Physician consultation rates and characteristics among workers with chronic pain or headache who participated in a behavioural change program: a retrospective database analysis using real-world healthcare data.

OBJECTIVE: To assess the potential benefit of a behavioural change programme in working individuals with chronic pain or headache, in the form of increased physician consultation. DESIGN: Retrospective observational database study. SETTING: Members of employment-based healthcare insurance in Japan. PARTICIPANTS: Individual-level data of working individuals aged <75 years from November 2019 through March 2020 were extracted from a database managed by MinaCare Co., Ltd. Included individuals had records of programme participation and chronic pain or headache (self-reported), and did not consult physicians for ≥3 months before programme participation. OUTCOME MEASURES: Physician consultation rates after participating in the programme were examined from December 2019 through March 2020, separately for chronic pain and headache. Baseline characteristics included age, pain numeric rating scale (NRS) score (for chronic pain), suspected migraine (for headache), labour productivity including absenteeism and presenteeism, and 4-month indirect costs in Japanese yen (JPY). RESULTS: The baseline mean age (±SD) of 506 individuals with chronic pain was 46.8±10.1 years; that of 352 individuals with headache was 43.6±9.9 years. Of those with chronic pain, 71.4% had an NRS score≥4, and 49.7% of those with headache had suspected migraine. Overall, 11.3% and 5.4% of those with chronic pain or headache consulted physicians, respectively. The mean baseline absenteeism and presenteeism were 1.5% and 19.1% in those with chronic pain, and 1.5% and 23.0% in those with headache. The baseline indirect costs were 586 941.6 JPY and 1 060 281.6 JPY among those with chronic pain or headache, respectively. CONCLUSION: Given that the individuals did not regularly consult physicians before the programme despite reporting substantial symptoms, our results suggest the potential benefit of educational programmes encouraging physician consultation. Further studies are required to evaluate how to effectively implement such educational programmes via healthcare insurers to reduce the burden of pain symptoms and overall medical costs.

The Use of a Network Analysis to Identify Associations and Temporal Patterns Among Non-communicable Diseases in Japan Based on a Large Medical Claims Database.

BACKGROUND: Reducing the considerable non-communicable disease (NCD) burden in the aging Japanese population depends on better understanding of the comorbid and temporal relationships between different NCDs. OBJECTIVE: We aimed to identify associations between NCDs and temporal patterns of NCDs in Japan using data from a large medical claims database. METHODS: The study used three-digit International Classification of Diseases, Tenth Revision codes for NCDs for employees and their dependents included in the MinaCare database, which covers the period since 2010. Associations between pairs of NCDs were assessed by calculating risk ratios. The calculated risk ratios were used to create a network of closely associated NCDs (risk ratio > 15, statistically significant) and to assess temporal patterns of NCD diagnoses (risk ratio ≥ 5). The Infomap algorithm was used to identify clusters of diseases for different sex and age strata. RESULTS: The analysis included 4,200,254 individuals (age < 65 years: 98%). Many of the temporal associations and patterns of the diseases of interest identified in this study were previously known. Regarding the diseases of interest, these associations can be classified as comorbidities, early manifestations initially diagnosed as something else, diseases attributable to or that cause the disease of interest, or caused by pharmacological treatment. International Classification of Diseases, Tenth Revision chapters that were most associated with other chapters included L Diseases of the skin and subcutaneous tissue. In the age-stratified and gender-stratified networks, clusters with the highest numbers of International Classification of Diseases, Tenth Revision codes included I Diseases of the circulatory system and F Mental and behavioral disorders. CONCLUSIONS: Our findings reinforce established associations between NCDs and underline the importance of comprehensive NCD care.

Physician visits and medication prescriptions for major chronic diseases during the COVID-19 pandemic in Japan: retrospective cohort study.

OBJECTIVES: There have been concerns that patients with chronic conditions may be avoiding in-person physician visits due to fear of COVID-19, leading to lower quality of care. We aimed to investigate changes in physician visits and medication prescriptions for chronic diseases before and during the COVID-19 pandemic at the population level. DESIGN: Retrospective cohort study. SETTING: Nationwide claims data in Japan, 2018-2020. PARTICIPANTS: Working-age population (aged 18-74 years) who visited physicians and received any prescriptions for major chronic diseases (hypertension, diabetes and dyslipidaemia) before the pandemic. OUTCOME MEASURES: The outcomes were the monthly number of physician visits, the monthly proportion of physician visits and the monthly proportion of days covered by prescribed medication (PDC) during the pandemic (April-May 2020, as the first state of emergency over COVID-19 was declared on 7 April, and withdrawn nationally on 25 May). RESULTS: Among 10 346 patients who visited physicians for chronic diseases before the pandemic, we found a temporary decline in physician visits (mean number of visits was 1.9 in March vs 1.7 in April; p<0.001) and an increase in the proportion of patients who did not visit any physicians during the pandemic (15% in March vs 24% in April; p<0.001). Physician visits returned to the baseline in May (the mean number of visits: 1.8, and the proportion of patients who did not visit any physicians: 9%). We observed no clinically meaningful difference in PDC between before and during the pandemic (eg, 87% in March vs 87% in April; p=0.45). A temporary decline in physician visits was more salient in seven prefectures with a larger number of COVID-19 cases than in other areas. CONCLUSIONS: Although the number of physician visits declined right after the COVID-19 outbreak, it returned to the baseline one month later; patients were not skipping medications during the pandemic.

[Studies on Monoamine Transporter Occupancy of Antidepressants using PET: Focusing on SERT and NET].

Monoamine transporter occupancy of antidepressants in the brain can be measured by positron emission tomography. For antidepressive effects to appear, serotonin transporter (SERT) occupancy should rise to 80% or higher. Despite a recent increase in the number of reports on norepinephrine transporter (NET) occupancy, estimating the threshold level of NET occupancy required for antidepressive effects is difficult based on the analysis of NET alone. Therefore, studies should be conducted on NET occupancy required for a valid treatment, including an ideal balance between SERT and NET occupancy. (Received 24 September 2020; Accepted December 18, 2020; Published June 1, 2021).

Antidyslipidemic Drug Prescriptions and Lipid Control Status After Unfavorable Annual Health Checkup Results: A Retrospective Cohort Study Using a Health Insurance Database.

BACKGROUND: Japanese employers are obligated to offer employees annual health checkups and guidance programs for their health promotion and maintenance to prevent cardiovascular (CV) and lifestyle-related diseases. Under these programs, checkup recipients are notified of the checkup results, and in case of abnormal findings, employers are expected to provide employees with follow-up encouragement to change their behavior; for example, with medical consultations or lifestyle modifications. However, the effect of these programs on behavioral changes and their subsequent clinical outcomes has not been clearly assessed. OBJECTIVE: The aim of this study was to investigate changes in CV risk management behaviors after receiving unfavorable health checkup results on serum lipid levels among subjects without antidyslipidemic drug prescription and uncontrolled lipid levels and at elevated risk of CV events in a real-world setting. PATIENTS AND METHODS: This retrospective cohort study used a Japanese employment-based health insurance database managed by MinaCare Co., Ltd. This study analyzed the data from the annual health checkups of recipients aged 20-74 years with data on their low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), and triglyceride (TG) values from 2015 to 2017, who had uncontrolled lipid levels based on their checkup results at baseline in 2015, and without prescription records of antidyslipidemic drugs. Lipid status was considered uncontrolled if any of the following were detected: LDL-c ≥ 140 mg/dL, HDL-c < 40 mg/dL, or TG ≥ 150 mg/dL. Changes in antidyslipidemic drug prescription, as a primary CV risk management behavior measure, and in lipid control status in 2016 and 2017 were investigated. Potential factors associated with lipid control were also explored using logistic regression analysis. RESULTS: Among 154,421 subjects without antidyslipidemic drug prescription and with uncontrolled lipid levels in 2015, 93.6% remained without antidyslipidemic drug prescription in both 2016 and 2017. Of these subjects, 76.8% and 76.4% continued having uncontrolled lipid levels in 2016 and 2017, respectively. Fewer subjects without prescription achieved lipid control than those with prescription. Various factors were associated with lipid control, with high LDL-c as the greatest risk factor for uncontrolled lipid levels. CONCLUSIONS: These results suggest that most health checkup recipients may not have changed their behaviors; that is, they may have not sought medical treatment and continued having uncontrolled lipid levels in the years following the unfavorable health checkup results. To encourage subjects to initiate desirable behavioral changes, more practical support may be essential.

Relationship of Annual Health Checkups with the Subject's Subsequent Behavior of Cardiovascular Risk Management in a Real-World Setting in Japan: A Retrospective Cohort Study on Changes in Antihypertensive Drug Prescription and Blood Pressure from 2015 to 2017.

BACKGROUND: In Japan, workers receive a health checkup annually, and based on the results, a follow-up health guidance or intervention is provided when deemed necessary. However, it remains unclear whether the current real-world health checkup and guidance programs in Japan successfully lead to behavioral changes or improvement of clinical outcomes in individuals who require cardiovascular (CV) risk management. OBJECTIVE: This study aimed to explore the association between health checkup and the subsequent behavior change in CV risk management in subjects with uncontrolled blood pressure (BP) without antihypertensive drug prescription, who can have increased risk of CV events. PATIENTS AND METHODS: This was a retrospective cohort study that used health-checkup and claims data from a Japanese healthcare database managed by MinaCare Co., Ltd. Of those aged 20-74 years with available data on systolic and diastolic BP from 2015 to 2017, data from individuals with uncontrolled BP who were not prescribed antihypertensive drugs within 6 months before their baseline health checkup in 2015 were extracted and analyzed. The primary outcome measures were changes in antihypertensive drug prescription and BP control status based on health-checkup results from the baseline year (2015) to 2017. CV risk-management behavior was also assessed using body mass index (BMI) and smoking status, as these are the major modifiable CV risk factors. RESULTS: Among 39,242 subjects with uncontrolled BP without antihypertensive drug prescription at baseline, 88.9% remained without prescription in 2016. Of the subjects without prescription, 62.9% continued to have uncontrolled BP. Both statuses of the major modifiable CV risk factors remained unchanged in 2016: 92.1% of obese subjects (BMI ≥ 25 kg/m2) at baseline remained obese, and 93.8% of smokers at baseline aged ≥ 40 years continued to smoke. Logistic regression analysis revealed that age 60-69 years (vs. 40-49 years), hypertension (HT) stage II (vs. stage I), HT stage III (vs. stage I), and BMI ≥ 25.0 kg/m2 (vs. < 25.0 kg/m2) were factors associated with uncontrolled BP in 2016 (subsequent year), regardless of antihypertensive drug prescription. CONCLUSIONS: Untreated HT for years increases the risk of CV events. These results suggest that current health-checkup and guidance programs are inadequately effective for behavioral change. Further practices for committing to lifestyle modifications and seeking medical advice based on their health-checkup results need to be undertaken to improve health behavior.

Clustering patients by depression symptoms to predict venlafaxine ER antidepressant efficacy: Individual patient data analysis.

OBJECTIVE: To identify clusters of patients with major depressive disorder (MDD) based on the baseline 17-item Hamilton Rating Scale for Depression (HAM-D17) items and to evaluate the efficacy of venlafaxine extended release (VEN) vs placebo, and the potential effect of dose on efficacy, in each cluster. METHODS: Cluster analysis was performed to identify clusters based on standardized HAM-D17 item scores of individual patient data at baseline from 9 double-blind, placebo-controlled studies of VEN for MDD. Change from baseline in HAM-D17 total score was analyzed using a mixed-effects model for repeated measures for each cluster; response and remission rates at week 8 were analyzed using logistic regression. Discontinuation rates were also evaluated in each cluster. RESULTS: In 2599 patients, 3 patient clusters were identified, characterized as High modified Core (mCore) Symptoms/High Anxiety (cluster 1), High mCore Symptoms/Medium Anxiety (cluster 2), and Medium mCore Symptoms/Medium Anxiety (cluster 3). Significant effects of VEN vs placebo were observed on change from baseline in HAM-D17 total score at week 8 for both clusters 1 and 2 (both P < 0.001), but not for cluster 3. In cluster 3, a significant treatment effect of VEN was observed at week 8 in the lower-dose subgroup but not in the higher-dose subgroup. All-cause discontinuation rates were significantly higher in placebo than VEN in each cluster. CONCLUSIONS: Three unique clusters of patients were identified differing in baseline mCore symptoms and anxiety. Cluster membership may predict efficacy outcomes and contribute to dose effects in patients treated with VEN. CLINICAL TRIALS REGISTRATION: NCT01441440; other studies included in this analysis were conducted before the requirement to register clinical studies took effect.

Venlafaxine ER Blocks the Norepinephrine Transporter in the Brain of Patients with Major Depressive Disorder: a PET Study Using [18F]FMeNER-D2.

BACKGROUND: The in vivo binding of clinical dose of venlafaxine on norepinephrine transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin transporter than that to norepinephrine transporter. Although serotonin transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of norepinephrine transporter occupancy in the human brain. METHODS: This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of norepinephrine transporter were also estimated. RESULTS: The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P = .0004 < .05/2). The norepinephrine transporter occupancy (8-61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. CONCLUSIONS: This study demonstrates that clinically relevant doses of venlafaxine extended-release block the norepinephrine transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin transporter and norepinephrine transporter blockades.

Factors impacting the efficacy of venlafaxine extended release 75-225 mg/day in patients with major depressive disorder: exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study in Japan.

PURPOSE: To explore the potential factors impacting the efficacy of venlafaxine extended release (ER) and treatment differences between 75 mg/day and 75-225 mg/day dose in patients with major depressive disorder (MDD). METHODS: We performed exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study conducted in Japan. A total of 538 outpatients aged 20 years or older with a primary diagnosis of MDD who experienced single or recurrent episodes were randomized into three groups: fixed-dose, flexible-dose, or placebo. Venlafaxine ER was initiated at 37.5 mg/day and titrated to 75 mg/day for both fixed-dose and flexible-dose group, and to 225 mg/day for flexible-dose group (if well tolerated). Efficacy endpoints were changes from baseline at Week 8 using the Hamilton Rating Scale for Depression-17 items (HAM-D17) total score, Hamilton Rating Scale for Depression-6 items score, and Montgomery-Asberg Depression Rating Scale total score. The following factors were considered in the subgroup analyses: sex, age, HAM-D17 total score at baseline, duration of MDD, duration of current depressive episode, history of previous depressive episodes, history of previous medications for MDD, and CYP2D6 phenotype. For each subgroup, an analysis of covariance model was fitted and the adjusted mean of the treatment effect and corresponding 95% CI were computed. Due to the exploratory nature of the investigation, no statistical hypothesis testing was used. RESULTS: Venlafaxine ER improved symptoms of MDD compared with placebo in most subgroups. The subgroup with a long duration of MDD (>22 months) consistently showed greater treatment benefits in the flexible-dose group than in the fixed-dose group. CONCLUSION: These results suggest that a greater treatment response to venlafaxine ER (up to 225 mg/day) can be seen in patients with a longer duration of MDD. Further investigations are needed to identify additional factors impacting the efficacy of venlafaxine ER.

Possibility of Database Research as a Means of Pharmacovigilance in Japan Based on a Comparison with Sertraline Postmarketing Surveillance.

BACKGROUND: Many pharmacoepidemiologic studies using large-scale databases have recently been utilized to evaluate the safety and effectiveness of drugs in Western countries. In Japan, however, conventional methodology has been applied to postmarketing surveillance (PMS) to collect safety and effectiveness information on new drugs to meet regulatory requirements. Conventional PMS entails enormous costs and resources despite being an uncontrolled observational study method. This study is aimed at examining the possibility of database research as a more efficient pharmacovigilance approach by comparing a health care claims database and PMS with regard to the characteristics and safety profiles of sertraline-prescribed patients. METHODS: The characteristics of sertraline-prescribed patients recorded in a large-scale Japanese health insurance claims database developed by MinaCare Co. Ltd. were scanned and compared with the PMS results. We also explored the possibility of detecting signals indicative of adverse reactions based on the claims database by using sequence symmetry analysis. Diabetes mellitus, hyperlipidemia, and hyperthyroidism served as exploratory events, and their detection criteria for the claims database were reported by the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS: Most of the characteristics of sertraline-prescribed patients in the claims database did not differ markedly from those in the PMS. There was no tendency for higher risks of the exploratory events after exposure to sertraline, and this was consistent with sertraline's known safety profile. CONCLUSIONS: Our results support the concept of using database research as a cost-effective pharmacovigilance tool that is free of selection bias . Further investigation using database research is required to confirm our preliminary observations.

Long-term function and psychosocial outcomes with venlafaxine extended release 75-225 mg/day versus placebo in the PREVENT study.

This post-hoc analysis evaluated long-term psychosocial outcomes in patients with recurrent major depressive disorder treated with venlafaxine extended release (ER) 75-225 mg/day or placebo. Patients who responded to 10-week venlafaxine ER 75-300 mg/day treatment and maintained response through a 6-month continuation treatment were assigned randomly to venlafaxine ER or placebo maintenance-phase treatment. Data from responders to acute and continuation venlafaxine ER 75-225 mg/day treatment were analyzed during 12-month maintenance treatment while receiving venlafaxine ER of up to 225 mg/day. Failure to maintain improvement in psychosocial functioning, on the basis of the Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey, was defined as loss of at least 50% of the improvement from acute-phase baseline achieved during acute and continuation treatment or dose escalation of more than 225 mg/day. The probability of remaining well (no failure to maintain improvement in functioning) was significantly higher through 12-month maintenance treatment for patients treated with venlafaxine ER 75-225 mg/day versus placebo Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey component summary scores (all P≤0.0351). Effects of up to 20 months of treatment with venlafaxine ER 75-225 mg/day on psychosocial functioning were consistent with the results for venlafaxine ER 75-300 mg/day.

A unique database for gathering data from a mobile app and medical prescription software: a useful data source to collect and analyse patient-reported outcomes of depression and anxiety symptoms.

A unique database named 'AN-SAPO' was developed by Iwato Corp. and Japan Brain Corp. in collaboration with the psychiatric clinics run by Himorogi Group in Japan. The AN-SAPO database includes patients' depression/anxiety score data from a mobile app named AN-SAPO and medical records from medical prescription software named 'ORCA'. On the mobile app, depression/anxiety severity can be evaluated by answering 20 brief questions and the scores are transferred to the AN-SAPO database together with the patients' medical records on ORCA. Currently, this database is used at the Himorogi Group's psychiatric clinics and has over 2000 patients' records accumulated since November 2013. Since the database covers patients' demographic data, prescribed drugs, and the efficacy and safety information, it could be a useful supporting tool for decision-making in clinical practice. We expect it to be utilised in wider areas of medical fields and for future pharmacovigilance and pharmacoepidemiological studies.

Restoring function in major depressive disorder: A systematic review.

BACKGROUND: Functional impairment contributes to significant disability and economic burden in major depressive disorder (MDD). Treatment response is measured by improvement in depressive symptoms, but functional improvement often lags behind symptomatic improvement. Residual deficits are associated with relapse of depressive symptoms. METHODS: A literature search was conducted using the following terms: "major depressive disorder," "functional impairment," "functional outcomes," "recovery of function," "treatment outcome," "outcome assessment," "social functioning," "presenteeism," "absenteeism," "psychiatric status rating scales," and "quality of life." Search limits included publication date (January 1, 1995 to August 31, 2016), English language, and human clinical trials. Controlled, acute-phase, nonrecurrent MDD treatment studies in adults were included if a functional outcome was measured at baseline and endpoint. RESULTS: The qualitative analysis included 35 controlled studies. The Sheehan Disability Scale was the most commonly used functional assessment. Antidepressant treatments significantly improved functional outcomes. Early treatment response predicted functional improvement, while baseline disease severity did not. LIMITATIONS: Clinical studies utilized various methodologies and assessments for functional impairment, and were not standardized or adequately powered. CONCLUSIONS: The lack of synchronicity between symptomatic and functional improvement highlights an unmet need for MDD. Treatment guided by routine monitoring of symptoms and functionality may minimize residual functional impairments.

A meta-analysis of the efficacy of venlafaxine extended release 75-225 mg/day for the treatment of major depressive disorder.

OBJECTIVE: To evaluate the short-term efficacy of venlafaxine extended release (ER) 75-225 mg/day compared with placebo for treating major depressive disorder (MDD) and to examine associations between baseline characteristics and efficacy outcomes in MDD patients treated with venlafaxine ER 75-225 mg/day. RESEARCH DESIGN AND METHODS: This meta-analysis included published and unpublished short-term, double-blind, placebo-controlled, Wyeth/Pfizer sponsored studies of venlafaxine ER at doses up to 225 mg/day in adults with MDD. CLINICAL TRIAL REGISTRATION: All trials were conducted before trial registration became mandatory. MAIN OUTCOME MEASURES: Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score was analyzed over time using a mixed-effects model for repeated measures with terms for study, treatment group, visit, interaction between treatment group and visit, and baseline score as a covariate. Associations between baseline demographic and clinical characteristics and the probability of HAM-D17 response and remission at week 8 were evaluated using logistic regression models, with terms for study, treatment group, and baseline characteristics in the models. Safety and tolerability was assessed based on adverse events (AEs) and discontinuations due to AEs. RESULTS: The full analysis set included 1087 patients from five studies that fulfilled selection criteria. Statistically significant separation between venlafaxine ER and placebo groups for HAM-D17 total score was seen at week 2 and all subsequent assessments (p-values <.0001). There was no significant interaction between treatment and baseline HAM-D17 total score. Probability of HAM-D17 remission at week 8 decreased with increasing baseline HAM-D17 total score (p = .0012; OR: 0.94); however, baseline HAM-D17 total score did not predict response. Discontinuations due to AEs were reported for 9.4% of venlafaxine-ER-treated patients compared with 3.6% of placebo-treated patients. Key limitations: Five studies met the criteria for inclusion. Several differences in design between included studies limited the analysis: one study did not include a week 3 assessment (the week 3 time point was therefore dropped from the analysis), one study had two venlafaxine ER dose arms, which were combined into one group for the meta-analysis, and mixed- and flexible-dose studies were pooled. CONCLUSIONS: Venlafaxine ER 75-225 mg/day effectively reduced symptoms of depression in patients with MDD overall and in patients with either lower (≤23) or higher (>23) HAM-D17 total score at baseline.

A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan.

The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75-225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (-10.76; P=0.031), but not in the flexible-dose (-10.37; P=0.106) group compared with placebo (-9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible-dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan.

Work productivity loss with depression, diagnosed and undiagnosed, among workers in an Internet-based survey conducted in Japan.

OBJECTIVE: The aim of this study was to investigate whether depression severity was associated with work impairments, regardless of the diagnosis. METHODS: We conducted a cross-sectional study among 17,820 Japanese workers using an Internet-based survey. Work impairments were assessed using the Work Productivity and Activity Impairment questionnaire. Participants were grouped according to whether they had a past-year diagnosis of depression by physicians and current depression severity assessed with the Patient Health Questionnaire-9. RESULTS: Among the undiagnosed, high severity respondents had greater overall work impairment than low severity respondents (33.3% vs 14.8%). Significant interactions between diagnosis and severity indicated greater impairments among undiagnosed than among diagnosed respondents (except on absenteeism). CONCLUSIONS: Depression severity was associated with work productivity loss, even among the undiagnosed, suggesting a need for early detection, referral, and treatment of depression in the workplace.

The function of filensin and phakinin in lens transparency.

PURPOSE: Beaded filaments are lens cell-specific intermediate filaments composed of two proteins: filensin and phakinin (CP49). Filensin and phakinin are believed to function in the maintenance of lens transparency. To elucidate the function of filensin and phakinin at the molecular level, we examined the degradation of these two proteins in normal and cataractous rat lenses. METHODS: A hereditary cataract model, the Shumiya cataract rat (SCR), was used for these studies. Anti-filensin antibodies were raised against three different regions of the protein, the rod domain, the inner region of the tail domain, and the outer region of the tail domain. Anti-filensin and anti-phakinin antibodies were used to examine the conformation of degradation of filensin and phakinin by western blot analysis and fluorescent immunocytochemistry of cryosectioned lenses. RESULTS: In the normal lens, filensin was processed from a 94 kDa protein to proteins of 50 kDa and 38 kDa. Similarly, phakinin was processed from a 49 kDa protein to one of 40 kDa. The concentrations of filensin and phakinin in the rat lens cortex fluctuated with age and decreased during cataractogenesis. The 50 kDa form of filensin decreased significantly before opacification. In the normal lens, phakinin, the filensin rod domain, and the filensin inner tail domain localized to membrane lining regions in the shallow cortex and to the central region of the cytoplasm in the deep cortex. The COOH-terminal domain of filensin localized to the membrane lining region in the deep cortex. In pre-cataractous lenses, phakinin and the filensin rod domain localized primarily to the membranes lining the shallow cortex region and were distributed throughout the cytoplasm of lens fiber cells in the deep cortex. CONCLUSIONS: The 50 kDa form of filensin is important for the localization of beaded filaments in lens fiber cells and for lens transparency.