The Burden of Attention-Deficit/Hyperactivity Disorder Traits in Adult Patients with Major Depressive Disorder in Japan.

Purpose: Symptoms of attention-deficit/hyperactivity disorder (ADHD) often overlap with and are hidden by those of mood disorders, including major depressive disorder (MDD), resulting in adult ADHD patients being misdiagnosed as MDD. This study aims to examine if diagnosed MDD patients are more likely to exhibit ADHD traits and if the presence of ADHD traits increases the humanistic burden, including the impairment of health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and health-care resource utilization (HRU), on MDD patients in Japan. Methods: This study utilized existing National Health and Wellness Survey (NHWS) data. The 2016 Japan NHWS is an internet-based survey comprising a total of 39,000 respondents, including those with MDD and/or ADHD. A randomly selected subset of the respondents responded to the Japanese-version Adult ADHD self-report scale (ASRS-v1.1; ASRS-J) symptom checklist. Respondents were considered ASRS-J-positive if the total score was ≥36. The HRQoL, WPAI, and HRU were assessed. Results: Among MDD patients (n = 267), 19.9% were screened ASRS-J-positive, while 4.0% of non-MDD respondents (n = 8885) were ASRS-J-positive. There was a significant association between MDD status and ASRS-J status (crude odds-ratio [OR]: 5.9) as well as between MDD status and ADHD-diagnosis status (crude OR: 22.6). MDD patients who were ASRS-J positive experienced significantly lower HRQoL and higher WPAI than those who were ASRS-J negative. Limitations of this study include potential recall bias owing to the self-report nature of the survey and lack of objective confirmation of MDD diagnosis through review of medical records. Conclusion: This study demonstrated a significant association between MDD status and exhibiting ADHD traits. Adult MDD patients screened ASRS-J-positive experienced significantly higher humanistic burden than patients screened ASRS-J-negative. Our results emphasize the importance of ensuring appropriate screening of ADHD and looking out for potentially hidden ADHD symptoms when diagnosing and treating MDD in adulthood.

Working Conditions, Work Productivity, Quality of Life, and Depressive Symptoms in Undiagnosed Adults with and without Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms During the COVID-19 Pandemic.

Purpose: This study aims to evaluate the impact of the COVID-19 pandemic on employment status, work productivity, quality of life (QOL), and depressive symptoms in undiagnosed adults with and without attention-deficit/hyperactivity disorder (ADHD) symptoms in Japan. Methods: An observational study used baseline data from a Japanese Medilead Healthcare Panel before the COVID-19 pandemic (October-December 2019). Eligible panel participants were then surveyed during the pandemic (March 2021). ADHD symptoms were screened using the Adult ADHD Self-Report Scale. Changes in QOL (EuroQol 5-Dimensions 5-Levels; EQ-5D-5L) and productivity impairment (Work Productivity and Activity Impairment scale; WPAI) from before to during the pandemic were analyzed in undiagnosed adults with and without ADHD symptoms. Unemployment rate and depressive symptoms (Patient Health Questionnaire; PHQ-9) during the pandemic were compared between groups. Results: Participants with (N=949) and without (N=942) ADHD symptoms completed the survey. The unemployment rate was not significantly different between participants with and without ADHD symptoms. Participants with ADHD symptoms were more likely to change jobs or employers during the pandemic. PHQ-9 scores in participants with ADHD symptoms were significantly higher than in those without ADHD symptoms (8.96 vs 3.57, respectively) during the pandemic. Before the pandemic, WPAI scores were significantly higher and EQ-5D-5L scores lower in participants with ADHD symptoms than in those without. Productivity improved and QOL was not altered during the pandemic in both groups, but productivity and QOL remained poorer among participants with ADHD symptoms than in those without. Conclusion: Productivity was improved among all participants during the COVID-19 pandemic, contrary to expectations. However, adults with ADHD symptoms consistently had lower productivity, poorer QOL, and more depressive symptoms than those without ADHD symptoms.

Efficacy of duloxetine in patients with knee osteoarthritis or chronic low back pain with early pain reduction: An exploratory post-hoc analysis of Japanese phase 3, 1-year extension studies.

BACKGROUND: Two previous phase 3, double-blind, randomized, placebo-controlled trials showed that duloxetine 60 mg/day for 14 weeks significantly improved pain and quality of life in Japanese patients with knee osteoarthritis or chronic low back pain. In their open-label extension studies, these improvements were maintained for ≥48 weeks. This post-hoc analysis assessed the relationship between initial response to duloxetine and long-term pain reduction and quality of life in patients with knee osteoarthritis or chronic low back pain. METHODS: Patients (knee osteoarthritis: N = 43; chronic low back pain: N = 41) were subdivided based on extent of pain reduction from baseline to Week 4 of duloxetine (≥30%, 10-30%, or <10% reduction in Brief Pain Inventory-Severity average pain score). Outcome measures were changes from baseline for Brief Pain Inventory-Severity and Brief Pain Inventory-Interference at regular intervals up to Week 65. RESULTS: Mean change from baseline in Brief Pain Inventory-Severity was greater in patients with ≥30% early pain reduction than in patients with <10% early pain reduction through Week 27 for both conditions, and also Weeks 47-65 for back pain. Compared with the <10% early pain reduction group, mean change from baseline in the average of seven Brief Pain Inventory-Interference domain scores was greater in the ≥30% or 10-30% early pain reduction groups for knee osteoarthritis (except Weeks 63-65), and in the ≥30% early pain reduction group for chronic low back pain through Week 19. CONCLUSIONS: These results suggest that patients with knee osteoarthritis who respond well to duloxetine in the first month might experience sustained, long-term pain relief with generally greater quality-of-life improvement than patients with poor initial response. Patients with chronic low back pain who had strong initial response may experience a greater long-term pain relief, but not greater quality-of-life improvement, than patients with poor initial response.

The Burden of Undiagnosed Adults With Attention-Deficit/Hyperactivity Disorder Symptoms in Japan: A Cross-Sectional Study.

Background Symptoms experienced by adult patients with attention-deficit/hyperactivity disorder (ADHD) frequently result in functional impairment across academic/occupational functioning, daily life, and social functioning. A substantial proportion of undiagnosed and untreated ADHD has been suggested in Japan. This study aims to better understand the potential undiagnosed ADHD population in Japan by quantifying the burden associated with ADHD symptoms through a comparison of the prevalence of comorbidities, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and healthcare resource utilization (HRU) between undiagnosed potential ADHD respondents who were screened positive and negative using Adult ADHD Self-Report Scale (ASRS)-v1.1. Methodology Respondents from Japan National Health and Wellness Survey 2016 who answered ASRS-v1.1 without an ADHD diagnosis were included. Respondents checking ≥4 items from ASRS-A and ≥9 from ASRS-A+B were classified as ASRS A+ (n = 309) and ASRS AB+ (n = 227), respectively. ASRS negative (n = 9,280) were respondents who were neither ASRS A+ nor ASRS AB+. Data on the presence of comorbidities, HRQoL, WPAI, and HRU were compared. Results ASRS A+ and ASRS AB+ respondents reported higher coexistence of mental comorbidities (depression, generalized anxiety disorder, bipolar disorder, obsessive-compulsive disorder, etc.), sleep problems (insomnia, narcolepsy, sleep apnea, etc.), and physical comorbidities (non-alcoholic steatohepatitis, allergy, and asthma). They also reported greater WPAI and HRU and lower HRQoL than matched ASRS-negative respondents. Conclusions A significantly higher burden was identified among undiagnosed adults with potential ADHD symptoms. Appropriate diagnosis may help those at risk or those who present with symptoms overlapping with ADHD.

Change in Antidepressant Use After Initiation of ADHD Medication in Japanese Adults with Comorbid Depression: A Real-World Database Analysis.

PURPOSE: To better understand the treatment of comorbid depression in adults with attention-deficit/hyperactivity disorder (ADHD) by investigating the prescription patterns of antidepressants, anxiolytics, and hypnotics after commencing ADHD medication. PATIENTS AND METHODS: In this retrospective observational study in Japan, the data of patients initiating ADHD medication while already receiving antidepressants (ADHD group) and of patients prescribed antidepressants but not diagnosed with ADHD (control group) were extracted from an electronic medical record database. Additionally, one-to-one matching for patients in both groups was performed using sex, age, baseline dosage of antidepressants, and any comorbid psychiatric disorders as covariates. The observation period included a 1-month baseline period and a 6-month follow-up period. The percentage of patients prescribed antidepressants and the mean prescribed dosages were compared between matched-cohort groups. Prescriptions for anxiolytics and hypnotics were also assessed. RESULTS: In the matched cohorts, consisting of 239 patients in the ADHD group and 239 patients from the unmatched control cohort of 10,485, the percentage of patients prescribed antidepressants decreased from baseline in both groups to 94.1% in the ADHD group and 89.5% in the control group during the first month of follow-up, and 77.0% and 78.7%, respectively, during the last month. There were no significant differences between groups in the percentages of patients prescribed antidepressants or in the mean prescribed dosages of antidepressants at any time point over the follow-up period. Prescribed dosages of anxiolytics and hypnotics tended to be lower in the ADHD group. CONCLUSION: The two groups were medicated similarly with respect to their depressive symptoms over 6 months. Our results suggest that in patients with ADHD and comorbid depression, which is more likely to be more severe than in depression without ADHD, depressive symptoms are managed following initiation of add-on ADHD medication, without requiring higher antidepressant dosages than in patients with depression only.

Efficacy and Safety of Medication for Attention-Deficit Hyperactivity Disorder in Children and Adolescents with Common Comorbidities: A Systematic Review.

INTRODUCTION: Comorbid psychiatric conditions in children and adolescents with attention-deficit hyperactivity disorder (ADHD) occur frequently, complicate management, and are associated with substantial burden on patients and caregivers. Very few systematic reviews have assessed the efficacy and safety of medications for ADHD in children and adolescents with comorbidities. Of those that were conducted, most focused on a particular comorbidity or medication. In this systematic literature review, we summarize the efficacy and safety of treatments for children and adolescents with ADHD and comorbid autism spectrum disorders, oppositional defiant disorder, Tourette's disorder and other tic disorders, generalized anxiety disorder, and major depressive disorder. METHODS: We searched MEDLINE, Embase, and ClinicalTrials.gov (to October 2019) for studies of patients (aged < 18 years) with an ADHD diagnosis and the specified comorbidities treated with amphetamines, methylphenidate and derivatives, atomoxetine (ATX), and guanfacine extended-release (GXR). For efficacy, placebo-controlled randomized controlled trials (RCTs) or meta-analyses of RCTs were eligible for inclusion; for safety, all study types were eligible. The primary efficacy outcome measure was ADHD Rating Scale IV (ADHD-RS-IV) total score. RESULTS: Of 2177 publications/trials retrieved, 69 were included in this systematic literature review (5 meta-analyses, 37 placebo-controlled RCTs, 16 cohort studies, 11 case reports). A systematic narrative synthesis is provided because insufficient data were retrieved to combine ADHD-RS-IV total scores or effect sizes. Effect sizes for ADHD-RS-IV total scores were available for ten RCTs and ranged from 0.46 to 1.0 for ATX and from 0.92 to 2.0 for GXR across comorbidities. The numbers and types of adverse events in children with comorbidities were consistent with those in children without comorbidities, but treatment should be individualized to ensure children can tolerate the lowest effective dose. CONCLUSION: Limited information is available from placebo-controlled RCTs on the efficacy (by ADHD-RS-IV) or safety of medication in children with ADHD and psychiatric comorbidities. Further studies are required to support evidence-based drug selection for these populations.

Efficacy of duloxetine for multisite pain in patients with knee pain due to osteoarthritis: An exploratory post hoc analysis of a Japanese phase 3 randomized study.

BACKGROUND: Central sensitization, including dysfunction of descending inhibitory pain pathways, may contribute to multisite pain in patients with chronic musculoskeletal conditions. Duloxetine is a centrally acting analgesic that effectively reduces pain in patients with knee osteoarthritis. Here we assessed the efficacy of duloxetine (60 mg/day) in Japanese patients (N = 353) with pain due to knee osteoarthritis based on the number of painful body sites, determined using the Michigan Body Map. METHODS: Post hoc analysis of a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT02248480). RESULTS: At Week 14, the change from baseline in Brief Pain Inventory-Severity average pain score ("pain reduction") was significantly greater with duloxetine compared with placebo in patients with 3, 4, or ≥5 painful sites, but not in patients with 1 or 2 painful sites. In patients with ≥3 painful sites (57% of patients), pain reduction was significantly greater with duloxetine (n = 100) compared with placebo (n = 101) throughout the study (least squares mean change from baseline to Week 14: -2.68 vs -1.68). Greater pain reduction with duloxetine (n = 77) than placebo (n = 75) also occurred in patients with ≤2 painful sites, although the between-group difference was significant only at Week 4. CONCLUSIONS: These results are consistent with duloxetine enhancing the activity of descending inhibitory pain pathways that are dysfunctional in patients with central sensitization and multisite pain. In addition, these results suggest that duloxetine may be an effective choice of analgesic for patients with knee osteoarthritis and multisite pain.

Efficacy and safety of guanfacine extended-release in Japanese adults with attention-deficit/hyperactivity disorder: Exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study.

AIM: Previously, we reported on the efficacy and safety of guanfacine extended-release (GXR) in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) from a phase 3, double-blind, placebo-controlled, randomized trial. In this exploratory post hoc analysis, we assessed the efficacy and/or safety of GXR in the following subgroups: ADHD-combined (ADHD-C) and ADHD-predominantly inattentive (ADHD-I) subtypes, age (≥31, <31 years), sex (male, female), and body weight (≥50, <50 kg). METHODS: The primary efficacy endpoint was change from baseline in the Japanese version of the investigator-rated ADHD-Rating Scale-IV (ADHD-RS-IV) with adult prompts (total scores) at week 10. RESULTS: The efficacy analysis population included 200 patients (GXR, 100; placebo, 100). ADHD-RS-IV total score effect sizes (GXR vs placebo) were similar across all subgroups (total population: 0.52, ADHD-C: 0.51, ADHD-I: 0.52, ≥31 years: 0.61, <31 years: 0.47, male: 0.50, female: 0.57). There were no major differences in the incidence/types of treatment-emergent adverse events (TEAEs) across the subgroups. The incidence of significant TEAEs (34.3%, 10.6%) and TEAEs leading to discontinuation (34.3%, 12.1%) were approximately three times higher in females than males, respectively. The incidence of TEAEs in patients weighing <50 kg and ≥50 kg was 100% and 73.6% during dose optimization and 40% and 24.4% during the maintenance period, respectively. CONCLUSION: Findings from this post hoc analysis in adults with ADHD support the efficacy and safety of GXR regardless of ADHD subtype, age, or sex and suggest that careful monitoring for TEAEs and GXR dose optimization is considered for all patients, as needed.

The Relationship Between Baseline Clinical Symptom Characteristics and Working Ability in Japanese Patients Treated for Major Depressive Disorder and Painful Physical Symptoms.

PURPOSE: The objective of this post hoc analysis was to explore the relationship, including changes over time, between baseline clinical symptom characteristics and working ability, judged by investigators, after 12 weeks of antidepressant monotherapy in Japanese patients with major depressive disorder (MDD) and painful physical symptoms (PPS) in a real-world clinical setting. PATIENTS AND METHODS: This prospective, observational study in patients treated with duloxetine or selective serotonin reuptake inhibitors was conducted from 2014 to 2016. Both treatment groups were pooled and divided into 2 groups, "working ability recovered" or "working ability not recovered," based on working ability at the end of the study. Patients were also divided into 4 subgroups by the presence or absence of previous depressive episodes and working ability. Main outcome measures included baseline demographics and clinical characteristics, and the 17-item Hamilton Rating Scale for Depression (HAM-D17). RESULTS: Comparison between "working ability recovered" (n=122) and "working ability not recovered" (n=91) showed that the percentage of patients with complications and psychotherapy at baseline, and baseline HAM-D17 total, insomnia, somatic, and anxiety scores, were significantly different. The results of subgroup analyses were mostly the same as the results analyzed by working ability alone. Although statistical differences were observed for some outcome measures, the differences at baseline, except use of psychotherapy, may not be applicable clinically, and there were no specific trends observed that could predict working ability. CONCLUSION: This post hoc analysis suggested that most baseline clinical characteristics, including the presence or absence of previous depressive episodes, were not predictive of working ability recovery. However, the use of psychotherapy in parallel with antidepressant monotherapy may be positively associated with working ability recovery. All outcome measures improved over time, reinforcing the importance of continuous treatment and observation to improve and accurately judge working ability in patients with MDD and PPS.

Relationship Between Pain Reduction and Improvement in Health-Related Quality of Life in Patients with Knee Pain Due to Osteoarthritis Receiving Duloxetine: Exploratory Post Hoc Analysis of a Japanese Phase 3 Randomized Study.

PURPOSE: This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT02248480) investigated relationships between changes in pain severity and changes in health-related quality of life (HRQoL) in duloxetine-treated patients with knee osteoarthritis (OA). PATIENTS AND METHODS: Patients with knee OA and Brief Pain Inventory (BPI) average pain score ≥4 received duloxetine 60 mg/day or placebo for 14 weeks. Spearman rank correlation coefficients were calculated for change in pain severity, as assessed by the BPI, and change in HRQoL, as assessed by the items of the (i) 36-item Short-Form Health Survey (SF-36; a generic measure of HRQoL) and (ii) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; an OA-specific measure of HRQoL). RESULTS: After 14 weeks of treatment, there was a significantly greater improvement (p<0.001) for duloxetine (n=177) vs placebo (n=176) in BPI average pain severity score and significantly greater improvements (p<0.01) for duloxetine vs placebo for 5 of the 8 SF-36 domains (including the Role-Physical, Bodily Pain, and Physical Functioning domains) and all 24 individual WOMAC items. The correlation between BPI change from baseline and SF-36 item change from baseline was statistically significant (p<0.05) for 2 of the 8 SF-36 items (Bodily Pain, Physical Functioning) in duloxetine-treated patients. The correlation between BPI change from baseline and WOMAC item change from baseline was statistically significant for 22 of the 24 WOMAC items in duloxetine-treated patients. CONCLUSION: This post hoc analysis suggested that the pain reduction observed in duloxetine-treated patients with knee OA was associated with improvements in OA-specific aspects of HRQoL, ie, pain and physical functioning.

Factors associated with diabetic polyneuropathy-related sensory symptoms and signs in patients with polyneuropathy: A cross-sectional Japanese study (JDDM 52) using a non-linear model.

AIMS/INTRODUCTION: To assess the prevalence of diabetic polyneuropathy (DPN)-related sensory symptoms/signs and associated factors in patients with polyneuropathy, considering non-linear effects for numerical variables. MATERIALS AND METHODS: A cross-sectional survey of patients with type 2 diabetes mellitus from 17 primary care clinics across Japan was carried out. DPN and DPN-related sensory symptoms/signs were diagnosed according to the Diabetic Neuropathy Study Group in Japan criteria. RESULTS: Of the 9,914 patients with type 2 diabetes mellitus in this study, 2,745 had DPN and 1,689 had DPN-related sensory symptoms/signs (61.5% of patients with DPN). There were significant correlations between DPN-related sensory symptoms/signs and smoking status (odds ratio 2.04 for current and 1.64 for former; P < 0.001 and P = 0.002, respectively), sex (odds ratio 0.56 for male/female; P < 0.001) and alcohol consumption (odds ratio 2.02 for former/never; P = 0.004). Based on the non-linear logistic regression model, significant correlations were observed between the presence of DPN-related sensory symptoms/signs and higher systolic blood pressure (SBP), longer diabetes duration, and decreasing age. The logarithm of odds for SBP increased until reaching approximately 130 mmHg, then it plateaued. CONCLUSIONS: Some modifiable factors assessed in the large survey database might be associated with DPN-related sensory symptoms/signs, namely smoking, alcohol consumption and SBP. Maintaining SBP <130 mmHg was associated with lower odds of DPN-related sensory symptoms/signs in patients with DPN.

Relationship Between Pain Alleviation and Disease-specific Health-related Quality of Life Measures in Patients With Chronic Low Back Pain Receiving Duloxetine: Exploratory Post Hoc Analysis of a Japanese Phase 3 Randomized Study.

This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT01855919) investigated relationships between pain severity (assessed by the Brief Pain Inventory [BPI]) and disease-specific health-related quality of life (assessed by the 24-item Roland-Morris Disability Questionnaire [RDQ-24]) in duloxetine-treated patients with chronic low back pain (CLBP). METHODS: Patients with CLBP duration >6 months and BPI average score ≥4 received duloxetine 60 mg/d (N = 230) or placebo (N = 226) for 14 weeks. Spearman rank correlation coefficients were calculated for (1) BPI change from baseline and RDQ item change from baseline and (2) BPI change from baseline and the RDQ item baseline score in duloxetine-treated patients. RESULTS: Duloxetine treatment significantly improved the RDQ-24 total score compared with placebo; the greatest improvements were observed for RDQ02, RDQ17, and RDQ13. The strongest correlations between BPI change from baseline and RDQ item change from baseline were for RDQ13, RDQ23, and RDQ10. The correlation coefficients for the correlations between BPI change from baseline and the RDQ item baseline score were generally small. DISCUSSION: This post hoc analysis suggested that improvement in pain severity was associated with improvement in the RDQ-24 total score and in some individual RDQ items in duloxetine-treated patients with CLBP. Furthermore, positive responses to duloxetine in terms of the RDQ13, RDQ23, and RDQ10 items may correlate with better pain responses. CLINICAL TRIAL REGISTRY: The study described in this manuscript was registered at www.clinicaltrials.gov (NCT01855919).

The added burden of depression in patients with osteoarthritis in Japan.

Objectives: In Japan, osteoarthritis (OA) is a leading source of pain and disability; depressive disorders may limit patients' ability to cope with OA. This study examined the incremental effect of depression on the relationship between OA and health-related outcomes. Methods: Data from the 2014 Japan National Health and Wellness Survey (N=30,000) were collected on demographics, OA characteristics, and health characteristics of patients with OA. Depression symptoms were measured, and outcomes included health-related quality of life (HRQoL), work productivity and activity impairment, and health care resource utilization. Generalized linear regression models controlling for confounders were used to predict health-related outcomes. Results: Of 565 respondents with OA, 63 (11%) had symptoms of moderate or severe depression. In adjusted models, HRQoL remained lower among respondents with than without depression (p<0.001). Higher levels of presenteeism (mean±SE: 50%±9% vs 23%±2%) and activity impairment (mean±SE: 57%±7% vs 30%±1%) were observed for patients with than without depression (p<0.001); however, there were no differences for absenteeism (p=0.534). Patients with depression (vs no depression) reported more health care provider visits, emergency room visits, and hospitalizations (for all, p<0.001). Conclusion: Depression heightens the health-related burden of OA. Greater attention to depression among patients with OA is warranted.

Analysis of HAM-D scores and working ability in an observational study of Japanese patients with major depressive disorder and painful physical symptoms treated with duloxetine or SSRI monotherapy.

OBJECTIVE: To investigate the relationship between Hamilton Depression Rating Scale (HAM-D) score and psychiatrists' judgment of working ability in patients with major depressive disorder (MDD) and painful physical symptoms. METHODS: This was a prospective, observational, 12-week study in patients who received duloxetine or a selective serotonin reuptake inhibitor. Patients were ≥20 years old, resided in Japan, and had at least moderate depression (Quick Inventory of Depressive Symptomatology ≥16) and at least moderate painful physical symptoms (Brief Pain Inventory-Short Form average pain ≥3). The main outcome in this post-hoc analysis was the HAM-D17 cutoff best corresponding with patients' working ability according to the investigator's judgment. Area under the receiver-operator curve was used to determine the time point with the strongest relationship between HAM-D17 and working ability. The optimal HAM-D17 cutoff was determined based on the maximum of sensitivity (true positive rate) minus ([1 minus specificity] [true negative rate]). For the evaluation of binary data, a mixed effects model with repeated measures analysis was used. RESULTS: For the estimation of the HAM-D17 cutoff, the area under the receiver-operator curve was maximal at 12 weeks, when a HAM-D17 score of 6 resulted in the best correspondence with working ability in the combined study population. At 12 weeks, a HAM-D17 score of 6 also resulted in the maximum predictive ability in each of the two treatment groups separately. For predicted working ability at 12 weeks, 52.7% of duloxetine-treated patients achieved the HAM-D17 cutoff of ≤6, whereas 48.5% of SSRIs-treated patients achieved HAM-D17 ≤6 (P=0.477). CONCLUSION: In this study of patients with major depressive disorder and painful physical symptoms, a HAM-D17 score ≤6 corresponded best with patients' working ability. This finding is consistent with previous studies showing that a HAM-D17 cutoff of ≤7 may overestimate functional recovery from MDD.

Response to duloxetine in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese Phase III randomized study.

PURPOSE: To assess whether patients with knee osteoarthritis pain who have early pain reduction or treatment-related adverse events of special interest (TR-AESIs; constipation, decreased appetite, malaise, nausea, somnolence, thirst) with duloxetine treatment are more likely to have later improvements in pain and quality of life (QOL) relative to placebo than patients without these early indicators. PATIENTS AND METHODS: This was a post hoc analysis of 14-week randomized trial of Japanese patients with knee osteoarthritis pain (Brief Pain Inventory [BPI]-Severity average pain score ≥4) receiving duloxetine 60 mg/day (n=177 analyzed) or placebo (n=176). Primary trial outcome was change from baseline in BPI-Severity average pain at Week 14. Subgroups included early pain reduction (≥30%, 10%-30%, or <10% decrease in BPI-Severity average pain at Week 4) and early TR-AESIs (with/without TR-AESIs by Week 2). Measures included changes from baseline in BPI-Severity average pain, QOL (BPI-Interference, Western Ontario and McMaster Universities Osteoarthritis Index), Patient Global Impression of Improvement (PGI-I), and response rate (proportion achieving ≥30% or ≥50% pain reduction at Week 14). RESULTS: The ≥30% early pain reduction subgroup (n=93) had significantly greater improvements in pain, QOL, and PGI-I and higher ≥30% and ≥50% response rates than placebo; the 10%-30% (n=45) and the <10% (n=33) pain reduction subgroups did not show the same (except 10%-30% group: PGI-I at Week 10 and some QOL at Weeks 10 and/or 14). Both TR-AESI subgroups (with, n=52; without, n=125) had significantly greater improvements in pain, PGI-I, and most QOL measures and higher response rates than placebo. CONCLUSION: Early efficacy responses to duloxetine treatment, but not early TR-AESIs, may predict later pain reduction and QOL improvements in Japanese patients with knee osteoarthritis pain. CLINICALTRIALSGOV: NCT02248480.

Duloxetine in patients with diabetic peripheral neuropathic pain in Japan: a randomized, doubleblind, noninferiority comparative study with pregabalin.

PURPOSE: Duloxetine and pregabalin are recommended as first-line treatments for diabetic peripheral neuropathic pain (DPNP). However, studies have not reported a direct comparison between duloxetine and pregabalin. We conducted a postmarketing, randomized, double-blind study to assess the noninferiority of duloxetine compared with pregabalin after 12 weeks of treatment in adult patients with DPNP in Japan (NCT02417935). PATIENTS AND METHODS: Patients (N = 303) with distal symmetrical DPNP were randomized to and were administered duloxetine (40-60 mg/day) or pregabalin (300-600 mg/day). The primary endpoint was the change from baseline in weekly mean of the 24-hour average pain score (numeric rating scale [NRS]). Noninferiority of duloxetine compared with pregabalin was assessed with the primary endpoint at week 12. Secondary measures, including night pain and worst pain, Brief Pain Inventory-Severity and Interference rating short form (BPI-SF), Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Improvement (PGI-I), and Neuropathic Pain Symptom Inventory (NPSI), health outcome measures (EuroQol 5-Dimension index and VAS), and safety were also assessed. RESULTS: For the 24-hour NRS average pain score, the difference between the duloxetine and pregabalin groups was 0.072 (95% CI: - 0.295, 0.439), and the upper bound of the 95% CI (0.439) did not exceed the predefined noninferiority margin (0.51), at the end of the study period. For secondary outcome measures (night pain, worst pain, BPI-SF, CGI-I, PGI-I, NPSI) and health outcome measures, both the duloxetine and pregabalin treatment groups showed an improvement from baseline with no significant between-group difference. Duloxetine and pregabalin were well tolerated and the safety profiles were consistent with previously reported results. CONCLUSION: This study demonstrated the noninferior efficacy of duloxetine compared with pregabalin in the treatment of adult patients with DPNP. The safety analyses showed an acceptable tolerability based on safety profiles of duloxetine and pregabalin.

Safety and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis: an open-label, long-term, Phase III extension study.

PURPOSE: To assess long-term safety, tolerability, and efficacy of duloxetine in Japanese patients with chronic knee pain due to osteoarthritis. METHODS: In this open-label extension study (NCT02335346), Japanese patients with knee osteoarthritis and pain (Brief Pain Inventory [BPI] - Severity average pain score ≥4 at start of randomized trial) who had previously received duloxetine 60 mg/day or placebo for 14 weeks in a double-blind randomized trial entered the extension and received duloxetine 60 mg/day for 48 weeks. The primary outcome was safety/tolerability, secondary outcomes were change in BPI-Severity (BPI-S) average pain, BPI-Interference (BPI-I), Patient Global Impression-Improvement (PGI-I), Clinical Global Impression-Improvement (CGI-I), 36-item Short-Form Health Survey (SF36), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and exploratory outcomes were knee range of motion (efficacy outcome) and Kellgren-Lawrence grade (safety outcome). RESULTS: Of 323 patients who completed the randomized trial, 93 (50 placebo, 43 duloxetine) entered the extension. Most patients (85, 91.4%) experienced an adverse event, most commonly constipation, nasopharyngitis, somnolence, and dry mouth (≥10% of patients). There were eight serious adverse events in seven patients and no deaths. No obvious duloxetine-related changes were observed in laboratory tests, vital signs, or electrocardiograms. The change from baseline in BPI-S average pain score was significant throughout the extension. Significant reductions in BPI-I, PGI-I, CGI-I, WOMAC, and SF36 scores were also maintained through 52 weeks. There were no substantial changes in range of motion or Kellgren-Lawrence grade. CONCLUSION: In Japanese patients with chronic knee pain due to osteoarthritis, long-term treatment with duloxetine was well tolerated and associated with sustained improvements in pain and health-related quality of life without radiographic deterioration.

Efficacy of duloxetine by prior NSAID use in the treatment of chronic osteoarthritis knee pain: A post hoc subgroup analysis of a randomized, placebo-controlled, phase 3 study in Japan.

BACKGROUND: A previously conducted placebo-controlled, randomized, phase 3 study of 353 Japanese patients with knee osteoarthritis (OA) showed significant improvements for duloxetine vs placebo in pain and health-related quality of life (HRQoL) (ClinicalTrials.gov Identifier: NCT02248480). Reported here are post hoc subgroup analyses evaluating the efficacy of duloxetine according to the pattern of prior nonsteroidal anti-inflammatory drug (NSAID) use. METHODS: Patients with knee OA pain received once-daily duloxetine or placebo for 14 weeks. Pain was evaluated using the Brief Pain Inventory (BPI) and HRQoL was evaluated using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Patients were divided into four subgroups based on their prior NSAID use: (i) no prior NSAID use; (ii) low-frequency NSAID use (<14 days/month); (iii) high-frequency transdermal NSAID use (transdermal NSAIDs only; ≥14 days/month for the 3 months before study entry); and (iv) high-frequency other NSAID use (eg, oral NSAIDs only, both oral and transdermal NSAIDs; ≥14 days/month for the 3 months before study entry). RESULTS: In each of the four prior NSAID use subgroups, there were greater reductions in BPI average pain severity score for duloxetine vs placebo at all timepoints during the 14-week treatment period; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, the proportion of patients achieving a ≥50% reduction in BPI average pain severity score was higher for duloxetine vs placebo. In each subgroup, there were greater reductions in WOMAC total score for duloxetine vs placebo at all timepoints; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, there were greater reductions at Week 14 in WOMAC pain, stiffness, physical function, and total scores for duloxetine vs placebo. CONCLUSIONS: Duloxetine was consistently effective with respect to pain relief and HRQoL in Japanese patients with knee OA pain, regardless of the pattern of prior NSAID use.

Association between presenteeism and health-related quality of life among Japanese adults with chronic lower back pain: a retrospective observational study.

OBJECTIVES: This study investigated the relationship between presenteeism and health-related quality of life (HRQoL) among Japanese adults with chronic lower back pain (CLBP). DESIGN: This was a retrospective, cross-sectional study. SETTING: Data were collected via a self-administered online survey of the Japanese adult general population. PARTICIPANTS: The present study used 2014 Japan National Health and Wellness Survey (NHWS) data (n=30 000). Specifically, data were included from NHWS respondents who self-reported being employed in the past week and having experienced LBP in the past month, with these symptoms lasting for at least 3 months (n=239). 84 (35.1%) participants in this study were female. PRIMARY AND SECONDARY OUTCOME MEASURES: Presenteeism and HRQoL were measured using the Work Productivity and Activity Impairment Questionnaire-General Health (categorical (none: 0%, low: 10%-20%, high: ≥30%) and continuous) and Medical Outcomes Study 36-Item Short Form Health Survey, respectively. Covariates included patient demographics, health characteristics, pain characteristics and depression severity (Patient Health Questionnaire). RESULTS: Presenteeism was reported by 77.4% of respondents. High (vs no) presenteeism related to more severe pain in the prior week (4.9±2.2 vs 3.6±2.1, p=0.001) and currently (5.1±2.1 vs 3.9±3.9, p=0.007), more pain sites (1.9±1.6 vs 1.1±1.4, p=0.004) and greater depression severity (7.5±6.5 vs 3.6±3.6, p<0.001). Adjusting for covariates, high (vs no) presenteeism related to lower mental and physical HRQoL. For low versus no presenteeism, significant HRQoL differences were observed in general health (43.0, 95% CI 40.3 to 45.6 vs 46.9, 95% CI 43.9 to 49.8, p=0.015). CONCLUSIONS: Most respondents experienced presenteeism. Those with high or low presenteeism had poorer HRQoL than respondents with no presenteeism. Monitoring presenteeism rates may help identify workers with an unmet need for better CLBP-related pain management.

A randomized, double-blind, placebo-controlled Phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis.

PURPOSE: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. PATIENTS AND METHODS: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. RESULTS: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (-2.57 vs. -1.80; adjusted mean difference: -0.77; 95% CI: -1.11 to -0.43; P<0.0001). Secondary efficacy endpoints and most HRQoL scales showed greater improvements in the duloxetine group than the placebo group. Adverse events observed in ≥5% of patients that were more frequent in the duloxetine than placebo group were somnolence, constipation, dry mouth, nausea, malaise, and decreased appetite. There were no marked changes in range of motion of the knee joint (efficacy), X-ray images, or Kellgren-Lawrence grade (safety) in either group. CONCLUSION: Duloxetine reduced pain and improved function in patients with knee osteoarthritis, without causing X-ray abnormalities or altered knee joint mobility. Reduced pain was associated with improved HRQoL. Adverse events were consistent with duloxetine's known safety profile.