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Major depressive disorder (MDD) is a clinically heterogenous condition and its treatment should be individualized according to the presence of particular symptom clusters. The aim of this pooled analysis was to investigate the effects of adjunctive brexpiprazole on different symptom clusters in MDD.Data were included from four similarly designed, short-term, randomized, double-blind, placebo-controlled studies of adjunctive brexpiprazole in adults with MDD and inadequate response to 2-4 antidepressant treatments (ADTs), including 1 administered by investigators. Mean changes from baseline and Cohen's d effect sizes (ES) versus placebo were determined for the following Montgomery-Åsberg Depression Rating Scale symptom clusters: core, anhedonia, dysphoria, retardation, vegetative, loss of interest, and lassitude.Over 6 weeks, ADT + brexpiprazole 2 mg (n = 486) showed greater improvement than ADT + placebo (n = 585) for all symptom clusters: core (ES = 0.36; p 0.0001), anhedonia (ES = 0.43; p 0.0001), dysphoria (ES = 0.27; p 0.0001), retardation (ES = 0.32; p 0.0001), vegetative (ES = 0.29; p 0.0001), loss of interest (ES = 0.30; p 0.0001), and lassitude (ES = 0.33; p 0.0001). Improvements of similar magnitude were observed for ADT + brexpiprazole 2-3 mg (n = 770) versus ADT + placebo (n = 788) (ES = 0.24-0.38; all clusters p 0.0001). In most cases, improvement over ADT + placebo was observed from Week 1 onwards.Post hoc analysis with no adjunctive active comparator.Patients receiving adjunctive brexpiprazole versus adjunctive placebo showed improvements across a range of MDD symptom clusters. Improvements appeared early (generally from Week 1) and were maintained over 6 weeks. These data indicate that adjunctive brexpiprazole may benefit multiple subtypes of patient with MDD and inadequate response to ADTs.

PURPOSE/BACKGROUND Heterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct trajectories of change exist for functioning during antidepressant treatment. METHODS/PROCEDURES This analysis explored distinct trajectories of functioning in MDD and tested whether they corresponded to trajectories of symptom change. Data were from 4317 patients and were pooled from 9 randomized placebo-controlled trials. Growth mixture modeling was used to identify trajectories of Hamilton Rating Scale for Depression (HRSD) and Sheehan Disability Scale (SDS) for placebo- and desvenlafaxine-treated patients. FINDINGS/RESULTS Three trajectories were identified for symptoms (HRSD) in patients receiving placebo (mean reduction baseline to week 8, -18.4 [most favorable] to -2.6 points [least favorable]). Four HRSD trajectories were identified for patients receiving desvenlafaxine (mean reduction from baseline to week 8, -17.2 [most favorable] to -2.6 points [least favorable]). Four trajectories were identified for functioning (SDS) in patients receiving placebo (mean reduction baseline to week 8, -13.6 [most favorable] to -0.8 points [least favorable]), and 3 for desvenlafaxine (-12.8 to -1.4 points, respectively). Percentages of agreement between most favorable HRSD and SDS trajectories were 75% (placebo) and 85% (desvenlafaxine), and for least favorable trajectories were 88% (placebo) and 80% (desvenlafaxine). IMPLICATIONS/CONCLUSIONS Distinct trajectories of change based on symptoms and functioning were identified among patients with MDD receiving desvenlafaxine and among patients with MDD receiving placebo. Differentiating subpopulations of patients has the potential to provide a more personalized treatment of patients with MDD.ClinicalTrials.govIdentifiers: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.

Switches between branded (reference) medications and the corresponding generic medications or between two different corresponding generic medications occur commonly during the treatment of central nervous system disorders. Prescribing a generic product in place of a reference product can reduce patient and pharmacy costs. But there can be implications. Planned or unplanned switches from one product to another during ongoing treatment may introduce variability in drug exposure which could in turn compromise efficacy and/or tolerability. Studies comparing the initiation of reference versus generic products do not provide clear evidence of the superiority of reference or generic products generally, whereas several studies examining a switch between reference and generic products suggest that reductions in efficacy or medication adherence and persistence may be associated with generic substitution. Clinicians should work with patients to facilitate a consistent supply of reference or generic drug product that provides stable exposure to avoid clinical deterioration or poor tolerability.

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 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.

Objective: This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development. Methods: This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors. Results: SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety. Conclusions: Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.

Supplemental digital content is available in the text., 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.

Background: Major depressive disorder is characterized by the presence of at least five of nine specific symptoms that contribute to clinically significant functional impairment. This analysis examined the effect of desvenlafaxine (50 or 100 mg) versus placebo on symptom cluster scores and the association between early improvement in symptom clusters and symptomatic or functional remission at week 8. Methods: Using data from nine double-blind, placebo-controlled studies of desvenlafaxine for the treatment of major depressive disorder ( N=4317), the effect of desvenlafaxine 50 or 100 mg versus placebo on scores for symptom clusters based on 17-item Hamilton Rating Scale for Depression items was assessed using analysis of covariance. Association between early improvement in symptom clusters (⩾20% improvement from baseline at week 2) and symptomatic and functional remission (17-item Hamilton Rating Scale for Depression total score ⩽7; Sheehan Disability Scale score Results: Desvenlafaxine 50 or 100 mg was associated with significant improvement from baseline compared to placebo for all symptom clusters ( pConclusion: Early improvement in symptom clusters significantly predicts symptomatic or functional remission at week 8 in patients with depression receiving desvenlafaxine (50 or 100 mg) or placebo. Importantly, patients without early improvement were less likely to remit.

Background: Guidelines recommend selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) as first-line treatments for major depressive disorder (MDD) ...

Objective.The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo.Methods.Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models.Results.Functional early improvement thresholds of 17%–32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981–8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant.Conclusion.Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

The common practice of switching between branded (reference) medications and their corresponding generic products, between generic products, or even from a generic product to a branded medication during the treatment of central nervous system (CNS) disorders may compromise efficacy and/or tolerability.We assessed the published literature from March 1, 2010 through June 30, 2017 via PubMed using the MeSH term 'generics, drugs' alone and in combination with class-specific terms (e.g., 'anticonvulsants', 'mood stabilisers'), for studies detailing outcomes following product switches.Although some studies comparing the initiation of reference versus generic drugs suggest equivalence between products, several studies detailing a switch between reference and generic products describe reductions in efficacy, reduced medication adherence and persistence, and increased overall health care resource utilization and costs associated with generic substitution.When product switches are considered, they should only proceed with the full knowledge of both patient and provider.

This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels.Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history.NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups-metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median-using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis.The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p 0.05).Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population).Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.

The primary objective of this post-hoc analysis was to evaluate the effect of short-term treatment with desvenlafaxine versus placebo on sexual dysfunction (SD), assessed from Arizona Sexual Experiences Scale scores, in adult outpatients with major depressive disorder. Data from three randomized, double-blind, placebo-controlled trials of 50 or 100 mg/day desvenlafaxine for major depressive disorder were pooled. SD status, determined from Arizona Sexual Experiences Scale scores, was assessed at baseline and week 8, last observation carried forward. Subgroup analyses addressed the effects of sex, baseline SD, and antidepressant response. At week 8, last observation carried forward (n=1562), SD rates were 54, 47, and 49% for 50 mg/day desvenlafaxine, 100 mg/day desvenlafaxine, and placebo, respectively [adjusted odds ratios (95% confidence interval) vs. placebo: 1.205 (0.928, 1.564) and 1.129 (0.795, 1.604), respectively]. The treatment by baseline SD interaction approached statistical significance (P=0.0663), mainly driven by poorer scores for desvenlafaxine versus placebo in the 100 mg group. Treatment by sex interactions were not statistically significant. Small but statistically significant treatment by sex interactions were observed for sex drive (P=0.0011) and ease of erection/lubrication (P=0.0151). Although there was no overall effect of desvenlafaxine on SD, a treatment by baseline SD interaction was suggested for 100 mg desvenlafaxine.

To evaluate the effect of the serotonin-norepinephrine re-uptake inhibitor desvenlafaxine on blood pressure and incidence of new onset hypertension in pooled short-term studies and in two longer-term, randomized withdrawal studies.Data from patients randomly assigned to desvenlafaxine 10 mg to 400 mg/day or placebo in 11 short-term (8-12 weeks), fixed-dose, double-blind, placebo-controlled studies of major depressive disorder (MDD) were pooled for analysis; two desvenlafaxine randomized withdrawal studies (36 and 46 weeks) were analyzed separately.www.clinicaltrials.gov , NCT00072774, NCT00073762, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT01432457, NCT00075257, NCT00887224.Outcomes included change from baseline in supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP), assessed using a mixed model repeated measures (MMRM) analysis, and incidence of hypertension (defined as three consecutive second SDBP measures ≥90 mm Hg AND increase of ≥10 mm Hg from baseline and/or SSBP ≥140 mm Hg AND increase of ≥10 mm Hg), analyzed using Cochran Mantel Hanzael tests. Potential predictors of change in SSBP and SDBP at LOCF were examined by including predictor variables in a regression model.In the pooled, short-term studies, mean changes from baseline over time in SSBP and SDBP were statistically significant compared with placebo for the desvenlafaxine doses of 10 mg/day or greater for SSBP (p ≤ 0.0004; MMRM) and 25 mg/day or greater for SDBP (p ≤ 0.0449; MMRM). The proportion of patients with new onset hypertension differed significantly from placebo for the 50, 200, and 400 mg/day doses (1.9%, 2.4%, 4.8%, respectively, vs 0.8%; all p ≤ 0.0244). Predictors of change in BP included baseline SDBP, baseline SSBP, dose, body mass index, gender, age, race, and history of hypertension.Data were pooled from studies which differed somewhat in study design and patient demographics. None of the studies were originally designed to examine treatment effects on BP. Study entry criteria limit generalization of these results to medically stable patients with a primary diagnosis of MDD.Short-term desvenlafaxine treatment was associated with small but statistically significant increases in SSBP and SDBP.

ObjectiveThis post-hoc pooled analysis evaluated categorical change in functional impairment in patients with major depressive disorder (MDD) treated with desvenlafaxine versus placebo and examined whether early improvement in functioning predicted functional outcomes at study endpoint.MethodsData were pooled from eight randomized, double-blind, placebo-controlled studies of desvenlafaxine for the treatment of MDD, including adults who were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo (N=3,384). Shift tables were generated for categorical changes in functional impairment from baseline based on Sheehan Disability Scale (SDS) subscale scores. The categories were none/mild (0–3), moderate (4–6), and marked/extreme (7–10). Treatment comparisons for prespecified shifts of interest and predictive value of week 2 or 4 improvement in SDS subscale scores for functional outcome at week 8 were assessed using logistic regression.ResultsGreater proportions of patients receiving desvenlafaxine 50 and 100 mg achieved improvement from baseline to week 8 for each prespecified shift endpoint versus placebo (all p ≤ 0.02). Early improvement in SDS subscale scores was a statistically significant predictor of functional outcome at week 8, both overall and for each treatment group (all pConclusionsTreatment with desvenlafaxine 50 or 100 mg/d led to significantly greater categorical improvement in functional impairment versus placebo, and improvement in SDS subscale scores significantly predicted functional outcome. Monitoring patient progress early in the course of antidepressant treatment using a functional assessment such as the SDS may help clinicians determine whether or not treatment adjustments are needed.

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-Asberg 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.

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.

This post hoc meta-analysis evaluated the efficacy and safety of desvenlafaxine 50 and 100 mg versus placebo across age groups and severity of depression at baseline in patients with major depressive disorder.Data from placebo and desvenlafaxine 50-mg and 100-mg dose arms were pooled from 9 short-term, placebo-controlled, major depressive disorder studies (N = 4279). Effects of age (18-40 years,40 to55 years, 55-65 years, and ≥65 years) and baseline depression severity (mild, 17-item Hamilton Rating Scale for Depression total score [HAM-D17] ≤18; moderate, HAM-D1718 to25; severe, HAM-D17 ≥25) on desvenlafaxine efficacy were assessed using analysis of covariance for continuous end points and logistic regression for categorical end points.Desvenlafaxine-treated (50 or 100 mg/d) patients had significantly (P0.05, 2-sided) greater improvement in most measures of depression and function compared with placebo for patients 18 to 40 years, older than 40 to younger than 55 years, and 55 to younger than 65 years, with no significant evidence of an effect of age. Desvenlafaxine significantly improved most measures of depression and function in moderately and severely depressed patients. There was a significant baseline severity by treatment interaction for HAM-D17 total score only (P = 0.027), with a larger treatment effect for the severely depressed group.Desvenlafaxine significantly improved depressive symptoms in patients younger than 65 years and in patients with moderate or severe baseline depression. Sample sizes were not adequate to assess desvenlafaxine efficacy in patients 65 years or older or with mild baseline depression.

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.

Studies with sPLA(2) Group X, and cPLA(2) α gene-targeted mice suggest that absence of sPLA(2) Group X results in protection from ischemia/reperfusion (I/R) injury in the heart, and absence of cPLA(2) α Group IV is protective in the brain. Although latter studies might suggest a similar deleterious role for cPLA(2) α in I/R injury in the heart, the pathophysiology of stroke is intricately related to excitotoxicity and cannot necessarily be extrapolated to the heart. We report here that unlike findings in the brain, cPLA(2) α((-/-)) mice have exaggerated injury following I/R in vivo. In contrast, there is no difference in injury induced by simulated ischemia in cardiomyocytes isolated from cPLA(2) α((-/-)) versus cPLA(2) α((+/+)) mice. This suggests that cPLA(2) α does not have an important cardiomyocyte autonomous effect on ischemic injury. Prostaglandin E(2) (PGE(2) ) levels are significantly reduced in the hearts of the cPLA(2) α((-/-)) mice, and the enhanced injury is ameliorated by treatment with the PGE analog, misoprostol. We demonstrate that cPLA(2) α is cardioprotective in vivo, and this is likely via cPLA(2) α-mediated production of cardioprotective eicosanoids. These studies are the first to identify a protective role for cPLA(2) in I/R injury in any organ and raise concerns over long-term inhibition of cPLA(2).

Rationale: Coronary artery ligation to induce myocardial infarction (MI) in mice is typically performed by an invasive and time-consuming approach that requires ventilation and chest opening (classic method), often resulting in extensive tissue damage and high mortality. We developed a novel and rapid surgical method to induce MI that does not require ventilation. Objective: The purpose of this study was to develop and comprehensively describe this method and directly compare it to the classic method. Methods and Results: Male C57/B6 mice were grouped into 4 groups: new method MI (MI-N) or sham (S-N) and classic method MI (MI-C) or sham (S-C). In the new method, heart was manually exposed without intubation through a small incision and MI was induced. In the classic method, MI was induced through a ventilated thoracotomy. Similar groups were used in an ischemia/reperfusion injury model. This novel MI procedure is rapid, with an average procedure time of 1.22±0.05 minutes, whereas the classic method requires 23.2±0.6 minutes per procedure. Surgical mortality was 3% in MI-N and 15.9% in MI-C. The rate of arrhythmia was significantly lower in MI-N. The postsurgical levels of tumor necrosis factor-α and myeloperoxidase were lower in new method, indicating less inflammation. Overall, 28-day post-MI survival rate was 68% with MI-N and 48% with MI-C. Importantly, there was no difference in infarct size or post-MI cardiac function between the methods. Conclusions: This new rapid method of MI in mice represents a more efficient and less damaging model of myocardial ischemic injury compared with the classic method.

Recent studies have shown that insulin growth factor‐1 (IGF‐1) and either erythropoietin (EPO) or the long‐acting EPO analog Darbepoetin alfa (DA) protect the heart against ischemia/reperfusion (I/R) and myocardial infarction (MI). The present study examined the cardioprotective effect of simultaneous treatments with IGF‐1 and DA in these models of cardiac injury. Rats were subjected to I/R or MI and were treated with IGF‐1, DA, and a combination of IGF‐1 and DA, or vehicle treatment. IGF‐1 and DA treatments imparted similar protective effect by reducing infarct size. Moreover, these treatments led to improvement of cardiac function after I/R or MI compared to vehicle. In the reperfused heart, apoptosis was reduced with either or both IGF‐1 and DA treatments as measured by reduced TUNEL staining and caspase‐3 activity. In addition, after MI, treatment with IGF‐1 or DA significantly induced angiogenesis. This angiogenic effect was enhanced significantly when IGF‐1 and DA were given simultaneously compared to vehicle or either agents alone. These data indicate simultaneous pharmacological treatments with IGF‐1 and DA protect the heart against I/R and MI injuries. This protection results in reduced infarct size and improved cardiac function. Moreover, this treatment reduces apoptosis and enhances angiogenesis in the ischemic heart.

Background— A salient characteristic of dysfunctional myocardium progressing to heart failure is an upregulation of the adenylyl cyclase inhibitory guanine nucleotide (G) protein α subunit, Gα i2 . It has not been determined conclusively whether increased Gi activity in the heart is beneficial or deleterious in vivo. Gi signaling has been implicated in the mechanism of cardioprotective agents; however, no in vivo evidence exists that any of the Gα subunits are cardioprotective. We have created a novel molecular tool to specifically address the role of Gi proteins in normal and dysfunctional myocardium. Methods and Results— We have developed a class-specific Gi inhibitor peptide, GiCT, composed of the region of Gα i2 that interacts specifically with G protein–coupled receptors. GiCT inhibits Gi signals specifically in vitro and in vivo, whereas Gs and Gq signals are not affected. In vivo expression of GiCT in transgenic mice effectively causes a “functional knockout” of cardiac Gα i2 signaling. Inducible, cardiac-specific GiCT transgenic mice display a baseline phenotype consistent with nontransgenic mice. However, when subjected to ischemia/reperfusion injury, GiCT transgenic mice demonstrate a significant increase in infarct size compared with nontransgenic mice (from 36.9±2.5% to 50.9±4.3%). Mechanistically, this post-ischemia/reperfusion phenotype includes increased myocardial apoptosis and resultant decreased contractile performance. Conclusions— Overall, our results demonstrate the in vivo utility of GiCT to dissect specific mechanisms attributed to Gi signaling in stressed myocardium. Our results with GiCT indicate that upregulation of Gα i2 is an adaptive protective response after ischemia to shield myocytes from apoptosis.

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 17 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.

Heart failure (HF) is a leading cause of morbidity and mortality in Western countries and projections reveal that HF incidence in the coming years will rise significantly because of an aging population. Pharmacologic therapy has considerably improved HF treatment during the last 2 decades, but fails to rescue failing myocardium and to increase global cardiac function. Therefore, novel therapeutic approaches to target the underlying molecular defects of ventricular dysfunction and to increase the outcome of patients in HF are needed. Failing myocardium generally exhibits distinct changes in beta-adrenergic receptor (betaAR) signaling and intracellular Ca2+-handling providing opportunities for research. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies to alter myocardial function and to target both betaAR signaling and Ca2+-cycling. In this review, we will discuss functional alterations of the betaAR system and Ca2+-handling in HF as well as corresponding therapeutic strategies. We will then focus on recent in vivo gene therapy strategies using the targeted inhibition of the betaAR kinase (betaARK1 or GRK2) and the restoration of S100A1 protein expression to support the injured heart and to reverse or prevent HF.

Background— The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an ideal vector supporting safe and long-term myocardial transgene expression. Methods and Results— Here, we show that the use of a recombinant adeno-associated viral (rAAV6) vector containing a novel cardiac-selective enhancer/promoter element can direct stable cardiac expression of a therapeutic transgene, the calcium (Ca 2+ )-sensing S100A1, in a rat model of heart failure. The chronic heart failure–rescuing properties of myocardial S100A1 expression, the result of improved sarcoplasmic reticulum Ca 2+ handling, included improved contractile function and left ventricular remodeling. Adding to the clinical relevance, long-term S100A1 therapy had unique and additive beneficial effects over β-adrenergic receptor blockade, a current pharmacological heart failure treatment. Conclusions— These findings demonstrate that stable increased expression of S100A1 in the failing heart can be used for long-term reversal of LV dysfunction and remodeling. Thus, long-term, cardiac-targeted rAAV6-S100A1 gene therapy may be of potential clinical utility in human heart failure.

OBJECTIVE This post hoc analysis compared body weight, body mass index (BMI), and BMI category changes in postmenopausal women treated with conjugated estrogens/bazedoxifene (CE/BZA) versus placebo in the Selective Estrogens, Menopause, and Response to Therapy (SMART) trials. METHODS Data were pooled from five randomized, double-blind, placebo- and active-controlled studies in postmenopausal women aged 40 to 75 years with a uterus given CE 0.45 mg/BZA 20 mg (n = 1,607), CE 0.625 mg/BZA 20 mg (n = 1,598), or placebo (n = 1,256) for at least 12 weeks and up to 2 years. Changes from baseline in body weight, BMI (kg/m(2)), and World Health Organization BMI category (underweight

OBJECTIVE To assess the effect of baseline body mass index (BMI) on efficacy and weight change in adults with major depressive disorder (MDD) treated with desvenlafaxine or placebo in a pooled, post hoc analysis. METHOD Adults with MDD were randomly assigned to placebo or desvenlafaxine (50 mg or 100 mg) in 8 short-term, double-blind studies and 1 longer-term randomized withdrawal study (the studies were published between 2007 and 2013). Change from baseline in 17-item Hamilton Depression Rating Scale (HDRS-17) total score at week 8 was analyzed in normal (BMI ≤ 25 kg/m(2)), overweight (25 kg/m(2) 30 kg/m(2)) subgroups using analysis of covariance (ANCOVA). Weight change was analyzed in BMI subgroups using ANCOVA and a mixed-effects model for repeated measures. RESULTS Desvenlafaxine 50 mg/d or 100 mg/d improved HDRS-17 scores significantly from baseline to week 8 (last observation carried forward) versus placebo in all BMI subgroups (normal: n = 1,122; overweight: n = 960; obese: n = 1,302; all P ≤ .0027); improvement was greatest in normal BMI patients. There was a statistically significant decrease in weight (< 1 kg) with short-term desvenlafaxine 50 mg/d and 100 mg/d versus placebo in all BMI subgroups (all P < .0001). In the randomized withdrawal study (n = 548), no statistically significant difference in weight was observed for desvenlafaxine versus placebo in any BMI subgroup. Baseline BMI predicted weight change in short-term and longer-term desvenlafaxine treatment. CONCLUSIONS Desvenlafaxine significantly improved symptoms of depression versus placebo regardless of baseline BMI. In all BMI subgroups, desvenlafaxine was associated with statistically significant weight loss (< 1 kg) versus placebo over 8 weeks, but no significant differences longer term. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00072774, NCT00277823, NCT00300378, NCT00384033, NCT00798707, NCT00863798, NCT01121484, NCT00824291, NCT00887224.

It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.

BACKGROUND: Myocardial infarction (MI) contains a risk factor for developing episodes of Major Depressive Disorder (MDD). Apoptosis is commonly observed in the reperfused myocardial infarcted heart, and recent findings suggest the existence of apoptosis in MDD. Cytokines, which are released by ischemic myocardium and which may induce apoptosis, have been proposed as a possible cause for MDD. METHODS: Myocardial infarction was produced in anesthetized rats by a 40-minute occlusion of the left anterior descending coronary artery followed by 72 hours of reperfusion. Determination of apoptosis was done in the amygdala, hippocampus and vermis of MI and Sham rats treated or not with pentoxyfilline (PTX), a cytokine synthesis inhibitor (10 mg/kg/day intraperitoneal). RESULTS: Compared to Sham rats, the amygdala of MI rats showed significantly reduced P13K activity, increased Bax/Bcl-2 ratio, caspase-3 activity, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells. The effect of MI on apoptosis was completely reversed in presence of PTX. No statistical difference was observed in the hippocampus and the vermis in the different groups for any of the biochemical measurements. CONCLUSIONS: These results indicated that MI induce apoptosis in amygdala by a cytokine-sensitive mechanism and may explain the MDD observed following myocardial infarction.

This study was designed to determine whether cardioprotection afforded by A2A adenosine receptor stimulation can be sustained and to determine the effect of an A2A adenosine receptor agonist on Akt and cAMP response element binding protein (CREB) activation, as well as Hsp27 and Hsp70 protein expression in such events. The left anterior descending coronary artery was occluded for 40 minutes in anesthetized rats followed by 72 hours of reperfusion. A2A agonist (CGS21680 at 0.2 microg/kg/min) was administered for 120 minutes, starting either 5 minutes before (early) or after (late) the beginning of reperfusion. Infarct size was reduced significantly in the early compared with the control group (35.2 +/- 1.9% and 52.5 +/- 3.4%, respectively; P < 0.05), whereas no difference was observed with the late group (44.5 +/- 7.1%). After 72 hours of reperfusion, drug administration was accompanied by Akt activation (early, 121.8 +/- 17.6%; late, 118.1 +/- 16.4%; P < 0.05), as well as elevated Hsp27 expression (early, 197.2 +/- 27.7%; late, 203.8 +/- 36.8%; P < 0.05); CREB activation and Hsp70 expression were not altered. In another set of experiments in which reperfusion was limited to 15 minutes, Akt was activated only in the early group (121.8 +/- 17.6%; P < 0.05). Moreover, CREB was activated in both the early and late groups (98.4 +/- 8.3% and 107.0 +/- 6.5%, respectively; P < 0.05), whereas Hsp27 and Hsp70 expression were not altered. These results demonstrate that A2A adenosine receptor activation induces a sustained cardioprotection only if the therapy is instituted before reperfusion. This myocardial protection is associated by an early prosurvival Akt activation. CREB activation and Hsp27 content do not seem to be associated with cardioprotection because they are enhanced in both treated groups, suggesting indirect A2A agonist and pathology-related effects.

Activation of myocardial A2A adenosine receptors during reperfusion has been shown to be cardioprotective. The intracellular mechanisms underlying this protection remain unknown. To understand the beneficial effects of activated A2A adenosine receptors in such a state, we investigated whether the enzymes phosphatidylinositol 3-kinase (PI3K) and caspase-3 can account for this post-ischemic cardioprotective effect in an anesthetized rabbit model of myocardial infarction (30 minutes ischemia; 5 hours reperfusion). Administration of the A2A agonist CGS21680 (0.2 microg/kg/min) 5 minutes before reperfusion began (Early) reduced infarct size expressed as a percentage of the area at risk (25.7 +/- 5.3% versus 46.5 +/- 5.3% for the control group; * P < 0.05). Treatment with the A2A agonist 5 minutes after the onset of reperfusion (Late) had no effect on infarct size (38.2 +/- 6.2%). In the presence of a selective inhibitor of PI3K (LY294002), the beneficial effects of CGS21680 on infarct size was no longer observed (43.9 +/- 7.9%). After 5 hours of reperfusion, higher PI3K activity in the ischemic region was observed in the Early group compared with the other experimental groups. Caspase-3 activity was not observed in these different groups. In another set of experiments, PI3K activity was significantly higher during the first 15 minutes of reperfusion in the Early group as compared with the Control group. Caspase-3 activity increased rapidly during the first 15 minutes of reperfusion in the Control group and remained stable in the Early group. These results indicated that post-ischemic cardioprotection afforded by A2A adenosine receptor activation is PI3K-dependent and modulate rapidly other signaling pathways such as caspase-3.

Objective: To evaluate relapse rates and predictors of relapse in 2 randomized, placebo-controlled trials of desvenlafaxine for major depressive disorder (MDD). Method: Study 1: week 8 responders to open-label desvenlafaxine 50 mg/d entered a 12-week open-label stability phase. Patients with a continuing, stable response at week 20 were randomly assigned to 6-month, double-blind treatment (desvenlafaxine 50 mg/d or placebo). Study 1 was conducted between June 2009 and March 2011 at 87 sites worldwide. Study 2: week 12 responders to open-label desvenlafaxine 200 or 400 mg/d were randomly assigned to 6-month, double-blind treatment (desvenlafaxine 200 mg/d, 400 mg/d, or placebo). Study 2 was conducted between June 2003 and August 2005 at 49 sites in Europe, the United States, and Taiwan. Relapse was assessed separately by study with log-rank test using protocol definitions of relapse and with 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 16 at any time during the double-blind phase. Kaplan-Meier estimates evaluated time to relapse, censoring data at months 1, 2, and 3 and overall; treatments were compared using hazard ratios. Cox proportional hazards models assessed relapse predictors. Results: Overall relapse rates for all definitions were significantly lower for desvenlafaxine versus placebo for both studies (all P ≤ .002). In study 1, rates were significantly lower for desvenlafaxine versus placebo at month 2 (P = .016) and month 3 (P = .007) using the protocol definition. In study 2, relapse rates were significantly lower for desvenlafaxine versus placebo at months 1, 2, and 3 for both definitions (P < .0001–.002). Hazard ratios were similar at months 1, 2, and 3 and overall for both studies (0.382–0.639). Conclusions: Desvenlafaxine 50 to 400 mg/d effectively prevented relapse at 6 months. Desvenlafaxine significantly prevented relapse early (month 1) versus placebo only in study 2. Trial Registration: ClinicalTrials.gov identifiers:NCT00887224 and NCT00075257

Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine , one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.

BackgroundThe predictive value of early functional improvement for treatment success at week 8 was assessed in a pooled analysis in patients with major depressive disorder (MDD).MethodsData were pooled from 7 double-blind studies in adult patients with MDD randomly assigned to desvenlafaxine 50 mg/d or placebo. Four levels of treatment success were determined at week 8 for patients with baseline Sheehan Disability Scale (SDS) score > 12 (N = 2156): functional response (SDS ≤12 and ≥50% improvement in SDS), functional/depression response (SDS ≤12 and ≥50% improvement in both SDS and 17-item Hamilton Rating Scale for Depression [HAM-D17] score), functional remission (SDS < 7), and functional/depression remission (SDS < 7 and HAM-D17 ≤7). Week 2 improvement in SDS was evaluated as a predictor of later functional response/remission using receiver operating characteristic analysis. Odds ratios (ORs) of the predictability of improvement thresholds were computed from a logistic regression model.ResultsThe proportion of patients achieving each level of treatment success was significantly greater for patients treated with desvenlafaxine (40%, 32%, 23%, 15%, respectively) vs placebo (31%, 22%, 17%, 10%; all P ≤ 0.002). Early change in SDS was a highly significant predictor of functional response/remission (ORs, 0.958–0.970; all P < 0.0001).DiscussionPatients’ early functional response to desvenlafaxine 50 mg/d is predictive of treatment success.

Background Diminished quality of life (QOL) is associated with major depressive disorder (MDD). Methods QOL was assessed in a post-hoc analysis of a double-blind, placebo-controlled trial. Employed adult outpatients with MDD were randomly assigned to 12 weeks of treatment with desvenlafaxine 50 mg/d or placebo. Changes from baseline in the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) item scores at week 12 were analyzed using analysis of covariance with treatment, region, and baseline in the model. Correlations between change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score and Q-LES-Q scores were computed. Results The intent-to-treat population included 427 patients. There were statistically significant improvements from baseline for desvenlafaxine vs placebo in 10 of 16 Q-LES-Q item scores ( P values ≤0.0441). The percentage of patients with severe QOL impairment (≥2 SD below community norm) at week 12 was significantly lower for desvenlafaxine (46%) vs placebo (62%; P =0.0024; baseline: 95% and 94%, respectively). Change in Q-LES-Q total score was highly correlated with change in HAM-D 17 score at week 12, LOCF ( P 17 total score at week 2 predicted change in Q-LES-Q total score at week 12 for the desvenlafaxine group ( F =24.89; P Limitations This analysis excluded patients who were unemployed, had severe comorbidities, and those taking multiple, concomitant medications. Conclusion Improvement in QOL and depressive symptoms was significantly greater for employed depressed patients treated with desvenlafaxine vs placebo.

Background: Studies have shown that the heterotrimeric G protein, Gq, is a critical molecule in the development of myocardial hypertrophy and heart failure (HF). In the present study, we examined whether Gq signaling is also a critical pathological trigger for adverse remodeling and HF after ischemic injury. Using cardiac-specific transgenic mice with expression of a specific Gq inhibitory peptide (GqI) that blocks Gq-GPCR coupling allowed us to investigate whether Gq inhibition can alter cardiac structure and functional changes after myocardial infarction (MI). Methods and Results: Cardiac-specific GqI transgenic (TG) and non-transgenic littermate control (NLC) mice were subjected to MI. Serial echocardiography performed before ischemia as well as 2, 4, 8 weeks after MI injury show that TG mice develop less progressive LV enlargement and dysfunction. The % LV EF and FS were significantly improved in the TG compared to NLC mice at 8 weeks post-MI. Consistently, cardiac contractility (+dP/dt) and relaxation (-dP/dt) were significantly improved in TG mice also when stimulated with isoproterenol. The LVEDP, the heart weight to body weight (BW) and lung to BW ratios were significantly less in TG mice, indicating that HF was limited with GqI expression. Moreover, TG mice have smaller infarcts, less LV dimensions and lower fibrosis in both the border zone and remote area with clearly more viable tissue in the scar region. Constantly, there are more micro-vessel and more BrdU(+) cardiomyocytes in the scar area and border zone at the 2 week post-MI in TG group. Western blot shows a consistent decrease in phosphorylated PKC substrates and higher levels of activated Akt in TG mice. Over expression of the GqI in cultured H9c2 myoblasts did lead to higher level of Ki67 positive cells (38.06±2.46%) than a control group (21.78±2.64%) and FACS analysis showed that Gq inhibition increased the % of H9c2 cells in S phase and G2/M phase compared to control cells. Conclusion: These data indicate cardiac specific Gq inhibition protects the heart against adverse LV remodeling and HF progression after MI. Mechanisms attributed to GqI expression appear to include improved myocyte survival, less fibrosis, and promotion of angiogenesis and cardiac repair through regeneration.

Rationale: Activation of prosurvival kinases and subsequent nitric oxide (NO) production by certain G protein–coupled receptors (GPCRs) protects myocardium in ischemia/reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases (GRKs), and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function. Objective: A loss of cardiac GRK2 activity is known to arrest progression of heart failure (HF), at least in part by normalization of cardiac β-adrenergic receptor (βAR) signaling. Chronic HF studies have been performed with GRK2 knockout mice, as well as expression of the βARKct, a peptide inhibitor of GRK2 activity. This study was conducted to examine the role of GRK2 and its activity during acute myocardial ischemic injury using an I/R model. Methods and Results: We demonstrate, using cardiac-specific GRK2 and βARKct-expressing transgenic mice, a deleterious effect of GRK2 on in vivo myocardial I/R injury with βARKct imparting cardioprotection. Post-I/R infarct size was greater in GRK2-overexpressing mice (45.0±2.8% versus 31.3±2.3% in controls) and significantly smaller in βARKct mice (16.8±1.3%, P 2 ARs abolished βARKct-mediated cardioprotection, suggesting that enhanced GRK2 activity on this GPCR is deleterious to cardiac myocyte survival. Conclusion: The novel effect of reducing acute ischemic myocardial injury via increased Akt activity and NO production adds significantly to the therapeutic potential of GRK2 inhibition with the βARKct not only in chronic HF but also potentially in acute ischemic injury conditions.

Chronic ventricular pressure overload states, such as hypertension, and elevated levels of neurohormones (norepinephrine, angiotensin II, endothelin-1) initiate cardiac hypertrophy and dysfunction and share the property of being able to bind to Gq-coupled 7-transmembrane receptors. The goal of the current study was to determine the role of endogenous cardiac myocyte Gq signaling and its role in cardiac hypertrophy and dysfunction during high blood pressure (BP). We induced renal artery stenosis for 8 weeks in control mice and mice expressing a peptide inhibitor of Gq signaling (GqI) using a 2 kidney, 1 clip renal artery stenosis model. 8 weeks following chronic high BP, control mice had cardiac hypertrophy and depressed function. Inhibition of cardiomyocyte Gq signaling did not reverse cardiac hypertrophy but attenuated increases in a profile of cardiac profibrotic genes and genes associated with remodeling. Inhibition of Gq signaling also attenuated the loss of cardiac function. We determined that Gq signaling downstream of angiotensin II receptor stimulation negatively impacted beta-adrenergic receptor (AR) responses and inhibition of Gq signaling was sufficient to restore betaAR-mediated responses. Therefore, in this study we found that Gq signaling negatively impacts cardiac function during high BP. Specifically, we found that inhibition of AT1-Gq signaling augmented betaAR mediated effects in a renal artery stenosis model of hypertension. These observations may underlie additional, beneficial effects of angiotensinogen converting enzyme (ACE) inhibitors and angiotensin receptor antagonists observed during times of hemodynamic stress.

Abstract Depression is diagnosed in 15–30% of patients following myocardial infarction (MI) and this may also be observed in the rat. We measured the effects of the antidepressant sertraline on behavioural and biochemical events following MI in a rat model. Following surgery, MI rats and sham controls were treated with sertraline (10 mg/kg, i.p.) or saline. Subgroups of rats were tested for behavioural depression 14 days after surgery. Apoptosis was estimated in other rats by measuring caspase-3 activity and TUNEL positive cells (3 days after surgery) in limbic structures (amygdale, hippocampus, hypothalamus, frontal and prefrontal cortices). Bax/Bcl-2 ratio was measured 14 days after surgery. Behavioural signs of depression (decreased sucrose intake and forced swimming time) were found in saline-treated MI rats but not in sertraline-treated rats. Compared with controls, caspase-3 activity and TUNEL positive cells were significantly increased in most limbic structures of MI rats. High prefrontal Bax/Bcl-2 ratio in MI rats correlated with low forced swimming time. Apoptosis was not found in sertraline-treated MI rats. These results establish the bases of a rat model of depression following MI and show for the first time that a selective serotonin reuptake inhibitor prevents both behavioural and biochemical markers in this model.

Myocardial G protein–coupled receptor kinase (GRK)2 is a critical regulator of cardiac β-adrenergic receptor (βAR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated βAR with a GRK2-derived peptide that binds G β γ (βARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and βARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (αMHC-Cre×GRK2 fl/fl) or only after administration of tamoxifen (αMHC-MerCreMer×GRK2 fl/fl) and examined the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 before coronary artery ligation prevented maladaptive postinfarction remodeling and preserved βAR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in postinfarction cardiac remodeling and heart failure and support therapeutic approaches of targeting GRK2 or restoring βAR signaling by other means to improve outcomes in heart failure.

Evidence has accumulated to suggest that cardiomyocyte apoptosis contributes significantly to the progression of heart failure. A salient characteristic of the failing heart is an upregulation of the adenylyl cyclase inhibitory G protein alpha subunit, Galpha(i2); however this upregulation has yet to be established as beneficial or deleterious. Of note, G protein-coupled receptor (GPCR) signaling through Gi has been implicated in the cardioprotective properties of adenosine, opioids, and bradykinin; however to date there has been no in vivo evidence that increased Gi in ischemic myocardium is cardioprotective. We have created a novel molecular tool to specifically address this question and other Gi-related mechanisms in the heart. We have developed a Gi inhibitor, GiCT - the carboxyl-terminal 63 amino acids of Galphai(i2), which represents the region of Gi that interacts specifically with GPCRs. Gi selectivity of GiCT has been shown in vitro as Gi signals are inhibited while Gs and Gq signals are not. Thus, a class-specific Gi inhibitor has been developed. We next created a transgenic mouse line with inducible, cardiac-specific expression of GiCT (Tg-GiCT mice). At baseline, Tg-GiCT mice display a structural and functional phenotype consistent with non-transgenic (nTg) mice. However, when subjected to stress in the form of myocardial ischemia/reperfusion (I/R) injury, Tg-GiCT mice demonstrate a significant increase in infarct size as compared to nTg mice. Furthermore, Tg-GiCT mice demonstrate increased myocardial apoptosis in response to I/R, with a resultant decrease in contractile performance. These results indicate first that ischemic damage induces apoptotic signals that can be countered by GPCR signaling specifically through Gi. Moreover, the beneficial survival effects of Gi signaling on the prevention of myocardial apoptosis in ischemia appears to outweigh any potential detrimental effects that Gi upregulation may have on contractility through inhibition of cAMP. Overall, our results demonstrate the in vivo utility of GiCT - to elucidate the novel finding that upregulation of Gi seen in dysfunctional myocardium induces survival signals and appears to be an adaptive mechanism post-ischemia to protect myocytes from apoptosis.

Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 μg/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 μg/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 ± 3.5% (vehicle) to 11.0 ± 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 ± 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium.

To determine the effect of a completely developed reperfused myocardial infarction model on beta-adrenoceptor responsiveness, we induced a 90-min regional ischemia followed by 72 h of reperfusion in dog hearts. Regional myocardial blood flow was determined after 60 min of ischemia using radioactive microspheres. beta-adrenoceptor density was reduced in the ischemic endocardium (95+/-16 fmol/mg) and epicardium (160+/-13 fmol/mg) compared to the nonischemic region (304+/-21 fmol/mg). beta-adrenoceptor density in the ischemic endocardium varied with the degree of collateral blood flow measured (r2=0.79, P

A multi watt CW 1.34 µm diode end-pumped Nd:YAP laser is described. Acoustooptic device is tested to obtain Q-switched operation. The influence of the Nd3+ doping level in YAP crystal on the laser efficiency, in CW and in Q-switched mode, is presented.