those patients who meet diagnostic criteria for schizophrenia so that they can be provided with the most effective treatment to prevent relapse.

Drs Catts and O’Toole make extremely compelling arguments against the practice of opting for more imprecise generic diagnoses early in the course of illness and delaying the diagnosis of schizophrenia. There was a time earlier in the history of EI when psychiatrists needed to be cautioned against jumping too quickly to a schizophrenia diagnosis. Given what we have now learned about the outcomes from schizophrenia and the consequences of relapse, I believe that psychiatrists are now better advised to make a diagnosis of schizophrenia once it can be made with confidence. Doing so provides an opportunity to ensure that patients receive the best advice and best services to maximize their likelihood of achieving long-term recovery.