Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia
Introduction
Although pharmacotherapy with antipsychotics has been a main strategy in treating schizophrenia, only 30–45% of patients experience and adequate response to these drugs (Andreasen et al., 2005, Bertelsen et al., 2009). Patients who respond poorly to treatment with two or more antipsychotic drugs are diagnosed as treatment-resistant schizophrenia (TRS) (Kane et al., 1988, Brenner et al., 1990). Clozapine has been established as the only effective agent for treatment-resistant cases, but some patients poorly respond even to this drug (Chakos et al., 2001, Henna Neto and Elkis, 2007). These data suggest the existence of subtypes in TRS and the importance of clarifying these subtypes in developing strategies for the prevention and treatment of schizophrenia.
One possible type of TRS may be related to antipsychotic-induced dopamine supersensitivity psychosis (DSP), which was first reported by Chouinard et al. (1978) and was recently classified as iatrogenic supersensitivity psychosis (Iyo et al., 2013, Seeman and Seeman, 2013). DSP is considered to develop following increases in antipsychotic dosages accompanying with relapses in patients with schizophrenia, although we should also take account of natural deterioration as a feature of schizophrenia. They progressively may show severer positive symptoms and need higher doses of antipsychotics, reaching TRS. Possible clinical features of this psychosis are co-existence of tardive dyskinesia (TD), relapse episodes immediately following treatment discontinuation (rebound psychosis) and/or developed tolerance to the drugs׳ antipsychotic effects despite continuous treatment (Chouinard, 1991, Moncrieff, 2006).
We recently proposed possible mechanisms underlying DSP and methods for the prevention and treatment of DSP on the basis of dopamine D2 receptor (DRD2) up-regulation (Iyo et al., 2013). In addition, antipsychotic-induced dopamine supersensitivity can be caused not only by an elevation in DRD2, but also by an increase in dopamine D2High receptors, which are known to represent the functional high-affinity state of the DRD2 (Seeman et al., 2005). Briefly, patients with DSP have an up-regulation and increasing supersensitivity of brain DRD2 induced by long-term over-blockade by antipsychotics and need higher dosages of antipsychotics to suppress the excessive dopamine neurotransmission via the increased DRD2. Higher antipsychotic dosages may yield higher fluctuation in the antipsychotic levels in the body since the elimination half-life from the body may be almost same regardless different dosages, leading to unstable psychotic symptoms. We hypothesized that an antipsychotic drug with a longer elimination half-life, which provides a stable plasma level, would produce a stable and optimal DRD2 blockade. Indeed, we reported that risperidone long-acting injectable form (LAI) combined with ongoing oral antipsychotics, which were gradually reduced to achieve maximal clinical effects with minimal side effects, improved refractory psychotic symptoms in the TRS patients with DSP significantly greater than those without DSP (Kimura et al., 2013, Kimura et al., 2014). It is suggested that there may be at least two types of TRS from the viewpoint of response to LAI, i.e., DSP and non-DSP. Therefore, it is important to further clarify subtypes in TRS, especially to explore the contributing roles of DSP.
The present study aims to compare the clinical characteristics of TRS between patients with and without DSP by examining the history of their symptoms, and to clarify the roles of DSP in TRS.
Section snippets
Subjects
The present study was conducted in three psychiatric hospitals. The study protocol was approved by the ethics committees of all relevant facilities and was conducted in accordance with the Helsinki declaration. All 611 patients diagnosed as having schizophrenia or schizoaffective disorder (DSM-IV-TR) in either the outpatient or inpatient divisions of the research facilities were screened as candidate participants, by investigation of medical charts. Among them, a total of 202 patients were
Results
All 611 patients in the research facilities were screened; among them, 147 TRS patients were included in the final analysis (Fig. 1).
Of the TRS patients, 106 (72.1%) were judged as having a history of DSP according to the criteria (Table 2). There were no significant differences in demographical indexes between the groups with and without DSP episodes (P>0.05). Furthermore, no difference in BPRS total score, positive symptoms, GAF or CGI-S was observed between the groups. Negative symptoms in
Discussion
The present study demonstrated that patients with DSP related to antipsychotic treatment comprised about 70% of the TRS patient group. There were no significant differences in most of the clinical characteristics at the current interview between the patient groups with and without DSP, but the patients with DSP showed greater severities in EPS than those without DSP, which did not essentially differ between analysis including and excluding TD. These suggest that DSP is an important subtype of
Contributors
Study concept and design: Kanahara, Iyo.
Acquisition of data: Suzuki, Kanahara, Yamanaka, Takase, Oda, Kimura.
Analysis and interpretation of data: Suzuki, Kanahara.
Drafting of the manuscript: Suzuki, Kanahara, Iyo.
Obtained funding: Kanahara.
Study supervision: Watanabe, Iyo.
Conflict of interest
Dr. Kanahara received grant funding from Ministry of Health, Labor and Welfare and SENSHIN Medical Research Foundation and reported honoraria from Eli Lilly, Otsuka and Janssen. Dr. Yamanaka reported honoraria from Otsuka, Dainippon Sumitomo, Janssen and Eli Lilly. Dr. Kimura reported honoraria from AstraZeneca, Janssen, Eli Lilly, Meiji Seika, Otsuka and Mochida. Dr. Watanabe reported honoraria from Eli Lilly, Dainippon Sumitomo, Astellas, GlaxoSmithKline, Mochida and Eisai. Dr. Iyo received
Acknowledgment
This study is supported by SENSHIN Medical Research Foundation in Japan (Heisei25-Ippan).
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