Impact of dopamine supersensitivity psychosis in treatment-resistant schizophrenia: An analysis of multi-factors predicting long-term prognosis

Abstract

Background

Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis (DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS.

Methods

Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups.

Results

All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS.

Conclusions

Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness.

Introduction

Approximately 20–30% of all patients with schizophrenia show little or no response to appropriate pharmacotherapy and are operationally defined as having treatment-resistant schizophrenia (TRS) (Kane et al., 1988). Over the last three decades, various attempts have been made to clarify factors predictive of poor prognosis or TRS. To date, the factors suggested to predict poor prognosis are male gender (Riecher-Rössler and Häfner, 2000), younger age at onset (Meltzer et al., 1997), lower premorbid social adaptation (Wiersma et al., 2000), and presence of family history of psychiatric disease (Murray and Van Os, 1998). In addition, duration of untreated psychosis (DUP) has been widely studied and longer DUP is now established as a predictive marker for a relatively short disease course (i.e., critical period) (Marshall et al., 2005, Perkins et al., 2005). There have also been numerous researches into the possible relationship between the initial response to antipsychotics and prognosis (i.e., early onset hypothesis; Kapur et al., 2005). Most of these studies demonstrated that the responsiveness at 2 to 6 weeks following treatment introduction for first-episode psychosis (FEP) was significantly predictive of the clinical improvement in the acute stage (Correll et al., 2003, Schennach-Wolff et al., 2011) or chronic disease course (Álvarez-Jiménez et al., 2012, Emsley et al., 2006).

There was, however, no evidence than any specific single factor was a definite predictor for TRS. As regards DUP, its effect on the long-term prognosis is unlikely to be as profound as its effect on the short-term prognosis (Kanahara et al., 2013, White et al., 2009). With respect to initial responsiveness to pharmacotherapy, most studies have been conducted from the viewpoint of prediction for remission, with only limited investigation of the possible role of pharmacotherapy in the development of TRS. Although it appears that these factors affect the clinical disease course by interacting with each other, there have been few studies investigating the ability of a combination of factors to predict the development to TRS. Furthermore, the predictive factors in previous studies were mostly limited to parameters related to the stage prior to disease onset or in the very early disease stage, and thus factors related to continuous treatment for the chronic stage were usually omitted.

Dopamine supersensitivity psychosis (DSP) is a clinical concept which is related to antipsychotics treatment (Chouinard, 1991, Iyo et al., 2013) and is characterized by withdrawal psychosis upon the cessation or dose reduction of antipsychotics (Moncrieff, 2006), the development of tolerance to the effects of antipsychotics (Kirkpatrick et al., 1992), tardive dyskinesia (TD; Chouinard and Chouinard, 2008), and acquired vulnerability to minor stress (Fallon et al., 2012). To compensate for these effects, the dosage of antipsychotic(s) is usually increased, and thus the patient in such cases meets the criteria for TRS (Chouinard, 1991, Iyo et al., 2013). As DSP is considered to be induced by dopamine D2-receptor supersensitivity by prolonged antipsychotic treatment, in addition to the dopamine supersensitivity already present in schizophrenia (Kirkpatrick et al., 1992, Iyo et al., 2013, Seeman, 2013, Seeman and Seeman, 2014), this psychosis may be involved in the development of treatment refractoriness. No studies, however, have reported to what extent DSP impacts the long-term prognosis in patients with schizophrenia.

In the present study we attempted to identify factors that are predictive of the prognosis of TRS and are specific to the different clinical stages of TRS. Thus, we considered potential predictive factors prior to the initiation of treatment for psychosis, e.g., DUP and premorbid social functioning, factors related to FEP, e.g., initial response to antipsychotic drugs and their dosages, and factors related to long-term antipsychotic treatment, such as DSP. In this way we sought both to clarify the impact of individual factors on prognosis, and also to examine possible interactions among these predictive factors.