Evaluation of the efficacy, safety and tolerability of herbal medicine for management of the behavioural and psychological symptoms of dementia
Creators: name: Hyde, Anna
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 420803
subject: Traditional Chinese medicine and treatments

description: Dementia involves a gradual loss of memory and cognitive skills. Over 50% of people with dementia also suffer from the behavioural and psychological symptoms of dementia (BPSD). BPSD refer to disturbed perception, thought content and mood associated with dementia, and include psychosis, agitation, aggression, irritability, depression, anxiety and abnormal motor activity. BPSD can have a negative impact on the progression of Alzheimer’s disease and related disorders and are associated with a greater level of caregiver distress. Currently recommended pharmacological treatments for dementia, including acetylcholinesterase inhibitors and memantine, focus on relieving cognitive symptoms, while BPSD are managed according to the presenting symptoms. Guidelines recommend non-pharmacological approaches for BPSD but selective serotonin reuptake inhibitors, analgesics and second generation antipsychotics may be used when other approaches fail. Pharmacological treatments for BPSD have limited benefit and safe prescribing is difficult as some may produce severe adverse effects and may worsen cognitive symptoms. Consequently, there is a pressing need for new approaches to BPSD management. Multiple clinical studies have reported that herbal medicines (HMs), such as Ginkgo biloba leaf extract, can alleviate BPSD as well as improve cognition in dementia. The present project aimed to determine the current state of evidence for HMs and propose future directions for the development of plant-based therapeutics for managing BPSD. Both historical use and contemporary clinical trials provide evidence for the use of herbs for management of memory impairment, cognitive symptoms of dementia and BPSD. Based on these findings, there is potential for identifying effective herbal interventions that could be fast-tracked into clinical use for this unmet need. Identification of useful compounds and their possible mechanisms of action may contribute to development of new therapeutic approaches and/or drug discovery. Notably, the acetylcholinesterase inhibitors galantamine and rivastigmine were discovered from plant-derived compounds. The objectives of this project were to assess the current state of evidence and its limitations regarding the efficacy, safety and tolerability of HMs for BPSD by systematically reviewing and analysing the results of clinical trials and the classical Chinese medicine literature on BPSD; identify any HMs that show potential benefit for BPSD; based on the best available evidence, select a herbal intervention suitable for further clinical investigation; and design a rigorous randomised controlled trial (RCT) to test the intervention that addresses the limitations of previous clinical studies. The comprehensive systematic review and meta-analysis included 31 controlled clinical trials testing 19 different HMs. Meta-analysis of well-designed, placebo-controlled studies indicated that the G. biloba leaf extract EGb 761® was safe and well-tolerated. Significant and clinically meaningful improvements in BPSD and cognition were detected at 24 weeks. However, independently funded studies of G. biloba leaf extract are needed to confirm these findings. Meta-analysis of randomised, comparative effectiveness studies of the Japanese multi-herb formula Yokukansan (Chinese: Yi gan san) showed no significant differences on BPSD outcomes when compared to standard pharmacotherapies used in Japan for BPSD management and superiority to no treatment. However, the only placebo-controlled study of Yokukansan for BPSD did not find any difference in BPSD outcomes at the end of four weeks treatment. Important limitations were identified in this trial which could have resulted in a false negative. These included its short duration, relatively small sample size, large improvement in the placebo group, and the use of a simplified outcome measure which could be less likely to detect changes in symptoms. Overall, the clinical evidence for Yokukansan suggested improvements in BPSD, notably in the clinically important symptoms of irritability/lability and agitation/aggression. An issue identified with Yokukansan was the increased risk of liquorice-induced hypokalaemia, which requires monitoring. Lack of replication and methodological issues in the studies testing other HMs precluded any conclusions for these other interventions. The classical Chinese medical literature was evaluated using the Zhong Hua Yi Dian database, using similar methods to a previous study which evaluated the herbs used for treatment of the cognitive symptoms of dementia. No specific term in the literature corresponded with BPSD, although terms for specific symptoms such as anxiety, depression and agitation were frequently mentioned in conjunction with terms for memory impairment. Some of the HMs described in the classical Chinese medical literature for treatment of memory impairments with mood and behavioural symptoms had also been tested in the clinical trial literature, including Glycyrrhiza uralensis, Poria cocos and Angelica species, which are ingredients of Yokukansan, but the most frequently cited herbs in the classical literature were generally not the same as the frequently tested HMs in clinical trials. The in vitro and in vivo literature showed evidence of relevance to treatment of BPSD for G. biloba, Yokukansan and their constituent compounds. For both these HMs, animal studies have reported anti-aggression-like, antidepressant-like, anxiolytic-like effects as well as benefits on abnormal motor activities and reduction in cognitive impairments and mental stress. Important activities of G. biloba leaf and Yokukansan of relevance to BPSD include modulation of neurotransmission, neuroendocrine regulation and antioxidant effects. The issue of wide variation in placebo effect sizes in BPSD studies was explored through meta-analysis of placebo data. Results showed that placebo effect sizes for BPSD have increased over time. Proposed new studies may therefore require larger sample sizes in order to be adequately powered. Based on the available evidence, it appears that EGb 761® provides small improvements in cognitive symptoms and reduces BPSD while Yokukansan can improve BPSD but not cognition, although it does not appear to have any negative effect on cognition. Both HMs are available commercially, are well characterised and are in widespread use but their combination has not been tested in a clinical trial. Notably, most studies of EGb 761® were conducted in Europe or Russia while Yokukansan was tested in Japan. Therefore, it was proposed that the combination of EGb 761® and Yokukansan at conservative dosages should be tested through an adequately powered, randomised, placebo-controlled clinical trial. A clinical trial protocol was designed which utilised validated diagnostic criteria and assessments relevant to an older population with BPSD, including assessments of caregiver distress associated with BPSD. Issues relating to informed consent from participants and their caregivers were addressed. Safety was an important consideration and was addressed through inclusion and exclusion criteria, careful monitoring of adverse events and strategies to reduce the risk of liquorice-induced hypokalaemia. The results of the RCT would provide useful data on the safety, tolerability and efficacy of this combined intervention in an Australian population with BPSD. The results would assist with clinical decision-making in the management of BPSD.