Montgomery-Asberg Depression Rating Scale Total Score Research Articles

Does early improvement in depressive symptoms predict subsequent remission in patients with depression who are treated with duloxetine?

PurposeIn this prospective study, we examined whether early reduction in depressive symptoms predicts later remission to duloxetine in the treatment of depression, as monitored using the Montgomery–Asberg Depression Rating Scale (MADRS).Patients and methodsAmong the 106 patients who were enrolled in this study, 67 were included in the statistical analysis. A clinical evaluation using the MADRS was performed at weeks 0, 4, 8, 12, and 16 after commencing treatment. For each time point, the MADRS total score was separated into three components: dysphoria, retardation, and vegetative scores.ResultsRemission was defined as an MADRS total score of ≤10 at end point. From our univariate logistic regression analysis, we found that improvements in both the MADRS total score and the dysphoria score at week 4 had a significant interaction with subsequent remission. Furthermore, age and sex were significant predictors of remission. There was an increase of approximately 4% in the odds of remission for each unit increase in age, and female sex had an odds of remission of 0.318 times that of male sex (remission rate for men was 73.1% [19/26] and for women 46.3% [19/41]). However, in the multivariate model using the change from baseline in the total MADRS, dysphoria, retardation, and vegetative scores at week 4, in which age and sex were included as covariates, only sex retained significance, except for an improvement in the dysphoria score.ConclusionNo significant interaction was found between early response to duloxetine and eventual remission in this study. Sex difference was found to be a predictor of subsequent remission in patients with depression who were treated with duloxetine, with the male sex having greater odds of remission.

Efficacy of lurasidone in major depression with mixed features: Pattern of improvement in depressive and manic symptoms

IntroductionEvidence indicates that manic symptoms, below the threshold for hypomania (mixed features), are common in individuals with major depressive disorder (MDD).Objectives/aimsTo evaluate the effect of lurasidone on specific depressive and manic symptoms, based on Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) items, in patients with MDD with mixed features.MethodsPatients meeting DSM-IV-TR criteria for MDD, who presented with 2–3 protocol-specified manic symptoms, were randomized to 6 weeks of double-blind treatment with lurasidone monotherapy 20–60 mg/d (n = 109) or placebo (n = 100). Change from baseline in the MADRS total, MADRS-6 core depression subscale, individual MADRS items, and total and individual items of the YMRS were analyzed by MMRM, and Cohen's d effect sizes (d) were calculated for week 6 change scores.ResultsLurasidone improved depressive symptoms at week 6 in the MADRS total score (–20.5 vs. –13.0; P < 0.0001; d = 0.8) and MADRS-6 core depression score (–13.0 vs. –8.5; P < 0.0001; d = 0.7). Significant improvement on lurasidone was observed at week 6 on all ten MADRS items (d = 0.36–0.78). Effect sizes for the MADRS-6 core depression subscale items ranged from 0.36 to 0.78 at week 6. Treatment with lurasidone was associated with significantly greater week 6 improvement on the YMRS (–7.0 vs. –4.9; P < 0.0001). Effect sizes for the 5 YMRS items with baseline item severity ≥ 2 ranged from 0.32 to 0.48.ConclusionsIn this study of MDD with mixed features, lurasidone was effective in treating the range of depressive and manic symptoms that patients presented with.Sponsored by Sunovion Pharmaceuticals Inc.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of vortioxetine 10 mg and 20 mg in adults with major depressive disorder.

Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter. To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder. This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR). Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. The primary endpoint was the least squares mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (≥ 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score ≥ 20, MADRS remission (total score ≤ 10), and change from baseline in Sheehan Disability Scale total score (all at week 8). A total of 462 subjects were randomized to placebo (n = 157), vortioxetine 10 mg (n = 155), and vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were -10.77 (± 0.807), -12.96 (± 0.832), and -14.41 (± 0.845) for the placebo, vortioxetine 10 mg (P = .058 vs placebo), and vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness. Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, vortioxetine was well tolerated in this study. ClinicalTrials.gov identifier: NCT01163266.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder.

This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. ClinicalTrials.gov identifier: NCT01179516.

Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial.

Mixed (subsyndromal hypomanic) features are prevalent in patients with bipolar depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with bipolar depression presenting with mixed features. Patients with a DSM-IV-TR diagnosis of major depressive episode associated with bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with bipolar depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. ClinicalTrials.gov identifier: NCT00868699.

Could the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) be used in depressed schizophrenia patients?

BackgroundDeveloping accurate and time-efficient tools to measure depressive symptoms in schizophrenia is important for research and clinical practice. This study tested the psychometric properties of the Chinese version of the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR) in depressed schizophrenia patients. MethodsThis study included 337 clinically stable patients with schizophrenia. The severity of depressive symptoms was assessed using the Montgomery–Asberg Depression Rating Scale (MADRS), QIDS-SR at baseline and 2 weeks later. Negative symptoms and extrapyramidal symptoms were measured with the negative symptom score of Brief Psychiatric Rating Scale (BPRS) and the Simpson–Angus Scale of Extrapyramidal Symptoms (SAS), respectively. ResultsInternal consistency (Cronbach׳s alpha) was 0.73 and 0.67 for QIDS-SR at the baseline and endpoint, respectively. The intra-class correlation coefficient (ICC) for test–retest reliability over the two weeks was 0.77. Two domains (involvement and energy) at baseline and one domain (energy) at endpoint had the highest item-total correlations. The QIDS-SR total score was significantly correlated with the MADRS total score at baseline (r=0.44, p<0.01). Weak correlations of the QIDS-SR score with the scores of the BPRS negative (r=0.18) and the SAS (r=0.05) indicate good discriminant validity. The QIDS-SR showed unidimensional measurement properties in exploratory factor analysis at both baseline. The main limitation of the study is that only clinically stable schizophrenia patients were included. ConclusionsThe QIDS-SR has acceptable psychometric properties in stable schizophrenia patients and may be useful in both research and clinical practice.

A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment

BackgroundThis phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. MethodsStudy design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6–18mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery–Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. ResultsFor the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. LimitationsStudy was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. ConclusionsFor patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression.

Efficacy of olanzapine monotherapy for treatment of bipolar I depression: a randomized, double-blind, placebo controlled study

Depression symptoms are now recognized to be the predominant cause of disability for bipolar disorder (BD) patients. The treatment strategies for the depressed phase of BD remain more anecdotal than data-based. Olanzapine has been investigated as an alternative to antidepressants and a mood stabilizer for acute bipolar depression. The purpose of this study was to assess the efficacy of olanzapine monotherapy for bipolar I depression. Sixty-eight patients with bipolar I depression were randomly assigned to treatment with olanzapine (mean final dose 14.4 mg/day) (n=34) or placebo (n=34) in a double-blind parallel-group study design. Planned assessments included Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Clinical Global Impressions-Severity of Illness scale (CGI-S), Clinical Global Impressions-Improvement scale (CGI-I), Hamilton Depression scale (HAMD), Hamilton Anxiety scale (HAMA), and Treatment Emergent Symptom Scale (TESS). Of the 68 patients who were randomly assigned, 57 (83.8 %) completed treatments. Improvements in MADRS total score, CGI-S, CGI-I, and HAMD in the olanzapine group were significantly greater relative to those in the placebo group during the 8-week follow-up period (p<0.001, p=0.0017, p=0.007, and p<0.001, respectively). Rates of categorical treatment response and remission in the olanzapine group (50.0 % and 35.3 %, respectively) were significantly higher than those in the placebo group (20.6 %, p=0.011 and 11.8 %, p=0.022, respectively). At the 8-week treatment, the mean weight and the total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels increased significantly in the olanzapine group (p=0.037, p=0.029, p=0.030, and p=0.028, respectively). Olanzapine is effective in the treatment of bipolar I depression but is associated with significant metabolic side effects.

A Randomized Controlled Trial of the Efficacy and Safety of Lisdexamfetamine Dimesylate as Augmentation Therapy in Adults With Residual Symptoms of Major Depressive Disorder After Treatment With Escitalopram

Evaluate the efficacy and safety of lisdexamfetamine dimesylate augmentation for major depressive disorder (MDD) in escitalopram nonremitters. In this proof-of-concept study (conducted from July 2009-August 2010) with a prespecified critical α = .10, adults with nonpsychotic MDD (DSM-IV-TR criteria) and residual depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 4) after 8 weeks of open-label escitalopram were randomized to 6 weeks of lisdexamfetamine dimesylate (20-50 mg/d) or placebo augmentation. The primary endpoint, Montgomery-Asberg Depression Rating Scale (MADRS) total score change in escitalopram nonremitters (MADRS total score > 10) from week 8 (augmentation baseline) to week 14/end of study, was assessed using analysis of covariance, with last observation carried forward. For nonremitters (placebo, n = 64; lisdexamfetamine dimesylate, n = 65), the least squares (LS) mean (90% CI) treatment difference for MADRS total score reduction at week 14/end of study (-2.3 [-4.5 to -0.1]; P = .0902) met the prespecified criterion for lisdexamfetamine dimesylate superiority (adjusted effect size, -0.3); the number needed to treat for MADRS remission (MADRS total score ≤ 10) was 6.7. The LS mean treatment difference in remitters was not statistically significant (1.2 [-1.6 to 4.0]; P = .4726). Among randomized participants, 49.4% (42/85) receiving placebo and 60.2% (53/88) receiving lisdexamfetamine dimesylate had ≥ 1 treatment-emergent adverse event, the most frequent with lisdexamfetamine dimesylate being dry mouth and headache (both 11.4%). Mean (SD) vital sign and electrocardiogram changes (placebo vs lisdexamfetamine dimesylate) were 0.5 (8.98) versus 2.3 (9.04) mm Hg (systolic blood pressure), -1.0 (7.19) versus 0.9 (6.61) mm Hg (diastolic blood pressure), -0.4 (7.39) versus 4.8 (8.64) beats per minute (heart rate), and -1.6 (11.23) versus -4.9 (11.84) milliseconds (Fridericia-adjusted QTc). Lisdexamfetamine dimesylate augmentation reduced depressive symptoms in participants with inadequate escitalopram response. ClinicalTrials.gov identifier: NCT00905424.

Efficacy and Safety of Levomilnacipran Sustained Release 40 mg, 80 mg, or 120 mg in Major Depressive Disorder

This phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fixed-dose levomilnacipran sustained release (SR) compared with placebo in patients with major depressive disorder (MDD); the study was conducted from September 2009-May 2011. Outpatients met DSM-IV-TR criteria for MDD with an ongoing major depressive episode ≥ 8 weeks' duration. After a 1-week placebo lead-in, patients were randomly assigned to receive placebo (n = 179) or levomilnacipran SR 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment, followed by a 2-week double-blind down-taper. The primary efficacy parameter was change from baseline on the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) total score. The prespecified secondary efficacy parameter was change from baseline in Sheehan Disability Scale (SDS) total score. Additional efficacy measures included the 17-item Hamilton Depression Rating Scale (HDRS(17)) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I). Safety and tolerability were also evaluated. The least squares mean difference (LSMD) for change from baseline in MADRS total score was significantly superior to placebo for all dose groups: -3.23 (P = .0186), -3.99 (P = .0038), and -4.86 (P = .0005) for levomilnacipran SR 40, 80, and 120 mg, respectively. The LSMD was significantly different for levomilnacipran SR 80 mg and 120 mg versus placebo on the SDS (-2.51 and -2.57, respectively, P < .05 for both doses), HDRS(17) (-2.09 and -2.34, respectively, P < .05 for both doses), CGI-S (-0.43 [P < .01] and -0.35 [P < .05], respectively), and CGI-I (-0.34 and -0.32, respectively, P < .05 for both doses) assessments. The most common treatment-emergent adverse events (≥ 10% of any treatment group) were headache, nausea, constipation, dry mouth, increased heart rate, and hyperhidrosis. Levomilnacipran SR demonstrated significant improvement in depressive symptoms and functioning relative to placebo. In this study, levomilnacipran SR was generally well tolerated. ClinicalTrials.gov identifier: NCT00969709.

A cross-cultural comparison study of depression assessments conducted in Japan

BackgroundThe advent of global clinical trials has necessitated the use of English-based rating instruments in diverse cultures where English is clearly not the primary language. The cross-cultural applicability of rating instruments developed in one language with only one cultural group is an important issue in both research and clinical settings where these instruments might be used. We examined the cross-cultural applicability of the Montgomery-Asberg Depression Rating Scale (MADRS) in Japan.MethodsAs part of a rater-training program for a clinical trial in Japan, we assessed inter-rater agreement using two videotaped MADRS interviews administered in Japanese and produced with English subtitles. We looked for possible interpretational variance that might have been generated by cultural differences between Japanese raters in Japan and English-speaking raters in the USA scoring the same interviews.ResultsThe US and Japanese raters demonstrated high inter-rater agreement and no significant scoring difference on the total MADRS score. The subtitles in English did not adversely affect the overall scoring.We separately analyzed the 10 individual items from each of the two MADRS interviews used for rater training. Of the 20 items, 18 were concordant between the US and Japanese raters. In one interview, the US raters scored lassitude significantly higher (p = 0.013) and the inability to feel significantly lower (p = 0.037) than the Japanese raters, reflecting a possible interpretational difference on these items.ConclusionAlthough developed in Europe, these findings support the general applicability of the MADRS to assess the severity of depressive symptoms in Japan. We did note significant scoring differences on 2 of the 20 individual items, suggesting a possible cultural difference. It is possible that more interviews might have revealed more interpretational differences. These findings highlight the need for cultural familiarity when assessing psychiatric patients.

A Randomized, Double-Blind, Placebo-Controlled 8-Week Trial of the Efficacy and Tolerability of Multiple Doses of Lu AA21004 in Adults With Major Depressive Disorder

Lu AA21004 is an investigational multimodal antidepressant. This randomized controlled trial evaluated the efficacy and tolerability of multiple doses of Lu AA21004 versus placebo in adults with major depressive disorder (MDD). Adults diagnosed with MDD (based on DSM-IV-TR criteria) with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 26 were randomly assigned (1:1:1:1) to receive Lu AA21004 1 mg, 5 mg, or 10 mg or placebo for 8 weeks (between August 2008 and August 2009). The primary endpoint was reduction in 24-Item Hamilton Depression Rating Scale (HDRS-24) total score after 8 weeks of treatment compared with placebo for Lu AA21004 10 mg. Additional outcomes included response and remission rates, Sheehan Disability Scale (SDS), Clinical Global Impressions-Global Improvement scale (CGI-I), MADRS total score, and HDRS-24 total score in subjects with baseline Hamilton Anxiety Rating Scale (HARS) score ≥ 20. Adverse events were assessed throughout the study. A total of 560 subjects (mean age = 46.4 years) were randomized. There was a statistically significant reduction from baseline in HDRS-24 total score at week 8 for Lu AA21004 10 mg vs placebo (P < .001). There were improvements (nominal P values < .05 with no adjustment for multiplicity) in HDRS-24 total score, response and remission rates, CGI-I score, MADRS total score, and HDRS-24 total score in subjects with baseline HARS score ≥ 20 at week 8 for all Lu AA21004 treatment groups vs placebo. No significant differences were seen in SDS scores between any dose of Lu AA21004 and placebo. The most common adverse events were nausea, headache, and dizziness. After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD. Lu AA21004 was well tolerated in this study. ClinicalTrials.gov identifier: NCT00735709.

Efficacy of adjunctive aripiprazole in major depressive disorder: a pooled response quartile analysis and the predictive value of week 2 early response.

To assess varying levels of response to aripiprazole adjunctive to standard antidepressant therapy (ADT) and the predictive value of an early response for a sustained response. This post hoc analysis of 3 similarly designed randomized, double-blind, placebo-controlled phase 3 studies investigated the efficacy and safety of adjunctive aripiprazole to standard ADT in patients with major depressive disorder (DSM-IV-TR criteria) who had a prior inadequate response to 1-3 ADTs (CN138-139 [September 2004-December 2006], CN138-163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Response levels were defined as percent decreases from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment, with a ≤ 25% decrease for minimal, > 25 to < 50% decrease for partial, ≥ 50% to < 75% decrease for moderate, and ≥ 75% decrease for a robust response to treatment. More patients receiving adjunctive aripiprazole exhibited a partial (23.9% vs 17.9%, P = .017), moderate (23.1% vs 15.0%, P < .001), and robust response (14.3% vs 7.4%, P < .001) compared with adjunctive placebo. Adjunctive aripiprazole treatment compared with adjunctive placebo treatment was associated with a significantly greater proportion of patients achieving an early response (week 2, ≥ 50% reduction in MADRS total score, n = 110/539 vs n = 47/525, P < .001, number needed to treat = 9) and an endpoint response (relative risk = 1.7, 95% CI = 1.4-2.0, P < .001, number needed to treat = 7). A univariate logistic regression analysis revealed that an early response was a significant predictor of endpoint remission (P < .001). Aripiprazole augmentation was associated with a significantly greater proportion of patients achieving a partial, moderate, or robust response to treatment compared with ADT alone. Patients showing an early response (week 2) to augmentation maintained their response through endpoint, suggesting that clinicians may make clinically meaningful decisions early during treatment. ClinicalTrials.gov identifiers: NCT00095823, NCT00095758, and NCT00105196.

Inverse correlation between clinical response to paroxetine and plasma drug concentration in patients with major depressive disorders

There are few data concerning a clear relationship between the clinical effect of paroxetine and plasma drug concentrations, although therapeutic ranges have been established for some tricyclic antidepressants. In this study, 120 patients with major depressive disorders were treated with 10-40 mg/day of paroxetine for 6 weeks, and a total of 89 patients completed the protocol. A clinical evaluation using the Montgomery-Asberg Depression Rating Scale (MADRS) was performed at 0, 1, 2, 4 and 6 weeks. Significant correlations were found between the plasma concentrations of paroxetine and the percentage improvement in the total MADRS scores (r = -0.282, p < 0.01) and the final MADRS scores at 6 weeks (r = 0.268, p < 0.05). The conventional receiver-operating-characteristic curve showed the fraction of true positive results and false negative results for various cut-off levels of paroxetine concentration for response and remission. The thresholds for both response and remission that gave the maximal sensitivity and specificity for paroxetine concentrations were 64.2 ng/ml. These results suggest that plasma paroxetine concentrations are negatively associated with improvement and that response occurs at the upper threshold of 64.2 ng/ml of paroxetine. These findings should be replicated with a larger patient sample.

Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials

BackgroundAsenapine demonstrated superiority over placebo for mania in bipolar I disorder patients experiencing acute current manic or mixed episodes in 2 randomized, placebo-and olanzapine-controlled trials. We report the results of exploratory pooled post hoc analyses from these trials evaluating asenapine's effects on depressive symptoms in patients from these trials with significant baseline depressive symptoms.MethodsIn the original trials (A7501004 [NCT00159744], A7501005 [NCT00159796]), 977 patients were randomized to flexible-dose sublingual asenapine (10 mg twice daily on day 1; 5 or 10 mg twice daily thereafter), placebo, or oral olanzapine 5-20 mg once daily for 3 weeks. Three populations were defined using baseline depressive symptoms: (1) Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥20 (n = 132); (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score ≥4 (n = 170); (3) diagnosis of mixed episodes (n = 302) by investigative site screening. For each population, asenapine and olanzapine were independently compared with placebo using least squares mean change from baseline on depressive symptom measures.ResultsDecreases in MADRS total score were statistically greater with asenapine versus placebo at days 7 and 21 in all populations; differences between olanzapine and placebo were not significant. Decreases in CGI-BP-D score were significantly greater with asenapine versus placebo at day 7 in all categories and day 21 in population 1; CGI-BP-D score reductions were significantly greater with olanzapine versus placebo at day 21 in population 1 and day 7 in populations 2 and 3.ConclusionsThese post hoc analyses show that asenapine reduced depressive symptoms in bipolar I disorder patients experiencing acute manic or mixed episodes with clinically relevant depressive symptoms at baseline; olanzapine results appeared to be less consistent. Controlled studies of asenapine in patients with acute bipolar depression are necessary to confirm the generalizability of these findings.

Effects of Adjunctive Aripiprazole on Sexual Functioning in Patients With Major Depressive Disorder and an Inadequate Response to Standard Antidepressant Monotherapy

To investigate the specific effect of adjunctive aripiprazole on sexual function in patients with major depressive disorder and a history of an inadequate response to antidepressant medication by controlling for improvement in depressive symptoms as measured by improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total scores. For this post hoc analysis, data were pooled from 3 multicenter, randomized, double-blind, placebo-controlled aripiprazole augmentation studies (CN138-139: June 2004-April 2006; CN138-163: September 2004-December 2006; and CN138-165: March 2005-April 2008). Outpatients who met DSM-IV-TR criteria for a major depressive episode that had lasted ≥8 weeks with an inadequate response to prospective antidepressant treatment were randomized to adjunctive aripiprazole or placebo for 6 weeks. Sexual functioning was assessed using the Massachusetts General Hospital Sexual Functioning Inventory (MGH-SFI). To assess whether adjunctive aripiprazole improves sexual functioning directly, rather than as an indirect effect of improvement in depression symptoms, the mean change in MGH-SFI item scores and overall improvement scores was assessed using analysis of covariance, with double-blind baseline and change in MADRS total score as covariates. Correlations between MGH-SFI items and MADRS total score and prolactin levels were also assessed. The analysis included 1,092 subjects (n=737 female and n=355 male). In the total population, adjunctive aripiprazole demonstrated statistically significant greater improvements versus placebo on the MGH-SFI item "interest in sex" (-0.34 vs -0.18, P<.05). In males, no significant treatment differences were observed. In females, improvements in sexual functioning with adjunctive aripiprazole versus placebo were found on the MGH-SFI items "interest in sex" (-0.41 vs -0.21, P<.05) and "sexual satisfaction" (-0.44 vs -0.25, P<.05). Aripiprazole adjunctive to antidepressant treatment can have some beneficial effects on sexual functioning in patients with major depressive disorder who respond inadequately to standard antidepressant treatment; the benefits in women were specific to sexual interest and satisfaction and were independent of the improvement in depressive symptoms. clinicaltrials.gov Identifiers: NCT00095823, NCT00095758, and NCT00105196.

Depressive symptoms following interferon-α therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor?

Interferon-α (IFN-α) therapy for the treatment of hepatitis C is known to induce depressive symptoms and major depression in a substantial proportion of patients. While immune activation and disturbances in peripheral tryptophan catabolism have been implicated, the exact underlying mechanism remains unknown. A role for brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders has recently emerged. This study examined whether depressive symptoms over time are associated with changes in serum BDNF concentration in hepatitis C patients treated with IFN-α, and whether BDNF mediates the effects of IFN-α-induced immune activation on depressive symptoms. For this purpose, 17 hepatitis C patients received IFN-α treatment with ribavirin. Patients were assessed before and at 1, 2, 4, 8, 12 and 24 wk after start of treatment. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, cytokine concentrations and serum BDNF levels were measured at all time-points. Serum levels of BDNF decreased during the course of treatment, and were significantly and inversely associated with total MADRS score. Furthermore, pro-inflammatory cytokine levels predicted lower subsequent BDNF levels, whereas low BDNF levels, as well as increased cytokine levels, were independently associated with the development of depressive symptoms during IFN-α treatment. These findings suggest that the effect of IFN-α-induced immune activation on depression may be explained in part by alterations in neuroprotective capacity, reflected by decreases in serum BDNF following IFN-α treatment.

P01-39 - Adjunctive aripiprazole in patients with major depressive disorder: efficacy data from three short-term studies

AimsTo evaluate the efficacy of aripiprazole as adjunctive treatment in patients with major depressive disorder (MDD) without psychotic features and an inadequate response to standard antidepressant therapy (ADT).MethodsData were collected from three identical, short-term, double-blind, placebo-controlled studies (CN138-139, CN138-163, CN138-165). After a single-blind prospective phase with placebo plus ADT, patients with inadequate response were randomized to 6-weeks’ treatment with adjunctive aripiprazole or placebo. The primary efficacy endpoint was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score during the double-blind phase. Secondary endpoints were response (≥50% reduction in MADRS total score), remission (MADRS total score ≤10 and ≥50% reduction in MADRS total score), and mean change in Hamilton Depression Rating Scale (HAM-D17) total score.ResultsIn all three studies, adjunctive aripiprazole was associated with a significantly greater reduction in MADRS total score than adjunctive placebo, with a treatment difference ranging between -3.73 and -2.84 (p≤0.001 in each study). Response and remission rates with adjunctive aripiprazole (32.4-46.6% and 25.4-36.8%, respectively) were also significantly higher than with adjunctive placebo (17.4-26.6% [p&lt; 0.05 in each study] and 15.2-18.9% [p&lt; 0.05 in each study]). Mean change in HAM-D17 total score ranged from -7.64 to -6.77 with adjunctive aripiprazole and from -5.12 to -4.41 with adjunctive placebo (p&lt; 0.001 for each study).ConclusionsResults of the three studies indicate that treatment with adjunctive aripiprazole and ADT is effective in improving the symptoms of MDD in patients who have had an inadequate response to ADT.

P01-101 - Unique: assessing the efficacy of quetiapine fumarate augmentation of SSRI or SNRI treatment in SSRI- or SNRI-resistant major depressive disorder

ObjectivesThe UNIQUE study assessed the effect of Quetiapine fumarate augmentation on the overall depression status of patients with major depressive disorder and who did not respond to any acute treatment with selective serotonin reuptake inhibitors (SSRIs) or selective noradrenalin reuptake inhibitors (SNRIs) and naïve to any atypical antipsychotics.MethodsBetween March 2006 and November 2007, 39 male and female patients, aged 18-65, were enrolled into this four-week, open label, non-comparative, multicentric, phase II prospective study. Treatment with Quetiapine fumarate began at enrolment, with a titration to a target dose of 300mg. The following scales were completed during all five visits: Montgomery-Asberg Depression Rating Scale (MADRS); Clinical Global Impression (CGI); Brief Psychiatric Rating Scale (BPRS); Sheehan Disability Scale (SDS).ResultsAll questionnaire mean scales were significantly reduced (Friedman P&lt; 0.0001) at the end of the study from baseline: MADRS 16.9 (12.8-21.0); CGI 1.94 (1.52-2.37); BPRS 10.3 (6.7-13.6); SDS 8.5 (5.6-11.5). Response, defined as a reduction in MADRS total score &gt;50% was observed in 45.9% of the 37 patients completing at least 2 weeks of the study and 37.8% were considered in remission e.g. MADRS total score ≤ 12 at visit 5.ConclusionsQuetiapine fumarate augmentation improved the overall depression status of patients resistant to SSRI or SNRI treatment.

P01-161 Cognitive and affective endophenotypes related to major depression are associated with P2RX7

Background:The P2RX7 gene encoding for purinergic receptor P2X has earlier been associated with a susceptibility to anxiety and affective disorders. The aim of our present study was to investigate the association of this polymorphism with different aspects and symptom clusters of major depression.Method:192 inpatients diagnosed with DSM-IV major depression and bipolar I and bipolar II depression aged 21-69 years (mean=48.2±11.05) participated in our study. All participants were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS). All patients were genotyped for the P2RX7 Gln460Arg SNP (rs2230912) using PCR. Association between genotype and MADRS scores was analysed with ANOVA controlling for age and gender.Results:rs2230912 genotype showed a significant association with depression indicated by the total MADRS score. We also found a significant genotype effect in case of the Affective and Cognitive clusters, but not on the Somatic and Psychomotor clusters of MADRS.Discussion:We managed to confirm earlier results concerning the association of the P2RX7 rs2230912 with major depressive disorder and bipolar depression. Furthermore, we found that this association is carried by the affective and cognitive symptoms associated with depression. Our results bring us closer to decomposing depression to endophenotypes more suitable for research and also for understanding the nature of affective disorders.This work was supported by EU-Hungarian fund, GVOP AKF 311 2004 050324/3.0, the Hungarian National fund, OTKA T048576 and Janos Bolyai Research Fellowship of the Hungarian Academy of Science.