Clinical Relevance of Skin Pain in Atopic Dermatitis.

Skin pain is increasingly recognized as an impactful symptom in atopic dermatitis (AD) because of its association with patient discomfort, disease burden, and reduced quality of life. Although the nature of skin pain in AD has not been systematically studied and is therefore not well understood, patients report soreness, discomfort, and tenderness that may reflect peripheral and central pain sensitization. The high prevalence of skin pain suggests that it is not adequately addressed by current therapies for AD and may be undertreated compared with other symptoms. This review discusses the clinical relevance of skin pain with respect to its experience, pathophysiology, relationship with itch, and treatment implications. Recent studies suggest that skin pain presents as a neuropathic symptom independent from itch and the “itch-scratch cycle”, and poses a unique burden to patients. Recognition of the significant consequences of skin pain and discomfort should reinforce the need to assess and treat this symptom in patients with moderate-to-severe AD. J Drugs Dermatol. 2020;19(10)921-926. doi:10.36849/JDD.2020.5498.

Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis.

BACKGROUND: Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS: We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS: In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS: In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).

Impact of Ixekizumab Treatment on Depressive Symptoms and Systemic Inflammation in Patients with Moderate-to-Severe Psoriasis: An Integrated Analysis of Three Phase 3 Clinical Studies.

BACKGROUND: Depression is a common comorbidity in psoriasis, and both conditions are associated with systemic inflammation. The efficacy of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, was evaluated in patients with moderate-to-severe plaque psoriasis (psoriasis) and depressive symptoms that were at least moderately severe. METHODS: Data were integrated from 3 randomized, double-blind, controlled phase 3 trials. At baseline and week 12, depressive symptoms and inflammation were assessed by the 16-item Quick Inventory of Depressive Symptomology - Self-Report (QIDS-SR16) and by a high-sensitivity assay of serum C-reactive protein (hsCRP), respectively. A subgroup of patients with at least moderately severe depressive symptoms at baseline (QIDS-SR16 total score ≥11) was analyzed. Improvement in psoriasis was assessed by the Psoriasis Area and Severity Index (PASI). RESULTS: Approximately 10% of the overall psoriasis population had at least moderately severe depressive symptoms at baseline. At week 12, comorbid patients treated with ixekizumab had significantly greater improvements in their QIDS-SR16 total score (ixekizumab 80 mg every 2 weeks [Q2W], -7.1; ixekizumab 80 mg every 4 weeks [Q4W], -6.1) vs. placebo (-3.4) (p < 0.001, both comparisons) and higher rates of remission of depressive symptoms (ixekizumab Q2W, 45.2%; ixekizumab Q4W, 33.6%) vs. placebo (17.8%) (p ≤ 0.01, both comparisons). Patients treated with ixekizumab also had significant reductions in hsCRP and PASI compared to placebo. Etanercept treatment was not associated with significant improvements in depressive symptoms compared to placebo. CONCLUSIONS: In this comorbid population, 12 weeks of ixekizumab therapy resulted in remission of depression for approximately 40% of patients and improved systemic inflammation as indicated by hsCRP.

Long-Term, Open-Label, Safety Study of Edivoxetine 12 to 18 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment.

Long-term safety, tolerability, and efficacy of adjunctive edivoxetine hydrochloride (hereafter edivoxetine), a highly selective and potent norepinephrine reuptake inhibitor, was assessed in patients with major depressive disorder (MDD) experiencing partial response to selective serotonin reuptake inhibitor treatment. Data are from a multicenter, 54-week, open-label trial of adjunctive edivoxetine 12 to 18 mg once daily in patients with MDD who had experienced partial response by history to 6 or more weeks of current selective serotonin reuptake inhibitor therapy and who had a 17-item GRID Hamilton Rating Scale for Depression total score 16 or higher at study entry. Safety measures included discontinuation rate, treatment-emergent adverse events, serious adverse events, and vital signs. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale. Of 608 patients, 328 (54%) completed the open-label adjunctive treatment. Study discontinuation due to adverse events occurred in 17.0%, and there were 13 serious adverse events (1 death). Treatment-emergent adverse events 5% or higher were nausea, hyperhidrosis, constipation, headache, dry mouth, dizziness, vomiting, insomnia, and upper respiratory tract infection. Mean increases were observed in systolic blood pressure (range, 0.0-2.3 mm Hg), diastolic blood pressure (range, 1.9-3.3 mm Hg), and pulse (range, 5.9-8.4 beats per minute). Mean improvements on the Montgomery-Åsberg Depression Rating Scale (-17.0) were observed from baseline to week 54. The safety profile from this study provides an overview of outcomes associated with edivoxetine and norepinephrine reuptake inhibition as an adjunctive treatment in patients with MDD who were treated up to 1 year.

Validation of the geriatric anxiety inventory in a duloxetine clinical trial for elderly adults with generalized anxiety disorder.

BACKGROUND: The Generalized Anxiety Inventory (GAI) has been developed for use in the assessment of anxiety symptoms in older adults (≥ 65 years), but previous validation work has not examined the psychometric qualities of the instrument in relation to treatment. The objective of this study was to examine the performance of the GAI for its internal reliability, convergent and divergent validity, and its sensitivity to treatment. METHODS: Elderly patients with generalized anxiety disorder (GAD) participated in a 10-week double-blind study of duloxetine treatment for patients with GAD. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAMA), the Hospital Anxiety and Depression Scale (HADS) anxiety and depression subscales, and the GAI. Internal reliability of the GAI was assessed with Cronbach's α. Correlations among the HAMA, HADS, and GAI scores were analyzed to determine convergent and divergent validity. Patients were also compared on remission status using recommended cut-off scores for the GAI. RESULTS: 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) for 10 weeks acute therapy. The mean change on the GAI was significantly greater with duloxetine compared with placebo treatment (-8.36 vs. -4.96, respectively, p ≤ 0.001). The GAI demonstrated good internal consistency, good convergent and divergent validity, but suggested cut-off values for caseness with the GAI did not correspond to remission status as measured by the HAMA. CONCLUSIONS: Within an elderly patient population with GAD, the GAI demonstrated sound psychometric qualities and sensitivity to change with treatment.

The Invisible Impact of a Visible Disease: Psychosocial Impact of Alopecia Areata.

INTRODUCTION: The physical impact of alopecia areata (AA) is visible, but the psychological and social consequences and emotional burden are often underrecognized. METHODS: In this cross-sectional study, 547 participants recruited via the National Alopecia Areata Foundation completed a survey encompassing demographics; AA illness characteristics; and five patient-reported outcome measures on anxiety and depression, perceived stress, psychological illness impact, stigma, and quality of life (QoL). Differences in disease severity subgroups were assessed via analysis of variance (ANOVA) and t tests. RESULTS: Mean age was 44.6 years, and 76.6% were female. Participants with more severe hair loss tended to report longer duration of experiencing AA symptoms (P < 0.001). Overall, participants reported negative psychological impact, emotional burden, and poor QoL due to AA. Participants with 21-49% or 50-94% scalp hair loss reported greater psychological impact and poorer QoL than those with 95-100% scalp hair loss (most parameters P < 0.05). Similar results were observed for eyebrow/eyelash involvement subgroups. CONCLUSIONS: These results suggest that participants with AA experience emotional burden, negative self-perception, and stigma, but the impact of AA is not dependent solely on the amount of hair loss. Lower impact among participants with 95-100% scalp hair loss may indicate that they have adapted to living with AA.

Clinical Outcomes for Uptitration of Baricitinib Therapy in Patients With Severe Alopecia Areata: A Pooled Analysis of the BRAVE-AA1 and BRAVE-AA2 Trials.

Importance: Baricitinib is an oral selective Janus kinase 1/2 inhibitor that has achieved clinically meaningful outcomes for scalp, eyebrow, and eyelash hair regrowth in patients with severe alopecia areata (AA) at week 36 of treatment. Treatment with baricitinib, 4 mg, has resulted in higher response rates than baricitinib, 2 mg, at weeks 36 and 52. Objective: To determine the efficacy of uptitration to baricitinib, 4 mg, for 24 weeks in patients who had previously not responded to baricitinib, 2 mg (Severity of Alopecia Tool [SALT] score of >20). Design, Setting, and Participants: BRAVE-AA1 and BRAVE-AA2 are multicenter, placebo-controlled, phase 3 randomized clinical trials that were initiated on September 24, 2018, and July 8, 2019, respectively, with follow-up to 200 weeks (data cutoffs of November 11, 2021, and November 5, 2021, respectively). This pooled analysis reports long-term extension data up to week 76. At baseline, 1200 adult patients with severe AA (SALT score ≥50) were randomly assigned in a 3:2:2 ratio to receive baricitinib, 4 mg; baricitinib, 2 mg; or placebo. Patients treated with baricitinib remained on the same treatment dose until week 52. Patients were considered nonresponders to baricitinib, 2 mg, if they had a SALT score greater than 20 after 52 weeks of therapy. Main Outcomes and Measures: The proportions of patients achieving a SALT score of 20 or lower and clinician-reported outcome for eyebrow hair loss and eyelash hair loss scores of 0 or 1 (full coverage or minimal gaps) with 2-point or higher improvements from baseline (among those with baseline scores ≥2 [significant gaps to no notable hair]) were analyzed through week 76. Results: At week 52, of the 340 patients (mean [SD] age, 38.4 [12.9] years; 212 [62.4%] female) treated with baricitinib, 2 mg, 212 (62.4%) had a SALT score higher than 20 and were uptitrated to baricitinib, 4 mg. Two-thirds of these patients (142 of 212 [67.0%]) had a baseline SALT score of 95 to 100, indicating very severe AA. At week 76, 55 of the 212 patients (25.9%) had achieved a SALT score of 20 or lower. During the same period, response rates for clinician-reported outcome scores of 0 or 1 increased from 19.3% (31 of 161 patients) to 37.9% (61 of 161 patients) for eyebrows and from 24.1% (33 of 137 patients) to 40.9% (56 of 137 patients) for eyelashes. Conclusions and Relevance: In this pooled analysis of the BRAVE-AA1 and BRAVE-AA2 trials, uptitration of baricitinib, 2 mg, to baricitinib, 4 mg, in those who did not respond to the 2-mg dose resulted in meaningful improvement of response rates over the subsequent 24 weeks for scalp, eyebrow, and eyelash hair loss. Trial Registration: ClinicalTrials.gov Identifiers: NCT03570749 and NCT03899259.

Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder.

OBJECTIVE: Data from a relapse prevention study of duloxetine treatment for adults with generalized anxiety disorder (GAD) were examined to identify predictors of relapse. METHODS: Patients responding to 6 months of open-label duloxetine treatment were randomized to continuation with duloxetine or withdrawal to placebo for a 6-month double-blind continuation phase (duloxetine, N= 216; placebo, N= 213). Post hoc analyses compared time to GAD relapse during continuation phase by using predictor variables that included patient demographics, symptom severity measures (Hamilton Anxiety Scale Scores [HAMA], Hospital Anxiety and Depression Scale), functional outcomes, and visual analogue scale (VAS) pain measures. Univariate and multivariate analyses were performed using predictor variables from time of randomization into the continuation, withdrawal phase. RESULTS: Severity of anxiety symptoms, degree of functional impairment, and severity of pain at time of randomization were significantly predictive of likelihood of relapse during the continuation phase. Multivariate backwards elimination analysis of significant univariate predictors identified HAMA item one (anxious mood) ≥ 1 and severity of pain while awake (≥ 30 on VAS) as the strongest predictors of GAD relapse. CONCLUSIONS: For patients with GAD responding to open-label treatment with duloxetine, residual symptoms related to anxious mood, pain severity, and psychosocial function were associated with increased relapse risk, although the greatest risk was associated with anxious mood and increased severity of pain while awake.

Current perspectives of the roles of the central norepinephrine system in anxiety and depression.

Norepinephrine (NE) is a major monoamine neurotransmitter that has widespread effects across multiple brain areas to regulate arousal and stress responses. The underlying function of the NE cortical system is to balance vigilance/scanning behavior with focused attention on novel environmental stimuli and the state of arousal. The central NE system is involved intrinsically with the stress response system, and dysregulation within the NE system has been implicated in the pathogenesis of anxiety and depressive disorders. Central NE activity paradoxically has either anxiogenic or anxiolytic effects, depending on whether the time course of the stress is acute or chronic, whether the stress is predictable or unpredictable, and which underlying brain regions are affected. Under conditions of chronic stress, NE system activity dysregulation of the hypothalamic-pituitary-adrenal system may turn a homeostatic stress response into a pathological stress response. Data suggest that the NE interplay with the serotonin system may exert neurobiological normalization of the pathophysiological state of anxious depression. Accordingly, pharmacological interventions targeting the NE system can result in anxiolytic, rather than anxiogenic, outcomes when used to treat patients with anxiety and depression.

Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial.

The objective was to examine duloxetine 60-120 mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (>or=50% reduction in Hamilton Anxiety Rating Scale total score to or=2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P

Functional outcomes in the treatment of adults with ADHD.

OBJECTIVE: ADHD is associated with significant functional impairment in adults. The present study examined functional outcomes following 6-month double-blind treatment with either atomoxetine or placebo. METHOD: Patients were 410 adults (58.5% male) with DSM-IV-defined ADHD. They were randomly assigned to receive either atomoxetine 40 mg/day to 80 mg/day (n = 271) or placebo (n = 139). The primary functional outcome measure was the Endicott Work Productivity Scale (EWPS), and the secondary measure was the Adult ADHD Quality of Life (AAQoL). Patients were seen for four visits in 6 months. RESULTS: At 6 months, both groups had nonsignificantly different improvements in EWPS total scores. Atomoxetine-treated patients showed significantly greater improvement than placebo-treated patients on the AAQoL after controlling for baseline severity of ADHD. Both treatment groups had low 6-month study completion rates. CONCLUSION: Following 6-month treatment with atomoxetine, adults with ADHD showed significantly greater improvement in functioning on disease-specific measures of quality of life than patients treated with placebo.

Efficacy of duloxetine for the treatment of generalized anxiety disorder: implications for primary care physicians.

OBJECTIVE: This study examined the efficacy and tolerability of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of patients with generalized anxiety disorder (GAD). METHOD: Patients were ≥ 18 years old and recruited from 5 European countries, the United States, and South Africa. The study had a 9-week, multicenter, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. A total of 513 patients (mean age = 43.8 years; 67.8% female) with a DSM-IV-defined GAD diagnosis received treatment with duloxetine 60 mg/day (N = 168), duloxetine 120 mg/day (N = 170), or placebo (N = 175). The primary efficacy measure was the Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included the Sheehan Disability Scale, HAM-A psychic and somatic anxiety factor scores, and HAM-A response, remission, and sustained improvement rates. The study was conducted from July 2004 to September 2005. RESULTS: Both groups of duloxetine-treated patients demonstrated significantly greater improvements in anxiety symptom severity compared with placebo-treated patients as measured by HAM-A total score and HAM-A psychic and somatic anxiety factor scores (p values ranged from ≤ .01 to ≤ .001). Duloxetine-treated patients had greater functional improvements in Sheehan Disability Scale global and specific domain scores (p ≤ .001) than placebo-treated patients. Both duloxetine doses also resulted in significantly greater HAM-A response, remission, and sustained improvement rates compared with placebo (p values ranged from ≤ .01 to ≤ .001). The rate of study discontinuation due to adverse events was 11.3% for duloxetine 60 mg and 15.3% for duloxetine 120 mg versus 2.3% for placebo (p ≤ .001). CONCLUSION: The results of this study demonstrate that duloxetine 60 mg/day and 120 mg/day were efficacious and well tolerated and thus may provide primary care physicians with a useful pharmacologic intervention for GAD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00122824.

Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

OBJECTIVE: Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. METHOD: Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. RESULTS: Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). CONCLUSIONS: Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. TRIALS REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340.

Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) appear to be an effective class of medications for the treatment of generalized anxiety disorder. Within the SSRI class, however, there have been no comparative treatment studies for this disorder. Therefore, in the present study, we compared the efficacy and tolerability of 2 SSRIs, paroxetine and sertraline, in the treatment of generalized anxiety disorder. METHOD: In this parallel-group, double-blind, flexible-dose study, 55 patients with primary generalized anxiety disorder (DSM-IV criteria) were randomly assigned to receive either paroxetine or sertraline treatment for 8 weeks. Primary efficacy measures were the mean changes in Hamilton Rating Scale for Anxiety (HAM-A) scores as well as responder and remission rates based on the Clinical Global Impressions scale. Secondary efficacy measures consisted of the Indiana University Generalized Anxiety Measurement Scale and self-report ratings of anxiety, and quality-of-life outcome. Tolerability was assessed using the Systematic Assessment for Treatment Emergent Events questionnaire for treatment-emergent symptoms. RESULTS: The intent-to-treat sample consisted of 53 patients who received medication for at least 1 week. Of the 53 patients, 43 completed the entire 8 weeks of treatment. Both paroxetine and sertraline resulted in significant decreases in mean HAM-A scores (paroxetine = 57% +/- 28%; sertraline = 56% +/- 28%). There were no differences between medication groups on response or remission rates, and tolerability was comparable. CONCLUSIONS: Both paroxetine and sertraline appear similarly effective and well tolerated for the treatment of generalized anxiety disorder.

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary.

OBJECTIVE: Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS). DESIGN: A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials. SETTING: Placebo-controlled, active-comparator, short- and long-term studies were reviewed. PARTICIPANTS: Adult (≥18 years) patients with MDD. MEASUREMENTS: Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures. RESULTS: Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p≤0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite. CONCLUSION: These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.

Duloxetine versus placebo in the treatment of patients with generalized anxiety disorder in China.

BACKGROUND: Duloxetine is approved for the treatment of generalized anxiety disorder (GAD) in the United States and elsewhere. This study aimed to assess the efficacy, tolerability, and safety of duloxetine in Chinese patients with GAD. METHODS: This 9-site study consisted of double-blind treatment for 15 weeks either with duloxetine 60 - 120 mg or with placebo. Patients with at least moderately severe GAD and a Sheehan Disability Scale (SDS) global functioning impairment total score ≥ 12 were included in this study. Patients who were randomly assigned to duloxetine received 60 mg for 7 weeks; at that point, for nonresponders the dose was increased to 120 mg for the remaining 8 weeks. The primary efficacy measure was mean change from baseline to endpoint on the Hospital Anxiety and Depression Scale-Anxiety subscale score (HADS-A). Secondary efficacy measures included the Hamilton Anxiety Rating Scale (HAMA), the SDS, and pain measures. Safety and tolerability were assessed. RESULTS: Baseline characteristics did not differ significantly between treatment groups. Mean age of the subjects (n = 210) was 37.6 years, 50.5% were female, and 74.3% completed the 15 weeks treatment. Patients treated with duloxetine had significantly greater improvement compared to placebo on the HADS-A (mean change -6.6 vs. -4.9, respectively, P = 0.022). Improvement in anxiety was greater with duloxetine treatment at 7 weeks and continued through 15 weeks for both the HADS-A and the HAMA total score (0.01 ≤ P < 0.05). Compared with placebo, duloxetine was also associated with greater improvement on most secondary measures, but not on the SDS global functioning score. Nausea, dizziness, and somnolence occurred significantly more frequently as treatment-emergent adverse events with duloxetine treatment compared with placebo treatment. CONCLUSIONS: Duloxetine 60 - 120 mg once daily is effective and well-tolerated for the treatment of patients with GAD in China.

Efficacy of duloxetine on painful physical symptoms in major depressive disorder for patients with clinically significant painful physical symptoms at baseline: a meta-analysis of 11 double-blind, placebo-controlled clinical trials.

OBJECTIVE: To review efficacy of duloxetine for physical symptoms and depressive illness in patients with at least mild to moderate major depressive disorder (MDD; DSM-IV) and clinically significant painful physical symptoms at baseline. DATA SOURCES: Global database of duloxetine clinical trials (Eli Lilly and Company). STUDY SELECTION: All 11 acute, double-blind, placebo-controlled studies of duloxetine (7 with duloxetine 60-mg doses and 4 with non-60-mg doses) in the database that used a scale to measure painful physical symptoms and were completed before March 17, 2011. DATA EXTRACTION: For each study, patients with clinically significant pain levels at baseline (Visual Analog Scale overall pain rating ≥ 30, Numerical Rating Scale score ≥ 3, or Brief Pain Inventory 24-hour average pain rating ≥ 3) were selected in order to determine the effect sizes of duloxetine (compared with placebo for each trial) on the pain and depression measures. Overall effect sizes for both painful physical symptoms and MDD were obtained from the mean of individual-trial effect sizes, and each effect size was weighted relative to the number of patients within each study. DATA SYNTHESIS: The overall mean effect sizes were as follows: painful physical symptoms-60-mg trials, 0.29 (95% CI, 0.06 to 0.52); non-60-mg trials, 0.13 (95% CI, -0.19 to 0.45); MDD-60-mg trials, 0.29 (95% CI, 0.18 to 0.40); non-60-mg trials, 0.16 (95% CI, 0.00 to 0.32). Across the 11 studies, the weighted effect size for painful physical symptoms was 0.26 (95% CI, 0.00 to 0.51) and for MDD, 0.25 (95% CI, 0.16 to 0.34). CONCLUSIONS: According to this meta-analysis, duloxetine 60 mg once daily is as effective in improving painful physical symptoms as it is for depression in patients with MDD and clinically significant painful physical symptoms. The results of this meta-analysis indicate that duloxetine has small effect sizes in reducing painful physical symptoms and depressive symptoms in patients with MDD and clinically significant pain levels at baseline. Thus, the results of the study permit one to conclude that duloxetine has a clinically significant impact on painful physical symptoms and in reducing the severity of depressive symptoms. However, the results do not address its efficacy compared to other alternatives, as in all studies the comparator was placebo.

Safety and tolerability of atomoxetine over 3 to 4 years in children and adolescents with ADHD.

OBJECTIVE: To assess the long-term safety and tolerability of atomoxetine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder treated for > or = 3 years. METHOD: Data from 13 double-blind, placebo-controlled trials and 3 open-label extension studies were pooled. Outcome measures were patient-reported treatment-emergent adverse events (AEs); discontinuations due to AEs, serious AEs, and changes in body weight, height, vital signs, electrocardiogram, and hepatic function tests. RESULTS: In total, 714 patients were treated with atomoxetine for > or = 3 years (mean follow-up 4.8 years [SD 1.1 years]), including a subset of 508 treated for > or = 4 years (mean follow-up 5.3 years [SD 0.8 years]). Most subjects were younger than 12 years at entry (73.8%), male (78.4%), and white (88.9%). The mean final daily dose of atomoxetine was 1.35 mg/kg (SD 0.37 mg/kg). No new or unexpected AEs were observed compared with acute-phase treatment. Less than 6% of patients exhibited aggressive/hostile behaviors, and less than 1.6% reported suicidal ideation/behavior. No clinically significant effects were seen on growth rate, vital signs, or electrocardiographic parameters, and < or = 2% of patients showed potentially clinically significant hepatic changes. CONCLUSION: Atomoxetine was safe and well tolerated for children and adolescents with > or = 3 and/or > or = 4 years of treatment.