eMindLog: Self-Measurement of Anxiety and Depression Using Mobile Technology.

BACKGROUND: Quantifying anxiety and depressive experiences permits individuals to calibrate where they are and monitor intervention-associated changes. eMindLog is a novel self-report measure for anxiety and depression that is grounded in psychology with an organizing structure based on neuroscience. OBJECTIVE: Our aim was to explore the psychometric properties of eMindLog in a nonclinical sample of subjects. METHODS: In a cross-sectional study of eMindLog, a convenience sample of 198 adults provided informed consent and completed eMindLog and the Hospital Anxiety and Depression Scale (HADS) as a reference. Brain systems (eg, negative and positive valence systems, cognitive systems) and their functional states that drive behavior are measured daily as emotions, thoughts, and behaviors. Associated symptoms, quality of life, and functioning are assessed weekly. eMindLog offers ease of use and expediency, using mobile technology across multiple platforms, with dashboard reporting of scores. It enhances precision by providing distinct, nonoverlapping description of terms, and accuracy through guidance for scoring severity. RESULTS: eMindLog daily total score had a Cronbach alpha of .94. Pearson correlation coefficient for eMindLog indexes for anxiety and sadness/anhedonia were r=.66 (P<.001) and r=.62 (P<.001) contrasted with the HADS anxiety and depression subscales respectively. Of 195 subjects, 23 (11.8%) had cross-sectional symptoms above the threshold for Generalized Anxiety Disorder and 29 (29/195, 14.9%) for Major Depressive Disorder. Factor analysis supported the theoretically derived index derivatives for anxiety, anger, sadness, and anhedonia. CONCLUSIONS: eMindLog is a novel self-measurement tool to measure anxiety and depression, demonstrating excellent reliability and strong validity in a nonclinical population. Further studies in clinical populations are necessary for fuller validation of its psychometric properties. Self-measurement of anxiety and depressive symptoms with precision and accuracy has several potential benefits, including case detection, tracking change over time, efficacy assessment of interventions, and exploration of potential biomarkers.

Bright Light Therapy as Augmentation of Pharmacotherapy for Treatment of Depression: A Systematic Review and Meta-Analysis.

BACKGROUND: Bright light therapy has demonstrated efficacy and is an accepted treatment for seasonal depression. It has been suggested that bright light therapy may have efficacy in nonseasonal depressions. Also, there is evidence that bright light therapy may improve responsiveness to antidepressant pharmacotherapy. DATA SOURCES: We searched PubMed/MEDLINE, PsycINFO, PsycARTICLES, CINAHL, EMBASE, Scopus, and Academic OneFile for English-language literature published between January 1998 and April 2016, using the keywords bright light therapy AND major depression, bright light therapy AND depress*, bright light therapy AND bipolar depression, bright light therapy AND affective disorders, circadian rhythm AND major depression, circadian rhythm AND depress*, and circadian rhythm AND affective disorder. STUDY SELECTION AND DATA EXTRACTION: Studies that reported randomized trials comparing antidepressant pharmacotherapy with bright light therapy ≥ 5,000 lux for ≥ 30 minutes to antidepressant pharmacotherapy without bright light therapy for the treatment of nonseasonal depression were included. Studies of seasonal depression were excluded. Following review of the initial 112 returns, 2 of the authors independently judged each trial, applying the inclusionary and exclusionary criteria. Ten studies were selected as meeting these criteria. Subjects in these studies were pooled using standard techniques of meta-analysis. RESULTS: Ten studies involving 458 patients showed improvement using bright light therapy augmentation versus antidepressant pharmacotherapy alone. The effect size was similar to that of other accepted augmentation strategies, roughly 0.5. CONCLUSIONS: Analysis of pooled data from randomized trials provides evidence for the efficacy of use of bright light therapy ≥ 5,000 lux for periods ≥ 30 minutes when used as augmentation to standard antidepressant pharmacotherapy in the treatment of major depressive disorder and bipolar depression without a seasonal pattern.

Incidence and Timing of Taper/Posttherapy-Emergent Adverse Events Following Discontinuation of Desvenlafaxine 50 mg/d in Patients With Major Depressive Disorder.

OBJECTIVE: The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy-emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate). METHOD: This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status. RESULTS: A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2. CONCLUSION: The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01056289.

Abrupt discontinuation compared with a 1-week taper regimen in depressed outpatients treated for 24 weeks with desvenlafaxine 50 mg/d.

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

BDNF, interleukin-6, and salivary cortisol levels in depressed patients treated with desvenlafaxine.

BACKGROUND: Relationships between brain-derived neurotrophic factor (BDNF), interleukin (IL)-6, and salivary cortisol and both depression severity and treatment response were assessed in patients enrolled in a double-blind, placebo-controlled trial of desvenlafaxine 50mg/d for MDD. METHODS: Outpatients with MDD were randomly assigned to 12weeks of double-blind treatment with desvenlafaxine 50mg/d or placebo (2:1). Baseline severity was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D17); treatment response at week 12 was based on HAM-D17 total score and response and remission status. Saliva (cortisol) and blood (BDNF, IL-6) samples for biomarker assay were collected at baseline and week 12. Spearman correlations were calculated between the biomarkers at baseline, and between biomarkers and HAM-D17 total score at baseline. Logistic regression analyses were used to assess whether baseline biomarker levels predicted treatment response at week 12, with and without adjustment for baseline HAM-D17 score, treatment, and geographic region. Similarly, an analysis of covariance was used to assess whether baseline disease severity predicted biomarker change at week 12. RESULTS: A total of 427 patients who received ≥1 dose of study drug and had baseline and ≥1 on-therapy primary efficacy evaluations were included in the analysis. At baseline, there was a statistically significant although weak correlation between levels of IL-6 and BDNF (Spearman correlation coefficient [rs]=0.120; P=0.014), but no significant correlation between baseline biomarker levels and baseline HAM-D17 total score (absolute value of all rs, ≤0.061). Desvenlafaxine 50mg/d treatment significantly reduced HAM-D17 total score from baseline at week 12 compared with placebo (P=0.006), but the three potential biomarkers did not predict treatment effects. No significant correlations were observed between the change from baseline in any biomarker level and change in HAM-D17 total score at week 12, either overall, or in desvenlafaxine or placebo groups (absolute value of all rs, 0.003-0.196). Baseline levels of BDNF, IL-6, and salivary cortisol did not significantly predict response to treatment at week 12. Although median increase in BDNF was not significantly different between desvenlafaxine (13.7%) and placebo (5.7%) groups, the increase was significantly greater (33.4% vs 4.3%; P=0.003) in patients with more severe depression at baseline (HAM-D17>22) vs those with less severe depression (HAM-D17≤22). No similar findings were observed for IL-6 or salivary cortisol. DISCUSSION: Weak or no relationships were observed at baseline between the potential biomarkers or between biomarkers and disease severity. While baseline biomarker level did not predict treatment response, improvement in BDNF was significantly greater among patients who were more severely depressed at baseline.

Influence of sex and menopausal status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: analysis of data from the PREVENT study.

OBJECTIVE: To evaluate the effects of sex and menopausal status on acute-, continuation-, and maintenance-phase treatment outcomes in patients with recurrent major depressive disorder (MDD). METHOD: This was a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) trial, a multiphase, multicenter, double-blind study in which adult outpatients with recurrent MDD (by DSM-IV criteria) were randomly assigned to 10 weeks of acute-phase venlafaxine extended release (ER) (75-300 mg/d) or fluoxetine (20-60 mg/d). Patients achieving response or remission had 6 months of continuation-phase treatment. Responding or remitting patients in the venlafaxine ER group were randomly assigned to venlafaxine ER or placebo for 2 consecutive 12-month maintenance phases; fluoxetine-treated patients continued receiving fluoxetine. The outcome measures for this analysis were acute- and continuation-phase response and remission rates (as measured by the 17-item Hamilton Depression Rating Scale) and time to depression recurrence in the maintenance phases according to sex and menopausal status at baseline. RESULTS: The intent-to-treat population comprised 781 patients in the venlafaxine ER group (65% women) and 266 patients in the fluoxetine group (61% women); 64% of all women were premenopausal, and 25% were postmenopausal (5% perimenopausal; not analyzed). At acute-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 44% vs 47% in men, 51% vs 52% in women, 50% vs 52% in premenopausal women, and 52% vs 55% in postmenopausal women. At continuation-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 71% vs 74% in men, 72% vs 67% in women, 72% vs 69% in premenopausal women and 71% vs 63% in postmenopausal women. Response rates were consistent with these findings. Based on a Cox proportional hazards model, sex was not a significant predictor of recurrence during the first or second maintenance phase (hazard ratio [HR] = 1.233; P = .3712 and HR = 1.103; P = .8075, respectively), and neither was menopausal status at acute-phase baseline (HR = 0.941; P = .8234 and HR = 0.531; P = .2065, respectively). CONCLUSIONS: In this study of patients with recurrent MDD, treatment outcomes with venlafaxine ER and fluoxetine did not differ on the basis of sex or menopausal status. Our confidence in these findings is limited by the lack of a placebo arm during the acute and continuation phases and by the small sample sizes for subgroup analyses in the maintenance phases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00046020.

Efficacy and safety of desvenlafaxine 50 mg/d in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder.

OBJECTIVE: Evaluate the 8-week efficacy and safety of desvenlafaxine at the recommended dose of 50 mg/d in perimenopausal and postmenopausal women with major depressive disorder (MDD) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. METHOD: This phase 4, multicenter, parallel-group, randomized, double-blind, placebo-controlled study was conducted from June 30, 2010, to June 8, 2011. Patients received placebo or desvenlafaxine 50 mg/d (1:1 ratio; n = 217 in each group). The primary outcome measure was the change at week 8 in the 17-item Hamilton Depression Rating Scale (HDRS17) total score. Secondary outcome measures included change in the Sheehan Disability Scale (SDS), the Clinical Global Impressions-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Visual Analog Scale-Pain Intensity (VAS-PI). RESULTS: At end point, compared to placebo, desvenlafaxine was associated with a significantly greater decrease in HDRS17 total scores (last-observation-carried-forward analysis; adjusted mean change from baseline -9.9 vs -8.1, respectively; P = .004) and significant improvements on the CGI-I (P < .001), MADRS (P = .002), SDS (P = .038), and VAS-PI (P < .001). Improvements on the SDS and VAS-PI reached significance by week 2. Desvenlafaxine was generally safe and well tolerated. CONCLUSIONS: Short-term treatment with desvenlafaxine 50 mg/d was effective for the treatment of MDD in perimenopausal and postmenopausal women, with significant benefits on pain and functional outcomes evident as early as week 2. The safety and tolerability of desvenlafaxine were consistent with data in other populations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01121484.

Sexual functioning in patients with recurrent major depressive disorder enrolled in the PREVENT study.

The incidence of treatment-emergent sexual dysfunction in the acute and continuation phases of the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study was assessed. Adult outpatients with recurrent major depressive disorder were randomly assigned to receive venlafaxine extended release (ER; 75-300 mg/day) or fluoxetine (20-60 mg/day). Sexual dysfunction was assessed using items from the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR). The baseline rates of sexual dysfunction based on the HAM-D(17) and IDS-SR items were 57.9% and 48.8%, respectively. The rates of new-onset sexual dysfunction for the venlafaxine ER-treated (44.8%, HAM-D(17); 38.4%, IDS-SR) and fluoxetine-treated patients (52.9%, HAM-D(17); 50.0%, IDS-SR) were similar; approximately 80% of the cases resolved during treatment. Treatment response was associated with lower rates of new-onset sexual dysfunction compared with nonresponse. The patients who remitted were the least likely to experience sexual dysfunction during antidepressant treatment.

The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder.

OBJECTIVE: To determine whether the combination of triiodothyronine (T3) plus sertraline at treatment initiation confers greater antidepressant efficacy than sertraline plus placebo in patients with major depressive disorder. METHOD: Eight-week, double blind, randomized placebo controlled clinical trial of 153 adult outpatients between 18 and 60 years of age, with DSM-IV defined major depressive disorder. Patients were treated with sertraline flexibly adjusted for tolerability and in a double blind fashion with placebo or T3 (25 µg/day in week 1 and increasing to 50 µg/day in week 2). Response was defined categorically as 50% reduction and total score less than 15 in 21-item Hamilton Rating Scale for Depression (HRSD-21) at week 8 and remission as HRSD-21 less than 8. RESULTS: There was no difference between treatment groups at final assessment; 65% of placebo and 61.8% of T3 treated subjects achieved response and 50.6% of placebo and 40.8% of T3 treated patients achieved remission. The mean daily dose at final assessment of sertraline and T3, respectively was 144.7 mg (± 48.7 mg) and 48.2 µg (± 7 µg). Median time to response did not differ between treatment groups. Baseline thyroid function tests did not predict response to sertraline treatment or T3 augmentation. CONCLUSIONS: These results do not support the routine use of T3 to enhance or accelerate onset of antidepressant response in patients with major depressive disorder.

A meta-analysis of factors impacting detection of antidepressant efficacy in clinical trials: the importance of academic sites.

Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant-placebo differences, we conducted a meta-analysis of all relevant phase II-IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D17) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (ß=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug-placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug-placebo separation for both HAM-D17 continuous score change (ß=2.24, p=0.034) and response rate (ß=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.

Recovery and subsequent recurrence in patients with recurrent major depressive disorder.

In contrast to "remission" from an episode of major depressive disorder (MDD), for which there is general agreement in the literature, the optimal definition of "recovery" from MDD is uncertain. Previous definitions of recovery have used inconsistent thresholds for symptom severity and duration of wellness. To address the effects of duration and degree of recovery from an episode of MDD on recurrence risk, and the impact of maintenance antidepressant treatment on recurrence, we analyzed 258 patients from a randomized, double-blind study of outpatients with recurrent MDD. All patients had responded to 8½ months of venlafaxine extended release and were subsequently randomized to receive venlafaxine ER or placebo during 2 consecutive 12-month maintenance phases. Four definitions of recovery were used to evaluate recovery rates and time to recurrence: (1) 17-item Hamilton Depression Rating Scale (HAM-D(17)) total score ≤3 with duration ≥120 days; (2) HAM-D(17) ≤3 with duration ≥56 days; (3) HAM-D(17) ≤7 with duration ≥120 days; and (4) HAM-D(17) ≤7 with duration ≥56 days. Recovery definitions using lower symptom severity and longer duration thresholds produced lower rates of recurrence. Patients on placebo were more likely to have a recurrence than patients on venlafaxine ER, with hazard ratio (HR) ranging from 2.5 among patients who recovered by the most relaxed criteria (definition 4), to 5.3 among patients who recovered by the most stringent criteria (definition 1). We conclude that protection against recurrence derives from the degree and duration of recovery, particularly for patients maintained on antidepressant medication.

Remission with venlafaxine extended release or selective serotonin reuptake inhibitors in depressed patients: a randomized, open-label study.

BACKGROUND: This randomized, open-label, rater-blinded, multicenter study compared treatment outcomes with the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine extended release (ER) with selective serotonin reuptake inhibitors (SSRIs) in primary care patients with major depressive disorder. METHOD: Study data were collected from November 29, 2000, to March 4, 2003. Outpatients who met diagnostic criteria for major depressive disorder according to the Mental Health Screener, a computer-administered telephone interview program that screens for the most common mental disorders, and had a total score on the 17-item Hamilton Depression Rating Scale (HDRS(17)) ≥ 20 were randomly assigned to receive up to 6 months of open-label venlafaxine ER 75-225 mg/d (n = 688) or an SSRI (n = 697): fluoxetine 20-80 mg/d, paroxetine 20-50 mg/d, citalopram 20-40 mg/d, and sertraline 50-200 mg/d. The primary outcome was remission (HDRS(17) score ≤ 7) at study end point using the last-observation-carried-forward method to account for early termination. A mixed-effects model for repeated measures (MMRM) analysis evaluated secondary outcome measures. RESULTS: Fifty-one percent of patients completed the study. Month 6 remission rates did not differ significantly for venlafaxine ER and the SSRIs (35.5% vs 32.0%, respectively; P = .195). The MMRM analysis of HDRS(17) scores also did not differ significantly (P = .0538). Significant treatment effects favoring the venlafaxine ER group were observed for remission rates at days 30, 60, 90, and 135 and a survival analysis of time to remission (P = .006), as well as Clinical Global Impressions-severity of illness scale (P = .0002); Hospital Anxiety and Depression Scale-Anxiety subscale (P = .03); 6-item Hamilton Depression Rating Scale, Bech version (P = .009); and Quick Inventory of Depressive Symptomatology-Self-Report (P = .0003). CONCLUSIONS: Remission rates for patients treated with venlafaxine ER or an SSRI did not differ significantly after 6 months of treatment. Results of most secondary analyses suggested that SNRI treatment had a greater antidepressant effect versus the SSRIs studied.

Patient outcomes with education, drug therapy, and support: a study of venlafaxine ER-treated outpatients with major depressive disorder.

OBJECTIVE: Dialogues Time to Talk (Dialogues) is a care management program that provides additional follow-up care and patient education for outpatients with major depressive disorder (MDD) starting venlafaxine extended release (ER) therapy. This study examined the effect of the Dialogues program on patient treatment satisfaction. METHODS: In this 6-month, open-label study, primary care patients with MDD received usual care and were randomly assigned to venlafaxine ER (75 to 225 mg/d) either alone or in combination with the Dialogues program (venlafaxine ER + D). The primary outcome was patient treatment satisfaction on day 112, measured by the 10- point Satisfaction with Depression Care Scale (SDCS). Secondary efficacy outcomes included the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, response (≥50% decrease from baseline HAM-D17 score), and remission (HAM-D17 ≤ 7). RESULTS: The modified intent-to-treat population included 263 patients in the venlafaxine ER group and 257 in the venlafaxine ER+D group. The percentage of patients with an SDCS "very satisfied" score (≥8) at day 112 was not significantly different in the venlafaxine ER and venlafaxine ER+D groups (63% and 58%, respectively; P = 0.22). No significant differences were found on any secondary outcomes. CONCLUSION: Among primary care patients starting venlafaxine ER for MDD, participation in the Dialogues program did not have a statistically significant effect on patient treatment satisfaction.

Retrospective analysis of suicidality in patients treated with the antidepressant desvenlafaxine.

The objective of this analysis was to assess the risk of increased suicidal thoughts and behavior (suicidality) with desvenlafaxine (administered as desvenlafaxine succinate) in patients with major depressive disorder (MDD). Data from 9 double-blind, 8-week studies in outpatients with MDD were analyzed retrospectively. Patients were randomly assigned to desvenlafaxine (n = 1834) or placebo (n = 1116). Adverse events (AEs) related to suicidality were identified by searching the AE database for text strings possibly related to suicidality; false positives were excluded. Narratives for each case were prepared and blinded for review. Events were classified according to the Columbia Classification Algorithm of Suicide Assessment. Odds ratios were calculated; chi tests were used to compare treatment groups. Occurrence of emerging or worsening suicidality, based on the 17-item Hamilton Rating Scale for Depression suicide item, was compared for desvenlafaxine and placebo using chi tests. In all, 17 (0.93%) of 1834 patients receiving desvenlafaxine and 8 (0.72%) of 1116 receiving placebo reported possible suicidality-related AEs. Events were relatively evenly distributed across treatment groups. One patient randomly assigned to desvenlafaxine treatment died of completed suicide during the on-therapy period. There were no significant differences between groups in the risk for any class of suicide-related events, including completed suicide or suicide attempt. Odds of emergence or worsening of suicidality 17-item (Hamilton Rating Scale for Depression suicide item) did not differ significantly between treatment groups. No evidence of a signal for increased suicidality was detected in adult patients treated with desvenlafaxine in short-term MDD trials. As suicidal events were extremely rare, a true increased risk cannot be ruled out.

Desvenlafaxine and weight change in major depressive disorder.

OBJECTIVE: To characterize weight change during short- and longer-term treatment with desvenlafaxine (administered as desvenlafaxine succinate) for major depressive disorder (MDD). METHOD: Data from 9 short-term, double-blind, placebo-controlled studies and 1 longer-term relapse-prevention trial conducted between September 2002 and January 2007 were analyzed. Adult outpatients with a primary diagnosis of MDD using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition received fixed- or flexible-dose desvenlafaxine or placebo for 8 weeks in the short-term studies. In the longer-term study, responders to 12 weeks of open-label desvenlafaxine treatment were randomly assigned to double-blind treatment with desvenlafaxine or placebo for 6 months. Mean weight changes and incidence of potentially clinically important changes were evaluated. RESULTS: In the short-term studies (desvenlafaxine: n = 1,834; placebo: n = 1,116), mean decreases in weight associated with desvenlafaxine were small but statistically significant compared with baseline (P < .05) and with placebo (final evaluation: -0.82 kg desvenlafaxine vs + 0.05 kg placebo; P < .001). Likewise, during the 12-week, open-label phase of the relapse-prevention study (n = 594), a small but statistically significant mean decrease in weight from baseline (-0.8 kg; P < .001) occurred. Small mean increases in weight (< 1 kg) were observed with both desvenlafaxine (n = 190) and placebo (n = 185) throughout the relapse-prevention phase, with no statistical difference between desvenlafaxine- and placebo-treated patients at the final evaluation. Less than 1% of desvenlafaxine-treated patients experienced a clinically meaningful weight change. CONCLUSIONS: Desvenlafaxine was not associated with clinically significant weight change during short- or longer-term treatment.

Depression or menopause? Presentation and management of major depressive disorder in perimenopausal and postmenopausal women.

OBJECTIVE: The purpose of this review was to examine the risk of depression onset in perimenopausal and postmenopausal women, discuss the importance and rationale for screening for major depressive disorder (MDD) in women in the menopausal transition, and review therapeutic options for management of MDD in perimenopausal and postmenopausal women. DATA SOURCES: PubMed was searched (1970 to 2008) using combinations of the following terms: major depressive disorder, perimenopause, postmenopause, mood disorder, risk factors, reproductive period, family practice, differential diagnosis, hormone, estrogen replacement therapy, reuptake inhibitors, and neurotransmitter. STUDY SELECTION: All relevant articles identified via the search terms reporting original data and published in English were considered for inclusion. Twenty-two cross-sectional and longitudinal studies were utilized to evaluate the relationship between the menopausal transition and risk of mood disorders and to formulate recommendations for screening and management of MDD in perimenopausal and postmenopausal women. DATA EXTRACTION: RESEARCH STUDIES UTILIZED THE FOLLOWING MEASURES: postal questionnaires, Women's Health Questionnaire, Beck Depression Inventory, Center for Epidemiologic Studies-Depression scale, Modified Menopause Symptom Inventory, 12-item symptom questionnaire, or Structured Clinical Interview for DSM-IV. DATA SYNTHESIS: Menopause is a normal, and for most women largely uneventful, part of life. For some women, however, the menopausal transition is a period of biologic vulnerability with noticeable physiologic, psychological, and somatic symptoms. The perimenopausal period is associated with a higher vulnerability for depression, with risk rising from early to late perimenopause and decreasing during postmenopause. Women with a history of depression are up to 5 times more likely to have a MDD diagnosis during this time period. CONCLUSIONS: Routine screening of this at-risk population followed by careful assessment for depressive symptoms can help identify the presence of MDD in the menopausal transition. Recognition of menopausal symptoms, with or without depression, is important given their potential impact on quality of life.

Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder.

INTRODUCTION: Venlafaxine, a serotonin-norepinephrine reuptake inhibitor antidepressant, is metabolized primarily by the cytochrome P450 2D6 enzyme into O-desmethylvenlafaxine (ODV). The ODV/venlafaxine ratio can be used to distinguish between extensive metabolizers (EMs) and poor metabolizers (PMs). OBJECTIVES: To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD). METHOD: Data from 4 double-blind, placebo-controlled studies of patients with MDD were pooled. Blood samples were analyzed for plasma concentrations of venlafaxine, ODV, total venlafaxine + ODV, and ODV/venlafaxine ratio. Patients were classified as EMs or PMs on the basis of ODV/venlafaxine ratios. Changes from baseline in depression scale scores were compared between EMs and PMs using t tests. Rates of response, remission, discontinuation, and adverse events (AEs) were compared for EMs and PMs using Fisher exact tests. RESULTS: Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P ≤ .020). A significantly greater percentage of EMs achieved response or remission by most measures compared with PMs (4 of 5 comparisons, P ≤ .015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs. Since there were no substantial differences between EMs and PMs in terms of venlafaxine dose or tolerability, these factors are not likely to account for the efficacy findings. CONCLUSIONS: Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.

Analysis of the effect of desvenlafaxine on anxiety symptoms associated with major depressive disorder: pooled data from 9 short-term, double-blind, placebo-controlled trials.

BACKGROUND: This analysis evaluated the effects of the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine (administered as desvenlafaxine succinate), on anxiety symptoms associated with depression. METHODS: Data were pooled from 9 randomized, placebo-controlled, double-blind, 8 week studies of desvenlafaxine (50-400 mg/day, fixed or flexible dose) in patients with major depressive disorder (MDD), without a primary anxiety diagnosis. Changes from baseline in scores on the anxiety/somatization factor of the 17-item Hamilton Rating Scale for Depression (HAM-D17) and on the Covi Anxiety Scale at the final evaluation (last observation carried forward) were compared between desvenlafaxine and placebo groups using analysis of covariance. RESULTS: In the overall data set (intent to treat n=2,913 [desvenlafaxine, n=1,805; placebo, n=1,108]), desvenlafaxine was associated with significantly greater reductions compared with placebo in scores on the HAM-D17 anxiety/somatization factor (-3.41 vs -2.92, P<.001) and Covi Anxiety Scale (-1.35 vs -1.04, P<.001). In the subset of fixed-dose studies, significant differences were observed for all dose groups on the HAM-D17 anxiety/somatization factor (P= or <.011), and for the 50, 100, and 200 mg/day dose groups on the Covi Anxiety Scale (all P= or <.015 vs placebo). CONCLUSIONS: Desvenlafaxine was associated with significantly greater improvement in anxiety symptoms compared with placebo in patients with MDD.

Clinical utility of desvenlafaxine 50 mg/d for treating MDD: a review of two randomized placebo-controlled trials for the practicing physician.

BACKGROUND: Major depressive disorder (MDD) is a common, seriously impairing illness. Desvenlafaxine (administered as desvenlafaxine succinate) is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States for the treatment of MDD. Short-term clinical studies have demonstrated the efficacy and safety of 50 to 400 mg/d doses, with no evidence that doses greater than 50 mg/d confer additional benefit. OBJECTIVE: This paper summarizes published data on the efficacy, safety, and tolerability of the desvenlafaxine 50-mg/d recommended therapeutic dose for MDD and discusses clinical practice considerations. METHODS: A systematic review of MEDLINE, PsycINFO, and PubMed (all years through June 2009) was performed using the terms desvenlafaxine, DVS, and ODV. The criteria for inclusion in the review were a double-blind design, a placebo control or active comparator group, the 50-mg desvenlafaxine dose group, and enrollment of patients with a diagnosis of MDD. Posters were included if they reported on a study that was subsequently published in a manuscript. RESULTS: Overall results of two randomized, placebo-controlled, 8-week clinical trials demonstrated the efficacy of desvenlafaxine 50 mg/d for MDD. Statistically significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score; P < 0.05). Significant differences were observed on several secondary measures (Montgomery Asberg Depression Rating Scale scores in both trials [P < 0.05]; Clinical Global Impressions-Improvement scores [P < or = 0.01], Clinical Global Impressions-Severity scores [P < or = 0.01], HAM-D(17) response [P < or = 0.01] and remission [P < 0.05] in one trial each). Functional outcomes measures (Sheehan Disability Scale total and World Health Organization 5-Item Well-Being Index scores) were significant in both trials (P < 0.05). Safety results indicate desvenlafaxine treatment was safe and well tolerated; findings were consistent with the SNRI class. The generalizability of these findings is limited by the study protocols, which excluded patients with unstable comorbid medical conditions and also those with other Axis 1 and 2 psychiatric illnesses. Additionally, comparisons with other SNRIs are challenging given differences in study design. Desvenlafaxine can be initiated with the 50-mg/d therapeutic dose without titration and provides efficacy with rates of discontinuation due to treatment-emergent adverse events similar to placebo. In vitro data indicate desvenlafaxine has minimal inhibitory effects on cytochrome P450 (CYP) 2D6 and clinical studies show desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism. In vitro data also indicate desvenlafaxine is not a substrate or inhibitor of the p-glycoprotein transporter. Plasma protein binding of desvenlafaxine is low (30%) and independent of drug concentration. Bioavailability is high at 80% after oral administration and is not affected by food. CONCLUSIONS: Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in two placebo-controlled trials. The metabolic profile of desvenlafaxine suggests a low risk of drug-drug interactions owing to minimal inhibitory effects on CYP2D6, lack of interaction with p-glycoprotein, and low protein binding.

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.