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Keywords:

  • brain-derived neurotrophic factor;
  • kamishoyosan;
  • Kampo medicine;
  • schizophrenia;
  • tardive dyskinesia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Abstract  The purpose of the present study was to evaluate the clinical effectiveness of kamishoyosan for antipsychotic-induced tardive dyskinesia, and to investigate the relationship between tardive dyskinesia and serum brain-derived neurotrophic factor (BDNF) levels. Sixty-nine schizophrenia patients were enrolled; of these, 49 presented with tardive dyskinesia while the remaining 20 patients showed no tardive dyskinesia. The tardive dyskinesia group was treated for 16 weeks with kamishoyosan and assessed using the abnormal involuntary movement scale. The abnormal involuntary movement scale scores in the tardive dyskinesia group were evaluated at baseline and after 4, 8, and 16 weeks of treatment. The BDNF levels of all subjects were measured at baseline in order to compare differences in serum BDNF levels between the tardive dyskinesia group and the non-tardive dyskinesia group, and to correlate the severity of tardive dyskinesia and serum BDNF in the tardive dyskinesia group. A meaningful reduction in total abnormal involuntary movement scale scores was observed in the tardive dyskinesia group treated with kamishoyosan at 4, 8, and 16 weeks of treatment (P < 0.01). No significant differences in serum BDNF levels were detected between the tardive dyskinesia group and the non-tardive dyskinesia group at baseline. Furthermore, no significant correlation was seen between the severity of tardive dyskinesia and serum BDNF levels. The present study suggests that kamishoyosan might be a promising adjunctive treatment for antipsychotic-induced tardive dyskinesia.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Tardive dyskinesia (TD) is a serious motor condition predominantly caused by long-term use of antipsychotics associated with the treatment of schizophrenia. This disease is generally characterized by abnormal involuntary movements of the tongue, lips, face, trunk, and extremities. TD is an irreversible condition and to date few effective treatment options exists. Accordingly, TD has presented a major obstacle to the pharmacotherapy of schizophrenia. While several theories have been proposed to explain the pathogenesis of TD, including neurotoxicity and abnormal neurotransmitter regulation, no consensus has been reached.1 Of these theories, the most popular involves supersensitivity of the dopamine system, such that long-term antipsychotic treatment leads to upregulation of post-synaptic dopamine receptors and dopaminergic neuron supersensitivity in the basal ganglia. These changes in turn induce abnormal involuntary movement.2,3 Another theory of TD pathogenesis relates to neuronal degeneration; in this scenario, antipsychotics stimulate production of neurotoxic free radicals that directly damage dopaminergic neurons.1,4–6

Recent evidence has suggested that brain-derived neurotrophic factor (BDNF), known to play a major role in neurogenesis and neuronal survival, has an important role in the pathogenesis of TD.7,8 It has been reported that BDNF levels were lower in patients with TD than those without the disease.9 These low BDNF levels were also related to the severity of TD symptoms and negative symptoms of schizophrenia.9 When taken as a whole, these data suggest that pathological alterations in dopaminergic neurons and changes in BDNF levels are key factors in the pathogenesis of TD, and identifying novel drug therapies that affect these targets is a high priority. Kamishoyosan is an herbal medicine used for the treatment of parkinsonism and convulsion in traditional Chinese medicine (TCM).10–13 Kamishoyosan has been reported to have effects on the γ-aminobutyric acid and dopamine systems, and can reduce antipsychotic-induced tremor in Parkinson's patients.12 In the present study we sought to assess the clinical effects of kamishoyosan and evaluate any associated neurotrophic effects in schizophrenia patients with TD.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Subjects

Subjects were inpatients from the psychiatric wards of Dongsuh Mental Hospital, Masan and Dongnae Mental Hospitals, Busan, Korea. The protocol for this study has been approved by the ethics committee of Dongsuh Mental Hospital, Masan and Dongnae Hospital, Busan, Korea. Subjects provided informed consent and were notified that they could withdraw from the study at any time. All subjects met the DSM-IV14 criteria for schizophrenia and were on a stable dose of antipsychotics for the last 3 months. Subjects who had major physical abnormalities or had a history of psychostimulant drug abuse were excluded from the study.

Preparation of kamishoyosan

In the present study authors used kamishoyosan that was manufactured by Han-Kook-Sin-Yak Pharmaceutical (Nonsan, Korea), who obtained the approval for its manufacturing from the Korean Food and Drug Administration (KFDA) and the Ministry of Health and Welfare. The ingredients of 5 g kamishoyosan and daily dose are listed in Table 1.

Table 1.  The herbal components of kamishoyosan
Herbal componentsKamishoyosan (5 g)
  1. Recommended dose of kamishoyosan is 15 g/day.

Glycyrrhizae radix extract0.67 g
Angelicae gigantis radix extract1.00 g
Bupleuri radix extract1.00 g
Gardeniae fructus extract0.67 g
Zingiberis rhizoma recens extract0.33 g
Cortex moutan radicis extract0.67 g
Atractylodis rhizoma alba extract1.00 g
Hoelen extract1.00 g
Paeoniae radix extract1.00 g
Menthae herba extract0.33 g

Study design

After a baseline evaluation based on Abnormal Involuntary Movement Scale (AIMS)15 scores, subjects with TD entered a 16-week open trial of kamishoyosan adjunctive treatment. The daily dose of kamishoyosan was 5 g/day, b.i.d. because authors wanted to determine the minimal effective dosage of kamishoyosan. AIMS evaluation was performed 4, 8, and 16 weeks after baseline evaluation. To correlate TD severity with serum BDNF, 5 mL venous blood was collected from subjects between 11:00 and 24:00 hours each day.

Diagnosis of TD

The AIMS scores were used to diagnose TD. AIMS was designed to evaluate abnormal involuntary movement of the face, extremities, and trunk. In the present study we adapted the criteria of Schooler and Kane for TD diagnosis.16 According to these criteria, TD is diagnosed when the AIMS score is >2 in at least two body areas, or >3 in one body area.

Serum BDNF levels

Five milliliters of blood were drawn from each subject into an anticoagulant-free vacuum tube. Blood samples were kept at room temperature for 1 h before serum was isolated (centrifugation at 2000 g for 10 min at 4°C). Serum BDNF was kept at −70°C before testing, and assayed within 1 month of blood collection using an ELISA kit (Promega, Madison, WI, USA). Briefly, 96-well immunoplates (Nunc, Roskilde, Denmark) were coated with monoclonal antimouse-BDNF antibody (100 μL/well) and incubated overnight at 4°C. The plates were then washed three times with wash buffer, after which Block and Sample 1X buffer (Promega) was added to wells (200 μL each) and incubated for 1 h at room temperature without shaking. Next, the plates were washed three times with wash buffer and the samples (1 : 100 dilution; 100 μL/well) were incubated with shaking for 2 h at room temperature. After an additional five washes, the immobilized antigen was incubated with an antihuman BDNF antibody for 2 h at room temperature with shaking. The plates were washed again with wash buffer, and then incubated with an anti-IgY horseradish-peroxidase-conjugated antibody for 1 h at room temperature with shaking. After another wash the plates were incubated with a TMB/peroxidase substrate solution (Promega) for 10 min and 1 mol/L phosphoric acid was added to the wells (100 μL/well). The colorimetric reaction product was measured at 450 nm using a microplate reader (Spectra III; SLT, Crailsheim, Germany). BDNF concentrations were determined from the BDNF standard curve (ranging from 7.8 to 500 pg/mL-purified mouse BDNF) incubated under similar conditions in each assay. All BDNF immunoassays were performed in duplicate.

Statistical analysis

The χ2 test and t-test were used for analysis of demographic data. The effect of kamishoyosan on total AIMS score in TD patients was evaluated using Wilcoxon's signed-ranks test. Kruskal–Wallis test and the Mann–Whitney U-test were used to assess changes in AIMS scores according to the categories of AIMS. The correlation between TD severity and serum BDNF levels was analyzed with Pearson's correlations test.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Demographics

Sixty-nine subjects were enrolled in the present study; 58 were male and 11 were female. Forty-nine subjects met the criteria for TD according to Schooler and Kane at baseline.16 The average total AIMS score of the 20 subjects without TD was 0 points. Thirty-nine male subjects and 10 female subjects had TD. Of the 69 total subjects, five subjects with TD and three subjects without TD were dropped from the study. Forty-four subjects with TD and 17 subjects without TD completed the entire 16-week trial. No significant differences were observed between the TD and non-TD groups with respect to gender, level of education, daily dosage of antipsychotic medication, duration of illness, and use of anticholinergic drugs. However, the average age was significantly higher in the TD group compared to patients without TD (P < 0.05). Table 2 shows the subjects' demographic data.

Table 2.  Subject data (n = 69)
 Male (n = 58)Female (n = 11)
With TD (n = 39)Without TD (n = 19)With TD (n = 10)Without TD (n = 1)
  1. CPZ, chlorpromazine; TD, tardive dyskinesia.

Age (years)52.5 ± 4.939.5 ± 4.954 ± 1.449
Education (years)10.5 ± 7.714 ± 2.811 ± 7.06
Duration of illness (years)25 ± 5.612.5 ± 4.99 ± 5.65
CPZ equivalent (mg/day)275 ± 35.31000 ± 1131.3913 ± 1113.6500
Use of anticholinergics51%52%70%100%
Duration of medication (month)85 ± 96.120.5 ± 13.559.8 ± 9.077.4

The mean total AIMS scores of the 44 subjects with TD decreased significantly (P < 0.01) at 4, 8, and 16 weeks of kamishoyosan treatment (Fig. 1). With respect to individual body areas, the mean AIMS score for the jaw in TD patients decreased significantly at 8 (P < 0.05) and 16 weeks (P < 0.01), while the mean AIMS score of the tongue decreased significantly at 4 (P < 0.01), 8 (P < 0.01), and 16 weeks (P < 0.01) of kamishoyosan treatment (Table 3). In addition, the mean AIMS score of the upper extremities decreased significantly in the TD group at 4 (P < 0.05), 8 (P < 0.05), and 16 weeks (P < 0.05) of treatment (Table 3). The mean AIMS scores of the face, lip, and lower extremities in the subjects with TD did not significantly change at any time point (Table 3).

image

Figure 1. Change in Abnormal Involuntary Movement Scale (AIMS) total scores in patients with tardive dyskinesia during 16-week adjunctive treatment of kamishoyosan. **P < 0.01 vs baseline.

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Table 3.  Changes in AIMS site scores (mean ± SD) during kamishoyosan treatment (n = 61)
PeriodBaseline4 weeks8 weeks16 weeks
  • P < 0.05 vs baseline;

  • ** 

    P < 0.01 vs baseline. AIMS, Abnormal Involuntary Movement Scale.

Facial expression0.33 ± 0.830.28 ± 0.800.29 ± 0.820.32 ± 0.83
Lips and perioral area0.53 ± 1.210.49 ± 1.180.42 ± 1.080.39 ± 0.99
Jaw0.78 ± 1.310.72 ± 1.260.69 ± 1.24*0.68 ± 1.22**
Tongue2.06 ± 1.271.89 ± 1.22**1.76 ± 1.21**1.77 ± 1.20**
Upper extremity1.33 ± 1.301.17 ± 1.26*1.11 ± 1.25**1.05 ± 1.20**
Lower extremity1.06 ± 1.130.96 ± 1.080.91 ± 1.080.86 ± 1.09
Trunk0.04 ± 0.200.04 ± 0.200.02 ± 0.150.00 ± 0.00

Some age- and sex-related effects of kamishoyosan treatment took place, because subjects >50 years had lower total AIMS score than those below 50 at 4 and 8 weeks, and female subjects had lower AIMS scores than male subjects at all time points. However, this trend was not significant. Adverse effects of kamishoyosan treatment were rare, with two subjects (4.5%) reporting transient nausea, diarrhea, and abdominal discomfort with spontaneous recovery. No serious adverse events occurred in this trial.

The mean baseline plasma BDNF concentration was 26.4 ± 8.8 ng/mL in the 44 TD subjects and 29.3 ± 6.6 ng/mL in the 17 non-TD subjects. No statistically significant difference was observed between the BDNF levels of the subjects with and without TD (Fig. 2). Moreover, no significant correlation was detected between the total AIMS scores of the 49 subjects with TD and baseline serum BDNF levels.

image

Figure 2. Mean serum brain-derived neurotrophic factor (BDNF) levels at baseline in patients with or without tardive dyskinesia (TD). n.s., not significant.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This is the first study to assess the clinical effectiveness of kamishoyosan in the treatment of TD. Although this trial had an open design and no AIMS evaluation was performed in the single-blind condition, the clinical effectiveness of kamishoyosan was observed within 4 weeks of treatment, gradually progressing over the 16 weeks of the study. Of the body areas assessed using AIMS, the tongue and upper extremities had significantly improved AIMS scores with kamishoyosan treatment. In the present study we observed improved TD symptoms, especially in the jaw, tongue, and upper extremities. We attribute these results to the effect of kamishoyosan on different body areas in patients with TD and to the relatively high AIMS scores of the jaw, tongue, and upper extremity at baseline.

At present no effective pharmacotherapy for TD is available. Lohr et al. reported that vitamin E was an effective treatment for TD, producing a 43% (3-point) reduction in the total AIMS scores after 8 weeks of a 36-week trial;17 but a 2-year double-blind placebo-controlled study by Adler et al. found no clinical effect of vitamin E in 158 subjects with TD.18 Zhang et al. and Lohr et al. reported that the treatment effect of vitamin E in TD was the result of anti-oxidant and neuroprotective effects.19,20 Anti-oxidant effects have been reported for constituent herbs of kamishoyosan glycyrrhizae radix,21 angelicae gigantis radix,22 cortex moutan radicis,23 paeoniae radix,24 and menthae herba.25 Therefore, we postulated that kamishoyosan has anti-oxidant effects in treating TD.

In the present study kamishoyosan produced an 18% (1.07-point) reduction in the total mean AIMS scores after 16 weeks of adjunctive treatment. Kamishoyosan was well tolerated, with transient mild gastrointestinal discomfort in two subjects. Risk factors for TD include old age, female sex, long-term and high-dose antipsychotic treatment, brain injury, and early experience with extrapyramidal symptoms. In the present study no significant differences were found in the duration of illness, antipsychotic dose, or duration of medication between subjects with and without TD. The average age was significantly older in the TD group, and TD was diagnosed more frequently in male subjects. In addition, kamishoyosan was more effective in patients older than under 50 years of age, although this trend was not significant. Furthermore, no significant difference in kamishoyosan effectiveness was observed between male and female subjects. However, anticholinergic drugs were used more frequently in the TD group than in the non-TD group.

Recently Tan et al. evaluated the relationship between TD and serum BDNF levels in an Asian population.9 They postulated that the pathogenesis of TD relies on the neurotoxic effects of antipsychotics and that decreases in nerve growth factors could be a risk factor for TD. After comparing the serum BDNF levels of subjects with and without TD, they reported a negative correlation between TD severity and the serum BDNF level, and lower serum BDNF levels in female than in male subjects. In the present study we assessed serum BDNF levels before beginning kamishoyosan treatment and observed no significant difference in the serum BDNF level between the subjects with and without TD. TD severity was not correlated with the serum BDNF level or gender. Because we assessed the serum BDNF levels only before kamishoyosan treatment, we were not able to evaluate the effects of kamishoyosan on the BDNF levels.

The present study had some limitations. The subjects were not matched according to gender and age, and age and gender differences were present between the TD and non-TD groups. In addition, the daily dose of kamishoyosan was maintained at 5 g/day b.i.d., although it would ideally be adjusted to maximize the clinical effectiveness. These issues notwithstanding, we showed that kamishoyosan is a promising adjunctive treatment for TD, and future blinded studies with larger populations are warranted.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This work was supported by a Korea Research Foundation grant (KRF-2001-041-F00180).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES
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