There may be subtypes in treatment-resistant schizophrenia (TRS), and one of the subtypes may be related to dopamine supersensitivity psychosis (DSP). In developing strategies for prevention and treatment TRS, it is important to clarify the role of DSP in TRS. TRS patients were recruited from 3 hospitals for the present study. Through chart reviews, all patients were judged as either TRS or not, and then possible TRS patients were investigated about their past/present histories of DSP episode(s) by direct interviews. We then compared each factor between the groups with and without DSP episode(s). Out of 611 patients screened, 147 patients met the criteria for TRS and were included in the present analysis. These were divided into groups with and without DSP, comprising 106 (72.1%) and 41 patients (27.9%), respectively. Clinical characteristics in the two groups were similar, except for drug-induced movement disorders (DIMDs), which were significantly more important in DSP patients. Of the DSP patients, 42% and 56% experienced rebound psychosis and tolerance to antipsychotic effects, respectively. The present study revealed that approximately 70% of TRS patients experienced one or more DSP episodes, which may have a strong impact on the long-term prognosis of patients with schizophrenia.
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 and 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 and 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 and 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 and 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 and 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 and 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.
