Does Symptom-Onset Treatment With Sertraline Improve Functional Impairment for Individuals With Premenstrual Dysphoric Disorder?: A Randomized Controlled Trial.

PURPOSE/BACKGROUND: Daily treatment with sertraline improves functional impairment among individuals with premenstrual dysphoric disorder (PMDD). We do not know whether treatment initiated at symptom onset also improves functional impairment. METHODS/PROCEDURES: This 3-site, double blind, randomized, clinical trial compared sertraline (25-100 mg) to similar appearing placebo, both administered at symptom onset, for reduction of PMDD symptoms. Ninety participants were allocated to sertraline and 94 participants to placebo. Functional outcomes from the Daily Ratings of the Severity of Problems included (1) reduced productivity or efficiency at work, school, home, or daily routine; (2) interference with hobbies or social activities; and (3) interference with relationships. Items were measured from 1 (no interference) to 6 (extreme interference) and averaged for the final 5 luteal phase days. This secondary analysis examined whether improvement in functional domains was greater for those allocated to sertraline compared with placebo. Second, we used causal mediation analyses to explore whether specific PMDD symptoms mediated functional improvement. RESULTS/FINDINGS: Only relationship functioning improved significantly with active treatment between baseline and the end of the second cycle (active group mean [SD] change, -1.39 [1.38]; placebo group mean change, -0.76 [1.20]; ß = -0.40; SE, 0.15; P = 0.009). The total effect of treatment on interference was -0.37 (95% confidence interval [CI], -0.66 to -0.09; P = 0.011). Given the nonsignificant direct effect (0.11; 95% CI, -0.07 to 0.29; P = 0.24) and significant indirect effect (-0.48; 95% CI, -0.71 to -0.24; P < 0.001), amelioration of anger/irritability likely mediated reductions in relationship interference. IMPLICATIONS/CONCLUSIONS: That anger/irritability mediates impairments in relationship functioning has face validity but should be replicated in other data sets. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00536198 .

Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials.

The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18-64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women-esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men-esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women-esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men-esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).

Evaluation of an Electronic Health Record Alert to Improve Screening and Management of Cardiovascular Disease and Stroke Factors in a High-Risk Population.

OBJECTIVES: Cardiovascular disease and stroke risk factor screening and management by primary care providers (PCPs) have a significant impact on their patients' health. The objective of this study was to investigate the effectiveness of an electronic health record (EHR) cardiovascular disease and stroke risk alert in improving the ability of PCPs to manage risk factors among women and men aged 45 years and older. METHODS: PCPs at a tertiary care hospital were randomized. The intervention group received an EHR alert, which calculated the individual patient risk and provided an order set incorporating the American Heart Association and American Stroke Association guidelines, whereas the control group used the EHR in the usual manner. Multilevel analysis compared the rate of prescriptions between the intervention and control groups. RESULTS: A total of 23 PCPs were randomized: 12 in the intervention group and 11 in the control group, attending to 7190 patients between September 2016 and January 2017. None of the providers in the intervention group used the programmed order set. Intervention group providers were significantly more likely to prescribe smoking cessation medication to women than to the control group (adjusted odds ratio 2.37, 95% confidence interval 1.23-4.57). There were no statistically significant differences between the intervention and control groups in the rate of other medication prescriptions. CONCLUSIONS: As measured by prescriptions for medications, other than those for smoking cessation, the EHR alert was not shown to be successful in increasing the management of high-risk patients. Physicians receiving numerous messages in the EHR may experience alert desensitization.

The effect of desvenlafaxine 50 mg/day on a subpopulation of anxious/depressed patients: a pooled analysis of seven randomized, placebo-controlled studies.

BACKGROUND: Desvenlafaxine (administered as desvenlafaxine succinate) for anxious depression was assessed in a post hoc analysis. METHODS: Data were pooled from patients randomly assigned to desvenlafaxine 50 mg/day or placebo in seven double-blind, fixed-dose studies in adults with major depressive disorder. Patients with "anxious depression" had baseline 17-item Hamilton Rating Scale for Depression, anxiety-somatization factor (HAM-D17 A/S) scores ≥7. Primary end point was change in HAM-D17 scores from baseline at week 8 (last observation carried forward), evaluated using analysis of covariance with treatment, study, and baseline value as covariates. RESULTS: A total of 1873/2706 (69%) patients were identified as "anxious depressed". Desvenlafaxine significantly improved HAM-D17 total scores versus placebo in anxious (adjusted mean [95% CI] -1.72 [-2.35, -1.09]; p < 0.001) and nonanxious (-1.48 [-2.40, -0.57]; p = 0.002) populations, with no significant treatment-by-anxiety interaction. Response and remission rates (HAM-D17 ) were significantly higher with desvenlafaxine compared with placebo in both populations. Treatment-emergent adverse events were reported by 78% and 69% (desvenlafaxine versus placebo, respectively) of anxious depressed patients and by 77% and 68% of nonanxious patients. CONCLUSION: Desvenlafaxine 50 mg/day significantly improved depressive symptoms compared with placebo in major depressive disorder patients with clinically relevant anxiety symptoms. Improvement in the HAM-D17 total score was similar for anxious/nonanxious groups.

Working with Survivors of Sex Trafficking: Mental Health Implications.

Human trafficking is one of the largest criminal enterprises in the world, generating an estimated $150 billion in illegal profits annually. Sex trafficking is the most common form of human trafficking, and survivors experience significant physical, emotional, and sexual trauma that places them at increased risk of poor health outcomes. As sex trafficking continues to disproportionately impact the physical and mental health of individuals belonging to marginalized groups, a multidisciplinary approach to combat trafficking will require collaboration between health services, law enforcement, and social services. Therefore, medical professionals should be familiar with screening protocols for trafficking and evidence based, trauma-informed mental health treatment interventions.

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Assessment of depressive symptoms and functional outcomes in patients with major depressive disorder treated with duloxetine versus placebo: primary outcomes from two trials conducted under the same protocol.

OBJECTIVE: Return of functional ability is a central goal in the treatment of major depressive disorder. We conducted two trials with the same protocol that was designed to assess functioning after 8 Weeks of treatment with duloxetine. METHODS: The a priori primary outcome was improvement in the Hamilton Depression Rating Scale (HAMD) item 7 (work/activities). Secondary outcomes included improvement in depressive symptoms assessed by the HAMD Maier subscale, and improvement in functioning assessed by the Sheehan Disability Scale (SDS), and the Social Adaptation Self-evaluation Scale (SASS). Patients were randomly assigned to duloxetine 60 mg/day (Trial I, n = 257; Trial II, n = 261) or placebo (Trial I, n = 127; Trial II, n = 131). Changes from baseline were analyzed using a mixed-effects model repeated measures approach. RESULTS: At Week 8, duloxetine was superior to placebo in improving HAMD work/activities (p < 0.001) in Trial II, but not Trial I (p = 0.051), and Maier scores (p < 0.01) in both trials. At Week 12, duloxetine was superior to placebo on improving SASS scores in both trials, and the SDS in Trial II. CONCLUSION: Treatment with duloxetine was associated with significant improvement in depressive symptoms compared with placebo, but improvement in HAMD work/activities was inconsistent at 8 weeks.

Multidisciplinary Management of Menopause: Symposium Proceedings.

This proceeding summarizes a symposium on multidisciplinary management of menopause held on July 30, 2021 as part of the Health of Women 2021 conference. The workshop featured presentations by national experts who provided insights into multidisciplinary approaches to the management of menopause, vasomotor symptoms and genitourinary syndrome of menopause, bone health (including osteoporosis, muscular strength, and mobility), as well as sexual and psychological health during menopause. In this study, we highlight the major points of each presentation and the resultant discussion.

Analysis by age and sex of efficacy data from placebo-controlled trials of desvenlafaxine in outpatients with major depressive disorder.

This pooled analysis evaluated the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of major depressive disorder (MDD) in patients grouped by age and sex. Nine clinical trials were pooled. Outpatients 18 years or older with MDD received desvenlafaxine 50, 100, 200, or 400 mg/d (men = 709; women = 1096) or placebo (men = 399; women = 709) for 8 weeks. Data were analyzed by sex and by age groups of 40 years and younger, 41 to 54 years, 55 to 64 years, and 65 years and older. The primary outcome was change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at the final evaluation. Secondary measures included response (> or =50% reduction in HAM-D17) and remission (HAM-D17 < or =7). No significant sex-treatment, age-treatment, or sex-age-treatment interactions were observed. Differences in the HAM-D17 change from baseline for desvenlafaxine versus placebo were -1.72 for women (P < 0.001) and -2.11 for men (P < 0.001); these changes were significant among women of the 18-to-40 (P = 0.01), 41-to-54 (P = 0.002), and 65-years-and-older subgroups (P = 0.02), and significant among men for the 18-to-40 (P = 0.03) and 41-to-54 subgroups (P = 0.002). The response rates for desvenlafaxine and placebo were 53% and 42% (P < 0.001), respectively, among women, and 53% and 41% (P < 0.001), respectively, among men; the remission rates were 31% and 21% (P < 0.001) and 34% and 26% (P = 0.007), respectively. The response rates were similar across age subgroups, with significant differences from placebo observed in the 18-to-40 (P < or = 0.05), 41-to-54 (P < or = 0.005), and 65-and-older subgroups (P = 0.02). The remission rates were significant versus placebo in the 41-to-54 (P = 0.006), 55-to-64 (P = 0.01), and 65-and-older (P = 0.02) subgroups among women but not in any age subgroup among men. Desvenlafaxine generally improved depressive symptoms across age and sex subgroups.

Early adverse events and attrition in selective serotonin reuptake inhibitor treatment: a suicide assessment methodology study report.

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of adverse effects or the frequency, intensity, or burden of adverse effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n = 265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific adverse effects were evaluated with the Systematic Assessment for Treatment Emergent Events--Systematic Inquiry, and at week 2, the Frequency, Intensity, and Burden of Side Effects Rating globally assessed adverse effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 adverse effect, either treatment-emergent or with worsening intensity, was independently associated with attrition. Global ratings of adverse effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific adverse effects at week 2 were related to patient attrition during SSRI treatment. Other factors seem to contribute to patient decisions about continuing with treatment.

Correlation between patient and clinician assessments of depression severity in the PREVENT study.

BACKGROUND: The degree of agreement between patient- and clinician-rated scales of depressive severity varies widely. This study analyzed agreement between commonly used depression rating scales in the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial. METHODS: The PREVENT trial was a multiphase, randomized, double-blind study of patients with recurrent major depressive disorder. This secondary analysis evaluated acute (10weeks) and continuation phase (6months) data. Pearson correlation coefficients at each acute-phase (weekly) and continuation-phase (monthly) visit were calculated for patient-rated (30-item Inventory of Depressive Symptomatology-Self-Rated [IDS-SR30] and clinician-rated (17-item Hamilton Rating Scale for Depression [HAM-D17] and Clinical Global Impressions-Severity [CGI-S]) measures and for response and remission. RESULTS: Data from 1,047 patients were analyzed. The respective correlation coefficients at baseline, week 10, and month 6 were: IDS-SR30: HAM-D17: 0.46, 0.75, 0.70; and for IDS-SR30: CGI-S 0.28, 0.67, 0.65. Agreement between IDS-SR30- and HAM-D17-defined remission and response was relatively poor: week 10, 0.52 and 0.34, respectively; month 6, 0.45 and 0.32, respectively. CONCLUSIONS: These findings suggest that patient-rated measures of depression severity do not correspond strongly with clinician ratings, and are particularly poor prior to the initiation of treatment.

Interpreting Premenstrual Symptoms Impact Survey scores using outcomes in health-related quality of life and sexual drive impact.

OBJECTIVE: To link the Premenstrual Symptoms Impact Survey (PMSIS) scores to health-related quality of life (HRQOL) and sexual drive impact associated with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). STUDY DESIGN: Secondary data analysis was performed using the online survey study for PMSIS development. Women were sorted into 10 mutually exclusive score levels (N = 949). Their responses to the SF-12v2 Health Survey and the sexual drive question were dichotomized to indicate the presence of limitations/impairment. Chi-square analysis was conducted to compare the differences in percentages of women with limitations across 3 representative PMSIS score levels containing (1) women with no indication of PMS, (2) women at risk for PMS but not PMDD, and (3) women at risk for PMDD. RESULTS: The higher the PMSIS score level (more severe impact), the greater the percentage of women reported functional limitations. Women either at risk for PMS or PMDD were significantly more likely to report limitations than women with no indication of PMS in all HRQOL areas except for 2 Physical Functioning items and 1 Mental Health item and the General Health item. Significantly more women with PMS (67.5%) and with PMDD (73.3%) reported sexual drive impact than in women with no PMS (45.7%). CONCLUSION: The associations between PMSIS score levels and the premenstrual symptoms' impact on HRQOL and sexual functioning assist the interpretation of PMSIS scores and use of the tool in reproductive-age women.

Prenatal Depression Severity and Postpartum Care Utilization in a Medicaid Population.

Background: Postpartum visits are a necessary continuum of medical care for women who are diagnosed with depression during pregnancy. However, postpartum care utilization is typically lower in populations who face adverse events and it is unclear to what extent having depression during pregnancy may compromise postpartum visit follow-up. Our study examined the association between severity of prenatal depression and postpartum care utilization among women on Medicaid. Materials and Methods: Data from a university-based, nonprofit managed care organization (2008-2012) were analyzed (N = 846). Prenatal depression severity and postpartum care utilization were determined using the International Classification of Diseases, Ninth Revision (ICD-9) codes, from medical claims records. Bivariate and multivariable logistic regression was conducted. Odds ratios and 95% confidence intervals (CIs) were calculated. Results: The majority (64.2%) of women received a mild/moderate prenatal depression diagnosis and 52.5% of the total sample attended their postpartum care visit. After adjusting for confounders, we found decreased odds of postpartum care utilization among women with less severe diagnoses. Women with a mild/moderate prenatal depression diagnosis were 12% less likely to attend the postpartum care visit compared with women with a severe prenatal depression diagnosis (adjusted odds ratio = 0.88, 95% CI = 0.65-1.19). However, this finding was not statistically significant. Conclusions: Our study did not yield evidence of a statistically significant relationship between prenatal depression severity and postpartum visit attendance among a sample of Medicaid beneficiaries. Additional research is needed to assess the association between prenatal depression severity and postpartum care use to enhance continuity of services for Medicaid-insured women into the postpartum period.

What predicts attrition in second step medication treatments for depression?: a STAR*D Report.

Attrition rates are high during treatment for major depressive disorder (MDD), and patients who drop out are less likely to reach remission. This report evaluates the incidence, timing, and predictors of attrition during second-step medication treatment. Outpatients in the multisite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study receiving a medication augmentation (n=563) or medication switch (n=723) for non-psychotic MDD after an unsatisfactory outcome with citalopram were evaluated to determine attrition rates and pretreatment sociodemographic or clinical predictors of attrition. Twenty percent of participants receiving a medication augmentation and 27% receiving a medication switch dropped out before 12 wk in the second treatment step. Remission rates were lower for dropouts [7% vs. 43% (medication augmentation); 12% vs. 31% (medication switch)]. For medication augmentation, Black and other non-Caucasian races, Hispanic ethnicity, younger age, family history of drug abuse, concurrent drug abuse, sociodemographic disadvantage, less symptom improvement with initial citalopram treatment, and greater symptom severity when beginning augmentation were associated with attrition. For medication switch, Black and other non-Caucasian races, younger age, more melancholic features, and lower exit doses but more severe side-effects with citalopram treatment were associated with attrition. Minority status, younger age, and greater difficulty with the first treatment step are risk factors for attrition in the second treatment step. Focus on patients with attrition risk factors for medication augmentation or switch strategies may enhance retention and improve outcomes.

Sex differences in response to citalopram: a STAR*D report.

OBJECTIVE: Controversy exists as to whether women with depression respond better to selective serotonin reuptake inhibitors (SSRIs) than men. The purpose of this report was to determine whether men and women differ in their responses to treatment with the SSRI citalopram using a large sample of real world patients from primary and psychiatric specialty care settings. METHOD: As part of the sequenced treatment alternatives to relieve depression (STAR *D) study, 2876 participants were treated with citalopram for up to 12-14 weeks. Baseline demographic and clinical characteristics and outcomes were gathered and compared between men and women. RESULTS: At baseline, women were younger, had more severe depressive symptoms and were more likely to have: early onset; previous suicide attempt(s); a family history of depression, alcohol abuse or drug abuse; atypical symptom features; and one or more of several concurrent psychiatric disorders. Despite greater baseline severity and more Axis I comorbidities, women were more likely to reach remission and response with citalopram than men. CONCLUSIONS: Women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.

An integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment of major depressive disorder.

INTRODUCTION: The safety and tolerability profiles of antidepressants can often influence the treatment choices of clinicians treating major depressive disorder. The purpose of this investigation was to characterize the safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in treating depression. METHODS: An integrated analysis of all short-term, randomized, double-blind, placebo-controlled registration studies for major depressive disorder (four flexible-dose and five fixed-dose studies) was performed. Adult outpatients with major depressive disorder received desvenlafaxine doses ranging from 50-400 mg/day or placebo for 8 weeks. Treatment-emergent adverse events, laboratory values, vital signs, and discontinuation symptoms were evaluated. In the subset of fixed-dose studies, dose-related effects were analyzed. RESULTS: In the overall population (placebo: n=1,116; desvenlafaxine: n=1,834), adverse events resulted in discontinuations in 3% of placebo-treated patients and 12% of desvenlafaxine-treated patients; in the subset of fixed-dose studies, the rates were 4% with placebo and increased with desvenlafaxine dose (50 mg/day: 4%; 400 mg/day: 18%). The most common treatment-emergent adverse event was transient nausea that was generally mild to moderate. The most common sexual dysfunction associated with desvenlafaxine treatment was erectile dysfunction in men (7% vs 1% with placebo) and anorgasmia in women (1% and 0%). One desvenlafaxine-treated patient died of a completed suicide; there were four suicide attempts (three desvenlafaxine, one placebo) and eight cases of suicidal ideation (five desvenlafaxine, three placebo) during the on-therapy period. Small but statistically significant changes in mean blood pressure occurred at all desvenlafaxine doses; clinically meaningful changes were observed in 1% of placebo-treated patients and 2% of desvenlafaxine-treated patients. Desvenlafaxine was associated with small but statistically significant mean changes in laboratory assessments, particularly lipid and liver enzyme elevations, and electrocardiograms; few cases of these changes were clinically relevant. CONCLUSION: Desvenlafaxine in the treatment of major depressive disorder exhibited a safety and tolerability profile generally consistent with the serotonin-norepinephrine reuptake inhibitor class. The most common adverse event was transient nausea. At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo.

An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder.

INTRODUCTION: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder. METHODS: A meta-analysis of individual patient data was performed on the complete set of registration trials (nine randomized, double-blind, placebo-controlled 8-week studies) of desvenlafaxine. Patients received fixed (50, 100, 200, or 400 mg/day; n=1,342) or flexible doses (100-400 mg/day; n=463) of desvenlafaxine or placebo (n=1,108). The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)); the primary intent to treat analyses used the last-observation-carried-forward method. RESULTS: Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D(17) total score was observed for the full data set (difference in adjusted means: -1.9; P<.001), each fixed-dose group (all P<.001), and the flexible-dose group (P=.024). Overall rates of HAM-D1(17) response (> or =150% decrease from baseline score: 53% vs 41%) and remission (HAM-D(17) < or =7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all P<.001). Discontinuation rates due to adverse events increased with dose (4% to 18%; placebo: 3%). CONCLUSION: Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.

Escitalopram versus SNRI antidepressants in the acute treatment of major depressive disorder: integrative analysis of four double-blind, randomized clinical trials.

INTRODUCTION: Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors. METHODS: Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake inhibitor (SNRI) (two trials with duloxetine and two with venlafaxine extended release) in outpatients (18-85 years of age) with moderate-to-severe major depressive disorder were pooled. The primary efficacy parameter in all four trials was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. RESULTS: Significantly fewer escitalopram (82/524) than SNRI (114/527) patients prematurely withdrew from treatment due to all causes (15.6% vs. 21.6%, Fisher Exact: P=.014) and adverse events (5.3% vs. 12.0%, Fisher Exact: P<.0001). Mean reduction in MADRS score from baseline to Week 8 was significantly greater for the escitalopram group versus the SNRI group using the last observation carried forward (LOCF) approach [mean treatment difference at Week 8 of 1.7 points (P<.01)]. Similar results were observed in the severely depressed (baseline MADRS score >or= 30) patient subset (mean treatment difference at Week 8 of 2.9 points [P<.001, LOCF]). Observed cases analyses yielded no significant differences in efficacy parameters. CONCLUSION: This pooled analysis indicates that escitalopram is at least as effective as the SNRIs (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment was better tolerated.

Clinical Characteristics and Treatment Response to Lisdexamfetamine Dimesylate Versus Placebo in Adults With Binge Eating Disorder: Analysis by Gender and Age.

OBJECTIVE: To describe clinical characteristics and lisdexamfetamine dimesylate (LDX) treatment effects, based on gender and age, in adults diagnosed with moderate to severe binge eating disorder (BED). METHODS: Adults diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined BED of moderate to severe severity were randomized to 12 weeks of dose-optimized LDX (50 or 70 mg) or placebo in 2 studies (conducted from November 26, 2012, to September 25, 2013 [study 1] and from November 26, 2012, to September 20, 2013 [study 2]). These post hoc analyses pooled data by gender (men vs women) and age (< 40 vs ≥ 40 years) across studies; reported P values are nominal (descriptive and unadjusted). RESULTS: The pooled safety analysis and full analysis sets included 745 and 724 participants, respectively (men, n = 105 and n = 97; women, n = 640 and n = 627; < 40 years, n = 398 and n = 386; ≥ 40 years, n = 347 and n = 338). Across subgroups, most participants had a body mass index ≥ 30 kg/m² (63.0%-75.5%). The mean baseline number of binge eating days/wk was comparable across gender (4.6-4.7) and age (4.6-4.9), as was Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total score (gender, 20.42-21.70; age, 21.40-21.63). Least squares mean (95% CI) treatment differences nominally favored LDX in all subgroups (all P < .001) for changes from baseline in binge eating days/wk at weeks 11-12 and in Y-BOCS-BE total score at week 12; no interactions by gender or age were reported. Consistent with the overall profile of LDX, across all subgroups LDX was associated with higher frequencies of treatment-emergent adverse events than placebo and with increases in blood pressure and pulse. CONCLUSIONS: Across gender and age, participants exhibited comparable clinical characteristics and responses to dose-optimized LDX compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01718483 and NCT01718509.

Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations.

There is a new appreciation of the perimenopause-defined as the early and late menopause transition stages as well as the early postmenopause-as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: (1) epidemiology; (2) clinical presentation; (3) therapeutic effects of antidepressants; (4) effects of hormone therapy; and (5) efficacy of other therapies (e.g., psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (i.e., vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (i.e., antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.