Takeshi Terao, MD, PhD, Department of Neuropsychiatry, Oita University Faculty of Medicine, Idaigaoka 1-1, Hasamamachi, Yufu, Oita 879-5593, Japan. Email: email@example.com
Loss of antipsychotic efficacy (tachyphylaxis), possibly linked to an increase in D2 receptor number and sensitivity, is a significant impediment to treatment in chronic schizophrenia patients. Animal studies, however, suggest that aripiprazole may be free from tachyphylaxis. The aim of the present study was to investigate this hypothesis. In this preliminary study, aripiprazole-treated patients were retrospectively investigated for the presence or absence of tachyphylaxis. Clinical Global Impression-Improvement (CGI-I) scores did not significantly change and there was no significant association of CGI scores with fixed dose duration. This suggests that aripiprazole may be free from tachyphylaxis.
ANTIPSYCHOTIC DRUGS OFTEN lose efficacy in chronic schizophrenia patients despite continuous treatment, and this may be linked to an increase in D2 receptor number and sensitivity.1 Uchida and Mamo comprehensively reviewed the literature with respect to antipsychotic dosing and highlighted the possibility of tachyphylaxis caused by the action of antipsychotic drugs on the dopamine system.2
More recently, Tadokoro et al. demonstrated that chronic treatment with haloperidol led to significant increases in locomotor response and D2 receptor density, compared with chronic treatment of either vehicle or aripiprazole, and that there were no significant differences between vehicle and aripiprazole.3 Although their study was performed on animals, if extrapolated to schizophrenia patients, hypothetically, there is a possibility that aripiprazole may be free from tachyphylaxis (i.e. aripiprazole may not entail loss of efficacy despite long-term treatment).
In the clinical setting, Pigott et al. showed that the mean Clinical Global Impression-Improvement Scale (CGI-I) scores at week 6 and at week 26 for 148 aripiprazole-treated patients with chronic schizophrenia were 3.67 and 3.74, suggesting that there was no tachyphylaxis in the study period.4 These findings support the hypothesis, but the treatment duration seems to be insufficient to substantiate this hypothesis.
In the present preliminary study, aripiprazole-treated patients were retrospectively investigated for the presence or absence of tachyphylaxis.
Fifty-one patients (14 patients from Oita University and 37 patients from Kurume University) with schizophrenia according to DSM-IV-TR and who received only aripiprazole treatment were identified for the study. Of these, 26 patients (14 patients from Oita University and 12 patients from Kurume University) were deemed eligible for inclusion because they had continued to receive aripiprazole for ≥4 weeks. The ethics committees of Oita University and of Kurume University approved the study and all the patients gave written informed consent.
Clinical improvement was assessed using CGI-I when titration of aripiprazole dose was completed, compared with the basal state (at the time of starting aripiprazole). The CGI scale is a 7-point scale requiring the clinician to assess how much the patient's illness has improved or worsened; it is rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; and 7, very much worse. Recently, Yamamoto et al. demonstrated that CGI-Change (CGI-C; same as CGI-I) scores were significantly and positively associated with changes in positive syndrome scale scores, negative syndrome scale scores, and general pathological syndrome scale scores.5
The 26 patients were 35.2 ± 16.0 years old (male, 13; female, 13). Their starting dose of aripiprazole was 6.8 ± 2.9 mg/day and the titrated dose was 20.4 ± 9.2 mg/day. Of them, the 12 patients from Kurume University had received aripiprazole for <8 weeks (short-term group) while the 14 patients from Oita University received aripiprazole for ≥8 weeks (long-term group). For the long-term group, CGI-I was reassessed when they were entered into the study and compared with the basal state. CGI-I scores were measured by each psychiatrist, who was blind to the study purpose and in charge of individual patients.
The short-term group consisted of seven male patients of 12 patients, while the long-term group had six male patients of 14 patients (n.s.). The mean age of the short-term group was 26.3 ± 12.6 years, whereas that of the long-term group was 42.9 ± 14.9 years (t = 3.0, P < 0.01). Furthermore, the short-term group had a significantly higher starting dose (5.4 vs 8.5 mg/day; t = 3.3, P < 0.01) and titrated dose (14.8 vs 27.0 mg/day; t = 4.5, P < 0.0001) than the long-term group. The duration between the commencement of aripiprazole and completing titration was 4.7 ± 1.6 weeks for the short-term group and 80.2 ± 54.0 weeks for the long-term group (t = 4.8, P < 0.0001). For the long-term group, the duration between completing titration and study entry (i.e. duration of fixed dose) was 110.9 ± 65.2 weeks and total duration between commencing aripiprazole and study entry was 191.1 ± 106.6 weeks.
First, between the short-term group and long-term group, CGI-I scores were compared at the time of completing titration. Second, in the long-term group, CGI-I scores were compared between commencing and completing titration and at the time of study entry. Furthermore, the association of CGI-I scores at the time of study entry was investigated with regard to duration of fixed dose (i.e. time between completing titration and study entry).
Statistical analysis was performed using t-test and Pearson's correlation. Significance was set at P < 0.05 (two-tailed).
At the time of completing titration, CGI-I score was 3.1 ± 1.7 for the short-term group and 2.1 ± 0.4 for the long-term group (t = −2.1, P < 0.05). These CGI-I scores were not significantly associated with age, starting dose, titrated dose, or the duration between commencement and titration.
In the long-term group, CGI-I score was 2.1 ± 0.4 at the time of completing titration and 2.6 ± 0.9 at the time of study entry (t = −1.4, n.s.). As shown in Figure 1, there was no significant association of CGI scores at the time of study entry with duration of fixed dose (i.e. duration between completing titration and study entry; r = −0.16, n.s.).
First, at the time of completing titration, CGI-I score of the long-term group was significantly better than that of the short-term group. Because CGI-I score was not significantly associated with age, starting dose, titrated dose, or titration duration, the reason for this difference is unknown. It should be noted, however, that the long-term group had significantly longer titration duration than the short-term group (80.2 vs 4.7 weeks). Although patient background and symptoms might have affected titration duration, the present findings suggest that improvement may be independent of treatment duration including titration duration, which is in agreement with the hypothesis that aripiprazole may be free from tachyphylaxis.
Second, in the long-term group, CGI-I score did not significantly change between titration completion and study entry (mean duration, 111 weeks). Moreover, there was no significant association of CGI score at the time of study entry with duration of fixed dose. If aripiprazole has the property of tachyphylaxis, CGI-I score might have significantly worsened compared to baseline, and might have been significantly associated with duration of fixed dose. Because such changes or associations were not detected, the present findings support the hypothesis that aripiprazole may be free from tachyphylaxis.
During long-term follow-up, drug compliance is a major issue, and it is very common in patients receiving chronic treatment of antipsychotics. If non-compliant, the process of tachyphylaxis may be interrupted. Nonetheless, if non-compliant, the effects of aripiprazole disappear and the CGI-I scores can worsen. But in fact, the CGI-I scores did not worsen. Taking four possible patterns into consideration (good compliance with tachyphylaxis; good compliance without tachyphylaxis; poor compliance with tachyphylaxis; poor compliance without tachyphylaxis), only the pattern of good compliance without tachyphylaxis could have kept the CGI-I scores as before. Therefore, the present findings suggest that the present patients had good compliance without tachyphylaxis.
As for limitations of the present study, the number of patients was small, measurement was approximate evaluation using CGI, and the study was of an open and retrospective nature. Further prospective studies are required to specifically investigate this important hypothesis.