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Center for Global Research Data

Determination of dopamine supersensitivity psychosis in randomized controlled studies of long-acting injectable vs. oral agents of the same atypical antipsychotic in schizophrenia subjects

Lead Investigator: Nobuhisa Kanahara, Chiba University Center for Forensic Mental Health
Title of Proposal Research: Determination of dopamine supersensitivity psychosis in randomized controlled studies of long-acting injectable vs. oral agents of the same atypical antipsychotic in schizophrenia subjects
Vivli Data Request: 5871
Funding Source: None
Potential Conflicts of Interest: Honoraria from Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Janssen Pharmaceutical K.K. Novartis Pharma K.K., Mochida Pharmaceutical Co., Ltd and Meiji Seika Pharma. Co., Ltd.
All processes in this research project, including planning, data analysis, interpretation of the outcomes, and writing manuscript, was not involved in any specific grant and agency in the public, commercial or not-for-profit sectors.

Summary of the Proposed Research:

Schizophrenia is a severe mental disorder encompassing a variety of psychiatric symptoms including positive symptoms such as delusion and hallucination, negative symptoms such as avolition and social withdrawal, and further cognitive impairments and mood dysregulation. This disorder affects approximately 1% of general population worldwide. Schizophrenia generally occurs in young people from late adolescence to early adulthood and profoundly burdens patients throughout their lives.

Both first-generation antipsychotics (FGA) long-acting injectables (LAIs) and second-generation antipsychotics (SGA)-LAIs are introduced to avoid relapse for patients with poor adherence to medication through secure drug delivery and to improve psychotic symptoms and extrapyramidal symptoms (EPS), neurological adverse events induced by antipsychotic, through stabilized pharmacokinetics (i.e., less fluctuation of drug’s blood concentration compared to oral agent). Several meta-analyses have strongly supported this effect of LAIs (Leuchit et al., 2011; Kishimoto et al., 2013; Zhao et al., 2016).

Ostuzzi et al. (2016) recently conducted a meta-analysis that measured the continuous ratio of antipsychotic treatment, derived from a total of 18 trials that compared between FGA/SGA-LAI and the same oral agent. Most antipsychotics such as risperidone, olanzapine, zuclopenthixol, fluphenazine and haloperidol failed to show superiority at a continuous ratio of each LAI to the corresponding oral agent. Aripiprazole was the only agent to marginally show the superiority in treatment continuity of aripiprazole once-monthly (AOM: once-monthly long-acting injectable aripiprazole). The authors concluded that LAIs were not necessarily advantageous compared to oral agents.

The most convincing reason for the lack of difference between the two forms is that under the structural trial settings like clinical trials, the adherence levels increased particularly in the patients assigned to the oral agent, thus diluting the superiority of LAIs that is observed in real-world applications. However, it is difficult to resolve this issue, since the randomized controlled trials (RCTs) contained several other problems, i.e., study subjects with comorbid disease or variations in the severity of psychopathology, and variations in the study design such as follow-up duration or dose setting. In this context, non-RCTs close to clinical practice may reflect true outcome that LAIs are advantageous to oral agents.

Patients with long-term exposure to antipsychotics, in particular under high-dose treatment, acquire hypersensitivity (i.e., hypersensitive to dopamine) of dopamine D2 receptors (DRD2) in their brains, which have been demonstrated in animal models. Such patients often clinically present with episodes of relapse and/or tardive dyskinesia (TD), all of which were referred to as neuroleptic-induced supersensitivity psychosis in the 1970s. This psychotic state is characterized by rebound psychosis which can appear immediately after stopping, tapering or switching on-going antipsychotic regimen, and by tolerance to antipsychotic’s effect regardless of further reinstitution or dosing-up of antipsychotic(s), in addition to TD (Chouinard, 1991). Neuroleptic-induced supersensitivity psychosis was afterwards renamed as dopamine supersensitivity psychosis (DSP)(Iyo et al., 2013). For such patients under treatment at a dose over the standard dose, i.e., possibly developing DSP, treatment with LAI could be useful; this approach provides a continuous blockade of DRD2 and stabilization of the blood concentrations of the agent. These outcomes could in turn reduce the amount of oral agents and the EPS and further could lessen the DRD2 hypersensitivity, all of which might contribute to the amelioration of DSP, that is, less vulnerability to change of antipsychotic regimen. However, such patients have a tendency toward psychotic relapse with unstable course of psychosis and vulnerability to stress, and therefore they may not be ideal targets in clinical trials.

Based on these findings, LAIs could be effective for patients with DSP. If an RCT is aimed mainly at patients with DSP, it would prove the superiority of LAI to oral agents. In other words, it is possible that, in the RCTs showing no difference in efficacy regarding treatment continuation between the two forms, no patients with DSP participated in the study, or that they were not included in the final analysis due to having dropped out during the study phase, since patients with DSP are vulnerable to the tapering or to the switching of the agent as often occurs in the initial stage of RCTs.

Requested Studies:

A Double-Blind, Randomized Study Comparing Intramuscular Olanzapine Depot to Oral Olanzapine and Low-Dose Depot in the Maintenance Therapy of Patients With Schizophrenia
Sponsor: Eli Lilly and Co.
Study ID: NCT00088491
Sponsor ID: 5985

A Randomized, Open-label Study Comparing the Effects of Olanzapine Pamoate Depot With Oral Olanzapine on Treatment Outcomes in Outpatients With Schizophrenia
Sponsor: Eli Lilly and Co.
Study ID: NCT00320489
Sponsor ID: 6390

Update: This data request was withdrawn on 31-Aug-2021 by the researcher.