Is there compelling evidence that schizophrenia long‐term treatment guidelines should be changed?
Authors: Stefan Leucht
Journal: World Psychiatry (2018)

For decades psychiatrists have tried to stop the “revolving door” phenomenon, meaning that patients with schizophrenia stop their antipsychotic treatment, relapse and have to be treated again, often leading to long rehospitalizations with a worse outcome than that of the previous episode. New findings on the long-term outcome of schizophrenia1, potential brain volume loss2, dopamine supersensitivity effects of antipsychotics3, and a study on “guided discontinuation” in first-episode patients4 challenge the usefulness of these attempts. K. Popper would say that scientific progress is made if existing knowledge is challenged by new evidence. The question, however, is whether the new evidence is compelling enough to justify major changes of treatment guidelines. The issue is complex, because several different lines of evidence must be considered together. In brief, my current understanding of this literature is the following. Recent studies showed that the long-term course of schizophrenia is not always chronic1. This finding is not new, as the classic follow-up studies, some from the pre-antipsychotic era, reported that a substantial proportion of patients do quite well after years to decades (see for example Ciompi5). These findings have not attracted enough attention. They are very good news, because in my opinion it is a major role of a doctor to give hope. Our clinical perception may be biased, because we usually see patients with a poor outcome. The ones with a good outcome may not come back to the clinic and may disappear from the system. Moreover, several other studies have found that approximately 20% of patients with a first episode of schizophrenia will not have a second one, implying that every fifth patient may be treated unnecessarily on the long term, but unfortunately we cannot predict in advance who these patients may be. The literature on the long-term outcome of schizophrenia is, however, extremely heterogeneous and difficult to interpret, in particular because different definitions of outcome and patient populations are used, limiting comparability. But, according to a methodologically sound review of follow-up studies, only 13.5% of patients recover in the long term6. The majority of national registry studies demonstrate that the mortality of untreated patients with schizophrenia is higher than that of those receiving antipsychotics7. In the long term, the multiple side effects of antipsychotics probably contribute to the excess mortality of schizophrenia, but they must be weighed against suicidality and self-neglect when patients are psychotic. Comparably benign antipsychotics are now available (for example, partial dopamine agonists) and many side effects are dose-related. The potential brain volume loss associated with antipsychotics worries me. As I am not a brain imaging researcher, it is difficult for me to understand whether the magnitude of this brain volume loss is relevant, and what is the relative contribution of the progress of the disease and of antipsychotic treatment to this loss. One study questioned clinical relevance, because the cognition of treated patients was better than that of untreated patients despite more brain volume loss in the former group8. That antipsychotic drugs can lead to dopamine supersensitivity effects has been hypothesized since the 1970s3, and there is important evidence from animal studies supporting this point of view. We addressed this issue from various angles in a comprehensive meta-analysis9, but did not find evidence to substantiate these effects in patients. I believe that these effects exist but, given the large effect size for relapse prevention of antipsychotics compared to placebo9, they do not explain all the superiority of antipsychotics over placebo. There are patients who need them continuously for symptom suppression. Wunderink et al4 found a better functional outcome at seven year follow-up in first-episode patients in whom gradual withdrawal and dose reduction of antipsychotics had been tried. It should be emphasized that these were first-episode patients (the data do not apply to chronic patients) in remission (not all first-episode patients reach a remission) and that in the initial randomized phase complete withdrawal was only possible in 20% of the patients (remarkably, again the magic 20%). These findings are interesting, but the follow-up phase of the study was naturalistic, making it hard to believe that the better outcome was caused by the withdrawal attempts. Replications with better methodology are needed; if they turn out positive, guideline changes would indeed be necessary. The main counterargument to these new findings is the high risk for relapse whenever patients stop their antipsychotics. Within one year, antipsychotics reduced the relapse risk from 64 to 27% in chronic patients and from 61 to 26% in first-episode patients9. Another systematic review in first-episode patients even reported that 77% of untreated patients compared to 3% of treated patients will relapse10. Very long-term placebo-controlled randomized studies, say with 5 to 10 year follow-up, are basically impossible for methodological reasons. But, in withdrawal studies, chronic patients who had been stabilized for up to 3-6 years with antipsychotics before randomization still benefitted from these medications, since their relapse risk was higher when they stopped the drugs compared to staying on them9. We found that the effect size of antipsychotics for relapse prevention is one of the largest of all medical drug treatments (keeping the limitations of such comparisons in mind)11. For example, antihypertensive drugs reduce the risk for cardiovascular events only from 18.1 to 14.1%11, but their use is not questioned. In acute treatment, psychiatrists often use non-evidence-based, highly irrational polypharmacy and high doses of antipsychotics. They should be avoided whenever possible. If such strategies have still been used, the first step in the maintenance phase is to reduce excessive doses (for example, to the middle of the range in the labels) and polypharmacy. This applies to all patients. Then, a distinction must be made between chronic and first-episode patients. Among the latter, 20% will not have a second episode, and some might actually not have schizophrenia. For example, it can be very hard to differentiate schizophrenia from drug-induced psychotic disorder. First-episode patients benefit as much from relapse prevention as multiple-episode patients, and to treat them for at least 1-2 years is evidence-based9, but remitted patients may want to find out whether they are among those who do not need long-term treatment. As relapses often occur only months after stopping antipsychotics, and if potential dopamine supersensitivity effects are taken seriously, any dose reduction must be made extremely carefully (an influential consensus conference recommended to reduce doses by no more than 20% every six months12). In those patients who have already had multiple episodes and who often have already tried several times to reduce or stop their treatment, further down titration may not be recommended, in particular if there are no important side effects. Finally, the clinical circumstances must be considered. If the acute episode was short and mild or the diagnosis unclear, or if there are important side effects, one might be more ready to attempt careful dose reduction. If in the acute phase there was a suicide attempt or an aggressive act (with potentially dire consequences for the patient, such as forensic treatment), one would be very hesitant. And, if patients have clearly improved but are still symptomatic despite treatment, attempts to reduce doses also appear counterintuitive. As – due to the subjectivity of psychiatric outcomes – there is room for interpretation, in the future the evidence will have to be presented such that patients can decide themselves. Stefan Leucht Department of Psychiatry and Psychotherapy, Technische Universität München Klinikum rechts der Isar, Munich, Germany