Dr Shin Yokoyama MD, PhD, Department of Psychiatry, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Email: firstname.lastname@example.org
Background: Serotonin–dopamine antagonists (SDAs) inhibit dopaminergic transmission in the mesolimbic system less than in the nigrostriatal dopaminergic pathway, which relates to the extrapyramidal side-effects of these drugs. The SDAs seem to have an adequate receptor binding profile for the management of the behavioral and psychiatric symptoms of dementia. However, clinicians are discouraged from prescribing SDAs for elderly patients because of an advisory statement from the US Food and Drug Administration that warns about an increased mortality rate among elderly patients treated with atypical antipsychotics.
Methods: We conducted a retrospective study involving 16 elderly patients (mean age 84.9 years; range 67–94 years) with delirium who were treated with one of two SDAs, namely perospirone (4–12 mg/day) or risperidone (1–2 mg/day). The time-course of their psychiatric symptoms was assessed using subcategories of the Delirium Rating Scale (DRS) before treatment and on Days 10 and 24 of treatment.
Results: Total DRS scores were significantly decreased from baseline in both treatment groups. Both agents led to significant improvements from baseline in psychomotor behavior and lability of mood. Of interest, perospirone decreased hallucinations and delusions and improved sleep–awake cycle disturbances compared with baseline. No serious side-effects were seen with either drug.
Conclusions: Both perospirone and risperidone are effective in the management of delirium in elderly patients. The improvement in the sleep–awake cycle with perospirone may be derived from its short pharmacological half-life.
In any clinical facility that treats senile patients, behavioral and psychological symptoms of dementia (BPSD) and delirium are serious psychiatric problems that require adequate treatment.1,2 Without proper antipsychotic medication, humanitarian care demands extraordinary human resources and unrealistic efforts of the part of nursing staff. The efficacy of the serotonin–dopamine antagonist (SDA) risperidone for delirium has been reported by some clinicians.3–5 Pharmacological intervention is needed for patients with severe senility,6,7 although the US Food and Drug Administration (FDA) warns physicians about the use of atypical antipsychotic medicines in senile patients.8,9 Therefore, evidence of both the safety and efficacy of antipsychotic medicines for BPSD and delirium in senile patients is required.10
Perospirone, another SDA that has been marketed in Japan since 2001, is a novel atypical antipsychotic medicine.11,12 Perospirone has a high binding affinity for dopamine D2, serotonin 5-HT2A, 5-HT1, and histamine H1 receptors.13 Perospirone and its hydroxyl metabolite ID-15036 are characterized by their short pharmacological half-life (2–2.5 h),14 which means that one can avoid the ‘hangover effect’ or somatic accumulation in senile patients who have reduced hepatic and/or renal function. A few reports have been published on the clinical effectiveness of perospirone for senile patients with delirium and/or BPSD.15–17
In the present retrospective study, we examined the clinical effects of both perospirone and risperidone on the psychiatric symptoms of senile patients using the Delirium Rating Scale (DRS).18,19
Sixteen senile patients who required psychiatric treatment because of their persisting delirium and/or BPSD (eight men and eight women) were investigated retrospectively in the present study. The mean (±SD) age of the subjects was 84.9 ± 6.6 years (range 67–94 yeras). The diagnosis of delirium was based on the criteria of the International Classification of Diseases and Related Health Problems, 10th revision (ICD-10),20 for mental and behavioral disorders (F05; delirium, not induced by alcohol and other psychoactive substances). Patients who had already been treated with antipsychotics were excluded from the study. Nine patients had been newly treated with perospirone and seven patients had been treated with risperidone.
For the perospirone group, we administered perospirone to patients at an initial dose of 4–8 mg/day and modified the dose within the range 4–12 mg at Day 10, if needed. The average dose of perospirone on the first day was 7.1 ± 1.8 mg/day. The mean age of patients treated with perospirone was 83.6 ± 6.6 years.
Risperidone was administered to patients at an initial dose of 1–1.5 mg/day and the dose was modified within the range 1–2 mg/day on Day 10, if needed. The average dose of risperidone on the first day was 1.1 ± 0.2 mg/day. The mean age of patients treated with risperidone was 84.4 ± 5.6 years.
The therapeutic effects of the SDAs were assessed at baseline and on Days 10 and 24 using the Delirium Rating Scale (DRS).18 Scores at Day 10 and 24 were compared with pretreatment scores. Two subcategories of DRS (temporal onset of symptoms and physical disorder) were excluded from the present study because they were not suitable for the assessment of the clinical course of delirium in our setting.19
Although the present study was retrospective, there was no bias in the choice of medicine (perospirone or risperidone) for the patients. Trained psychiatrists assessed the DRS of each of the patients each time.
All patients were evaluated on Days 10 and 24. In the risperidone group, only four (57.1%) patients remained on treatment by Day 24 (two patients required a change of antipsychotics and one patient was transported to another hospital). Because of the small number of patients, we avoided statistical comparisons of the data between baseline and Day 24 in the risperidone group.
The present study was approved by the Ethical Committee of Shinshu University School of Medicine. The plan of the retrospective study was explained to patients or their families by letter. All families provided verbal informed consent prior to participation in the study.
Statistical analyses were performed using analysis of variance followed by Bonferroni's post hoc test. Differences in means were considered statistically significant at P < 0.01.
Changes in mean DRS scores according to drug before treatment and on Days 10 and 24 are shown in Fig. 1. Pretreatment DRS scores in the two treatment groups were not significantly different. The mean (±SD) DRS score before perospirone treatment (n = 9) was 22.8 ± 2.9. This decreased significantly to 16.3 ± 5.9 (n = 9) on Day 10 (P < 0.01 vs baseline) and to 13.3 ± 4.3 (n = 9) on Day 24 (P < 0.01 vs baseline). Similarly, the average mean score before risperidone treatment was 23.0 ± 2.8 (n = 7). This decreased to 18.6 ± 4.4 (n = 7) on Day 10 (P < 0.01 vs baseline). The mean score of the risperidone-treated group was not calculated on Day 24 because the number of subjects in the group at that time was too small (n = 4).
Table 1 shows subcategories (perceptual disturbance, hallucinations, delusions, psychomotor behavior, cognitive status during formal testing, sleep–awake cycle disturbance, lability of mood, variability of symptoms) of DRS scores for both treatment groups. Several items on the DRS significantly improved from baseline with perospirone treatment, including psychomotor behavior, sleep–awake cycle disturbances and lability of mood (P < 0.01). Treatment with risperidone led to significant improvements in psychomotor behavior, lability of mood and variability of symptoms (P < 0.01). The sleep–awake cycle was not significantly restored in the risperidone-treated group.
Table 1. Improvement of symptoms within Delirium Rating Scale subcategories compared with pretreatment scores after 10 days treatment with perospirone or risperidone
DRS, Delirium Rating Scale; NA, no P value is available because little or no difference existed between pretreatment and Day 10.
2.9 ± 0.3
2.5 ± 0.9
2.6 ± 0.5
2.6 ± 0.5
2.0 ± 0.4
1.4 ± 1.0
2.3 ± 0.5
2.1 ± 0.4
2.8 ± 0.4
1.7 ± 1.4
2.7 ± 0.8
2.7 ± 0.8
2.7 ± 0.6
1.6 ± 0.8
2.9 ± 0.4
1.7 ± 0.8
Cognitive status during formal testing
3.1 ± 0.7
2.7 ± 1.0
2.6 ± 0.8
2.6 ± 0.8
Sleep–awake cycle disturbance
2.7 ± 0.7
1.6 ± 1.3
2.7 ± 0.5
2.3 ± 1.1
Lability of mood
2.5 ± 0.8
1.5 ± 0.8
3.1 ± 0.4
1.9 ± 1.1
Variability of symptoms
3.3 ± 1.0
2.0 ± 1.8
3.7 ± 0.8
2.3 ± 1.4
Four of nine patients (44%) in the perospirone-treated group showed minor adverse events during the first 10 days, including somnolence (two patients) and dizziness (two patients). Similarly, four of seven patients (57%) in the risperidone-treated group showed adverse events during the first 10 days, including somnolence (one patient), dizziness (two patients) and extrapyramidal symptoms (one patient).
In the present study, we demonstrated that perospirone produced significant decreases in DRS scores similar to risperidone in senile patients with psychiatric symptoms. The clinicopharmacological efficacy of the SDAs for delirium and/or BPSD corresponded with other reports about risperidone3–5 and perospirone.15–17
Major attention should be focused on the restoration of the sleep–awake cycle. Perospirone, with its short pharmacological half-life,14 may be a practical medicine for the pharmacotherapy of senile patients. Specifically, if the drug's half-life is comparatively short, the timing of oral administration of perospirone could be adjusted (e.g. between 1500 and 2100 hours) according to the time-dependent fluctuation of the symptoms of each patient. As Ito16 and Komori et al.17 indicated, such adjustment of the dosing time could reduce the hangover sedative effects of the medicine and restore the sleep–awake cycle, which would lead to an improvement in the quality of the daytime lives of the patients.
Although there were no differences in side-effects between the two treatment groups in the present study, the short pharmacological half-life of perospirone may make it more convenient to control its side-effects compared with risperidone. Compared with perospirone, its bioactive metabolite (ID-15036) has approximately one-eighth the affinity for the D2 receptor but almost equal affinity for the 5HT2A receptor.14,21 Such characteristics support the use of perospirone in the treatment of senile patients who are especially vulnerable to extrapyramidal symptoms.
There are several limitations to the present study, including the small size of the treatment groups, the retrospective nature of the trial and the open-label design. In addition, the efficacy of perospirone was not compared against placebo or risperidone. Moreover, after the FDA advisory stating that atypical antipsychotics increase mortality among elderly patients,8 we could not add new cases to our study for ethical reasons. Although there are systematic difficulties in conducting large, double-blind studies on the effects of atypical antipsychotics on BPSD in senile patients, the need to establish effective pharmacotherapy for these symptoms is urgent.
In conclusion, perospirone could be an adequate clinicopharmacological candidate for psychiatric problems in senile patients.