長谷川 章

AIM: Multiple risk factors are involved in geriatric syndrome (GS) occurring in older adults. Although drug therapy often contributes to GS, the specific causes among older adults in Japan remain unclear. In this study, we examined the possible prescribing cascade rate among older outpatients eligible for Late-stage Elderly Health Insurance and elucidated the differences between GS and GS associated with medication (GSAM) trends. METHODS: This retrospective study enrolled patients from health insurance claims data in Japan between October 2018 and March 2019; hospitalized patients were excluded. Two groups were identified among the participants with GS: GS (no use of GS-causing medications) and possible-GSAM (p-GSAM; use of GS-causing medications). The collected data were analyzed using the Bell Curve for Excel, and statistical significance was set at P < 0.05. RESULTS: In total, 137 781 outpatients were enrolled. Of the 32 259 outpatients who did not use GS-causing medications, 7342 were classified into the GS group. Among 105 522 outpatients who used GS-causing medications, 8347 were classified as having p-GSAM. The mean number of prescriptions was significantly higher in the p-GSAM group than in the GS group (P < 0.01). Furthermore, all GS symptoms showed significant differences, with impaired appetite being the most prevalent in the p-GSAM group than in the GS group (P < 0.01). A possible prescribing cascade was suspected in 2826 (33.9%) of 8347 outpatients in the p-GSAM group. CONCLUSION: Impaired appetite in patients taking GS-causing medications might lead to prescribing cascades. Further studies are needed to prevent such prescribing cascades. Geriatr Gerontol Int 2024; 24: 61-67.

OBJECTIVE: To compare the performance of the diagnostic model for fall risk based on the short physical performance battery (SPPB) developed using commercial machine learning software (MLS) and binomial logistic regression analysis (BLRA). METHODS: We enrolled 797 out of 850 outpatients who visited the clinic between March 2016 and November 2021. Patients were categorized into the development (n = 642) and validation (n = 155) datasets. Age, sex, number of comorbidities, number of medications, body mass index (BMI), calf circumference (left-right average), handgrip strength (left-right average), total SPPB score, and history of falls were determined. We defined fall risk by an SPPB score of ≤6 in men and ≤9 in women. The main metrics used for evaluating the machine learning model and BLRA were the area under the curve (AUC), accuracy, precision, recall (sensitivity), specificity, and F-measure. The commercial MLS automatically calculates the parameter range of the highest contribution. RESULTS: The participants included 797 outpatients (mean age, 76.3 years; interquartile range, 73.0-81.0; 288 men). The metrics of the current diagnostic model in the commercial MLS were as follows: AUC = 0.78, accuracy = 0.74, precision = 0.46, recall (sensitivity) = 0.81, specificity = 0.71, F-measure = 0.59. The metrics of the current diagnostic model in the BLRA were as follows: AUC = 0.77, accuracy = 0.75, precision = 0.47, recall (sensitivity) = 0.67, specificity = 0.77, F-measure = 0.55. The risk factors for falls in older adult outpatients were handgrip strength, female sex, experience of falls, BMI, and calf circumference in the commercial MLS. CONCLUSIONS: The diagnostic model for fall risk based on SPPB scores constructed using commercial MLS is noninferior to BLRA.

OBJECTIVE: To investigate the effects of discontinuing antihypertensive drugs on the characteristics of patients with frailty syndrome. METHODS: This prospective pilot study was conducted between March 2016 and July 2019. Among patients who visited the frailty clinic within this period, outpatients who received antihypertensive drugs at their first visit and were followed-up for about 1 year were enrolled. Participants who discontinued or continued antihypertensive drugs during 1 year of follow-up were classified into a discontinuation group or continuation group, respectively. Each domain in the Kihon checklist (KCL), fall risk score, short physical performance battery (SPPB) score, and skeletal muscle index (SMI) were assessed at the first visit and 1-year follow-up assessment, and were compared between the two groups. RESULTS: Among 498 patients who attended the frailty clinic, 78 were enrolled (discontinuation group, n = 19; continuation group, n = 59). At the first visit, SMI scores were significantly higher in the discontinuation versus continuation group. At the 1-year assessment, physical strength in the KCL for the discontinuation group and various SPPB scores for both groups were significantly improved, and the fall risk score was improved in the continuation group. CONCLUSION: Discontinuation of antihypertensive drugs may positively affect physical performance.

Clinically, juveniles are more sensitive to stress than adults, and exposure to stress as juveniles prolongs psychiatric symptoms and causes treatment resistance. However, the efficacy of antidepressants for juveniles with psychiatric disorders is unknown. In the present study, we investigated whether the expression or development of impaired social behavior was attenuated by memantine, a non-competitive NMDA receptor antagonist. In addition, we clarified the molecular mechanisms related to intracellular signal transduction through NMDA receptors and the ameliorating effect of memantine in mice with impaired social behavior. Acute administration of memantine before the social interaction test, but not before exposure to social defeat stress, attenuated social behavioral impairment. A single social defeat stress increased the phosphorylation of NMDA receptor subunit GluN2A and extracellular-signal-related kinase 1/2 (ERK1/2). Memantine inhibited the increase of phosphorylated GluN2A and ERK1/2 resulting from social interaction behavior. In both GluN2A deficient and pharmacological blockaded mice, social behavioral impairment was not observed in the social interaction test through regulation of ERK1/2 phosphorylation. These findings suggest that memantine ameliorates social behavioral impairment in mice exposed to a single social defeat stress as juveniles by regulating the NMDA receptor and subsequent ERK1/2 signaling activation. Memantine may constitute a novel therapeutic drug for stress-related psychiatric disorders in juveniles with adverse juvenile experiences.

The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl-threo-β-benzyloxyaspartate (dl-TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl-TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.

The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the impairment of social behaviors in this model, as this system is known to be involved in many central pathologies. Acute administration of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, attenuated the expression of impairment of social behaviors. Lack of the NMDA receptor GluN2A subunit or acute administration of ifenprodil, an NMDA receptor GluN2B subunit antagonist, did not cause an effect. There were no significant changes in NMDA function, as determined by the ratios of phosphorylated NMDA receptor subunits in the prefrontal cortex and hippocampus. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, a selective AMPA receptor antagonist, prevented the effect of ketamine on the expression of impairment of social behaviors. On the contrary, the ratio of phosphorylated AMPA receptor GluA1 subunit in the hippocampus was significantly increased in the non-tested, defeated group. Ketamine increased the level of total protein, but not the ratio of phosphorylated GluA1 in the hippocampus of the non-tested, defeated group. In conclusion, exposure to social defeat stress as juveniles may induce the expression of impairment of social behaviors in adolescents via functional changes in GluA1. Activators of AMPA receptor signaling, such as ketamine, may constitute a novel treatment strategy for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

BACKGROUND: Extensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. METHODS: Juvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress. RESULTS: Stress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects. CONCLUSIONS: These findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors.