Yi-gan san for the treatment of borderline personality disorder: an open-label study

BACKGROUND: Numerous medications have been tested on patients with borderline personality disorder (BPD). Although many of these medications have been demonstrated to be useful, no clear main treatment for BPD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Recent studies indicate that the traditional Chinese herbal medicine yi-gan san (YGS, yokukan-san in Japanese) may be safe and useful in treating behavioral and psychological symptoms in dementia patients. We aimed at evaluating both efficacy and safety of yi-gan san in patients with well-defined BPD. METHODS: Twenty female outpatients diagnosed with BPD according to DSM-IV criteria and the revised Diagnostic Interview for Borderlines completed a 12-week open-label study with yi-gan san at an average daily dosage of 6.4+/-1.9 g (2.5-7.5 g). Psychometric instruments to assess efficacy included the Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scales for Depression (HAM-D), Global Assessment of Functioning (GAF), Clinical Global Impression Scale (CGI), and Aggression Questionnaire (AQ). RESULTS: Most psychometric scale scores exhibited a highly significant improvement (total BPRS; BPRS somatic concern, anxiety, tension, depressive mood, hostility, suspiciousness, motor retardation, uncooperativeness, and excitement subscale; CGI; GAF; AQ) over time. CONCLUSIONS: In this open-label pilot study, patients treated with YGS showed statistically significant reduction on self-rated and clinician-rated scales. The present findings suggest that yi-gan san might be effective for the treatment of a number of BPD symptoms, including low mood, impulsivity, and aggression.     

Botulinum toxin in the treatment of orofacial tardive dyskinesia: a single blind study

OBJECTIVE: Orofacial tardive dyskinesia (OTD) is difficult to treat and Botulinium Toxin A (BTA) may be an option. METHODS: In a single blind (raters were blind) study (N=12, duration 33 weeks) OTD was treated with Botulinum Toxin A in three consecutive sessions with increasing dosages. The severity was measured with the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Overall there was a non-significant reduction in the severity of OTD (p=0.15). However, in the patients with no change in their antipsychotic medication (N=8) the reduction was significant (p=0.035). After the study, 50% of the patients preferred to continue the Botulinum Toxin A treatment. CONCLUSION: BTA was well tolerated and showed a non-significant improvement for OTD. A larger double blind study is warranted.     

Involvement of the benzodiazepine system in the anxiolytic-like effect of Yokukansan (Yi-gan san)

The traditional Japanese Kampo medicine Yokukansan (YKS, Yi-gan san in Chinese) has been demonstrated to improve the behavioral and psychological symptoms of dementia (BPSD), such as anxiety, hallucinations, agitation and irritability. The aim of this study was to elucidate the mechanism of the anxiolytic-like effects of YKS and Chotoko, which is an active component of YKS. Oral treatment with YKS (300 and 1000 mg/kg) significantly increased the number of head-dipping behaviors in mice in the hole-board test. Head-dipping behavior in mice was also significantly increased by treatment with Chotoko (50 and 100 mg/kg, p.o.). In addition, oral treatment with the water-extracted fractions from YKS (YKS-W; 250 and 500 mg/kg, p.o.) and Chotoko (Chotoko-W; 10 and 30 mg/kg) significantly increased the number of head-dipping behaviors in mice. On the other hand, treatment with the methanol-extracted fraction of YKS (YKS-Met; 15 and 30 mg/kg, p.o.) did not affect head-dipping behavior. The total distance and number of rearing behaviors were not affected by treatment with any of these drugs. The increase in the number of head-dipping behaviors by treatment with YKS-W (500 mg/kg, p.o.) and Chotoko-W (30 mg/kg, p.o.) was inhibited by pretreatment with the benzodiazepine receptor antagonist flumazenil (1 mg/kg, i.v.). In the elevated plus-maze test, the percentage of time spent in open arms was increased in YKS (1000 mg, p.o.) treatment. Based on these results, we suggest that YKS produces an anxiolytic-like effect mediated by the benzodiazepine system. Chotoko is an effective component of YKS for producing an anxiolytic-like effect. The effective compound(s) should be contained, at least in part, in the water-soluble fraction of YKS.     

伴发迟发性运动障碍的精神分裂症患者血清脑源性神经营养因子水平的对照研究

目的 探讨外周血清脑源性神经营养因子(brain derived neurotrophic factor,BDNF)浓度与精神分裂症伴发的迟发性运动障碍(tadrive dyskinesia,TD)的关系.方法 收集精神分裂症伴发TD患者61例、不伴发TD的患者78例,以及正常对照102名.用酶联免疫吸附法检测BDNF水平,采用不自主运动量表(abnormal involuntary movement scale,AIMS)评估TD的严重程度,阳性和阴性症状量表(positive and negative symptom scale,PANSS)评估患者精神症状.结果 TD组、非TD组和对照组的BDNF水平分别为(9.35±1.60)μg/L、(10.12±2.03)μg/L、(12.27±2.7)μg/L,3组的差异有统计学意义(F=37.8,P<0.01);两两比较显示,TD组和非TD组均低于对照组(P<0.01),而TD组又低于非TD组(P<0.05).使用典型和非典型抗精神病药物患者之间的BDNF水平差异无统计学意义(P>0.05).TD组BDNF水平与AIMS总分、年龄、总病程负相关(r分别为-0.24、-0.32、-0.22,P均小于0.05),而在非TD组BDNF水平与上述因素均无相关(P>0.05).结论 精神分裂症伴发TD患者外周BDNF浓度下降,且其水平与异常运动严重程度相关,提示BDNF可能在TD的病理生理中发挥作用.     

阿立哌唑与利培酮口服液治疗门诊老年期痴呆精神行为症状的对照研究

目的 探讨阿立哌唑和利培酮口服液治疗门诊老年期痴呆精神行为症状(BPSD)的疗效和安全性.方法 将68例老年期痴呆伴BPSD患者随机分成阿立哌唑组35例,利培酮口服液组33例,疗程8周,采用痴呆病理行为评定量表(BEHAVE-AD)及激越性问卷(CMAI)评定疗效,采用治疗中需处理的不良反应症状量表(TESS)评定副反应.结果 两组治疗后第6、8周末BEHAVE-AD和CMAI评分与治疗前比较均显著下降(P＜0.01),两组之间比较治疗前及治疗后各时间点比较BEHAVE-AD评分差异无统计学意义(P＞0.05).两组不良反应比较,阿立哌唑组不良发生率明显低于利培酮口服液组,差异有统计学意义(P＜0.01).结论 阿立哌唑和利培酮口服液治疗老年期痴呆伴发BPSD均有较好疗效,两者总体疗效、起效时间相当,而阿立哌唑的安全性优于利培酮口服液.     

Prevalence and risk factors for tardive dyskinesia: a study in an Italian population of chronic schizophrenics

Summary The aim of this study was to evaluate tardive dyskinesia (TD) (prevalence and possible risk factors, pharmacological and clinical), in a population of schizophrenic patients after prolonged institutionalization. A total of 148 patients (80 male, 68 female) aged between 28 and 87 years (mean 55, SD 11) diagnosed according to DSM III were included in the study and assessed for the presence and severity of TD using the Abbreviated Rockland Simpson Scale for TD. Of the examined population, 32% were found to be affected by TD. Patients over 55 years had a relative risk of TD that was 2.3 times higher than in subjects under 55 (P<0.05). The most frequent movements were orofacial (60%) and in the extremities (56.4%). No significant relationship between duration of neuroleptic treatments, illness or hospitalization, anticholinergic drugs and TD prevalence was found. Severity was related to age, since there was a positive linear relationship between age and Simpson Scale scores (r=0.45,P<0.01).     

A prospective study of tardive dyskinesia in Japan

Summary A large-scale, prospective study of tardive dyskinesia (TD) was performed in 11 psychiatric facilities in Japan. A total of 1595 psychiatric patients were enrolled in this study in 1987. The progress of these patients, with the exception of 490 dropouts, has now been followed up to 1988. The prevalence of TD at study entry was 7.6%, the annual incidence rate was 3.7% and the annual remission rate was 28.7%. Newly developed TD patients tended to be older, to have undergone more psychosurgery, and to have had lower neuroleptic doses than the patients who had not developed TD, whereas no specific variable could be detected as a factor associated with remission of TD. The results suggest that the incidence of TD is lower in Japan than that in Europe and North America.     

Tardive dystonia and severe tardive dyskinesia. A comparison of risk factors and prognosis

Nine tardive dystonia cases were compared with 13 tardive dyskinesia cases selected for the severity and persistence of their involuntary movements. Both groups were neurological referrals from an identical source. While advanced age and female preponderance were prominent features in tardive dyskinesia, onset in most tardive dystonia cases occurred in young adulthood, and the sex distribution showed a slight majority of males. Other differences in the dystonia group included gait abnormalities in four cases, lower tolerance of neuroleptic discontinuance, with the reappearance of psychoses, and a poorer prognosis for reversibility after follow-up. In fact, none of the dystonia patients reversed as opposed to seven of the tardive dyskinesia patients. In order to identify the full spectrum of tardive dystonia and exclude any referral bias, systematic epidemiological studies on psychiatric populations should include young adults of both sexes.     

Baclofen (Lioresal®) in the treatment of neuroleptic-induced tardive dyskinesia

A double-blind cross-over trial of the effects of baclofen and placebo was carried out in 20 female inpatients suffering from neuroleptic-induced tardive dyskinesia. After 14 days of treatment 15 patients showed improvement on baclofen, whereas none showed improvement on placebo; baclofen was thus significantly more effective than placebo. Baclofen is a GABA-like drug which passes through the blood-brain barrier and which reduces the neuroleptic-induced increase of dopamine turn-over. In tardive dyskinesia is found dopaminergic hypersensitivity, and baclofen is supposed to exert its action by inhibiting the dopaminergic activity. Side effects, although temporary, were observed in the form of sedation, muscular hypotonia, dizziness, vomiting, and muscular rigidity. One patient developed a depression. Baclofen or other gabergic drugs used in the treatment of dyskinesias do not increase the dopaminergic hypersensitivity, which is part of the pathogenesis of these conditions; gabergic therapy must therefore be preferred to treatment with dopamine receptor blocking drugs.     

Tiapride in the treatment of tardive dyskinesia

The effect of Tiapride on dyskinesia was evaluated in 12 patients with tardive dyskinesia in a double-blind controlled cross-over trial. The effect was measured by a Doppler-radar device and by counting the number of involuntary movements from video-recordings. Besides these methods, subjective assessments were made on analogue scales by family, nurses and attendant doctors. The subjective evaluation appeared to be useless because of many inconsistent answers. The quantitative methods revealed a significant diminution of the involuntary movements in the Tiapride therapy period (P less than 0.01). It appears that tiapride is an effective drug in the treatment of tardive dyskinesia. No clinically important side-effects have been observed. The drug appeared not to induce parkinsonism.     

Sustained improvement in tardive dyskinesia with diazepam: Indirect evidence for corticolimbic involvement

A rater-bind, ABA's design study of 21 cases indicates that diazepam significantly improves tardive dyskinesia and that some of the improvement persists for an extended period after diazepam is withdrawn. Since benzodiazepine receptors and sites of action seem to be mainly in the neocortex (especially frontal), limbic cortex, and deep limbs nuclei, and these structures provide most of the input into the nigrostriatopallidal system that probably regulates its role in voluntary movement, it may be suggested that impaired corticolimbic control of basal ganglia may be a factor in the pathogenesis of tardive dyskinesia.     

No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients

OBJECTIVE: This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. METHODS: Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. RESULTS: The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. CONCLUSION: These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients.     

重复经颅磁刺激对阿尔茨海默病患者精神行为症状的疗效分析

目的 探讨重复经颅磁刺激（rTMS）对轻、中度阿尔茨海默病（AD）患者精神行为症状（BPSD）的疗效.方法 将38例有BPSD的AD患者随机分为rTMS治疗组（20例）和对照组（18例）,分别接受20次5 Hz rTMS真刺激和伪刺激治疗,治疗期间维持原有的胆碱酯酶抑制剂治疗.治疗前及治疗后2周、6周采用神经精神科问卷（NPI）观察疗效,采用治疗不良反应量表（TESS）观察不良反应.结果 38例患者均完成治疗,治疗6周时治疗组NPI评分（16.69±6.62）分较治疗前（27.65±4.38）分明显降低,差异有统计学意义（t=6.16,P＜0.05）;且显著低于对照组（23.44±5.49）分,差异有统计学意义（t=3.33,P＜0.05）.两组TESS总评分比较差异无统计学意义（x^2=2.06,P＞0.05）.结论 rTMS可能是控制轻、中度AD患者BPSD的一种有效而安全的治疗方法.     

The effects of behavioral and psychological symptoms on caregiver burden in frontotemporal dementia,Lewy body dementia,and Alzheimer's disease: clinical experience in China

Background and aims: Caregivers of individuals with neurodegenerative diseases, including frontotemporal dementia (FTD), Lewy body dementia (DLB), and Alzheimer's disease (AD), experience high levels of psychological and physical stress, likely due to behavioral and psychological symptoms of dementia (BPSD). This study is the first to simultaneously evaluate the effects of BPSD on caregiver burden in these three types of dementia.

Method: A total of 214 dementia patients, including probable FTD (n = 82), DLB (n = 22), and AD (n = 110), as well as their primary caregivers, were assessed using psychological inventories and cognitive evaluation. The FTD group was further divided into the three established clinical variants: behavioral variant frontotemporal dementia (bvFTD, n = 51), non-fluent variant primary progressive aphasia (nfvPPA, n = 15), and semantic variant primary progressive aphasia (svPPA, n = 16). Cognitive impairment and neuropsychiatric symptoms were assessed using the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test, and Neuropsychiatric Inventory (NPI), respectively. Caregiver burden was assessed using the Zarit Burden Inventory (ZBI).

Results: FTD patients had higher NPI and ZBI scores than DLB and AD patients, whose scores were similar. Logistic regression analysis revealed that the factors influencing caregiver burden for each group were: FTD: total NPI scores, agitation, and aberrant motor behavior; bvFTD: total NPI scores; DLB: total NPI scores; and AD: total NPI scores, onset age, apathy, and ADL. Caregivers of bvFTD patients had the highest levels of burden, which were significantly greater than for caregivers of nfvPPA, svPPA, DLB, and AD patients.

Conclusion: BPSD was highly correlated with emotional burden in caregivers of FTD, DLB, and AD patients. The highest burden was observed in bvFTD caregivers.     

Ethical questions in the treatment of subjects with dementia. Part I. Respecting autonomy: awareness, competence and behavioural disorders

The document deals with some ethical issues raised by the treatment of demented people. In particular the conceptual and empirical aspects of the assessment of awareness and competence of these patients are analysed, as well as the dilemmas related to the treatment of behavioral disorders.     

Evidence for using dextromethorphan-quinidine for the treatment of agitation in dementia

Behavioral and psychological symptoms including agitation are common in dementia, and are associated with decreased quality of life, increased risk of institutionalization, and greater patient and caregiver distress. Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability, prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia. The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect, and may be effective in managing agitation in dementia. A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo. Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia, and was well tolerated. Although promising, further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.     

Changes in negative symptoms and the risk of tardive dyskinesia: a longitudinal study. UK700 Group

OBJECTIVE: To examine whether the development of tardive dyskinesia (TD) is accompanied by a parallel process of worsening negative symptoms in a longitudinal study. METHOD: A sample of 708 psychotic patients were followed over a period of 2 years, using the Abnormal Involuntary Movement Scale and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Of 361 individuals with no prior evidence of dyskinesia, 46 (13%) developed TD by year 2. Independent of the effects of male sex (odds ratio (OR)=2.18, 95% confidence interval: 1.00-4.74), age (OR per quartile group = 1.39, 95% CI: 1.01-1.90), duration of exposure to antipsychotic medication (OR = 2.35 per 8 months, 95% CI: 1.17-4.72) and average SANS score (OR per quartile group = 1.38, 95% CI: 0.99-1.93), worsening of negative symptoms over the 2 previous years was associated with TD onset (OR per quartile group = 1.46, 95% CI: 1.07-2.00). CONCLUSION: The development of TD is linked, independent of the effect of antipsychotics and older age, to an illness-related pathological process, characterized by worsening negative symptoms.     

Oxidative stress in tardive dyskinesia: Genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes

Introduction

Tardive dyskinesia (TD) is a potentially irreversible side effect of antipsychotic medication treatment that occurs in approximately 25% of chronically treated schizophrenia patients. Oxidative stress has been one of the proposed mechanisms influencing TD risk. Pae et al. (2004) originally reported a significant association between TD and the NADPH quinine oxidoreductase 1 (NQO1) gene Pro187Ser (C609T, rs1800566) polymorphism in Korean schizophrenia patients; however, subsequent studies have not consistently replicated these findings. Similarly, Hori et al. (2000) reported an association between TD and the Manganese superoxide dismutase SOD2 (MnSOD) gene Ala9Val (rs4880) polymorphism in a Japanese sample, but most research groups failed to replicate their positive findings.

Aims

We investigated the role of the NQO1 polymorphism Pro187Ser and SOD2 (Ala9Val) in a group of well-characterized schizophrenia patients (N = 223) assessed for TD. We also performed a meta-analysis of all the previously published TD studies, including data from our sample, on these polymorphisms, Pro187Ser (N = 5 studies) and Ala9Val (N = 9 studies).

Results

We did not observe a significant association of the Pro187Ser or Ala9Val polymorphism with TD occurrence or AIMS scores in our Caucasian and African American samples when analyzed independently. Meta-analysis did not reveal a significant association of the Pro187Ser/Ala9Val alleles or genotypes with TD occurrence.

Conclusions

Neither the NQO1 Pro187Ser nor the SOD2 Ala9Val appear to play a major role in TD risk, although additional polymorphisms should be tested before the role of NQO1 and SOD2 in TD can be completely excluded.     

美金刚与奥氮平治疗老年期痴呆的行为和精神症状对照研究

目的 探讨美金刚与奥氮平治疗老年期痴呆的行为和精神症状(BPSD)的疗效及不良反应.方法 将86例老年期BPSD患者分为美金刚组与奥氮平组,治疗8周.在治疗前、治疗2周末、4周末和8周末,采用痴呆病理行为评定量表(BEHAVE-AD)评定疗效,简易精神状况检查量表(MMSE)评定患者认知功能,日常生活能力量表(ADL)评定患者生活质量,治疗中需处理的不良反应症状量表(TESS)评定不良反应.结果 美金刚组在治疗后第2、4、8周末BEHAVE-AD评分较奥氮平组显著下降(t=2.12、t=2.23、t=2.28,P＜0.05).美金刚组在治疗后第8周末MMSE评分较治疗前显著升高(t=2.33,P＜0.05),奥氮平组治疗前后MMSE评分差异无显著性(t=0.42,P＞0.05),两组比较差异有显著性(t=2.04,P＜0.05).两组治疗后第8周末ADL评分显著下降(t1=2.35,t2=2.49,P＜0.05),两组比较差异无显著性(t=0.45,P＞0.05).美金刚组不良反应少于奥氮平组(x2=5.09,P＜0.05),两组在锥体外系反应(EPS)、口干、嗜睡、体质量增加方面差异有显著性(x2=4.62～6.86,P＜0.05).结论 美金刚对老年期痴呆患者的认知功能及行为和精神症状的改善均有效,且安全可靠.