The long‐term treatment of schizophrenia with antipsychotics: a perennial debate
Authors: W. Wolfgang Fleischhacker
Journal: World Psychiatry (2018)

A number of thoughts come to mind, when revisiting the recent debate around the benefit/risk ratio of antipsychotic maintenance treatment in schizophrenia patients. First, it appears difficult to explain why one of the best documented findings in psychiatric treatment research, namely the fact that continuous intake of antipsychotics prevents relapses with a number-needed-to-treat of 31, a success rate which must be seen with envy from the perspective of other medical specialties, is questioned on the basis of a handful of studies of suboptimal methodological rigor2. Second, one wonders why historical hypothetical constructs, such as “supersensitivity psychosis”3, which have not proven reasonably valid ever since they were originally put forward, experience a sudden renaissance. Third, it is interesting to note how renowned clinician researchers, when reviewing the topic based on the same datasets, come to, at least subliminally, divergent conclusions, advocating the judicious use of antipsychotics on one hand4 and providing cautionary criticism on the other5. Last, I find it disconcerting that rigorously designed state of the art clinical trials, fulfilling both the demands of academic psychopharmacology and the rules and guidelines of registration agencies, are still discussed with a scepticism of an almost paranoid quality just because they are “industry sponsored”. Let me set the record straight: I am absolutely in favour of iconoclastic paradigm shattering, if it is evidence based. This is one of the guiding principles of scientific research, to either replicate or falsify. However, in my humble view, I fail to find substantial evidence from a significant number of clinical trials which convincingly puts the principle fact that antipsychotics prevent relapse in schizophrenia into question. Needless to say, this does not obviate the necessity to adjust the finer details of antipsychotic relapse prevention. More recently, treatment expectations have extended beyond the mere prevention of the recurrence of psychotic symptoms. This takes me from my more general points to issues which more specifically address Correll et al's review6. While the authors provide a thoughtful, balanced and clinically most useful discussion of the topic, two issues, in my mind, deserve additional attention. One of them deals with outcome assessment and the other with psychosocial outcomes. I would like to elaborate on assessment methodology from three perspectives: diagnosis, safety monitoring and quantifying psychosocial outcomes. With respect to the first, it needs to be acknowledged that schizophrenia is still a somewhat elusive concept. Despite the efforts of the DSM-5 and the forthcoming ICD-11, the heterogeneity of the syndrome, both with respect to psychopathological presentation and neurobiological underpinnings, has left us with a certain degree of diagnostic uncertainty. Obviously, this inhomogeneity also impinges upon the quality of clinical trials, leaving us with a considerable degree of variance, even when looking at clearly defined outcome measures such as symptom recurrence. This implies that, as evidenced in basically all other fields of medicine, we are left with group findings based on mean values, which allow us only limited predictions of individual outcomes. Although personalized or precision medicine is on everybody's wish list in our field as well, it has not yet become a clinical reality, although there is some light at the end of the tunnel7. A problem which appears somewhat easier to solve is that of reliably assessing safety and tolerability. Many clinical trialists still rely on spontaneous reporting of adverse events. This is notoriously unreliable, especially in a disorder with well-known communicative and cognitive impairments. Standardized rating scales for all adverse events, such as those available for extrapyramidal motor side effects, need to be implemented into clinical trials, especially into phase II and phase III studies. The discrepancy between rating scale based and subjectively assessed adverse events has been well documented for motor side effects8. In this context, I would also like to underscore the difficulties in reliably documenting psychosocial outcomes, starting by pointing to the difficulties in assessing quality of life from either a subjective or an objective perspective in patients suffering from reality distortion. This becomes even more challenging when considering the influence of sociocultural and geopolitical diversity in larger scale multicenter, often international, clinical trials. The same holds true when considering other relevant psychosocial outcomes, such as employment rates, which differ tremendously based on regional specifics. Even within the same country, recruiting patients from diverse socioeconomic backgrounds renders the interpretation of the obtained results very difficult. Lastly, I would like to underscore the importance of stigma and discrimination from two different points of view, namely those caused by a psychotic relapse and by the side effects of medication. Starting with the latter, those of us with enough experience in the field to still remember heavily parkinsonized and akathisic patients on antipsychotics do appreciate the fact that these side effects, albeit not totally eliminated, are, in the true sense of the word, considerably less visible with new generation antipsychotics. Apart from the subjective discomfort that patients with motor side effects experience, this also considerably lessens the stigma caused by medication, as patients are less obviously “disturbed” in their motor appearance. On a different but related note, stigma and discrimination can also be among the sequelae of psychotic symptoms, and the negative impact that unusual, odd and sometimes dangerous behaviour can have on psychosocial (re-)integration cannot be appreciated enough. It has been well documented that reducing antipsychotic dose below a critical level, or discontinuing medication altogether, enhances the risk for residual symptoms and/or relapse9. In an ideal world, society may find a certain level of symptom acceptable, if the patient does not subjectively suffer, yet, unfortunately, we do not live in this ideal world, and symptoms such as those experienced by schizophrenia patients still lead to a considerable amount of stigma and discrimination, which must not be underestimated. All in all, I fully agree with Correll et al that the bulk of the available evidence still supports the judicious evidence-based use of maintenance antipsychotic treatment in most patients suffering from schizophrenia. Involving patients and, if available, significant others in treatment considerations is a conditio sine qua non. In addition, regular risk/benefit assessments, as well as medication adjustments based on a monitoring of symptom and safety/tolerability levels, are an obvious requirement. Although we may not yet have the tools to provide predictive personalized medicine, individualized care based on these considerations allows to optimize management options for every person affected with this serious mental disorder. W. Wolfgang Fleischhacker Division of Psychiatry I, Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University Innsbruck, Innsbruck, Austria