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P.2.c.006 Efficacy and clinical relevance of vilazodone in the treatment of major depressive disorder: a pooled analysis of phase III clinical trials
P.2.c. Affective disorders and antidepressants − Antidepressants (clinical) P.2.c.005 A comparison of the effect on pain symptoms between SSRIs, SNRIs and mirtazapine D.B. Park1 ° , Y.S. Lee1 , H.J. Lee1 , W.H. Song1 , D.H. Han1 , C. Na1 1 Chung-Ang University Hospital, Psychiatry, Seoul, South-Korea Purpose of the study: Selective serotonin reuptake inhibitors (SSRIs), Serotonin and noradrenaline reuptake inhibitors (SNRIs), Mirtazapine are widely used in psychological disorder including major depressive disorder, somatoform disorder, and posttraumatic stress disorder. Patients with major depressive disorder, somatoform disorder, or post-traumatic stress disorder usually complain somatic pain such as headache, myalgia, abdominal pain, and so forth. Most clinicians are reported to control pain symptoms using SSRIs, SNRIs, or Mirtazapine. But there are no enough data comparing the effect on the pain between SSRIs, SNRIs, and Mirtazapine. We assessed the effects of antidepressants on the relief of pain in the patients with major depressive disorder, somatoform disorder, or post-traumatic stress disorder. Methods used: 85 patients, who were hospitalized at department of psychiatry, Chung-Ang university hospital (Seoul) from 1 January 2011 to 31 December 2011, were enrolled in the study. All the subjects had been diagnosed with major depressive disorder, somatoform disorder, or post-traumatic stress disorder in accordance with DSM-IV-TR criteria. patients divided by medications into three groups: SSRIs group, SNRIs group, and Mirtazapine group. Depressive symptoms were assessed by specialists in psychiatry using the Korean version of the Hamilton depression rating scale (K-HDRS) on admission and 2 weeks later. And somatic symptoms also were assessed by specialists in psychiatry using Visual analogue scale (VAS) on admission and 2 weeks later. Summary of results containing real data and Appropriate statistical assessments: There are no significant differences in demographical data between SSRIs group, SNRIs group, and Mirtazapine groups. And there are no significant differences in K-HDRS in admission, and VAS in admission between SSRIs group, SNRIs group, and Mirtazapine group. And there are no significant differences in K-HDRS change rates between SSRIs group, SNRIs group, and Mirtazapine group (c2 = 1.63, p = 0.44). On the other hand, VAS change rates show marked difference between three groups by 35% change on VAS (c2 = 7.56, p = 0.02), Mirtazapine group (RR35 = 67.6%) is about twice as good as SSRIs group (RR35 = 37.5%) and SNRIs group (RR35 = 37.5%) for pain symptoms. Conclusions: The current study showed that there was no significant difference in the antidepressant effects between SSRIs, SNRIs, and Mirtazapine. However, there was significant difference in the change of somatic symptoms between three antidepressants. Mirtazapine showed great effectiveness on the relief of somatic symptoms, compared to SSRIs and SNRIs.
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P.2.c.006 Efficacy and clinical relevance of vilazodone in the treatment of major depressive disorder: a pooled analysis of phase III clinical trials A. Khan1 , W. Song2 , J. Edwards3 ° , A. Ruth4 1 Northwest Clinical Research Center, Belleview, USA; 2 Forest Research Institute, Biostatistics, Jersey City, USA; 3 Forest Research Institute, Medical Affairs, Jersey City, USA; 4 Prescott Medical Communications Group, Chicago, USA Objective: Beyond efficacy, the clinical relevance of antidepressant treatment has been evaluated using measures such as response, remission, and the number needed to treat (NNT) or harm (NNH). Vilazodone, a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is FDA approved for treatment of major depressive disorder (MDD) in adults. Data from the positive Phase III vilazodone trials (NCT00285376; NCT00683592) were pooled to evaluate efficacy across depressive symptoms and clinical relevance relative to placebo. Methods: Data from 2 double-blind, randomized, placebocontrolled trials of similar design and conduct (1-week screening followed by 8-week double-blind treatment) were pooled for analyses. Participants were 18−70 years of age with DSM-IV-TRdefined MDD and a minimum score 22 on the 17-item Hamilton Depression Rating Scale (HAMD17 ). Patients randomized to vilazodone were titrated to a target dose of 40 mg, taken once daily (QD) with food, over a 2-week period (10 mg QD for 7 days, 20 mg QD for the next 7 days, and 40 mg QD thereafter). The primary efficacy parameter was MontgomeryAsberg Depression Rating Scale (MADRS) total score change from baseline to Week 8 analyzed using an analysis of covariance (ANCOVA) model based on the Intent-to-Treat (ITT) population and the last observation carried forward (LOCF) approach. Response (MADRS 50% improvement from baseline; HAMD17 50% improvement from baseline; CGI-I score 2) and remission (MADRS 10; MADRS 12) were analyzed. Post hoc analyses estimated the treatment effect of vilazodone versus placebo on MADRS single items, the number needed to treat (NNT) for response (MADRS 50% improvement) and remission (MADRS 10), and the number needed to harm (NNH) for adverse events (AEs) and AE discontinuations. Results: The ITT population comprised 431 vilazodone- and 432 placebo-treated patients. Vilazodone significantly improved MADRS total score relative to placebo with a least squares mean difference (LSMD) of −2.79 (P < 0.0001). Response was significantly greater for vilazodone versus placebo on all measures: MADRS (42% vs 29%, P = 0.0002); HAMD17 (44% vs 33%, P = 0.0007); and CGI-I (49% vs 35%, P < 0.0001). Remission was significantly greater for vilazodone versus placebo using both criteria; MADRS 10 (29% vs 20%, P = 0.0041) and MADRS 12 35% vs 22%, P < 0.001). Significant improvement in LSMD in favor of vilazodone versus placebo was seen in the change from baseline on every MADRS single item: apparent sadness, −0.24; reported sadness, −0.29; inner tension, −0.31; reduced sleep, −0.30; reduced appetite, −0.20; concentration difficulties, −0.24; lassitude, −0.27; inability to feel, −0.25; pessimistic thoughts, −0.35; suicidal thoughts, −0.29 (P < 0.01 for all). The NNT (95% CI) for response and remission was 8 (5, 17) and 12 (7, 37), respectively; the NNH (95% CI) for AE discontinuations was 26 (15, 106). Conclusions: Vilazodone showed broad efficacy across depression symptoms. Significantly better response and remission indi-
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cated clinical relevance for vilazodone; NNT and NNH analyses suggested a lower risk of AE discontinuation relative to clinically meaningful improvement for vilazodone. An NNT 10 for response is generally regarded as evidence for clinical relevance in depression treatment. Disclosure statement: J. Edwards is an employee of Forest Research Institute. This paper is financially supported by Forest Laboratories, Inc.
P.2.c.007 Predictors of relapse in a fixed-dose, randomized, double-blind, 52-week relapse prevention trial of selegiline transdermal system A. Patkar1 ° , S. Jang1 , S. Jung1 , C. Pae1 , Y. Jae1 , K. Portland2 1 Duke University, Department of Psychiatry and Behavioral Sciences, Durham, USA; 2 Dey Pharma L.P., Medical Affairs, Basking Ridge, USA Purpose: Major depression is a chronic disorder with at least 75% of patients experiencing recurrences and/or relapses. Recurrent episodes and relapses have also been shown to be predictors of treatment resistance in MDD when compared to single episode depression. The variability in treatment relapse in major depressive disorder (MDD) has led to investigations of the relevance of patient characteristics as predictors of relapse. Despite consistent evidence for efficacy, the clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to safety concerns about food and drug interactions. Selegiline transdermal system (STS), US FDA approved for major depressive disorder, was developed to overcome the limitations of oral MAOIs, in particular, dietary restrictions. Labeling for STS 6 mg/24 hr requires no restrictions, while 9 mg/24 hr and 12 mg/24 hr doses necessitate dietary modifications. In clinical trials without dietary modifications, there were no reports of hypertensive crisis associated with STS. Selegiline transdermal system (STS) has been demonstrated to be an effective and well-tolerated acute and maintenance treatment for MDD [1], [2]. STS delivers sustained blood levels of monoamine oxidase inhibitor (MAOI) directly into systemic circulation, avoiding the need for a tyramine-restricted diet at the 6 mg/day dose. To date, predictors of response or relapse with STS have not been assessed. The purpose of this post hoc analysis was to examine clinical characteristics predictive of relapse in a 52-week controlled, pivotal trial of selegiline transdermal system (STS) [1]. Method: After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 hrs) or placebo. Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of 14 and a CGI-S score of 3 with at least 2-point increase from the beginning of double blind phase on 2 consecutive visits. Pretreatment demographics, illness course, treatment resistance and symptom domains were studied to identify predictors of relapse. Results: Significantly fewer STS patients (16.8%) relapsed compared to placebo (30.7%) (p < 0.005) and had a significantly longer time to relapse than did placebo (p < 0.005) across the 52 week trial. Baseline total HAMD-28 score, somatic anxiety, recurrent MDD, atypical depression, and analgesic use (celecoxib, naproxen) predicted relapse. Significant predictors of differential outcome were identified: (1) high baseline HAMD-28 score (p < 0.001), high somatic anxiety (p < 0.05) and celecoxib
use (p < 0.05) predicted relapse with STS; (2) atypical symptoms (p < 0.05), recurrent episodes (p < 0.05) and naproxen use (p < 0.01) predicted relapse with placebo. Conclusions: For patients on STS, higher baseline depression severity, somatic anxiety or receiving celecoxib predicted relapse, while predictors of relapse with placebo were atypical or recurrent depression or naproxen use. The results are in line with previous research on the utility of MAOIs for patients with anxiety and/or atypical symptoms and provide indirect evidence of treatment specificity by identifying characteristics which may be of value in selection of patients for STS treatment. References [1] Amsterdam, J.D., Bodkin, J.A., 2006. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol 26, 579–586. [2] Patkar, A.A., Pae, C.U., Masand, P.S., 2006. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. CNS Spectr 11, 363–375. Disclosure statement: Funding for this study was provided by Dey Pharma, L. P., d/b/a Mylan Specialty. Kimberly Blanchard Portland is a full-time employee of Dey Pharma, L. P., d/b/a Mylan Specialty.
P.2.c.008 Efficacy of venlafaxine extended release monotherapy for first episode depression with painful physical symptoms X. Huang1 ° , C. Li2 , Y.L. Luo2 , J.L. Ji1 , B. Wang2 1 Zhongshan Hospital Fudan University, Dept. of Psychological Medicine, Shanghai, China; 2 Shanghai Mental Health Center Shanghai Jiaotong University, Dept. of Psychiatry, Shanghai, China Objective: To evaluate the effectiveness, tolerability and safety of venlafaxine extended release (XR) monotherapy in the treatment of first episode major depressive disorder (MDD) associated with painful physical symptoms. Methods: This was a multi-center, open-label, 8-week, realworld study. Participants were first episode outpatient adults who presented with the chief complaint of chronic pain and met diagnosis criteria for Major Depressive Disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). At baseline, all patients were required to have a 17-item Hamilton depression rating scale (HAM-D17 ) total score of 18 and coexist pain symptoms for at least 1 month with Visual analog scales (VAS) >30. Patients received venlafaxine XR 75 to 225 mg/day monotheraphy (N = 102) for 8 weeks. Patients were evaluated at weeks 2, 4, 6 and 8, for a total of 5 study visits. Data analysis was performed on the intent-to-treat (ITT) population using the last-observation-carried-forward (LOCF) methods for missing data. Descriptive statistics were used to summarize the demographic and safety measures. For the comparisons of the difference from baseline, mixed effect model under SAS version 9.2 was applied to analyze all patients with at least 1 post baseline assessment, with gender, age, duration of depression, duration of pain, dose as fixed effect, subject as random effect. Point estimates and their associate 90% confidence intervals were constructed for the difference. The primary efficacy endpoint was the baseline-toendpoint change in mean HAM-D17 scores. Results: Of the 102 outpatients enrolled in this therapy phase, 86 (84.3%) completed the study. Venlafaxine XR treatment was followed by a significant decrease on the HAM-D17 scores
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P.2.c.006 Efficacy and clinical relevance of vilazodone in the treatment of major depressive disorder: a pooled analysis of phase III clinical trials A. Khan1 , W. Song2 , J. Edwards3 ° , A. Ruth4 1 Northwest Clinical Research Center, Belleview, USA; 2 Forest Research Institute, Biostatistics, Jersey City, USA; 3 Forest Research Institute, Medical Affairs, Jersey City, USA; 4 Prescott Medical Communications Group, Chicago, USA Objective: Beyond efficacy, the clinical relevance of antidepressant treatment has been evaluated using measures such as response, remission, and the number needed to treat (NNT) or harm (NNH). Vilazodone, a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is FDA approved for treatment of major depressive disorder (MDD) in adults. Data from the positive Phase III vilazodone trials (NCT00285376; NCT00683592) were pooled to evaluate efficacy across depressive symptoms and clinical relevance relative to placebo. Methods: Data from 2 double-blind, randomized, placebocontrolled trials of similar design and conduct (1-week screening followed by 8-week double-blind treatment) were pooled for analyses. Participants were 18−70 years of age with DSM-IV-TRdefined MDD and a minimum score 22 on the 17-item Hamilton Depression Rating Scale (HAMD17 ). Patients randomized to vilazodone were titrated to a target dose of 40 mg, taken once daily (QD) with food, over a 2-week period (10 mg QD for 7 days, 20 mg QD for the next 7 days, and 40 mg QD thereafter). The primary efficacy parameter was MontgomeryAsberg Depression Rating Scale (MADRS) total score change from baseline to Week 8 analyzed using an analysis of covariance (ANCOVA) model based on the Intent-to-Treat (ITT) population and the last observation carried forward (LOCF) approach. Response (MADRS 50% improvement from baseline; HAMD17 50% improvement from baseline; CGI-I score 2) and remission (MADRS 10; MADRS 12) were analyzed. Post hoc analyses estimated the treatment effect of vilazodone versus placebo on MADRS single items, the number needed to treat (NNT) for response (MADRS 50% improvement) and remission (MADRS 10), and the number needed to harm (NNH) for adverse events (AEs) and AE discontinuations. Results: The ITT population comprised 431 vilazodone- and 432 placebo-treated patients. Vilazodone significantly improved MADRS total score relative to placebo with a least squares mean difference (LSMD) of −2.79 (P < 0.0001). Response was significantly greater for vilazodone versus placebo on all measures: MADRS (42% vs 29%, P = 0.0002); HAMD17 (44% vs 33%, P = 0.0007); and CGI-I (49% vs 35%, P < 0.0001). Remission was significantly greater for vilazodone versus placebo using both criteria; MADRS 10 (29% vs 20%, P = 0.0041) and MADRS 12 35% vs 22%, P < 0.001). Significant improvement in LSMD in favor of vilazodone versus placebo was seen in the change from baseline on every MADRS single item: apparent sadness, −0.24; reported sadness, −0.29; inner tension, −0.31; reduced sleep, −0.30; reduced appetite, −0.20; concentration difficulties, −0.24; lassitude, −0.27; inability to feel, −0.25; pessimistic thoughts, −0.35; suicidal thoughts, −0.29 (P < 0.01 for all). The NNT (95% CI) for response and remission was 8 (5, 17) and 12 (7, 37), respectively; the NNH (95% CI) for AE discontinuations was 26 (15, 106). Conclusions: Vilazodone showed broad efficacy across depression symptoms. Significantly better response and remission indi-
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cated clinical relevance for vilazodone; NNT and NNH analyses suggested a lower risk of AE discontinuation relative to clinically meaningful improvement for vilazodone. An NNT 10 for response is generally regarded as evidence for clinical relevance in depression treatment. Disclosure statement: J. Edwards is an employee of Forest Research Institute. This paper is financially supported by Forest Laboratories, Inc.
P.2.c.007 Predictors of relapse in a fixed-dose, randomized, double-blind, 52-week relapse prevention trial of selegiline transdermal system A. Patkar1 ° , S. Jang1 , S. Jung1 , C. Pae1 , Y. Jae1 , K. Portland2 1 Duke University, Department of Psychiatry and Behavioral Sciences, Durham, USA; 2 Dey Pharma L.P., Medical Affairs, Basking Ridge, USA Purpose: Major depression is a chronic disorder with at least 75% of patients experiencing recurrences and/or relapses. Recurrent episodes and relapses have also been shown to be predictors of treatment resistance in MDD when compared to single episode depression. The variability in treatment relapse in major depressive disorder (MDD) has led to investigations of the relevance of patient characteristics as predictors of relapse. Despite consistent evidence for efficacy, the clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to safety concerns about food and drug interactions. Selegiline transdermal system (STS), US FDA approved for major depressive disorder, was developed to overcome the limitations of oral MAOIs, in particular, dietary restrictions. Labeling for STS 6 mg/24 hr requires no restrictions, while 9 mg/24 hr and 12 mg/24 hr doses necessitate dietary modifications. In clinical trials without dietary modifications, there were no reports of hypertensive crisis associated with STS. Selegiline transdermal system (STS) has been demonstrated to be an effective and well-tolerated acute and maintenance treatment for MDD [1], [2]. STS delivers sustained blood levels of monoamine oxidase inhibitor (MAOI) directly into systemic circulation, avoiding the need for a tyramine-restricted diet at the 6 mg/day dose. To date, predictors of response or relapse with STS have not been assessed. The purpose of this post hoc analysis was to examine clinical characteristics predictive of relapse in a 52-week controlled, pivotal trial of selegiline transdermal system (STS) [1]. Method: After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 hrs) or placebo. Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of 14 and a CGI-S score of 3 with at least 2-point increase from the beginning of double blind phase on 2 consecutive visits. Pretreatment demographics, illness course, treatment resistance and symptom domains were studied to identify predictors of relapse. Results: Significantly fewer STS patients (16.8%) relapsed compared to placebo (30.7%) (p < 0.005) and had a significantly longer time to relapse than did placebo (p < 0.005) across the 52 week trial. Baseline total HAMD-28 score, somatic anxiety, recurrent MDD, atypical depression, and analgesic use (celecoxib, naproxen) predicted relapse. Significant predictors of differential outcome were identified: (1) high baseline HAMD-28 score (p < 0.001), high somatic anxiety (p < 0.05) and celecoxib
use (p < 0.05) predicted relapse with STS; (2) atypical symptoms (p < 0.05), recurrent episodes (p < 0.05) and naproxen use (p < 0.01) predicted relapse with placebo. Conclusions: For patients on STS, higher baseline depression severity, somatic anxiety or receiving celecoxib predicted relapse, while predictors of relapse with placebo were atypical or recurrent depression or naproxen use. The results are in line with previous research on the utility of MAOIs for patients with anxiety and/or atypical symptoms and provide indirect evidence of treatment specificity by identifying characteristics which may be of value in selection of patients for STS treatment. References [1] Amsterdam, J.D., Bodkin, J.A., 2006. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol 26, 579–586. [2] Patkar, A.A., Pae, C.U., Masand, P.S., 2006. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. CNS Spectr 11, 363–375. Disclosure statement: Funding for this study was provided by Dey Pharma, L. P., d/b/a Mylan Specialty. Kimberly Blanchard Portland is a full-time employee of Dey Pharma, L. P., d/b/a Mylan Specialty.
P.2.c.008 Efficacy of venlafaxine extended release monotherapy for first episode depression with painful physical symptoms X. Huang1 ° , C. Li2 , Y.L. Luo2 , J.L. Ji1 , B. Wang2 1 Zhongshan Hospital Fudan University, Dept. of Psychological Medicine, Shanghai, China; 2 Shanghai Mental Health Center Shanghai Jiaotong University, Dept. of Psychiatry, Shanghai, China Objective: To evaluate the effectiveness, tolerability and safety of venlafaxine extended release (XR) monotherapy in the treatment of first episode major depressive disorder (MDD) associated with painful physical symptoms. Methods: This was a multi-center, open-label, 8-week, realworld study. Participants were first episode outpatient adults who presented with the chief complaint of chronic pain and met diagnosis criteria for Major Depressive Disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). At baseline, all patients were required to have a 17-item Hamilton depression rating scale (HAM-D17 ) total score of 18 and coexist pain symptoms for at least 1 month with Visual analog scales (VAS) >30. Patients received venlafaxine XR 75 to 225 mg/day monotheraphy (N = 102) for 8 weeks. Patients were evaluated at weeks 2, 4, 6 and 8, for a total of 5 study visits. Data analysis was performed on the intent-to-treat (ITT) population using the last-observation-carried-forward (LOCF) methods for missing data. Descriptive statistics were used to summarize the demographic and safety measures. For the comparisons of the difference from baseline, mixed effect model under SAS version 9.2 was applied to analyze all patients with at least 1 post baseline assessment, with gender, age, duration of depression, duration of pain, dose as fixed effect, subject as random effect. Point estimates and their associate 90% confidence intervals were constructed for the difference. The primary efficacy endpoint was the baseline-toendpoint change in mean HAM-D17 scores. Results: Of the 102 outpatients enrolled in this therapy phase, 86 (84.3%) completed the study. Venlafaxine XR treatment was followed by a significant decrease on the HAM-D17 scores