Dosage, effectiveness, and safety of sertraline treatment for posttraumatic stress disorder in a Japanese clinical setting: a retrospective study.

BACKGROUND: Many of the posttraumatic stress disorder (PTSD) treatment guidelines recognize the use of selective serotonin reuptake inhibitors as first-line pharmacological treatment. In Japan, there were no published studies investigating the effectiveness and safety of sertraline for PTSD in a clinical setting. METHODS: We conducted a retrospective medical chart review of the dosage, effectiveness, and safety of sertraline for the PTSD treatment in Japan. Data were collected from medical charts of patients of PTSD, caused by various types of trauma, who were treated with sertraline between July 2006 and October 2012 during their regular clinical practice. To evaluate the effectiveness, the investigators retrospectively assessed the severity and improvement of the symptoms using the Clinical Global Impressions - Severity and the Clinical Global Impressions - Improvement. RESULTS: The study population was 122 Japanese patients aged ≥18 years with a diagnosis of PTSD who were treated with sertraline (median duration, 10.6 months). Doses ranged from 12.5 to 150 mg/day, mostly 25 and 50 mg/day. The median duration of observation was 10.8 months. Out of those, 50% of patients were regarded as responders by using the Clinical Global Impressions - Improvement at the end of sertraline treatment or the last observation. Two-thirds (65.6%) of patients improved in the severity of PTSD, as assessed by Clinical Global Impressions - Severity, whereas 32.8% showed no change, and 1.6% worsened. Subgroups analyses and logistic regression analyses suggested that the type of traumatic events was the factor with the highest influence on the response rate. The adverse events in this chart review were consistent with the known safety profile of sertraline. There were no reports of serious or severe adverse events considered to be related to sertraline. CONCLUSIONS: Our study suggested the effectiveness of sertraline for the treatment of PTSD in a Japanese clinical setting, and the obtained safety profile was consistent with the generally known safety profile of sertraline. TRIAL REGISTRATION: ClinicalTrials.gov (Identification No. NCT01607593 ). Registered May 21, 2012.

Influence Diagnostics of a Region of Interest in Multi-regional Clinical Trials.

Multi-regional clinical trials (MRCTs) are an efficient way to enable recruitment of the planned number of subjects within a reasonable timeframe in drug development for rare diseases. One of the aim of MRCTs is to evaluate the applicability of overall trial results to a region of interest. Various statistical methods proposed for this purpose are primarily relying on regional estimates from subgroup analyses of a region of interest, thus they may not work well for studies with small sample size in rare diseases. This paper, instead, presented how to apply influence diagnostics to assessing influence of a region of interest on the overall results in MRCTs and showed this approach could be an analysis option for MRCTs in rare diseases through Monte Carlo simulation and analysis of an MRCT.

Contact Dermatitis after Prescription of an Ophthalmic Ointment Containing Fradiomycin Sulfate: A Retrospective Database Study Using Japanese Health Insurance Claims Data.

BACKGROUND: Topical ointments containing fradiomycin sulfate, such as fradiomycin sulfate/methylprednisolone (F/M) and fradiomycin sulfate/betamethasone sodium phosphate (F/B), are known to cause allergic contact dermatitis (CD) in some patients, especially when used for the periocular region. F/M is commonly prescribed to patients for various conditions; however, there are no reports with respect to the incidence of CD caused by F/M in actual practice. OBJECTIVE: The aim was to investigate the incidence of CD using a data-based retrospective cohort study. METHODS: Using a Japanese health insurance claims database [MinaCare Co. Ltd. healthcare database (MinaCare HDB)], a comparative assessment was conducted of F/M and another combination drug (F/B) and two single-drug treatments (ophthalmic ointments with either an antibiotic or a steroid). The total data set consisted of 1,176,082 individuals in the MinaCare HDB, with 54,016 having received prescriptions for one of the four investigational drug regimens. RESULTS: Overall, the incidences of CD were similar in three of the four groups in this study (F/M 0.091; F/B 0.092; steroids 0.102), while being lower in the fourth group (antibiotics 0.060). Even after confirmation of a diagnosis of CD, prescriptions for the investigational drugs were repeatedly filled for some patients. CONCLUSION: This study demonstrated that there was no clear difference in the incidence of CD after filling prescriptions for F/M, F/B, and ophthalmic ointment containing a steroid, while the incidence with antibiotics was lower by 0.03-0.04 compared with the other groups. Considering the observation that the investigational drugs were repeatedly prescribed even after the diagnosis of CD, it is critical that the risk of CD with these prescribed topical ointments is better understood by primary care physicians in order to take appropriate countermeasures.

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.

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.

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.