Faculty Bibliography

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.

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.

OBJECTIVE:This study assessed the efficacy, safety, and tolerability of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine and the selective serotonin reuptake inhibitor escitalopram for major depressive disorder (MDD) in postmenopausal women. METHODS:In this randomized, double-blind study, postmenopausal outpatients (aged 40-70 y) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition MDD received flexible-dose desvenlafaxine (100-200 mg/d) or escitalopram (10-20 mg/d) for 8 weeks. Acute-phase responders, that is, women with a 50% or greater reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, were eligible to continue the same double-blind treatment in the 6-month continuation phase. The primary efficacy outcomes were mean change from baseline in HAM-D17 total score (acute phase), analyzed using a mixed-effects model for repeated measures, and the proportion of women who maintained response (continuation phase), analyzed using logistic regression. RESULTS:Reductions in HAM-D17 total score at acute-phase endpoint were similar for desvenlafaxine- and escitalopram-treated women (-13.6 vs -14.3, respectively; P = 0.24). No significant difference was observed between groups at continuation-phase endpoint in the proportion of women who maintained response (desvenlafaxine, 82%; escitalopram, 80%; P = 0.70). In both phases, desvenlafaxine and escitalopram were generally safe and well tolerated. CONCLUSIONS:Among postmenopausal outpatients with MDD, there were no significant differences in the efficacy of desvenlafaxine and escitalopram based on primary efficacy analyses. The results do not support the overall hypothesis that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine has an efficacy advantage for the treatment of MDD in postmenopausal women because, in this particular subgroup, desvenlafaxine failed to prove superiority over escitalopram. Safety and tolerability were comparable.

INTRODUCTION/BACKGROUND: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/OBJECTIVE:To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD). METHOD/METHODS: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.

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.

OBJECTIVE:Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication. METHOD/METHODS:Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire. RESULTS:Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone. CONCLUSION/CONCLUSIONS:Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.

In this meta-analysis, we compare the relative efficacy of venlafaxine to selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder classified according to baseline disease severity. Data from 31 double-blind randomised clinical trials comparing venlafaxine and SSRIs (intent-to-treat n = 6,492) were pooled. For this secondary analysis, patients were stratified into groups based on baseline HAM-D(17) total score (>or=30, <30, >or=25, and <25). Remission rates (HAM-D(17) < 8) were analyzed for each subgroup using Fisher's exact test to compare treatment effects between venlafaxine and SSRIs; last observation carried forward (LOCF) and observed cases (OC) data were analyzed. The number needed to treat (NNT) to benefit was determined for each analysis. Statistically significant remission rate differences, favoring venlafaxine, were seen in LOCF and OC analyses for each subgroup. In patients with baseline HAM-D(17) < 25 (n = 3,928) the differences were (LOCF) 7.3 [P < 0.001; NNT = 14] and (OC) 6.2 [P = 0.003; NNT = 16], and in patients with baseline HAM-D(17) >or= 25 (n = 2,564) were (LOCF) 5.7 [P = 0.002; NNT = 17] and (OC) 6.7 [P = 0.009; NNT = 15]. In patients with baseline HAM-D(17) < 30 (n = 5,836) the differences were (LOCF) 6.4 [P < 0.001; NNT = 16] and (OC) 5.5 [P = 0.001; NNT = 18], and in patients with baseline HAM-D(17) >or= 30 (n = 656) were (LOCF) 8.9 [P = 0.015; NNT = 11] and (OC) 14.8 [P = 0.003; NNT = 7]. In conclusion, these analyses demonstrate that venlafaxine may be superior to SSRIs in achieving remission in both mild/moderate and severely depressed patients. The greater difference in remission rates among patients with baseline HAM-D(17) >or= 30 suggests a more pronounced clinical benefit that may be achieved with venlafaxine in severely depressed patients.

BACKGROUND:Cytokines of the innate immune response may contribute to behavioral alterations that resemble major depression as manifested in medically healthy individuals. METHODS:To explore potential similarities and differences between cytokine-induced depression and idiopathic major depression in healthy subjects, dimensional analyses comparing specific symptom dimensions of depression were conducted in 20 patients with malignant melanoma administered the innate immune cytokine, interferon (IFN)-alpha, and 28 medically healthy subjects with major depression of similar age and gender distribution. The Hamilton Rating Scale for Depression was used to assess severity of individual depressive symptoms. RESULTS:Severity of symptoms of anxiety, depressed mood, and impaired work/activities were comparable between patients with IFN-alpha-induced depression and medically healthy depressed patients. Interestingly, however, compared to medically healthy patients with major depression, patients with IFN-alpha-induced depression reported significantly greater psychomotor retardation and weight loss and significantly less severe feelings of guilt. LIMITATIONS/CONCLUSIONS:The relatively small sample size limited statistical power to detect small differences in symptom expression among groups. CONCLUSIONS:The data suggest that there is considerable overlap in symptom expression between cytokine-induced depression and idiopathic depression in medically healthy subjects. Nevertheless, differences in isolated symptom domains suggest that cytokines may preferentially target neurocircuits relevant to psychomotor activity (e.g. basal ganglia), while having a limited effect on cognitive distortions regarding self-appraisal.

INTRODUCTION/BACKGROUND: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/CONCLUSIONS: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.