A prospective, randomized, and controlled study comparing two treatment strategies
Dose REduction of Antipsychotics vs Maintenance treatment
in patients with schizophrenia spectrum disorder after
Stratification based on patients' psychotic PHENotype
a precision medicine approach

DreamsPhen is a project of the CDC research program.

Introduction

Antipsychotics have dramatically accelerated the symptomatic improvement of psychotic episodes. However, the benefit of their maintenance for every patient with schizophrenia spectrum disorder (SSD) remains disputed. This is reflected by the recent shift in the guidelines for maintenance treatment in both first episode (FE-SSD) and chronic (C-SSD) SSD patients.

Rationale

The rationale of the Dreams-Phen project is based on five main arguments.

1. In terms of benefit/risk ratio, it seems reasonable to discuss a dose reduction (DR) of antipsychotics (that can eventually reach discontinuation) in clinically stabilized SSD patients with residual symptoms. In fact, the long-term use of antipsychotics is suspected to account for the increasing health inequalities and mortality gap of SSD relative to the normal population. Furthermore, DR reduces antipsychotic-side effects and improves cognition in both FE-SSD and C-SSD.
2. In terms of relapse risk, although most of the studies that have compared the maintenance of antipsychotic treatment (MT) to the DR/discontinuation strategy in SSD patients have shown a higher rate of psychotic relapse with DR, the clinical relevance of these "relapses" may have been overestimated. In fact, they mostly consisted of a mild and transient increase of psychotic symptoms and did not come with a new hospitalization, self-harm or aggressive behaviors. Furthermore, the dose minimization strategy (DM, i.e. the reduction of the antipsychotic dose to its minimal effective dose, MinED) did not come with an increased risk of relapse.
3. From the patients' perspective, experiencing mild and transient increase of psychotic symptoms seems to be less important than the gain of improved social functioning and cognitive capacities and lowering the discomfort associated with antipsychotics’ side effects. Wunderink et al. (2013)'s observational study has shown that in fact, 7 years after a first episode of psychosis, patients in the DR arm were functioning significantly better than patients in the MT arm on a variety of outcomes, and were 2.3 times more likely to achieve functional remission (40% vs 18%, p = 0.004). Hence, goals that are not directly related to clinical measures are more valued by patients and should be considered first.
4. Given that the DR/discontinuation protocols used in the vast majority of the studies were possibly too fast (most often occurring within a period under 12-months), the increase of psychotic relapse in the DR group may have led psychiatrists to falsely conclude that DR is risky or should be avoided in SSD, thereby preventing psychiatrists from questioning whether the tapering methods employed were themselves inadequate. Very recently, Horowitz et al have proposed psychopharmacology-driven hyperbolic tapering schemas to best minimize both the risk of relapse and that of supersensitivity psychosis in SSD patients. This schema extends the duration of tapering over several months.
5. Given that SSD concerns a very heterogeneous group of patients with diverging clinical presentations, outcomes, and severity, we argue that the DR strategy would particularly benefit patients presenting with specific psychotic phenotypes called cycloid psychoses (CP), i.e. motor psychosis, confusional psychosis or anxiety-happiness psychosis. This is for at least two reasons: 1) CP is associated with a purely remitting-relapsing course and with good long-term prognosis; 2) CP is associated with an increased sensitivity for antipsychotics-induced side-effects when antipsychotics are taken at usual dosage.

Originality

With regard to the published literature and current trials on DR/discontinuation, the following methods make this project original and innovative:

1. The use of functional remission as main outcome criteria. This is more aligned with patients’ hopes, and fits with the main objective put forth by most SSD management guidelines. This means that less value will be given to mild increase of psychotic symptoms, and significant relapse will be considered, yet only as secondary outcome criteria.
2. The optimization of the tapering protocol, based on a two-step DM/DR schema as a compromise between speed and safety. The first DM step will consist of reducing the antipsychotic dosage to its minimal effective dose. Then the DR will follow Horowitz et al. hyperbolic tapering schemas, eventually until discontinuation.
3. The use of a patient stratification strategy (precision medicine approach) with the identification of patients with cycloid psychoses, as the most likely to achieve good life-long functional outcome (and tolerate DR). As the direct implementation of new guidelines in daily practice is often wishful thinking rather than reality, we hope that this study will empower psychiatrists to adapt the aims of treatment to align with those of their patients, and to determine for whom, when, how, and by how much antipsychotic doses should be minimized.

Hypotheses

We hypothesize that:

1. CP represent a particular phenotype within SSDs for which a DR/discontinuation strategy should be systematically proposed, as they are most likely to achieve functional remission even without antipsychotics;
2. Non-CP patients may also benefit from DR, but may be less likely to tolerate DR and less likely to achieve functional remission.   

Articles

Berna F, Schorr B, Javelot H, Dormegny-Jeanjean LC, Foucher JR. Real-world effectiveness studies of low doses of antipsychotics. The Lancet Psychiatry 2022; 9:536 (doi) (letter, supplementary material)

Berna F, Javelot H, Schorr B, Cuny M, Clauss-Kobayashi J, Mainberger O, Dormegny-Jeanjean LC, de Billy C, Foucher JR. Réduire ou arrêter les antipsychotiques dans la schizophrénie : une pure folie ? Minute Pharmacopsy Juin 2022 (article in French)

Foucher JR, Gawlik M, Roth JN, de Billy C, Jeanjean LC, Obrecht A, Mainberger O, Clauss JME, Elowe J, Weibel S, Schorr B, Cetkovich-Bakmas M, Morra C, Rebok F, Ban T, Bollmann B, Roser MM, Hanke M, Jabs BE, Franzek EJ, Berna F, Pfuhlmann B. "Wernicke-Kleist-Leonhard phenotypes of endogenous psychoses: a review of their validity". Dialogues Clin Neurosci. 2020;22(1):37-49. Une introduction à la classification de Leonhard.

Foucher JR, Greene V. "La CIM et le DSM ou l'impossible validation: pourquoi le ver est dans le fruit". Annales Médico-psychologiques 2010; 168(8):609-615.

Foucher JR, de Billy C, Obrecht A, Mainberger O, Schorr B, Bonah C, Clauss J, Berna F. "Bases épistémologiques de la recherche sur les psychoses : quelle solution pour le choc des cadres paradigmatiques ?" Annales Médico-psychologiques (sous presse, accepté en octobre 2018).

E-book pour liseuse (format epub)

"Pour une psychopathologie différentielle des psychoses endogènes". du Séminaire de psychopathologie différentielle des psychoses endogènes reprend en grande partie cette page avec des additions.

Présentations

"A patient stratification approach based on the cycloid psychoses phenotypes to guide the dose reduction strategy following a psychotic episode: the Dream-Sphen project". Prof. Fabrice Berna, University of Strasbourg, France. 1st WKL-IS quaterly web-conference - 1st octobre 2021. Lecture (12 min), Discussion (23 min)

"Epistémologie des classifications". Cours du séminaire de psychopathologie différentielle (2012).

"Epistémologie des classifications en psychiatrie". Cours du séminaire de psychopathologie différentielle (2017) - vidéo (youtube) ou présentation interactive (HTML5).