Background
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. Pharmacological medication has been a mainstay in treating patients with the disease, but only one-third of patients successfully recover to their premorbid functioning level without any significant psychotic symptoms; the majority of patients have some remaining symptoms, and their symptoms are often exacerbated during the long-term disease course [
1]. In clinical practice, such recurrent episodes often exhibit insufficient or no response to antipsychotics.
The reasons why some patients who respond well to treatment for their first-episode psychosis (FEP) subsequently develop treatment-resistant schizophrenia (TRS) are not well understood. Several clinical trials have reported that approximately 15% of patients with schizophrenia show no response to the first antipsychotic in their FEP, whereas 75% of FEP patients show a significant response [
2‐
4]. On the other hand, it has been estimated that about 30–40% of all patients eventually fulfill the criteria of TRS [
5,
6]. These data suggest that among patients eventually classified as having TRS, a few demonstrate TRS at an early treatment phase while the rest transit into TRS at various later time-points during their disease course.
Recent studies have suggested that there may be two patterns of development to TRS: an immediate transition to TRS from the time of treatment introduction (i.e., early TRS) and a later transition to TRS after a significant improvement (i.e., later TRS) [
7,
8]. In addition, younger onset, higher initial negative symptoms and longer duration of untreated psychosis (DUP) have been proposed as factors predictive of transition to TRS [
8]. Despite these findings, however, the detailed process of development to TRS remains to be elucidated. For example, it is unclear whether patients who meet the criteria of early TRS will continue to meet the TRS criteria thereafter. In order to more clearly clarify the process to TRS and to exclude, to the greatest degree possible, any ambiguity in the diagnosis of TRS, we considered that it would be reasonable to focus exclusively on patients undergoing long-term treatment who were currently diagnosed with TRS. Therefore, we decided to retrospectively compare duration and clinical factors of FEP between current TRS patients and non-TRS patients. We hypothesized that subjects with current TRS would have previously exhibited poorer improvement during treatment of their FEPs compared to subjects without TRS. To examine this, we compared the duration of initial hospital admission, which we defined as the period from treatment introduction to successful discharge (with successful discharge defined as a subsequent 3 months of successful treatment in an outpatient clinic), among subjects with and without current TRS.
Discussion
There were two main findings in the present study. 1) Although the TRS group showed slightly worse recovery from their FEP than the Non-TRS group in terms of GAF scores, there was no difference in the duration of initial hospital admission (defined as the period from treatment introduction to successful discharge, with successful discharge meaning 3 months of successful outpatient treatment) between the two groups, and 2) the patients in the TRS group experienced either one of two contrasting courses at the early disease stage: a) acute-onset psychosis, requiring hospital admission to introduce treatment and then a long hospital stay for FEP, or b) insidious onset without hospital admission and subsequent treatment with a relatively small dose of antipsychotics. The latter finding of dual early-stage courses helps to clarify the subtleties of the former finding that there were no differences in factors other than GAF at the end of FEP between the TRS and Non-TRS groups. That is, the fact that the FEP profile of the TRS group exhibited two distinct patterns dilutes the essential difference in the FEP profiles between the TRS and the Non-TRS groups. However, our results strongly indicate that poorer response or longer time course to improvement of either positive or negative symptoms following initiation of medications is a marker of risk for TRS.
No definitive definition of FEP duration has been established in either the clinical or research fields. Onset is generally defined as the appearance of positive symptoms, but it has proven difficult to determine the ending time point in a uniform manner across studies. This is partly because about 15% of patients under FEP do not respond to treatment [
3,
4]. This is one of the reasons why, in the present study, we used the date of successful discharge from the hospital (not requiring subsequent readmission within 3 months) as an alternative endpoint of FEP. In addition, the medical insurance system of Japan encourages both a hospital admission shorter than 3 months and the avoidance of readmission within 3 months following discharge, by reducing reimbursement revenues unless these criteria are fulfilled. This peculiarity of the Japanese insurance system was also part of our rationale for using an absence of readmission for 3 months from the previous discharge as part of our definition of FEP duration in the present study.
Our present finding that patients who go on to develop TRS are more likely to have exhibited poor improvement during their FEP is in agreement with several clinical trials. Namely, several studies have reported that a poorer response to an initial pharmacological medication was closely related to a lower likelihood of recovery [
13‐
17]. However, in the present study the TRS patients did not show an improvement of FEP symptoms extremely poorly at the 6th month compared to the Non-TRS patients (GAF score of 50.1 points vs. 61.0 points). This result was partly due to both the varied GAF scores in the TRS group (Fig.
3a) and the relatively low average GAF in the Non-TRS group, i.e., only 28.6% (
n = 52) of the 182 subjects of the Non-TRS group achieved a GAF of > 70 points (Table
1).
In this study, the more important finding was that there were two distinctive subtypes of TRS patients. The TRS patients with admission for FEP had a GAF of only 53 points after 6 months, which is almost the same as their duration of initial hospital admission (169.3 days). That is, they were discharged from the hospital regardless of whether or not their improvement was sufficient after a half year of intensive medication and effortful care. On the other hand, the TRS patients without admission did not require hospital admission for their FEP and were treated under a relatively low dose of antipsychotics thereafter, implying that negative symptoms will be evident in this subtype. It is unlikely that more patients with intolerance to antipsychotics as a TRS subtype were included in the group of TRS patients without admission, since only four patients with intolerance to antipsychotics belonged to each of the two TRS subgroups. Therefore, higher susceptibility to extrapyramidal symptoms did not account for the low dose in the subgroup of TRS patients without admission. Furthermore, their DUPs, one of the best known predictors of treatment refractoriness, were similar or rather shorter than those of the Non-TRS group, indicating that there was no relationship between DUP and future development to TRS. Gender also showed no relation to TRS.
The two subtypes of TRS, however, were very similar in terms of the course following the initial hospital admission. That is, they did not differ in subsequent hospital admission times or durations, and both experienced gradual increases in antipsychotic dosage. Surprisingly, the duration from treatment introduction until meeting the TRS criteria was longer than previously thought. In this study, the duration was 3195 days on average (=8.75 years) or 2539 days (=6.96 years) in the TRS group with hospital admission and 3886 days (=10.65 years) in the TRS group without admission. The value in the TRS group without admission tended to be longer than that in the TRS group with hospital admission, but not significantly so (p = 0.070). These long durations until meeting the poor-responder criteria of TRS diagnosis may be related to long-term treatment with single or combined antipsychotic(s) from relatively few classes, which in turn might be related to the lack of availability of clozapine in Japan before 2009.
Lally and colleagues prospectively followed 246 patients with schizophrenia for 5 years and then studied their process of transition to TRS [
7]. They found that 81 patients (33.7%) eventually fulfilled the TRS criteria, and 56 (70%) of these 81 patients showed no response to FEP treatment and directly met the TRS criteria (so-called “early TRS”), while the other 24 (30%) were improved by FEP medication but subsequently transitioned to TRS (so-called “late TRS”). Lally et al. speculated that the latter type may be related to dopamine supersensitivity psychosis.
Demjaha et al. reported the outcome of a 10-year follow-up of 434 patients in the same area (London) as in the study by Lally et al., presumably with a different cohort [
8]. Among the 343 patients included in their final analysis, 74 patients (23%) were diagnosed as having TRS, 62 patients (84%) and 12 patients (16%) being diagnosed with early and late-TRS, respectively, which were quite similar to the results of Lally’s study. In summary, they concluded that the process of development to TRS could be divided into two such types of early disease course toward TRS. Since their studies differed from ours in terms of follow-up duration and clinical parameters (i.e., GAF and antipsychotic dose in our study vs. remission and clozapine treatment in theirs), a direct comparison between their results and our present findings is impossible. However, in our study there were 11 TRS patients who showed a good response to FEP treatment and realized a GAF score of 70 points or higher, which may correspond to the “late TRS” category in the studies of Lally et al. and Demjaha et al., indicating that the individual TRS subtypes overlap.
Our results suggest that there may be two additional subtypes within the early-TRS category, i.e., the category of patients who never achieve remission in early-stage treatment. The first group would consist of patients requiring a lengthy hospital stay with acute onset and profound positive symptoms, and second group would be those whose onset develops slowly with high negative symptoms. This strongly underscores the need for further study on the early process of TRS.
There are several limitations of the present study to consider, and caution should be taken in generalizing the results. Most importantly, the patients who dropped out of the analysis because they were transferred between hospitals and thus had insufficient available data made up a significant part of our cohort. The major reason for transferring to another hospital was the necessity of a longer hospital stay due to the severity of symptoms; if all TRS patients were included, the actual duration of initial hospital admission could have been longer than the calculated duration. This could constitute a form of selection bias. Second, the study design was retrospective, and considered only the duration of hospital admission, limiting complete clarification of the early process of schizophrenia. Therefore, a score of “0” for the initial hospital admission did not necessarily reflect the pathological process of schizophrenia, but might have been influenced by other factors such as the family’s support and residential area, etc. Third, since the overall data were derived from a real-world clinical setting, our results were influenced by physicians’ opinions on pharmacological medication as well as our domestic medical environment in Japan. For example, introduction of clozapine into clinical practice was delayed until 2009 in Japan. This delay could have led to continuous treatment in using the same regimen of antipsychotics without adjusting dosage or switching to a different class of agents even in patients who had failed to respond to previous treatments.