Efficacy and safety of lemborexant in midlife women with insomnia disorder.

OBJECTIVE: Insomnia is common in midlife women. The efficacy and safety of lemborexant (LEM), a competitive dual orexin receptor antagonist, was assessed for 12 months in a subgroup of midlife women (age, 40-58 y) from Study E2006-G000-303 (Study 303; SUNRISE-2). METHODS: This was a randomized, double-blind, placebo (PBO)-controlled (first 6 mo) study of adults with insomnia disorder ( N = 949). During treatment period 1 (TP1), participants received PBO or LEM 5 mg (LEM5) or 10 mg (LEM10). During TP2 (second 6 mo), LEM participants continued their assigned dose; PBO participants were rerandomized to LEM5 or LEM10. Assessments included patient-reported sleep- and fatigue-related measures and treatment-emergent adverse events. RESULTS: The midlife female subgroup comprised 280 of 949 participants (TP1: PBO, n = 90 of 318 [28.3%]; LEM5, n = 82 of 316 [25.9%]; LEM10, n = 108 of 315 [34.3%]). At 6 months, median changes from baseline in subjective sleep-onset latency (in minutes) were -17.9, -20.7, and - 30.4 for PBO, LEM5, and LEM10 (vs PBO: LEM5, P = not significant; LEM10, P = 0.0310). At 6 months, mean changes from baseline in subjective wake after sleep onset (in minutes) were -37.0 (59.6), -50.1 (74.5), and -54.5 (65.4) for PBO, LEM5, and LEM10 (vs PBO: LEM5 and LEM10, P = not significant), with benefits sustained through 12 months. Greater decreases from baseline (improvement) in Insomnia Severity Index total score and Fatigue Severity Scale total score were seen with LEM versus PBO at 6 months; benefits continued through 12 months. Most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS: Consistent with the total population, subjective sleep parameters improved, and improvement was sustained over time in midlife women. LEM was well tolerated, suggesting that LEM may be a potential treatment option for midlife women with insomnia.

Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder.

OBJECTIVE/BACKGROUND: Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant. PATIENTS/METHODS: This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores. RESULTS: Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (-7.1, -7.2, -5.2, respectively), 3 (-8.6, -8.9, -6.1, respectively), and 6 (-9.9, -9.8, -7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (-11.1 and -11.2, respectively) and 12 (-11.5 and -11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (≥7-point ISI score decrease from baseline) were observed with LEM5 (44%-57%) and LEM10 (44%-52%) versus placebo (30%-41%). At months 1, 3, and 6, more remitters (ISI total score <10 and < 8) were observed with LEM5 (30%-44% and 22%-34%, respectively) and LEM10 (31%-41% and 22%-31%, respectively) versus placebo (18%-28% and 11%-21%, respectively). CONCLUSIONS: Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

Impact of sertraline daily treatment regimen on adherence, persistence and healthcare resource utilisation in patients with major depressive disorder or obsessive-compulsive disorder: A real-world evidence analysis from the United States.

OBJECTIVE: To generate real-world evidence (RWE) from the United States to assess the impact of pill burden and the importance of achieving a stable daily dose of sertraline (time taken, number of dose adjustments needed) on adherence/persistence and healthcare resource utilisation (HCRU). METHODS: Retrospective analysis of the PharMetrics® Plus database (1 October 2012 to 31 March 2020) in the United States. Eligible patients had major depressive disorder (MDD) or obsessive-compulsive disorder (OCD) and ≥1 claim for sertraline during index period (1 April 2013 to 31 March 2019, allowing 6-months prior, 1-year post-index follow-up). Patients who achieved stable daily dose of sertraline (>90 days on same dose) were categorised into five cohorts, depending on pill burden/daily dose: Cohort (1): 1 × 50 mg/d; Cohort (2): 1 × 100 mg/d; Cohort (3): 2 × 50 mg/d; Cohort (4): 1.5 × 100 mg/d; Cohort (5): 3 × 50 mg/d. Impact of pill burden on adherence/persistence and HCRU was assessed among cohorts using logistic regression analysis, and between patients who did vs did not stabilise on therapy. P < .05 was considered significant for all analyses. RESULTS: Of 224 412 eligible patients, 108 729 stabilised on sertraline (50, 100 or 150 mg/d) and formed Cohorts 1-5. Stabilised patients on lower pill burden had statistically higher adherence and were more likely to remain persistent throughout 1-year post-index period vs patients on higher pill burden but same overall dose (100 mg/d [Cohort 2 vs 3] and 150 mg/d [Cohort 4 vs 5], respectively). Patients who did not stabilise had significantly lower adherence/persistence vs patients who achieved stable daily dose (Cohorts 1-5 combined). Persistence improved when stable daily dose was achieved quickly (within 1-4 months) and efficiently (within 1-3 dose adjustments). Probability of HCRU increased for patients who did not stabilise on their initial prescription. CONCLUSION: Simplifying treatment regimen and decreasing pill burden improved adherence and/or persistence with sertraline therapy (100 or 150 mg/d). Patients achieving stable daily dose of sertraline in an efficient and timely manner were more likely to remain persistent throughout 1-year follow-up.

Economic and Humanistic Burden Associated with Depression and Anxiety Among Adults with Non-Communicable Chronic Diseases (NCCDs) in the United States.

INTRODUCTION: Patients with both major depressive disorder (MDD) and generalized anxiety disorder (GAD) in addition to one or multiple comorbid non-communicable chronic diseases (NCCDs) face unique challenges. However, few studies have characterized how the burden of co-occurring MDD and GAD differs from that of only MDD or only GAD among patients with NCCDs. METHODS: In this study, we used Medical Expenditures Panel Survey data from 2010-2017 to understand how the economic and humanistic burden of co-occurring MDD and GAD differs from that of MDD or GAD alone among patients with NCCDs. We used generalized linear models to investigate this relationship and controlled for patient sociodemographics and clinical characteristics. RESULTS: Co-occurring MDD and GAD was associated with increases in mean annual per patient inpatient visits, office visits, emergency department visits, annual drug costs, and total medical costs. Among patients with 3+ NCCDs, MDD or GAD only was associated with lower odds ratios (ORs) of limitations in activities of daily living (ADLs; 0.532 and 0.508, respectively) and social (0.503, 0.526) and physical limitations (0.613, 0.613) compared to co-occurring MDD and GAD. Compared to patients with co-occurring MDD and GAD, having MDD only or GAD only was associated with significantly lower odds of cognitive limitations (0.659 and 0.461, respectively) in patients with 1-2 NCCDs and patients with 3+ NCCDs (0.511, 0.416). DISCUSSION: Comorbid MDD and GAD was associated with higher economic burden, lower quality of life, and greater limitations in daily living compared to MDD or GAD alone. Health-related economic and humanistic burden increased with number of NCCDs.

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

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

Economic and humanistic burden associated with noncommunicable diseases among adults with depression and anxiety in the United States.

Aims: This study estimated the economic and humanistic burden associated with chronic non-communicable diseases (NCCDs) among adults with comorbid major depressive and/or any anxiety disorders (MDD and/or AAD).Materials and methods: A retrospective analysis was conducted using the Medical Expenditure Panel Survey data (2010-2015). The analytic cohort included adults (≥18 years) with MDD only (C1), AAD only (C2), or both (C3). The presence of either of 6 NCCDs (cardiovascular diseases [CVD], pulmonary disorders [PD], pain, high cholesterol, diabetes, and obesity) were assessed. Study outcomes included healthcare costs, activity limitations, and quality of life. Multivariate regressions were conducted in each of the 3 cohorts to evaluate the association between the presence of NCCDs and outcomes.Results: The analytic sample included 9,160,465 patients: C1 (4,391,738), C2 (3,648,436), C3 (1,120,292). Pain (59%) was the most common condition, followed by CVD (55%), high cholesterol (50%), obesity (42%), PD (17%), and diabetes (14%). Mean annual healthcare costs were the greatest for C3 ($14,317), followed by C1 ($10,490) and C2 ($7,906). For C1, CVD was associated with the highest increment in annual costs ($3,966) followed by pain ($3,617). For C2, diabetes was associated with the highest incremental annual costs ($4,281) followed by PD ($2,997). For C3, cost trends were similar to those seen in C2. NCCDs resulted in a significant decrease in physical quality of life across all cohorts. Pain was associated with a significantly higher likelihood of self-reported physical, social, cognitive, and activity limitations compared to those without pain.Conclusions: 60% of patients with MDD and/or AAD had at least one additional NCCD, which significantly increased the economic and humanistic burden. These findings are important for payers and clinicians in making treatment decisions. These results underscore the need for development of multi-pronged interventions which aim to improve quality of life and reduce activity limitations among patients with mental health disorders and NCCDs.

Economic burden associated with inadequate antidepressant medication management among patients with depression and known cardiovascular diseases: insights from a United States-based retrospective claims database analysis.

Aims: The current study examined the association between insufficient major depressive disorder (MDD) care and healthcare resource use (HCRU) and costs among patients with prior myocardial infarction (MI) or stroke.Methods: This was a retrospective study conducted using the MarketScan Claims Database (2010-2015). The date of the first MI/stroke diagnosis was defined as the cardiovascular disease (CVD) index date and the first date of a subsequent MDD diagnosis was the index MDD date. Adequacy of MDD care was assessed during the 90 days following the index MDD date (profiling period) using 2 measures: dosage adequacy (average fluoxetine equivalent dose of ≥20 mg/day for nonelderly and ≥10 mg/day for elderly patients) and duration adequacy (measured as the proportion of days covered of 80% or higher for all MDD drugs). Study outcomes included all-cause and CVD-related HCRU and costs which were determined from the end of the profiling period until the end of study follow-up. Propensity-score adjusted generalized linear models (GLMs) were used to compare patients receiving adequate versus inadequate MDD care in terms of study outcomes.Results: Of 1,568 CVD patients who were treated for MDD, 937 (59.8%) were categorized as receiving inadequate MDD care. Results from the GLMs suggested that patients receiving inadequate MDD care had 14% more all-cause hospitalizations, 4% more all-cause outpatient visits, 17% more CVD-related outpatient visits, 13% more CVD-related emergency room (ER) visits, higher per patient per year CVD-related hospitalization costs ($21,485 vs. $17,756), higher all-cause outpatient costs ($2,820 vs. $2,055), and higher CVD-related outpatient costs ($520 vs. $434) compared to patients receiving adequate MDD care.Limitations: Clinical information such as depression severity and frailty, which are potential predictors of adverse CVD outcomes, could not be ascertained using administrative claims data.Conclusions: Among post-MI and post-stroke patients, inadequate MDD care was associated with a significantly higher economic burden.

Healthcare resource use and cost associated with timing of pharmacological treatment for major depressive disorder in the United States: a real-world study.

Background: Guidelines recommend selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) as first-line treatments for major depressive disorder (MDD) and emphasize the importance of early pharmacological treatment as key factors to treatment success.Objectives: To compare the MDD-related healthcare resource utilization (HCRU) and cost among patients (1) with early vs late pharmacological treatment initiation and (2) achieving minimum therapeutic dose (MTD) early vs late.Methods: The MarketScan database (2010-2015) was used. Adults who were newly-treated with SSRI/SNRI within 12 months after the initial MDD diagnosis (index) were included. Patients who initiated SSRI/SNRI within 2 weeks of the index date were defined as early initiators; those who reached MTD within 4 weeks of index date were defined as early MTD achievers. MDD-related HCRU and costs per year after the index date were compared between early and late initiators and between early and late achievers using propensity score matching and generalized linear models.Results: Of the 55,539 patients, 60% were early initiators and 61% were early MTD achievers. The mean number of MDD-related outpatient visits per year were significantly higher for late initiator (6.7 vs 4.2, p < .001) and late MTD achievers (6.5 vs 4.5, p < .001) vs their early counterparts. Mean annual MDD-related outpatient, drug, and total cost were significantly higher for late initiators and MTD achievers vs the early groups.Conclusions: There is an opportunity to improve outcomes by treating MDD patients with SSRI/SNRI within 2 weeks and at or above the MTD within 4 weeks of diagnosis or less.

Cardiovascular hazards of insufficient treatment of depression among patients with known cardiovascular disease: a propensity score adjusted analysis.

Aims: The association between depression care adequacy and the risk of subsequent adverse cardiovascular disease (CVD) outcomes among patients with a previous diagnosis of myocardial infarction (MI) or stroke is not well defined. Methods and results: This retrospective cohort study used commercial claims data (2010-2015) and included adults with newly diagnosed and treated major depressive disorder (MDD) following an initial MI or stroke diagnosis. Depression care adequacy was assessed during the 3-month period following the MDD diagnosis index date using two measures: antidepressant dosage adequacy and duration adequacy. Cox models adjusted for the propensity of receiving adequate depression care were used to compare the risk of a composite CVD outcome (MI, stroke, congestive heart failure, and angina) as well as each individual CVD event between patients receiving adequate vs. inadequate depression care. A total of 1568 patients were included in the final cohort. Of these, 937 (59.8%) were categorized as receiving inadequate depression care based on at least one of the two treatment adequacy criteria. Propensity score adjusted Cox models showed that depression care inadequacy was associated with a significantly higher risk of the composite CVD endpoint [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04-1.39], stroke (HR 1.20, 95% CI 1.02-1.42), and angina (HR 1.95, 95% CI 1.21-3.16) with no significant interaction based on cohort included (MI vs. stroke) or the definition of inadequate depression (dose vs. duration inadequacy) (Pinteraction > 0.05). Conclusion: Inadequate MDD care was associated with a higher risk of adverse CVD events. These findings reveal a significant unmet clinical need in patients with post-MI or post-stroke MDD that may impact CVD outcomes.

Speed of Improvement in Symptoms of Depression With Desvenlafaxine 50 mg and 100 mg Compared With Placebo in Patients With Major Depressive Disorder.

PURPOSE/BACKGROUND: This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo. METHODS: Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests. RESULTS: In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD. IMPLICATIONS/CONCLUSIONS: These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.

Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: A pooled analysis.

Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder ( n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D17) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D17 psychomotor retardation factor, and Montgomery-Åsberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p⩽0.005). Both early improvement in HAM-D17 psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p⩽0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D17 psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement.

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

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

Restoring function in major depressive disorder: A systematic review.

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

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

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

Analysis of treatment patterns and persistence on branded and generic medications in major depressive disorder using retrospective claims data.

BACKGROUND: In major depressive disorder (MDD), treatment persistence is critical to optimize symptom remission, functional recovery, and health care costs. Desvenlafaxine tends to have fewer drug interactions and better tolerability than other MDD drugs; however, its use has not been assessed in the real world. OBJECTIVE: The aim of the present study is to compare medication persistence and concomitant MDD drug use with branded desvenlafaxine (Pristiq®) compared with antidepressant drug groups classified as 1) branded selective serotonin reuptake inhibitors (SSRIs; ie, escitalopram [Lexapro™]) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs; ie, venlafaxine [Effexor®], duloxetine [Cymbalta®]) and 2) generic SSRIs/SNRIs (ie, escitalopram, citalopram, venlafaxine, fluvoxamine, fluoxetine, sertraline, paroxetine, and duloxetine). PATIENTS AND METHODS: MDD patients (ICD-9-CM codes 296.2, 296.3), with ≥2 prescription fills for study drugs and 12-month preindex continuous enrollment from the MarketScan Commercial Claims and Encounters Database (2009-2013), were included. Time-to-treatment discontinuation (prescription gap ≥45 days) was assessed using the Kaplan-Meier curve and Cox model. Concomitant MDD drug use was compared. RESULTS: Of the 273,514 patients included, 14,379 patients were initiated with branded desvenlafaxine, 50,937 patients with other branded SSRIs/SNRIs, and 208,198 patients with generic SSRIs/SNRIs. The number of weeks for treatment discontinuation for branded desvenlafaxine were longer (40.7 [95% CI: 39.3, 42.0]) compared with other branded SSRIs/SNRIs (28.9 [95% CI: 28.4, 29.1]) and generic SSRIs/SNRIs (33.4 [95% CI: 33.1, 33.7]). Adjusting for baseline characteristics, patients who were prescribed with other branded SSRIs/SNRIs were 31% and generic SSRIs/SNRIs were 11% more likely to discontinue treatment compared with branded desvenlafaxine. In sensitivity analysis, the risk of discontinuation was within 10% of branded desvenlafaxine for branded duloxetine, generic escitalopram, and generic venlafaxine. Concomitant MDD drug use was higher among branded desvenlafaxine patients (43.8%) compared with other branded SSRIs/SNRIs (39.8%) and generic SSRIs/SNRIs (36.4%). CONCLUSION: MDD patients on branded desvenlafaxine were more persistent with treatment compared with those on other branded or generic SSRI/SNRI therapies. Future research should include assessments of underlying factors on the treatment persistence in MDD patients.

Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder.

OBJECTIVE: The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder. METHODS: Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings. RESULTS: In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms. CONCLUSION: These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile. CLINICAL TRIALS REGISTRY: NCT00257166 and NCT00265330 at ClinicalTrials.gov.

Ziprasidone in adolescents with schizophrenia: results from a placebo-controlled efficacy and long-term open-extension study.

OBJECTIVE: The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia. METHODS: Subjects ages 13-17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings. RESULTS: Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 [0.78] for ziprasidone and -12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥ 10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥ 500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures. CONCLUSIONS: Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile. CLINICAL TRIALS REGISTRY: NCT00257192 and NCT00265382 at ClinicalTrials.gov .

Risk for adverse events and discontinuation due to adverse events of ziprasidone monotherapy relative to placebo in the acute treatment of bipolar depression, mania, and schizophrenia.

OBJECTIVE: This study aimed to examine the risk difference (RD) in the discontinuation due to adverse events, akathisia, overall extrapyramidal symptoms (EPS), reported-somnolence, and 7% or greater weight gain between ziprasidone monotherapy and placebo in the acute treatment of bipolar depression (BPD), bipolar mania (BPM), and schizophrenia. METHODS: Pooled data from 9 randomized, double-blind, placebo-controlled, acute studies of ziprasidone in BPD, BPM, and schizophrenia were used. The number needed to treat to harm (NNTH) of ziprasidone relative to placebo was estimated when an RD was statistically significant. RESULTS: The RD in discontinuation due to adverse events or 7% or greater weight gain between ziprasidone and placebo was not significant in all 3 psychiatric conditions. The risk for akathisia with ziprasidone was significantly higher in BPD with an RD of 2.3% (NNTH = 44) and in BPM with an RD of 8.4% (NNTH = 12). Risk for overall EPS with ziprasidone was significantly higher in BPM with an RD of 8.7% (NNTH = 12) and schizophrenia with an RD of 3.3% (NNTH = 30). Risk of reported-somnolence with ziprasidone was also significantly higher in BPD with an RD of 11.8% (NNTH = 8), BPM with an RD of 14.3% (NNTH = 7), and schizophrenia with an RD of 7% (NNTH = 14). Dose-dependent increase in the risk for reported somnolence with ziprasidone was observed in BPD and schizophrenia. CONCLUSIONS: Ziprasidone was associated with significant differential adverse effects relative to placebo in BPM, BPD, and schizophrenia with no significant difference in weight gain in all 3 groups. Self-reported somnolence was increased across the 3 conditions. Subjects with BPM were more vulnerable to EPS than those with BPD or schizophrenia.

Early prediction of clinical and functional outcome in schizophrenia.

UNLABELLED: The objective of this paper was to investigate the prognostic and predictive value of a small panel of independent and clinically important factors based on symptom improvement, baseline cognitive impairment, and weight change during the early treatment phase. METHODS: The study sample was based on a double-blind, 6-month continuation study of ziprasidone and olanzapine (N=94). We developed a parsimonious 6-month GAF prediction function using a logistic regression model, and evaluated its predictive accuracy and performance using bootstrap estimates of c-statistics and error in predicted probability. RESULTS: At up to 6 months of follow-up, 52 (55%) of all subjects treated with ziprasidone or olanzapine met the responder criterion of ≥50% improvement in GAF. At Week 2 (acute phase), the majority of ziprasidone (75%) and olanzapine (70%) patients showed greater than 25% improvement in the BPRS psychotic symptom subscale score. These early psychotic symptom responders (Week 2) showed significantly greater improvement in global functioning than early non-responders at all time points (Week 6 and Month 6) (all p's<0.05), confirming early response as an indicator of continued responsiveness to treatment over at least 6 months. A multivariate prediction function based on baseline neurocognitive scores and GAF, early reduction of psychotic symptoms at 2 weeks, and percentage of weight change observed at 6 weeks (All p's <0.05), showed statistically acceptable predictive performance (boostrap c-statistics=0.8598). CONCLUSIONS: Our findings suggest that a parsimonious model incorporating a psychotic symptom assessment score, baseline neurocognitive performance, and risk of weight gain can be developed for predicting patients' likelihood of achieving favorable, long-term treatment outcomes.

Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia Trial.

Available data on antipsychotic-induced metabolic risks are often constrained by potential confounding effects due to prior antipsychotic treatment. In this study, we assessed the baseline prevalence of metabolic abnormalities and changes following treatment with five commonly-used antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine or ziprasidone) in first-episode, partially antipsychotic-naive patients with schizophrenia in the European first-episode schizophrenia trial (EUFEST). Overall baseline prevalence of metabolic syndrome (MetS) was 6.0%, with similar rates observed in the antipsychotic-naive patients (5.7%, 9/157) and in the other patients with only a brief prior exposure to antipsychotics (6.1%, 20/326). These results are consistent with the MetS prevalence rate estimated in a general population of similar age. Examination of individual risk factors showed 58.5% of subjects had one or more elevated metabolic risks at baseline: 28.5% demonstrated suboptimal HDL; 24.2% hypertension; 17.7% hypertriglyceridemia; 8.2% abdominal obesity; 7.3% hyperglycaemia. Increase in body weight (kg/month) occurred in patients treated with haloperidol (0.62 S.E. 0.11), amisulpride (0.76 S.E. 0.08), olanzapine (0.98 S.E. 0.07) and quetiapine (0.58 S.E. 0.09), which was significantly greater than that in the ziprasidone group (0.18 S.E. 0.10). The incidence rate of new diabetes cases over a 52-wk follow-up period was 0.82% (4/488). More patients experienced worsening rather than improvement of hypertriglyceridemia or hyperglycaemia in all treatment groups. Our findings suggest that in first-episode, partially antipsychotic-naive patients, the baseline prevalence rate of MetS appears to be no higher than that in the general population, but serious underlying individual risk factors nevertheless existed.