Clinical meaningfulness of duloxetine's effect in Chinese patients with chronic pain due to osteoarthritis: post hoc analyses of a phase 3 randomized trial.

PURPOSE: To evaluate the analgesic effect of duloxetine in Chinese patients with osteoarthritis (OA) of the knee/hip at individual patient level and report the relationship between pain intensity reduction, overall improvement, and physical functioning. PATIENTS AND METHODS: Post hoc analysis of 13-week, phase 3, parallel-group, randomized, placebo-controlled study of duloxetine in Chinese patients with OA pain. Patients were randomized (1:1, computer-generated, interactive web-response system) to duloxetine (60 mg once daily, n=202) or placebo (n=207). Patients, investigators, and study staff were blinded throughout the study. Duloxetine's efficacy was evaluated using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and the Osteoarthritis Research Society International and Outcome Measures in Rheumatology (OARSI-OMERACT) responder criteria. Analyses were conducted on all randomized patients with a baseline and at least one post-baseline observation. RESULTS: At study endpoint, the percentage of patients experiencing ≥30% pain intensity reduction (30% responders) was significantly higher in the duloxetine group than in the placebo group (63.4% vs 49.7%; P=0.008). The percentage of patients experiencing ≥50% pain intensity reduction (50% responders) in the duloxetine group was numerically higher than in the placebo group (42.8% vs 34.5%; P=0.098). Most of the 30% and 50% responders to duloxetine treatment felt either "very much improved" or "much improved" on the Patient Global Impression-Improvement at endpoint. The 30% and 50% responders to duloxetine treatment also experienced greater improvements in the Western Ontario and McMaster Universities Osteoarthritis Index physical function scores at endpoint compared with non-responders. The overall percentage of OARSI-OMERACT responders was significantly higher in the duloxetine group vs the placebo group (70.1% vs 54.9%; P=0.003). CONCLUSION: Based on IMMPACT and OARSI-OMERACT criteria, the analgesic effect of duloxetine was associated with clinically relevant benefits in Chinese patients with OA of the knee/hip. CLINICALTRIALSGOV IDENTIFIER: NCT01931475.

Maintenance of effect of duloxetine in Chinese patients with pain due to osteoarthritis: 13-week open-label extension data.

BACKGROUND: The objectives of this study were to assess the maintenance of effect of duloxetine 60 mg once-daily (QD) in Chinese patients with chronic pain due to osteoarthritis (OA) of the knee or hip and to provide additional long-term safety data. METHODS: This was an open-label, extension phase of a randomized, double-blind, placebo-controlled clinical trial. Eligible patients were outpatients who met the American College of Rheumatology clinical and radiographic criteria for OA with a rating ≥4 on Brief Pain Inventory (BPI) 24-h average pain. After completing the 13-week placebo-controlled phase, patients originally assigned to placebo were titrated to duloxetine 60 mg QD (PLA_DLX), whereas patients originally assigned to duloxetine 60 mg QD remained on the same dose of duloxetine (DLX_DLX) for another 13 weeks. The maintenance effect of duloxetine 60 mg QD during the extension phase was evaluated by a 1-sided 97.5% confidence interval (CI) of the baseline-to-endpoint change in the extension phase for patients who took duloxetine and reported ≥30% reduction in BPI average pain at the end of placebo-controlled phase (placebo-controlled phase duloxetine responders). Other BPI severity and interference items, as well as safety and tolerability, were assessed. RESULTS: Of 342 patients entering the extension phase, 162 (97.6%) DLX_DLX-treated patients and 157 (89.2%) PLA_DLX-treated patients completed this phase. Most patients (76.0%) were female. Mean age was 60.6 years. Mean BPI average pain was 5.5 at baseline of the placebo-controlled phase. Among 113 placebo-controlled phase duloxetine responders, mean change in BPI average pain during the extension phase was - 0.59 (from 2.47 to 1.88); the upper bound of the 1-sided 97.5% CI was - 0.31 and less than the pre-specified non-inferiority margin of a 1.5-point increase (p < 0.001). Significant within-group improvements in all BPI items were observed for both PLA_DLX and DLX_DLX groups during the extension phase (all p < 0.01). No deaths or suicide-related events occurred. Seven (4.0%) PLA_DLX-treated patients and no DLX_DLX-treated patients discontinued due to an adverse event. CONCLUSION: The analgesic effect of duloxetine 60 mg QD among treatment responders was maintained for the entire duration of the extension phase. Duloxetine 60 mg QD was well tolerated during the extension phase. TRIAL REGISTRATION: ClinicalTrials.gov identification number NCT01931475 . Registered 29 August 2013.

Safety and Effectiveness of Once-Daily Tadalafil (5 mg) Therapy in Korean Men with Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms in a Real-World Clinical Setting: Results from a Post-Marketing Surveillance Study.

PURPOSE: The aim of this study was to investigate the safety and effectiveness of tadalafil 5 mg once daily (quaque die [everyday], QD) among Korean men with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in a real-world clinical setting. MATERIALS AND METHODS: This was a single-country, prospective, observational cohort study in which patients newly prescribed tadalafil 5 mg QD for the treatment of BPH/LUTS were followed-up for 12±2 or 24±2 weeks, or to the last treatment, during post-marketing surveillance. Safety was evaluated in terms of the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Effectiveness was assessed by changes in the International Prostate Symptom Score (IPSS) from baseline to each endpoint. RESULTS: All patients receiving ≥1 dose of tadalafil 5 mg QD (N=637) were included in the safety population. Two percent of patients (n=13) experienced 15 TEAEs of mild (n=10; 66.7%) or moderate (n=5; 33.3%) severity. No severe TEAEs and no SAEs were reported. Effectiveness evaluations included all patients receiving tadalafil who had both baseline and endpoint observations (12-week, N=265; 24-week, N=44). Compared with baseline, the mean IPSS total score (±standard error) significantly improved by 4.7±0.3 and 6.4±0.7 points at the 12- and 24-week endpoints, respectively (p<0.0001), with significant improvements also observed on the storage, voiding, and quality of life subscores. In total, 69.1% of the patients had a clinically meaningful ≥3-point improvement in the IPSS total score. CONCLUSIONS: Tadalafil 5 mg QD was well tolerated and effective in Korean men with BPH/LUTS in a real-world clinical setting.

Functional Impairment and Painful Physical Symptoms in Patients with Major Depressive Disorder Treated with Antidepressants: Real-World Evidence from the Middle East.

BACKGROUND: The Global Burden of Disease 2010 study reported the relative size of major depressive disorder (MDD) burden to be greater in the Middle East and North Africa than anywhere else. However, little research has been carried out to examine the comparative effectiveness of antidepressants in this region. OBJECTIVE: To assess and compare functioning levels in Middle Eastern patients with MDD treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI), and to examine the impacts of depression-related pain on functioning by the type of treatment. METHOD: This post-hoc analysis, which focused on Middle Eastern patients, used data from a 6-month prospective observational study that included 1,549 MDD patients without sexual dysfunction. Levels of functional impairment and depression-related pain were assessed using the Sheehan Disability Scale (SDS) and the modified Somatic Symptom Inventory, respectively. A mixed model with repeated measures (MMRM) was employed. RESULTS: The mean age of the patients was 37.3 (SD=8.4) years, and 34.6% were female. Patient functioning was, on average, moderately impaired at baseline, but improved substantially during follow-up in both the duloxetine (n=152) and the SSRI (n=123) cohorts. The MMRM results showed a lower level of functional impairment at 24 weeks in the duloxetine cohort than in the SSRI cohort (p<0.001). Pain severity at baseline was positively associated with functional impairment during follow-up only in the SSRI cohort (p=0.003). CONCLUSION: Duloxetine-treated MDD patients achieved better functioning than SSRI-treated patients. This treatment difference was partly driven by depression-related pain.

Recovery in patients with major depressive disorder (MDD): results of a 6-month, multinational, observational study.

Not all individuals treated for major depressive disorder (MDD) achieve recovery. This observational study examined the recovery rates in MDD patients and the patient characteristics associated with achieving recovery in a naturalistic clinical setting. Recovery was defined as having both clinical and functional remission. Data for this post hoc analysis were taken from a 24-week prospective, observational study that involved 1,549 MDD patients. Clinical remission was assessed using the 16-item Quick Inventory of Depressive Symptomatology Self-Report and functional remission through the Sheehan Disability Scale and no days of reduced productivity in the previous week. Generalized estimating equation regression models were used to examine the baseline factors associated with recovery during follow-up. Clinical and functional remission was achieved in 70.6% and 56.1% of the MDD patients, respectively. MDD patients who achieved recovery (52.1%) were significantly less likely to have impaired levels of functioning, concurrent medical or psychiatric conditions, low levels of education, or nonadherence to therapy at follow-up. The level of functioning during the index episode seems to be a better predictor of recovery than symptom severity. Therefore, the level of functioning should be considered while determining recovery from depression.

Monoclonal antibodies for chronic pain: a practical review of mechanisms and clinical applications.

Context: Monoclonal antibodies are being investigated for chronic pain to overcome the shortcomings of current treatment options. Objective: To provide a practical overview of monoclonal antibodies in clinical development for use in chronic pain conditions, with a focus on mechanisms of action and relevance to specific classes. Methods: Qualitative review using a systematic strategy to search for randomized controlled trials, systematic and nonsystematic (narrative) reviews, observational studies, nonclinical studies, and case reports for inclusion. Studies were identified via relevant search terms using an electronic search of MEDLINE via PubMed (1990 to June 2017) in addition to hand-searching reference lists of retrieved systematic and nonsystematic reviews. Results: Monoclonal antibodies targeting nerve growth factor, calcitonin gene-related peptide pathways, various ion channels, tumor necrosis factor-α, and epidermal growth factor receptor are in different stages of development. Mechanisms of action are dependent on specific signaling pathways, which commonly involve those related to peripheral neurogenic inflammation. In clinical studies, there has been a mixed response to different monoclonal antibodies in several chronic pain conditions, including migraine, neuropathic pain conditions (e.g., diabetic peripheral neuropathy), osteoarthritis, chronic back pain, ankylosing spondylitis, and cancer. Adverse events observed to date have generally been mild, although further studies are needed to ensure safety of monoclonal antibodies in early stages of development, especially where there is an overlap with non-pain-related pathways. High acquisition cost remains another treatment limitation. Conclusion: Monoclonal antibodies for chronic pain have the potential to overcome the limitations of current treatment options, but strategies to ensure their appropriate use need to be determined.

Lost in transition: A review of the unmet need of patients with attention deficit/hyperactivity disorder transitioning to adulthood.

This review discusses the unmet needs of patients with attention deficit/hyperactivity disorder (ADHD) who are transitioning into adulthood. Although awareness and recognition of ADHD in children, adolescents, and adults have improved in recent years, there is often an interruption in management of the disorder when adolescent patients transition to adult health care services. This review has the following objectives: (1) to identify key issues patients with ADHD (with or without an early diagnosis) face during transition into adulthood; (2) to review the current clinical practice and country-specific approaches to the management of the transition into adulthood for patients with ADHD; (3) to discuss challenges facing clinicians and their patients when drug treatment for ADHD is initiated; (4) to review current ADHD guidelines on transition management in Hong Kong, Singapore, South Korea, Turkey, and Africa; and (5) to examine economic consequences associated with ADHD. The review suggests that the transition period to adult ADHD may be an underresearched and underserved area. The transition period plays an important role regarding how ADHD symptoms may be perceived and acted upon by adult psychiatrists. Further studies are needed to explore the characteristics of the transition period. If only a fraction of adolescents go on to have mental disorders during adulthood, especially ADHD, it is crucial to identify their characteristics to target appropriate interventions at the beginning of the course of illness. There continues to be low recognition of adult ADHD and a severe lack of medical services equipped to diagnose and care for patients with ADHD transitioning from child to adult services.

Functioning in patients with major depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia.

PURPOSE: To assess and compare the levels of functioning in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. PATIENTS AND METHODS: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 patients with major depressive disorder without sexual dysfunction. The present analysis focused on a subgroup of patients from East Asia (n=587). Functioning was measured using the Sheehan Disability Scale (SDS). Depression severity was assessed using the 16-item Quick Inventory of Depressive Symptomatology-Self Report. PPS were rated using the modified Somatic Symptom Inventory. A mixed model with repeated measures was fitted to compare the levels of functioning between duloxetine-treated (n=227) and SSRI-treated (n=225) patients, adjusting for baseline patient characteristics. RESULTS: The mean SDS total score was similar between the two treatment cohorts (15.46 [standard deviation =6.11] in the duloxetine cohort and 16.36 [standard deviation =6.53] in the SSRI cohort, P=0.077) at baseline. Both descriptive and regression analyses confirmed improvement in functioning in both groups during follow-up, but duloxetine-treated patients achieved better functioning. At 24 weeks, the estimated mean SDS total score was 4.48 (standard error =0.80) in the duloxetine cohort, which was statistically significantly lower (ie, better functioning) than that of 6.76 (standard error =0.77) in the SSRI cohort (P<0.001). This treatment difference was more apparent in the subgroup of patients with PPS at baseline. Similar patterns were also observed for SDS subscores (work, social life, and family life). CONCLUSION: Depressed patients treated with duloxetine achieved better functioning compared to those treated with SSRIs. This treatment difference was mostly driven by patients with PPS at baseline.

Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

OBJECTIVE: We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. METHODS: Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. RESULTS: Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p < 0.01) greater improvements in the SDS total score versus treatment with placebo. Higher SDS (p < 0.0001) or 17-item Hamilton Depression Rating Scale baseline scores (p < 0.01) predicted lower probability of functional improvement after treatment with duloxetine or SSRIs. Female gender (p ≤ 0.05) predicted higher probability of functional improvement after treatment with duloxetine or SSRIs. CONCLUSIONS: Treatment with SSRIs and duloxetine improved functional impairment in patients with major depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint.

Real-world outcomes in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia.

INTRODUCTION: This study compared treatment outcomes in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. METHODS: This post-hoc analysis of data from a 6-month prospective observational study involving 1,549 major depressive disorder patients without sexual dysfunction focused on a subgroup of patients from East Asia (n = 587). Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16 ), whereas quality of life (QoL) was measured using EuroQoL instruments. PPS were rated using the modified Somatic Symptom Inventory. Multiple regression analyses were performed to compare the treatment outcomes. RESULTS: Duloxetine-treated patients had higher odds of achieving remission (odds ratio = 2.578, P < 0.001) and response (odds ratio = 2.704, P < 0.001) during follow-up, compared with SSRI-treated patients. They also had lower levels of disease severity and higher levels of QoL during follow-up. A similar pattern was observed in each subgroup of patients with and without PPS at baseline, but the effects of duloxetine relative to SSRIs were in general greater in patients with PPS. DISCUSSION: Patients treated with duloxetine had better treatment outcomes in terms of remission, response, depressive symptoms, and QoL, compared with SSRIs. Treatment with duloxetine may have additional advantages for patients with concurrent PPS.

Caregiving for patients with Alzheimer's disease or dementia and its association with psychiatric and clinical comorbidities and other health outcomes in Brazil.

OBJECTIVES: Individuals with dementia due to Alzheimer's disease often receive care from family members who experience associated burden. This study provides the first broad, population-based account of caregiving-related health outcome burden in Brazil. METHODS: Data were analyzed from the 2012 National Health and Wellness Survey in Brazil (n = 12,000), an Internet-based survey of adults (aged 18+ years), using stratified sampling by sex and age to ensure demographic representation of Brazil's adult population. Caregivers of individuals with Alzheimer's disease or dementia were compared with non-caregivers on comorbidities, productivity impairment, health-related quality of life, resource utilization, sociodemographic/health characteristics and behaviors, and Charlson comorbidity index scores. Regression models assessed outcomes associated with caregiving, adjusting for potential confounds. RESULTS: Among 10,853 respondents, caregivers' (n = 209) average age was 42.1 years, 53% were female, and 52% were married/living with a partner. Caregivers versus non-caregivers (n = 10,644) were more frequently obese, smokers, insured, employed, college-educated, and wealthier and had higher Charlson comorbidity index, all p < 0.05. Adjusting for covariates, caregiving was associated with significantly increased risk of depressive symptoms (odds ratio [OR] = 2.008), major depressive disorder (OR = 1.483), anxiety (OR = 1.714), insomnia (OR = 1.644), hypertension (OR = 1.584), pain (OR = 1.704), and diabetes (OR = 2.103), all p < 0.015. Caregiving was also associated with lower health utilities (-0.024 points) and mental health status (-1.70 points), higher rates of presenteeism-related impairment (32.7% greater) and overall work impairment (35.9% greater), and higher traditional provider visit rates (28.7% greater), all p < 0.035. CONCLUSIONS: Caregiver status was found to be a factor associated with worse health outcomes and psychiatric and clinical disorders.

Health-related quality of life in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in a naturalistic outpatient setting.

PURPOSE: To assess the levels of quality of life (QoL) in major depressive disorder (MDD) patients treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic clinical setting mostly in the Middle East, East Asia, and Mexico. PATIENTS AND METHODS: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 MDD patients without sexual dysfunction. QoL was measured using the EQ-5D instrument. Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16), while pain severity was measured using the pain items of the Somatic Symptom Inventory. Regression analyses were performed to compare the levels of QoL between duloxetine-treated (n=556) and SSRI-treated (n=776) patients, adjusting for baseline patient characteristics. RESULTS: These MDD patients, on average, had moderately impaired QoL at baseline, and the level of QoL impairment was similar between the duloxetine and SSRI groups (EQ-5D score of 0.46 [SD =0.32] in the former and 0.47 [SD =0.33] in the latter, P=0.066). Both descriptive and regression analyses confirmed QoL improvements in both groups during follow-up, but duloxetine-treated patients achieved higher QoL. At 24 weeks, the estimated mean EQ-5D score was 0.90 in the duloxetine cohort, which was statistically significantly higher than that of 0.83 in the SSRI cohort (P<0.001). Notably, pain severity at baseline was also statistically significantly associated with poorer QoL during follow-up (P<0.001). In addition, this association was observed in the subgroup of SSRI-treated patients (P<0.001), but not in that of duloxetine-treated patients (P=0.479). CONCLUSION: Depressed patients treated with duloxetine achieved higher QoL, compared to those treated with SSRIs, possibly in part due to its moderating effect on the link between pain and poorer QoL.

Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials.

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Should Unexplained Painful Physical Symptoms be Considered within the Spectrum of Depressive Symptoms?

OBJECTIVE: To examine whether painful physical symptoms (PPS) can be considered within the spectrum of depressive symptoms. METHODS: Data for this post-hoc analysis were taken from a 6-month observational study mostly conducted in East Asia, Mexico, and the Middle East of 1,549 depressed patients without sexual dysfunction at baseline. Both explanatory and confirmatory factor analyses (EFA and CFA) were performed on the combined items of the 16-item Quick Inventory of Depressive Symptomatology Self-Report and the Somatic Symptom Inventory (seven pain-related items only). An additional second-order CFA was also conducted to examine an association between retained factors and the overall "depressive symptoms" factor. In addition, Spearman's correlation was used to assess levels of correlation between retained factors and depression severity as well as quality of life. RESULTS: Both EFA and CFA suggested and validated a four-factor solution, which included a pain factor. The other three factors identified were a mood/cognitive factor, a sleep disturbance factor, and an appetite/weight disturbance factor. All four factors were significantly associated with the overall factor of depression. They were also highly correlated to depression severity and quality of life (p<0.001 for all). The levels of correlations with the pain factor were generally greater than those with the appetite/weight factor and similar to those with the sleep factor. CONCLUSION: It may be reasonable to consider PPS within a broad spectrum of depressive symptoms. At least, they should be routinely assessed in patients with depression. Further research is warranted to validate these preliminary findings.

Predictors of remission in the treatment of major depressive disorder: real-world evidence from a 6-month prospective observational study.

BACKGROUND: This study examined potential predictors of remission among patients treated for major depressive disorder (MDD) in a naturalistic clinical setting, mostly in the Middle East, East Asia, and Mexico. METHODS: Data for this post hoc analysis were taken from a 6-month prospective, noninterventional, observational study that involved 1,549 MDD patients without sexual dysfunction at baseline in 12 countries worldwide. Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Depression-related pain was measured using the pain-related items of the Somatic Symptom Inventory. Remission was defined as a QIDS-SR16 score ≤5. Generalized estimating equation regression models were used to examine baseline factors associated with remission during follow-up. RESULTS: Being from East Asia (odds ratio [OR] 0.48 versus Mexico; P<0.001), a higher level of depression severity at baseline (OR 0.77, P=0.003, for Clinical Global Impression of Severity; OR 0.92, P<0.001, for QIDS-SR16), more previous MDD episodes (OR 0.92, P=0.007), previous treatments/therapies for depression (OR 0.78, P=0.030), and having any significant psychiatric and medical comorbidity at baseline (OR 0.60, P<0.001) were negatively associated with remission, whereas being male (OR 1.29, P=0.026) and treatment with duloxetine (OR 2.38 versus selective serotonin reuptake inhibitors, P<0.001) were positively associated with remission. However, the association between Somatic Symptom Inventory pain scores and remission no longer appeared to be significant in this multiple regression (P=0.580), (P=0.008 in descriptive statistics), although it remained significant in a subgroup of patients treated with selective serotonin reuptake inhibitors (OR 0.97, P=0.023), but not in those treated with duloxetine (P=0.182). CONCLUSION: These findings are largely consistent with previous reports from the USA and Europe. They also highlight the potential mediating role of treatment with duloxetine on the negative relationship between depression-related pain and outcomes of depression.

Efficacy and safety of duloxetine in the treatment of older adult patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This was a flexible-dosed study to evaluate the efficacy and safety of duloxetine 30-120 mg once daily in the treatment of generalized anxiety disorder (GAD) in older adult patients. METHODS: Patients with GAD, who were at least 65 years of age, were randomly assigned to double-blind treatment with either duloxetine (N = 151) or placebo (N = 140). The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) total score, and the primary endpoint was at week 10. Global functioning was assessed by the Sheehan Disability Scale (SDS). Safety and tolerability was assessed by the occurrence of treatment-emergent adverse events, serious adverse events, laboratory analyses, and vital signs. Analyses were conducted on an intent-to-treat basis. RESULTS: The overall baseline mean HAM-A total score was 24, and SDS global score was 14. Completion rates were 75% for placebo and 76% for duloxetine. At week 10, duloxetine was superior to placebo on mean changes from baseline in HAM-A total scores (-15.9 vs. -11.7, p < 0.001) and in SDS global scores (-8.6 vs. -5.4, p < 0.001). Treatment-emergent adverse events occurred in ≥5% of duloxetine-treated patients and twice the rate than with placebo including constipation (9% vs. 4%, p = 0.06), dry mouth (7% vs. 1%, p = 0.02), and somnolence (6% vs. 2%, p = 0.14). CONCLUSION: Duloxetine treatment was efficacious in the improvement of anxiety and functioning in older adult patients with GAD, and the safety profile was consistent with previous GAD studies.

The role of descending inhibitory pathways on chronic pain modulation and clinical implications.

The treatment and management of chronic pain is a major challenge for clinicians. Chronic pain is often underdiagnosed and undertreated, and there is a lack of awareness of the pathophysiologic mechanisms that contribute to chronic pain. Chronic pain involves peripheral and central sensitization, as well as the alteration of the pain modulatory pathways. Imbalance between the descending facilitatory systems and the descending inhibitory systems is believed to be involved in chronic pain in pathological conditions. A pharmacological treatment that could restore the balance between these 2 pathways by diminishing the descending facilitatory pain pathways and enhancing the descending inhibitory pain pathways would be a valuable therapeutic option for patients with chronic pain. Due to the lack of evidence for pharmacological options that act on descending facilitation pathways, in this review we summarize the role of the descending inhibitory pain pathways in pain perception. This review will focus primarily on monoaminergic descending inhibitory pain pathways and their contribution to the mechanism of chronic pain and several pharmacological treatment options that enhance these pathways to reduce chronic pain. We describe anatomical structures and neurotransmitters of the descending inhibitory pain pathways that are activated in response to nociceptive pain and altered in response to sustained and persistent pain which leads to chronic pain in various pathological conditions.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

OBJECTIVE: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. METHOD: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. RESULTS: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. CONCLUSIONS: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

Use of antidepressants in the treatment of depression in Asia: guidelines, clinical evidence, and experience revisited.

Major depressive disorder is prevalent worldwide, and only about half of those affected will experience no further episodes or symptoms. Additionally, depressive symptoms can be challenging to identify, with many patients going undiagnosed despite a wide variety of available treatment options. Antidepressants are the cornerstone of depression treatment; however, a large number of factors must be considered in selecting the treatment best suited to the individual. To help support physicians in this process, international and national treatment guidelines have been developed. This review evaluates the current use of antidepressant treatment for major depressive disorder in six Asian countries (China, Korea, Malaysia, Philippines, Taiwan, and Thailand). No remarkable differences were noted between Asian and international treatment guidelines or among those from within Asia as these are adapted from western guidelines, although there were some local variations. Importantly, a shortage of evidence-based information at a country level is the primary problem in developing guidelines appropriate for Asia, so most of the guidelines are consensus opinions derived from western research data utilized in western guidelines. Treatment guidelines need to evolve from being consensus based to evidence based when evidence is available, taking into consideration cost/effectiveness or cost/benefit with an evidence-based approach that more accurately reflects clinical experience as well as the attributes of each antidepressant. In everyday practice, physicians must tailor their treatment to the patient's clinical needs while considering associated external factors; better tools are needed to help them reach the best possible prescribing decisions which are of maximum benefit to patients.

A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability.

OBJECTIVE: The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability. METHODS: Literature databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms. RESULTS: Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events. CONCLUSIONS: Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success.