Taking a Bleulerian perspective: a role for negative symptoms in the staging model?
Authors: Lex Wunderink
Journal: World Psychiatry (2017)

In their well-wrought overview of the evidence on interventions to improve the outcomes of first-episode psychosis, Fusar-Poli et al1 adopt a revised staging approach. One of the most prominent new features of this model is the distinction of three different clinical stages of high risk for psychosis, starting with a stage defined by negative and cognitive symptoms (1a), followed by one characterized by attenuated psychotic symptoms (1b), and one of short-lived remitting psychotic episodes (1c). These stages precede the stage 2 full-blown first-episode psychosis, defined by early full recovery. Though the authors acknowledge the lack of a pathogenetically driven staging model, and imply that the joints of nature could have to be carved at different places the more pathogenesis is clarified, their revised model does account for the early initial prodromal state as delineated in German literature, starting with early cognitive and negative symptoms, even before the first positive symptoms emerge. The transition rate at 2-year follow-up from stage 1a to full-blown psychosis (stage 2) has been shown to amount to 3%, while it is 19% from stage 1b and 39% from stage 1c2. Stage 1a seems a valuable addition to the staging model, on several grounds. Negative symptoms are the most important predictor of outcome in first-episode and early-onset psychosis according to a number of studies3, 4. Long-term functional outcome of first-episode psychosis is highly correlated to negative symptomatology, much more so than to positive symptom severity or duration of untreated psychosis5. In spite of the relatively low transition rate to a full-blown psychotic stage (symptomatic outcome), due to the poor specificity of sole negative symptoms, the prediction of diminished functional capacity irrespective of diagnosis might be stronger than transition rate to psychosis would suggest. Maybe the emphasis on positive symptomatology in the current staging models has something to do with the different treatment perspectives of the two symptom dimensions: as Fusar-Poli et al emphasize, there is still not much we can do against negative symptoms, while positive symptoms are far more amenable to treatment, particularly with antipsychotic drugs. The less complicated operationalization of criteria for and assessment of positive vs. negative symptoms may also have contributed to the less prominent role of the latter in staging and operationalized criteria. Fusar-Poli et al provide one more argument to emphasize the importance of negative symptoms. They cite the literature showing that recovery rates (one in seven) and associated disability (11th cause of disability worldwide in 2013) have not improved over the past 70 years, and that antipsychotics can reduce some symptoms, but have little impact on the outcome of the illness6. This is in line with the lack of stringent evidence for a robust effect of antipsychotics on relapse prevention on the long term7. If the dopamine blockade exerted by antipsychotics is now mostly considered a symptomatic therapy, not really altering the course of the disease, one might wonder whether the derangement of the dopamine system during florid psychotic episodes is at the core of the disease, or mainly a consequence of primary derangements higher upstream, e.g. in the GABA-ergic parvalbumin interneuron system, and/or the glutamatergic input into that and other systems8. If this is the case, there might be other trajectories leading to dopamine derangement, perhaps more benign and self-limited9, not based on a more fundamental interneuron deficiency, but on environmental factors such as cannabis use or traumatic experiences. Following this somewhat speculative reasoning, the lack of specificity of the stages 1b and 1c, mainly based on positive symptoms, would be the consequence of the heterogeneous causes of excessive dopamine activity (associated with positive symptoms), of which the more persistent negative symptom-related lack of inhibitory power due to GABA-ergic deficits would be only one. In a brain with a primary dysfunctional excitation-inhibition balance, episodes of positive symptoms might represent a decompensated stress-adaptive mechanism driven by dopamine. Thus, the occurrence of positive episodes embedded in a negative syndrome is probably what should really warn us for prognostic risks. The poor prognosis associated with the diagnosis of schizophrenia might be mainly attributable to this combination. After all, the negative symptom dimension is one of the main constituents of the operational criteria for a schizophrenia diagnosis, with its persistence in time, association to relapse proneness and functional decline, and poor response to treatment. Though essential knowledge is lacking to refute or confirm this hypothesis, it might be worthwhile for research purposes to suggest a staging approach using both symptom dimensions, with negative symptoms not limited to stage 1a, but also running along the other stages, at least including stage 2, that are currently only operationalized by positive symptoms and relapse. Regarding the treatment recommendations for stage 2, the first episode with full recovery, the authors do acknowledge the symptomatic nature of antipsychotic treatment. Though the persistence or not of negative symptoms is not mentioned, most first-episode psychosis samples include patients with persisting negative symptoms after treatment response. Fusar-Poli et al mention the conceivable advantages of the recommendation by ourselves and a number of other authors10 to individually adjust dosage reduction of antipsychotics to the lowest dose that is still effective to redress positive symptoms. This is aimed to prevent not only extrapyramidal and metabolic side effects, but also the induction of subjective side effects due to dopamine blockade in the ventral striatum and reward circuits, which may be denoted as subtle extrapyramidal side effects. The authors argue in favour of research into the characteristics of patients who will do better on low doses or even discontinuation of antipsychotics. However, their suggestion to exclude patients with a schizophrenia diagnosis might have been worded better by suggesting research across all non-affective psychosis categories, investigating the role of baseline negative symptoms as a very suspect candidate for predicting unsuccessful dosage reduction, more relapses and shorter time to first relapse with respect to symptomatic outcome, and failure to regain functional capacity with respect to functional outcome. At present, it is unknown whether higher maintenance doses of antipsychotics would lead to better outcomes in patients with more severe negative symptoms, since antipsychotics tend to worsen these symptoms, probably also affecting functional outcome. However, the dopamine system, in a number of these patients, might be so brittle that dosage reduction inevitably leads to relapse. On the other hand, patients who use cannabis at baseline might have a more important environmental causation of their dopamine derangement, tend to show less negative symptoms, and may be less likely to respond unfavourably to dosage reduction11. Several trials are now underway to clinically evaluate dosage reduction in remitted first-episode schizophrenia patients, that will hopefully answer some of these questions. Finally, the authors’ view that in later stages (3 and 4) dosage reduction will probably not be an answer, while the still underused and often delayed antipsychotic drug clozapine might substantially improve outcome, though convincing, requires a more substantial research support. Lex Wunderink Department of Research and Education, Friesland Mental Health Services, Leeuwarden, The Netherlands