Key Messages

• In older adults with clinical Alzheimer’s-type dementia (CATD) and behavioral and psychological symptoms of dementia (BPSD):

  • Evidence was insufficient for the traditional Japanese herbal mixture, Yokukansan, versus placebo for agitation, aggression, psychosis, serious adverse events, or withdrawals due to adverse events.
  • There was no evidence for any supplements versus placebo for disinhibited sexual behavior or quality of life, and no evidence at 24 weeks or longer for depression, anxiety, or general behavior.

Eligible Studies

We identified one eligible publication of one unique trial that compared efficacy of supplements with placebo for BPSD outcomes in adults with CATD and BPSD.³⁷⁸ This trial had low risk of bias (ROB).

Baseline Study Characteristics

Participants (n=145) had probable CATD by clinical criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM) III or National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders (NINCDS-ADRDA); baseline Mini-Mental State Exam (MMSE) 1-26; Neuropsychiatric Inventory Brief Questionnaire Form (NPI-Q) score >4; and sum of NPI-Q agitation/aggression and irritability subcategory scores >2.³⁷⁸ Mean participant age was 78 years, 58 percent were female, and 97 percent were community dwelling. Race was not reported. Mean baseline MMSE and NPI-Q scores were 19.4 and 9.5, respectively. Participants were randomized to Yokukansan 7.5 grams/day (n=70) or placebo (n=75) for 4 weeks. Yokukansan dose could be decreased to 5.0 grams/day based on tolerability and response.

Outcomes

For efficacy, there was no statistically significant difference between Yokukansan and placebo for change in general behavior (NPI-Q scores) (-2.3 vs. -2.0, p=0.523) or in NPI-Q subcategory scores, such as the Agitation/Aggression, Delusion, Hallucination, and Disinhibition subscales (no data reported). Evidence was considered insufficient to draw conclusions about between group differences for all these outcomes. No studies reported data on disinhibited sexual behavior at 2 weeks or longer, or on depression, anxiety, quality of life, or caregiver outcomes at 24 weeks or longer.

For harms, evidence was insufficient to draw conclusions about between treatment group differences in serious adverse events (2 Yokukansan participants vs. 1 placebo participant) or withdrawals due to adverse events (1 participant in each treatment group), and no studies reported data on confusion, somnolence, falls, extrapyramidal symptoms, stroke, or mortality.

Appendix I provides detailed evidence tables and strength of evidence for key comparisons and outcomes.

Variation in Outcomes by Participant or Drug Characteristics

In post hoc analyses, treatment efficacy was compared between Yokukansan and placebo in subgroups defined by MMSE <20, age <74 years, moderate to severe agitation/aggression defined by baseline NPI-Q subcategory score >2, and baseline hallucinations. In participants scoring below 20 on the baseline MMSE (n=73), treatment groups did not significantly differ for NPI-Q total scores (p=0.086), but participants assigned Yokukansan had a greater decrease than placebo in the NPI-Q Agitation and Aggression Subscale (‑0.68 vs. ‑0.22, p=0.007). In participants <74 years old (n=35), Yokukansan resulted in a greater decrease in the NPI-Q agitation and aggression subscale than placebo (‑0.94 vs. ‑0.5, p=0.049). In participants with baseline moderate to severe agitation/aggression (n=91), Yokukansan was associated with a greater decrease in the NPI-Q Agitation and Aggression Subscale than placebo (p=0.050). Finally, in participants with baseline hallucinations (n=20), those assigned Yokukansan had a greater decrease in NPI-Q scores than those assigned placebo (p=0.019). No adjustments for multiple comparisons or tests for interaction were reported.

No studies reported whether differences in treatment efficacy and harms between Yokukansan and placebo varied as a function of Yokukansan dose, duration, or delivery route.