Correspondence: Dr Tomihisa Niitsu MD PhD, Research Center for Child Mental Development, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba 260-8670, Japan. Email: firstname.lastname@example.org
Pharmacotherapies for the behavioural and psychological symptoms of dementia are limited; novel agents for the symptoms are still needed. Herein, we report the case of an 80-year-old male patient with Alzheimer's disease whose severe agitation, insomnia and sexual delusions were successfully treated with a traditional natural Japanese (Kampo) medicine, keishi-ka-ryukotsu-borei-to. We found that administrating keishi-ka-ryukotsu-borei-to increased his serum luteinizing hormone level, which could be inversely associated with his behavioural and psychological symptoms. This report suggests that keishi-ka-ryukotsu-borei-to is a possible alternative treatment for the behavioural and psychological symptoms of dementia, especially sexual delusions.
In clinical practice, atypical antipsychotics are used off-label to treat the behavioural and psychological symptoms of dementia (BPSD), although great care needs to be exercised because of possible side effects. This means that there is still a strong need for safer and more effective pharmacological agents to treat BPSD.
Kampo, a traditional natural Japanese medicine, originated in China and was introduced to Japan in the middle of the sixth century. It has been customized and modified in Japan for over a thousand years. To date, the Japanese Ministry of Health, Labour and Welfare has approved more than 210 Kampo prescriptions for clinical use, in the same way as conventional medicines. Keishi-ka-ryukotsu-borei-to (KRBT), one of these approved prescriptions, is composed of seven crude drugs (cinnamon bark, peony root, jujube fruit, oyster shell, fossilized bone, glycyrrhiza, and ginger rhizome) and has been used as a treatment for nocturnal enuresis in children, neurasthenia, sexual neurasthenia, pollution and impotence.
In this paper, we report a case of an elderly male patient with Alzheimer's disease (AD) whose BPSD were successfully treated with KRBT.
Mr A, an 80-year-old man with no history of psychiatric illness, gradually began to show increasing cognitive dysfunction, delusions of robbery, and wandering due to dementia. He engaged in aggressive behaviour driven by a delusion that he had lost his testes and was initially referred to a urological clinic. Urological examination found no genital abnormalities, and he was then referred to our psychiatric clinic. His Hasegawa's Dementia Scale-Revised (HDS-R) score was 21 at the first assessment. HDS-R is the most frequently used screening instrument for AD in Japan (the cut-off is 20/21). His blood profile was within normal limits. A magnetic resonance imaging scan showed moderate enlargement of the cerebral ventricles and sulci, as well as frontoparietal and hippocampal atrophy within the brain (Fig. 1). A single-photon emission computed tomography brain scan showed moderate hypoperfusion of the medial temporal lobe, posterior cingulate gyrus, and parietal association area (Fig. S1). Based on these findings, the patient was diagnosed with AD and prescribed donepezil at 5 mg per day. At the age of 81, his HDS-R score fell to 18, and he began to show severe agitation, insomnia and delusions. Tiapride at 50 mg per day and yokukansan (YKS; a Kampo prescription) at 7.5 g per day were added to his therapy. His agitation and insomnia improved slightly over 9 months, but his delusions did not. Eventually, his agitation and insomnia gradually deteriorated again, while his HDS-R score decreased to 10. In addition, he developed the severe sexual delusion that he had lost his testes, and he wore women's clothes, introducing himself as ‘Ms A’. The Neuropsychiatric Inventory (NPI) total score at this time was 76.
YKS medication was switched to KRBT at 7.5 g per day, and his BPSD such as agitation, insomnia and sexual delusions improved within 4 days. His NPI total score improved from 76 to 35 (Table 1). After 5 months, we found that his serum luteinizing hormone (LH; 7.8 mIU/mL) and follicle-stimulating hormone (FSH; 40.0 mIU/mL) levels were increased, while his serum testosterone level (7.1 ng/mL) remained normal.
Table 1. Changes of NPI scores and gonadotropin levels correlated with KRBT medication
Pretreatment of KRBT
Pre-assessment during the first KRBT treatment
2 weeks after the interruption of KRBT
4 weeks after the restart of KRBT
8 weeks after the restart of KRBT
aRanges within parentheses are the normal ranges for an adult man.
In order to assess the association between KRBT and the patient's gonadotropins, we interrupted his KRBT medication. After 2 weeks of interruption, his serum LH level (4.8 mIU/mL) returned to the normal level of an adult man (0.8–5.7 mIU/mL), whereas his NPI score increased from 35 to 64 and his BPSD deteriorated. Serum testosterone levels also decreased (5.7 ng/mL), although his FSH levels (37.4 mIU/mL) remained above those of a normal adult man (2.0–8.3 mIU/mL). KRBT was prescribed again and his BPSD gradually improved. After 4 weeks, his NPI score decreased from 64 to 29, whereas his serum LH level (8.4 mIU/mL) once again increased to an abnormally high level for an adult man. His HDS-R score remained at 10 during this period, and no other adverse effects of medication were noted.
This case demonstrates that the Kampo prescription, KRBT, is an effective treatment for BPSD associated with AD. It also suggests that KRBT therapy alters LH serum levels, which may contribute to its therapeutic action. Currently, YKS is commonly used in combination with donepezil against BPSD in AD patients, as accumulating reports demonstrate the ability of YKS to ameliorate the effects on BPSD. It is generally preferred over KRBT. However, in this case, neither YKS nor tiapride improved our patient's BPSD, particularly his sexual delusions. We hypothesized that these delusions were caused by sexual neurasthenia or a loss of sexual desire. Therefore, we switched his therapy from YKS to KRBT, which is often used for sexual neurasthenia and a loss of sexual desire in Kampo medicine, which succeeded in improving his BPSD.
Accumulating evidence suggests that LH and FSH plays a role in the pathophysiology of AD, but this is inconclusive.[6-9] In this case, it is difficult to exclude the possibility that increased FSH serum levels were associated with the patient's BPSD, but his FSH serum levels remained higher than a level deemed normal in adult men, regardless of fluctuations in his BPSD. Therefore, his FSH serum levels may have had no major association with his BPSD. In contrast, his BPSD deteriorated when his LH serum level normalized. Therefore, it is possible that his BPSD showed an inverse correlation with his LH serum levels and that increased LH serum levels improved his BPSD. Although LH increased to a level deemed abnormal in adult men, we postulate that this increase conferred a beneficial rather than harmful effect on this patient's BPSD.
It is reported that lower testosterone levels are associated with a cognitive decline in elderly men. In this case, sustained KRBT medication increased serum testosterone levels, although they remained within normal limits. In addition, raised LH levels may have stimulated testosterone production. It is probable that elevated testosterone levels conferred a beneficial effect on this patient's BPSD. The clinical benefits associated with reducing LH levels in patients with AD remain to be determined.[6-8]
There are few studies focused on the associations between levels of gonadotropins and sexual delusions. A study reported that male patients with paranoid schizophrenia and delusions about other people perceiving them as homosexual showed lower prolactin serum levels and higher oestradiol serum levels compared to those of the healthy male heterosexual controls. Our AD patient's prolactin serum levels stayed within normal limits of adult men, regardless of fluctuations in his sexual delusions. Therefore, his prolactin serum levels may have had no association with his sexual delusions. Unfortunately, no data on his oestradiol serum levels were available. Further studies focused on the associations between gonadotropins and sexual delusions are of great interest.
To our knowledge, this is the first clinical report demonstrating that a natural or Kampo medicine, officially approved for clinical use in Japan, could alter gonadotropin levels while at the same time ameliorating the effects of BPSD. Although the exact therapeutic mechanism for KRBT is still unknown, this case study suggests that it can be a valid alternative approach for treating BPSD in AD. Further studies are needed to confirm its therapeutic action, as well as its effect on gonadotropins.
The authors wish to thank the staff at Sannou Hospital (Chiba, Japan) for their assistance. The authors have no conflicts of interest to declare and received no financial support for on this report.