Effects of risperidone on amino acid metabolism, glucose, and kidney function in healthy adults: A pilot randomized controlled trial

Effects of risperidone on amino acid metabolism, glucose, and kidney function in healthy adults: A pilot randomized controlled trial | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var 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Koshino , Keisuke Horikoshi , Taichiro Minami , Keisuke Sako , Shunsuke Tsuge , Akira Tamai , Ryo Nishioka , Taro Miyagawa , Kiyoaki Ito , Shinji Kitajima , Ichiro Mizushima , Akinori Hara , Norihiko Sakai , Miho Shimizu , Toshiaki Tokumaru , Makoto Tsubomoto , Mitsuru Kikuchi , Masashi Kinoshita , View ORCID Profile Mitsutoshi Nakada , Masashi Mita , Yasunori Iwata , Takashi Wada doi: https://doi.org/10.1101/2025.04.24.25326340 Megumi Oshima 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Megumi Oshima Tadashi Toyama 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan 2 Department of Nephrology, Faculty of Medical Sciences, University of Fukui , Fukui, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yusuke Nakade 3 Department of Clinical Laboratory, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sakae Miyagi 4 Innovative Clinical Research Center, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hisayuki Ogura 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shiori Nakagawa 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Takahiro Yuasa 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Akihiko Koshino 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Keisuke Horikoshi 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Taichiro Minami 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Keisuke Sako 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shunsuke Tsuge 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Akira Tamai 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ryo Nishioka 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Taro Miyagawa 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kiyoaki Ito 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shinji Kitajima 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ichiro Mizushima 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Akinori Hara 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Norihiko Sakai 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Miho Shimizu 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Toshiaki Tokumaru 5 Department of Nutrition, Kanazawa University Hospital , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Makoto Tsubomoto 6 Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mitsuru Kikuchi 6 Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences , Kanazawa, Japan 7 Research Center for Child Mental Development, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Masashi Kinoshita 8 Department of Neurosurgery, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mitsutoshi Nakada 8 Department of Neurosurgery, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mitsutoshi Nakada Masashi Mita 9 KAGAMI INC. , 7-7-15, Saito-Asagi, Ibaragi, Osaka, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yasunori Iwata 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: iwatay{at}staff.kanazawa-u.ac.jp Takashi Wada 1 Department of Nephrology and Rheumatology, Kanazawa University , Kanazawa, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract D-serine administration prevents kidney damage in murine models of acute kidney injury, and risperidone inhibits the activity of D-amino acid oxidase, which regulate plasma D-amino acid levels. This pilot randomized controlled trial investigated the effects of risperidone on glucose, amino acid metabolism, and kidney function in healthy adults. Healthy adults with a homeostasis model assessment of insulin resistance (HOMA-IR) of ≥ 1.6 and estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73m 2 were randomly assigned to the risperidone and control groups. The risperidone group received 0.5 mg/day risperidone for 4 days. The primary outcome was mean change in HOMA-IR on day 5, and the secondary outcomes were changes in D-amino acid levels, eGFR, and urinary albumin. Seven participants were randomized to the risperidone and control groups. The changes in HOMA-IR, eGFR, and urinary albumin on day 5 were not significantly different between the two groups (all p>0.05). Mean changes in plasma D-serine level and urinary D-serine/creatinine ratio were significantly higher in the risperidone group than in the control group (0.2 vs. −0.3 nmol/mL, p=0.03 and 38.2 vs. −25.8 nmol/mL, p=0.01, respectively). Short-term risperidone affects D-serine metabolism without instigating acute adverse effects on kidney or glucose homeostasis in healthy individuals. Clinical Trial Registry number This study was registered with the Japan Registry for Clinical Trials (jRCTs041210165). Introduction Chronic kidney disease (CKD), which impacts more than 10% of the global population, is associated with severe outcomes, including end-stage kidney disease and cardiovascular complications.[ 1 ] Despite the demonstrated efficacy of several therapeutic agents, such as renin-angiotensin system inhibitors and sodium-glucose cotransporter-2 inhibitors, in slowing CKD progression, the residual risk for disease progression remains significant.[ 2 , 3 ] Thus, the development of novel therapeutic approaches are urgently needed to mitigate the risk and progression of CKD in the general population. The renoprotective roles of D-amino acids, such as D-serine and D-alanine, have been demonstrated in several recent in vitro and in vivo studies.[ 4 – 6 ] For example, the oral administration of D-serine and D-alanine alleviated kidney damage in a murine model of acute kidney injury induced by ischemia/reperfusion,[ 4 , 5 ] whereas elevated D-serine levels were associated with tissue remodeling in a nephrectomy model.[ 6 ] Clinical studies have also found that the plasma D-serine and D-alanine concentrations are higher in patients with CKD than in healthy individuals,[ 7 , 8 ] suggesting their potential as biomarkers and therapeutic targets in kidney diseases. Risperidone, an atypical antipsychotic agent widely used for the treatment of schizophrenia, exerts its primary effects through the antagonism of D2 dopamine and 5-HT2A serotonin receptors.[ 9 ] Additionally, risperidone also inhibits [d]{.smallcaps}-amino acid oxidase, which degrades D-serine and D-alanine.[ 10 – 12 ] In a previous observational study of patients in routine clinical care, we reported that risperidone use was associated with a reduced risk of decline in kidney function in patients with schizophrenia,[ 13 ] raising the possibility that the effects of risperidone on D-amino acid metabolism might be a contributor to its protective effect against kidney injury. Despite the evidence supporting the renoprotective effect of risperidone, its impact on the amino acid profile of humans remains unclear. Additionally, the interplay of risperidone with kidney function and glucose metabolism has not been well-studied in individuals without psychiatric conditions. Therefore, we conducted a pilot randomized controlled trial to investigate the impact of short-term risperidone administration on the amino acid profile, kidney function, and glucose metabolism in healthy adults. Our findings offer insights into the pharmacological effects of risperidone on D-serine and D-alanine levels, laying the foundation for novel therapeutic strategies targeting D-amino acid in patients with CKD. Materials and Methods Study design and participants This pilot, open-label, randomized controlled trial evaluated the efficacy of administration of risperidone for 4 days in healthy volunteers. The study protocol was approved by the Medical Ethics Committee of Kanazawa University (approval no: 2021-004) and was registered at jRCT (jRCTs041210165). The study was conducted in accordance with the the Declaration of Helsinki. The participants were recruited between March 22, 2022 and July 20, 2023. Written informed consent was obtained from all participants prior to enrollment. The study enrolled healthy adults aged 20–65 years who met the following criteria: 1) no history of psychiatric or neurologic disorders, 2) fasting blood glucose levels < 140 mg/dL, 3) homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 1.6, 4) estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m², 5) both aspartate and alanine transaminase levels < 30 IU/L, 6) no history of arrhythmias or congenital long QT syndrome, 7) no history of cancer within the past five years, and 8) presence of bowel movements at least once every four days, regardless of laxative use. Participants fulfilling the following criteria were excluded from the study: 1) any medically diagnosed condition currently under treatment, 2) history of hypersensitivity to risperidone, paliperidone, or their components, 3) pregnancy or breastfeeding, 4) participation in another clinical study within the last 3 months prior to the initiation of risperidone administration, 5) deemed unsuitable for study participation for any reason by the principal or sub-investigator, and 6) currently holding a faculty or staff position of the department in which the principal investigator is affiliated. Eligible participants were randomized at a 1:1 ratio to the risperidone and control groups within 30 days of the study enrollment (S1 Fig). Randomization was centrally performed in the registration center using minimization, with age and sex as allocation adjustment factors. A sample size estimation was not performed due to the absence of prior data on effect size. Interventions Participants in the risperidone group were administered 0.5 mg risperidone (Risperdal ® OD, 0.5 mg) once daily at bedtime for 4 days. The lowest available dosage of 0.5 mg/day was chosen to prioritize participant safety. To ensure compliance, participants in the risperidone group were instructed to return any remaining tablets at the end of the study for collection. The study was conducted in an outpatient setting, and no participants was hospitalized during the intervention. Regardless of the group assignment, all participants visited the study site on days 1, 5, and 9 after study initiation. To minimize interference with the gut microbiota, participants were asked to restrict the consumption of foods containing probiotics, such as yogurt, fermented beverages, natto, miso, pickles, and kimchi, starting one week before the study initiation and continuing throughout the follow-up period. Participants were also restricted from using antimicrobials and Lactobacillus preparations. Furthermore, participants were advised to avoid activities requiring alertness, such as driving or operating hazardous machinery, and to abstain from alcohol to reduce the risk of adverse events during the risperidone administration period. Laboratory measurements Participants underwent blood tests after fasting or at least 6 hours after meals and early morning urine tests at baseline and on days 5 and 9 after study initiation. Blood parameters that were assessed included leukocytes, erythrocytes, and platelet counts; hemoglobin; hematocrit; total protein; serum albumin; aspartate and alanine aminotransferases; blood urea nitrogen; creatinine; uric acid; sodium; potassium; calcium; inorganic phosphorus; fasting blood glucose; hemoglobin A1c; insulin; C-peptide; total cholesterol; high-density lipoprotein cholesterol; and triglycerides. The following equation proposed by the Japanese Society of Nephrology was used to calculate eGFR: eGFR (mL/min/1.73 m 2 ) = 194 × serum creatinine (mg/dL) −1.094 × age (years) −0.287 × 0.739 (if female).[ 15 ] The urine albumin to creatinine ratio (UACR) was also assessed. All blood and urinary parameters were measured by an independent laboratory at BML Inc. (Tokyo, Japan) using automated clinical testing technology. The results of all urinary parameters were normalized to urine creatinine to correct for differences in concentrations uniquely related to the hydration status or the urine volume of the participant.[ 16 ] Plasma and urinary levels of DL-serine and alanine at baseline and on day 5 were determined using a two-dimensional high-performance liquid chromatography system (DASH 27B3X00322000001) by KAGAMI INC. (Osaka, Japan), according to a previously described protocol with modifications.[ 4 , 5 , 14 ] Intestinal bacterial flora analysis was conducted based on 16S ribosomal ribonucleic acid (rRNA) sequencing of fecal samples using QIIME2 (version 2021.2) by Takara Bio’s Biomedical Center (Shiga, Japan). Microbiome analysis included alpha diversity, such as number of operational taxonomic units, Chao-1 index, and Shannon index, and beta diversity, such as weighted Unifrac and Bray-Curtis distances, and relative abundance, with a sampling depth of 10,000 sequences. Study endpoints The primary study endpoint was the mean change in HOMA-IR from baseline to 5 days between groups. Intention-to-treat analyses were performed according to the randomly assigned groups. The secondrary endpoints included the mean changes in the following parameters from baseline to 5 days between groups: plasma and urine DL-serine and DL-alanine levels, eGFR, blood pressure, body mass index, blood glucose, hemoglobin A1c, insulin, C-peptide, and UACR. Safety was monitored by assessing adverse events, medical interviews, and the review of laboratory values during the study period. Statistical analysis For baseline participant characteristics, continuous variables were presented as means with standard deviations and categorical variables were presented as numbers with percentages. For the primary and secondary endpoints, Student’s t -test was used to compare mean changes in clinical and laboratory parameters from baseline to days 5 and 9 between the risperidone and control groups. All analyses were performed using Stata version 18 (Stata Corp, College Station, TX). A two-sided p value of <0.05 was considered statistically significant. Results Baseline characteristics of the participants Between March and November 2022, a total of 8 participants were randomized to the risperidone and control groups (n = 4 participants per group), 1 participant declined to complete the study, and 7 completed the protocol treatment ( Fig 1 ). In the risperidone and control groups, the mean participant age was 35 and 29 years, 1 (33%) and 2 (50%) of the participants were male, the mean HOMA-IR was 2.0 and 1.6, and the mean eGFR was 90 and 92 mL/min/1.73 m 2 , respectively ( Table 1 ). The baseline participant characteristics were comparable between the two groups, except for body mass index, which was likely to be higher in the risperidone group than in the control group. Download figure Open in new tab Fig 1. Flowchart of the study View this table: View inline View popup Table 1. Baseline participant characteristics in the risperidone and control groups Comparison of changes in DL-amino acid levels At baseline, the mean (± SD) plasma D-serine levels were 1.8 ± 0.3 nmol/mL and 1.9 ± 0.1 nmol/mL in the risperidone and control groups, respectively. The mean plasma D-serine level increased by 0.24 ± 0.36 nmol/mL on day 5 compared to the baseline in the risperidone group and decreased by −0.32 ± 0.13 nmol/mL during the same time period in the control group ( Fig 2A and S1 Table). The mean plasma D-serine level was 0.56 (95% CI 0.07–1.05) nmol/mL higher in the risperidone group than in the control group on day 5 after the study initiation (p = 0.03). Similarly, the mean change in urinary D-serine-to-creatinine ratio was significantly higher in the risperidone group than in the control group (38.2 ± 19.8 and −25.8 ± 23.4 mmol/g Cr; respectively; between-group difference: 64.0 mmol/g Cr, 95% CI 20.8–107.2; p = 0.01) compared to the control group. Download figure Open in new tab Fig 2. Mean plasma and urine DL-serine (A) and DL-alanine (B) levels during follow-up in the risperidone and control groups The mean changes in plasma D-alanine level and urinary D-alanine-to-creatinine ratio were numerically higher in the risperidone group than in the control group, with no statistical difference (0.54 vs. −0.31 nmol/mL, p = 0.25 and 24.98 vs. −9.42 nmol/mL, p = 0.20, respectively) ( Fig 2B and S1 Table). Conversely, no significant changes were observed in plasma and urinary L-serine and L-alanine levels during the follow-up period and these parameters did not significantly differ between the two groups ( Fig 2 and S1 Table). Effects of risperidone on clinical and laboratory parameters The mean change in HOMA-IR was not statitically significantly different between the risperidone and control groups during the treatment period (0.88 ± 0.58 and 0.42 ± 1.00, p = 0.51) ( Fig 3 and Table 2 ). The change in mean blood glucose from the baseline to day 5 after study initiation was marginally higher in the risperidone group than in the control group (4.0 ± 2.0 vs. −1.3 ± 3.0 mg/dL, respectively; p = 0.048). The mean change in eGFR did not differ between the risperidone and control groups (1.0 ± 8.7 and −0.4 ± 15.6 mL/min/1.73 m 2 , respectively; p = 0.90). The changes in mean blood pressure, body mass index, hemoglobin A1c, insulin, C-peptide, and UACR were not statistically significantly different between the two groups ( Table 2 ). Download figure Open in new tab Fig 3. Mean homeostatic model assessment of insulin resistance (HOMA-IR) (A), fasting blood glucose (B), and estimated glomerular filtration rate (eGFR) (C) levels during follow-up in the risperidone and control groups View this table: View inline View popup Table 2. Mean changes in clinical and laboratory parameters in the risperidone and control groups Exploratory analysis to assess the effects of risperidone on additional clinical and laboratory parameters (S2 Table) revealed no significant changes in body weight, HOMA for β-cell function, aspartate and alanine aminotransferase, uric acid, total and high-density lipoprotein cholesterol, and triglycerides after 4 days of risperidone administration. Effects of risperidone on the fecal microbiome In the 16S rRNA analysis, no significant differences were observed in alpha diversity (species richness) metrics of the fecal microbiome on day 5 compared to the baseline in both risperidone and control group (paired t -test, p > 0.10) (S2 Fig). For beta diversity (overall structural similarity and variation), the weighted Unifrac distances were visually unchanged, and the Gray-Curtis distances were similar (p = 0.81) between the risperidone and control groups during the treatment period (S2 Fig). Safety All adverse events observed during the study are presented in Table 3 . All participants reported a total of eight non-serious adverse events. In the risperidone group, two participants experienced somnolence, and one participant experienced abdominal distension. One participant in each group reported blood pressure of > 140/90 mmHg. No participant in the risperidone group reported hypotension or dizziness, and no serious adverse events were recorded. View this table: View inline View popup Download powerpoint Table 3. Safety in the risperidone and control groups Discussion In this open-label, randomized pilot clinical trial, we found that the short-term administration of risperidone led to an increase in plasma and urinary D-serine levels in healthy adults with normal kidney function. Additionally, risperidone did not adversely eGFR levels or insulin resistance. Overall, these results suggest that risperidone impacts D-serine metabolism without an acute adverse impact on kidney function or glucose homeostasis in healthy individuals. The significant elevation in D-serine levels observed immediately after risperidone administration is a notable finding, which is likely attributable to risperidone-mediated inhibition of D-amino acid oxidase, preventing D-serine degradation.[ 10 , 17 ] The contribution of dietary and microbial factors to D-serine levels should also be considered. D-serine is present in various food sources, including fermented products rich in D-amino acids due to microbial fermentation by serine racemase.[ 18 – 21 ] Although fecal D-serine levels were not measured in the present study, we aimed to minimize confounding mediated dietary factors through the restriction of the intake of fermented foods, antibiotics, and lactic acid supplements during the study period, ensuring that the observed changes in D-serine were attributable to risperidone administration rather than the impact of dietary or gut microbiota-related factors. Short-term risperidone administration did not affect kidney function in healthy individuals enrolled in our study. Few studies have investigated the efficacy and safety of risperidone on kidney function, with contradictory findings. Results from several retrospective cohort studies suggest that risperidone does not increase the risk of acute kidney injury compared to typical antipsychotics.[ 22 , 23 ] In a previous retrospective observational study, we also found that risperidone use was associated with a lower risk of decline in kidney function in patients with schizophrenia.[ 13 ] However, a population-based cohort study reported an increased risk of acute kidney injury-related hospitalizations in elderly patients treated with atypical antipsychotics, including risperidone.[ 24 ] These discrepancies underscore the need for further studies to elucidate the kidney safety profile of risperidone particularly in vulnerable populations such as elderly individuals and patients with CKD. We also found a slight increase in blood glucose levels during risperidone administration. Given the high variability of glucose levels influenced by diet and lifestyle, this change might not be directly related to risperidone administration. Additionally, no significant changes were observed in other glucose metabolism markers, including HOMA-IR and insulin, indicating that risperidone might have a limited impact on glycemic control during short-term use. These results align with previous studies reporting the relatively modest effect of risperidone on glucose metabolism compared to other atypical antipsychotics, which are known for their association with metabolic side effects.[ 25 , 26 ] This study has several limitations. First, the open-label design might have introduced performance bias due to the lack of blinding. Second, we focused exclusively on a healthy population in a pilot study with a small samle size and short follow-up period, which limited the robustness of the safety data. Longer-term clinical trials in patients with CKD are warranted to assess the sustained effects and safety of risperidone in this patient population. Finally, the study was conducted in a Japanese population and our findings might not be generalizable to other ethnic groups with different genetic or dietary backgrounds. Conclusion In conclusion, short-term administration of risperidone at 0.5 mg over 4 days effectively increased plasma D-serine concentrations in healthy participants. Although a slight increase in blood glucose levels was observed, other markers of glucose metabolism and kidney function remained stable during the study period. These findings suggest that risperidone modulates D-serine metabolism without acute adverse effects on kidney function or glucose homeostasis in healthy individuals. These findings provide a foundation for future studies exploring the therapeutic applications of risperidone in kidney disease, and the potential safety and efficacy of risperidone in modulating D-serine metabolism warrant further investigation in clinical trials including patients with CKD. Data Availability Data described in the manuscript will be considered for availability upon request to the corresponding author. https://jrct.mhlw.go.jp/latest-detail/jRCTs041210165 Financial Disclosure Statement This study was supported by KAGAMI INC.. MM is the founder and CEO of KAGAMI INC., a startup company working on chiral amino acid analysis and research for medical applications. MO is supported by a grant from the 2021 public offering research on clinical research by Kanazawa University Hospital and Initiative for Realizing Diversity in the Research Environment, MEXT. Other authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Supporting information S1 Fig. Study design S2 Fig. Alpha (A) and beta (B) diversities of the fecal microbiome in the risperidone and control groups S1 Table. Mean changes in plasma and urine dl-serine and alanine levels in the risperidone and control groups. Abbreviations; Cr, creatinine. S2 Table. Mean changes in clinical and laboratory parameters in the risperidone and control groups. Abbreviations; HOMA-β, Homeostatic model assessment of beta cell function; HDL, high density lipoprotein. Acknowledgments The authors thank the participants who took part in the study. We would like to acknowledge Yuko Oyama, Mari Shimizu, and Eri Umeda at Kanazawa University, who have assisted in sample collection and processing. 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Share Effects of risperidone on amino acid metabolism, glucose, and kidney function in healthy adults: A pilot randomized controlled trial Megumi Oshima , Tadashi Toyama , Yusuke Nakade , Sakae Miyagi , Hisayuki Ogura , Shiori Nakagawa , Takahiro Yuasa , Akihiko Koshino , Keisuke Horikoshi , Taichiro Minami , Keisuke Sako , Shunsuke Tsuge , Akira Tamai , Ryo Nishioka , Taro Miyagawa , Kiyoaki Ito , Shinji Kitajima , Ichiro Mizushima , Akinori Hara , Norihiko Sakai , Miho Shimizu , Toshiaki Tokumaru , Makoto Tsubomoto , Mitsuru Kikuchi , Masashi Kinoshita , Mitsutoshi Nakada , Masashi Mita , Yasunori Iwata , Takashi Wada medRxiv 2025.04.24.25326340; doi: https://doi.org/10.1101/2025.04.24.25326340 Share This Article: Copy Citation Tools Effects of risperidone on amino acid metabolism, glucose, and kidney function in healthy adults: A pilot randomized controlled trial Megumi Oshima , Tadashi Toyama , Yusuke Nakade , Sakae Miyagi , Hisayuki Ogura , Shiori Nakagawa , Takahiro Yuasa , Akihiko Koshino , Keisuke Horikoshi , Taichiro Minami , Keisuke Sako , Shunsuke Tsuge , Akira Tamai , Ryo Nishioka , Taro Miyagawa , Kiyoaki Ito , Shinji Kitajima , Ichiro Mizushima , Akinori Hara , Norihiko Sakai , Miho Shimizu , Toshiaki Tokumaru , Makoto Tsubomoto , Mitsuru Kikuchi , Masashi Kinoshita , Mitsutoshi Nakada , Masashi Mita , Yasunori Iwata , Takashi Wada medRxiv 2025.04.24.25326340; doi: https://doi.org/10.1101/2025.04.24.25326340 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Nephrology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15228) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6599) Geriatric Medicine (668) Health Economics (997) Health Informatics (4536) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3332) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9231) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a005d9335af641e2',t:'MTc3OTU1ODA1NA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();