Guidelines for clinical evaluation of chronic kidney disease in early stages : AMED research on regulatory science of pharmaceuticals and medical devices.

BACKGROUND: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5-1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. METHODS: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. RESULTS: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. CONCLUSION: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors.

Coronavirus disease 2019 vaccination effectiveness based on the 2021 Japanese dialysis registry.

AIM: The effectiveness of the coronavirus disease (COVID-19) vaccine in Japanese patients undergoing haemodialysis has previously not been evaluated on a large scale. We analyzed data from the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR), covering nearly all Japanese patients undergoing dialysis (~95% coverage), to examine the association between COVID-19 vaccination and infection or mortality. METHODS: We used data from the JRDR end-of-year surveys conducted in 2020 and 2021, including information on the COVID-19 vaccination and infection months. COVID-19 infection incidence and its associated mortality rates based on vaccination status (time updated) and odds ratio (OR) (vaccinated vs. unvaccinated) were estimated monthly from April 2021, when vaccination commenced in Japan. RESULTS: COVID-19 infection analysis included 228 865 patients (215 941 vaccinated and 12 924 unvaccinated patients at the end of 2021). The age- and sex-adjusted ORs (aORs) were significantly lower in August, September, October and November 2021, especially in September (aOR [95% confidence interval (CI)]: 0.25 [0.18-0.36]). Additional adjustments for past medical history and laboratory results rarely affected these results. Similarly, in the COVID-19-related mortality analysis with 228 731 patients, including 216 781 vaccinated and 11 950 unvaccinated at the end of 2021, COVID-19-related mortality risk was significantly lower in the vaccinated group in August, September, October and November (aOR [95% CI]: August, 0.32 [0.12-0.84], September, 0.04 [0.01-0.11]; October, 0.10 [0.01-0.81]; November, 0.05 [0.00-0.79]). CONCLUSION: In Japanese patients undergoing haemodialysis, the first or second COVID-19 vaccine dose was significantly associated with decreased COVID-19 infection and mortality rates, suggesting its effectiveness in this population.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

eGFR slope as a surrogate endpoint for end-stage kidney disease in patients with diabetes and eGFR > 30 mL/min/1.73 m2 in the J-DREAMS cohort.

BACKGROUND: An analysis of European and American individuals revealed that a reduction in estimated glomerular filtration rate (eGFR) slope by 0.5 to 1.0 mL/min/1.73 m2 per year is a surrogate endpoint for end-stage kidney disease (ESKD) in patients with early chronic kidney disease. However, it remains unclear whether this can be extrapolated to Japanese patients. METHODS: Using data from the Japan diabetes comprehensive database project based on an advanced electronic medical record system (J-DREAMS) cohort of 51,483 Japanese patients with diabetes and a baseline eGFR ≥ 30 mL/min/1.73 m2, we examined whether the eGFR slope could be a surrogate indicator for ESKD. The eGFR slope was calculated at 1, 2, and 3 years, and the relationship between each eGFR slope and ESKD risk was estimated using a Cox proportional hazards model to obtain adjusted hazard ratios (aHRs). RESULTS: Slower eGFR decline by 0.75 mL/min/1.73 m2/year reduction in 1-, 2-, and 3-year slopes was associated with lower risk of ESKD (aHR 0.93 (95% confidence interval (CI) 0.92-0.95), 0.84 (95% CI 0.82-0.86), and 0.77 (95% CI 0.73-0.82), respectively); this relationship became more apparent as the slope calculation period increased. Similar results were obtained in subgroup analyses divided by baseline eGFR or baseline urine albumin-creatinine ratio (UACR), with a stronger correlation with ESKD in the baseline eGFR < 60 mL/min/1.73 m2 group and in the baseline UACR < 30 mg/gCre group. CONCLUSION: We found that changes in the eGFR slope were associated with ESKD risk in this population.

A case of malignant hypertension as a presentation of atypical hemolytic uremic syndrome.

INTRODUCTION: Malignant hypertension (mHTN) damages multiple target organs, including the kidneys. mHTN has been regarded as one of the causes of secondary thrombotic microangiopathy (TMA); however, a high prevalence of complement gene abnormalities was recently reported in cohorts of mHTN. CASE REPORT: We herein describe a 47-year-old male who presented with severe hypertension, renal failure (serum creatinine (sCr): 11.6 mg/dL), heart failure, retinal hemorrhage, hemolytic anemia, and thrombocytopenia. Renal biopsy findings were consistent with acute hypertensive nephrosclerosis. The patient was diagnosed with secondary TMA associated with mHTN. However, his previous medical history of TMA of unknown origin and family history of atypical hemolytic uremic syndrome (aHUS) suggested as aHUS presenting mHTN, and genetic testing revealed a pathogenic C3 mutation (p.I1157T). The patient required plasma exchange and hemodialysis for 2 weeks and was able to withdraw from dialysis by antihypertensive therapy without eculizumab. Renal function gradually improved to a sCr level of 2.7 mg/dL under antihypertensive therapy for 2 years after the event. There was no recurrence, and renal function was preserved throughout a 3-year follow-up. DISCUSSION: mHTN is a common presentation of aHUS. In cases of mHTN, abnormalities in complement-related genes may be involved in the development of the disease.

CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank.

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

Analysis of inflammatory cytokines and estimated glomerular filtration rate decline in Japanese patients with diabetic kidney disease: a pilot study.

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6Rß, sCD163, sIL-6Rα, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m2/year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database.

OBJECTIVE: Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS: At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m2, and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m2 per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P heterogeneity ≥ 0.35). CONCLUSIONS: The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.

Infection prevention measures for patients undergoing hemodialysis during the COVID-19 pandemic in Japan: a nationwide questionnaire survey.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic affecting a variety of medical treatments, including hemodialysis. This study aims to investigate the implementation of infection control measures, to examine the shortage of personal protective equipment (PPE) and disinfectants, and to quantify the number of nosocomial COVID-19 transmissions in hemodialysis facilities in Japan during the pandemic. METHODS: We conducted a nationwide questionnaire survey between 20 October and 16 November 2020 (i.e., between the "second wave" and "third wave" in Japan) in the 4198 dialysis facilities of the Japanese Association of Dialysis Physicians and the Japanese Society for Dialysis Therapy. A total of 2227 facilities (53.0%) responded. The questionnaire consisted of (i) characteristics of facilities, (ii) infection prevention measures in routine dialysis practices, (iii) shortage of PPE, (iv) feasibility of various isolation measures, and (v) nosocomial transmission. RESULTS: Half of the responding facilities were hospitals with multiple departments, and the other half were clinics specialized in dialysis. Several infection prevention measures such as health checks of staff and patients, donning of masks before and after hemodialysis, and disinfection of frequently contacted areas were implemented during the COVID-19 pandemic. There was a significant improvement in the implementation rate of these measures during the pandemic, compared to before it, which reached over 90%. More than half of the facilities reported a shortage of disposable masks (67.2%) and hand sanitizer alcohol (56.7%). Isolation of COVID-19 patients in private rooms was possible only in 52.7% of the facilities. The majority of facilities (73.3%) could not accept COVID-19 dialysis patients due to lack of space and manpower. Nosocomial transmission of COVID-19 occurred in 4.0% of the facilities. Of those infected, 51.9% were staff. CONCLUSIONS: This survey revealed that most hemodialysis facilities in Japan had improved implementation of infection control measures and had shortage of PPEs and disinfectants, though some facilities did not implement infection prevention measures adequately, mainly due to the limited space of the facility. It may be recommended that each facility immediately establishes isolation measures to prepare for the pandemic of COVID-19. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41100-021-00350-y.

Nationwide survey of the coronavirus disease 2019 prevention and treatment systems for kidney disease patients: a study of Japanese Society of Nephrology-certified educational facilities.

BACKGROUND: There are no reports of a large-scale survey on the infection prevention measures against coronavirus disease 2019 (COVID-19) in nephrology facilities. This study investigated the facility-level nephrology practices adopted during the COVID-19 pandemic and their associated challenges. Additionally, the treatment patterns and outcomes of chronic kidney disease (CKD) patients with COVID-19 were reviewed. METHODS: We conducted a nationwide questionnaire survey of 704 educational facilities that were certified by the Japanese Society of Nephrology (JSN) from October 20, 2020 to November 16, 2020. The questionnaire reviewed the facility characteristics, infection prevention measures taken during routine nephrology practice, impact of COVID-19 on nephrology practice, experiences in managing CKD patients with COVID-19, and nosocomial transmission in the nephrology unit. RESULTS: Of the 347 facilities that responded, 95.1% checked outpatients' body temperatures and COVID-19 symptoms at their visits. To reduce face-to-face contact, 80% and 70% of the facilities lengthened the intervals between outpatient visits and introduced online/telephonic consultations, respectively. As a result, more than half of the hospitals experienced a decrease in the numbers of outpatients and inpatients (64% and 50%, respectively). During the study period, 347 facilities managed 479 CKD patients with COVID-19. Oxygen administration and mechanical ventilation were performed for 47.8% and 16.5% of the patients, respectively, with a 9.2% total mortality rate. CONCLUSION: This survey demonstrated that JSN-certified educational nephrology facilities adopted multiple measures to manage the COVID-19 pandemic; however, they faced several challenges. Sharing these experiences could standardize these approaches and prepare us better for the future.

The role of anti-complement factor H antibodies in the development of atypical haemolytic uremic syndrome: a possible contribution to abnormality of platelet function.

Atypical haemolytic uremic syndrome (aHUS) is associated with complement system abnormality, such as production of complement factor H (CFH) autoantibodies. The growing evidence indicates complement overactivation on platelets is intimately involved in aHUS pathogenesis, besides endothelial injury. We here showed plasma from patients with anti-CFH antibodies induced aggregation of washed platelets, while purified anti-CFH antibodies suppressed aggregation. This suggested anti-CFH antibody itself suppressed thrombosis, while other plasma factor including complement factors could overactivate the platelets, leading to aggregation, which augmented the notion the state of complement activation influenced by anti-CFH antibodies is important in the aggregation of platelets in aHUS.

Profiles of Coagulation and Fibrinolysis Activation-Associated Molecular Markers of Atypical Hemolytic Uremic Syndrome in the Acute Phase.

AIM: Atypical hemolytic uremic syndrome (aHUS), characterized by thrombotic microangiopathy (TMA), is a genetic, life-threatening disease which needs many differential diagnoses. This study aimed to reveal coagulation and fibrinolysis profiles in aHUS and secondary TMA patients. Furthermore, we investigated whether aHUS patients progress to, and meet, disseminated intravascular coagulation (DIC) criteria. METHODS: The acute phase samples were available in 15 aHUS and 20 secondary TMA patients. We measured PT-ratio, activated partial thromboplastin time (APTT), fibrinogen, fibrin degradation product (FDP), fibrin monomer complex (FMC), antithrombin (AT), plasmin-α2 plasmin inhibitor complex (PIC), and von Willebrand factor antigen (VWF:Ag). We examined and compared these tests among aHUS, secondary TMA patients, and healthy volunteer (HV), and evaluated whether patients with aHUS and secondary TMA met DIC criteria. RESULTS: PT-ratio, APTT, FDP, FMC and PIC in patients with aHUS and secondary TMA were higher than those in HV. Fibrinogen and AT showed no significant difference among three groups. VWF:Ag was higher in only aHUS patients. No tests showed significant difference between aHUS and secondary TMA patients. Three aHUS patients out of 15 met DIC criteria. CONCLUSION: We revealed the profiles and distributions of coagulation and fibrinolysis tests of aHUS and secondary TMA patients. All tests were enhanced compared to HV; however, our results showed the no specificities in distinguishing aHUS from secondary TMA patients. We also clarified that some aHUS patients fulfilled DIC diagnostic criteria, indicating that DIC itself cannot be an exclusion criterion of aHUS.

Umbilical Cord Blood Transplantation-associated Nephrotic Syndrome Successfully Treated by Low-density Lipoprotein Apheresis.

The development of nephrotic syndrome (NS) after umbilical cord transplantation (UBT) has been reported in only four cases to date. We herein report the case of a 50-year-old woman who developed NS 94 days after UBT. She fell into oliguria and required dialysis. A kidney biopsy revealed focal and segmental glomerulosclerosis. Although glucocorticoid monotherapy did not improve her condition, the addition of low-density lipoprotein (LDL) apheresis resulted in remission of NS, a drastic improvement in her renal function, and withdrawal from dialysis. To the best of our knowledge, this is the first report of UBT-associated NS treated with LDL apheresis.

Changes in disability-free life expectancy (DFLE) at birth between 2000 and 2010 across Japanese prefectures.

OBJECTIVES: The second phase of Healthy Japan 21 seeks to increase disability-free life expectancy (DFLE) more than life expectancy (LE) between 2013 and 2022. In the face of the rising incidence of disability, the feasibility of achieving this goal remains unclear. METHODS: We examine changes in DFLE at birth between 2000 and 2010 across 47 prefectures, with particular attention given to changes in the absolute number of years and in the proportion of disability-free life years. RESULTS: Although LE increased across all prefectures, there is a variation in DFLE. While the number of disability-free life years increased in many parts of the country, some prefectures had decreases in DFLE. Downturns become particularly evident when DFLE is interpreted in relative terms. The proportion of life spent without disability declined in the majority of prefectures. CONCLUSIONS: Results from subnational level analyses suggest that the rate of increase in DFLE lagged behind that in LE across Japanese prefectures during the past decade. More policy attention should be devoted to health-promotion initiatives at the prefecture level to achieve the nationwide health agenda.

Response rate obtained using milnacipran depending on the severity of depression in the treatment of major depressive patients.

Milnacipran--a new specific serotonin and noradrenaline reuptake inhibitor--is as effective as tricyclic antidepressants and exhibits a higher remission rate for major depressive patients than selective serotonin reuptake inhibitors. However, the effectiveness of milnacipran for severe major depressive patients had not been studied adequately. The study included 96 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery-Asberg Depression Rating Scale (MADRS) was 21 or higher. Of these, 16 patients were excluded because 10 did not complete the study, and 6 showed poor compliance. Finally, 80 patients were included. We defined patients with a baseline MADRS score of > or = 31 points as "severe" (n = 25). The remaining patients were classified as "moderate" (31 > MADRS score > or = 25, n = 30) and "mild" (MADRS score < 25, n = 25) using the median score of those patients as the cutoff. Milnacipran was administered twice daily for 6 weeks. The initial total dose was 50 mg/d; after a week it was increased to 100 mg/d. The response rates were 72%, 70%, and 44% in the "severe," "moderate," and "mild," respectively. No significant differences were found between "severe" and the "moderate"; however, significant differences were observed between "severe" and "mild" and "moderate" and "mild." These results demonstrated that milnacipran is almost equally effective in "severe" and "moderate." This study suggested that milnacipran has a reliable antidepressant effect in treating severe and moderate major depressive patients.

Remarkable effect of selegiline (L-deprenyl), a selective monoamine oxidase type-B inhibitor, in a patient with severe refractory depression: a case report.

A 34-year-old man presented with severe refractory depression. He had failed to respond to various antidepressants, augmentation therapy with lithium carbonate, and modified electroconvulsive therapy. Switching from amoxapine 150 mg/day to selegiline 7.5 mg/day, a selective monoamine oxidase type-B inhibitor, produced a dramatic reduction in hypobulia and lassitude, leading to a complete remission of all depressive symptoms. The patient reverted to his former position at work after an interval of approximately 3 years. Although the biologic basis of the antidepressant effect of selegiline in this patient is unknown, it is suggested that the enhancement of dopaminergic neurotransmission or elevation of brain-derived neurotrophic factor levels in the brain by administration of selegiline is involved in the recovery of this patient from severe refractory depression. This report indicates the antidepressant effect of selegiline in a refractory depressed patient.

Marked effect of milnacipran combined with olanzapine for a delusional depressive patient.

This report is the first to describe the use of milnacipran and olanzapine in combination in the treatment of delusional depression. The patient was a 55-year-old woman, and the combination treatment brought her marked amelioration of delusional depression without significant side effects. This suggests that the combination therapy of milnacipran and olanzapine is efficacious and safe in the treatment of delusional depression.