Depression Rating Scale Total Score Research Articles

Extended-release quetiapine fumarate (quetiapine XR) monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder

BackgroundPatients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge. MethodsThis 6-week, randomised, open-label, rater-blinded trial evaluated once-daily extended-release quetiapine fumarate (quetiapine XR; 300mg/day) as add-on to ongoing antidepressant and quetiapine XR monotherapy (300mg/day) compared with add-on lithium (0.6–1.2mmol/L) in patients with treatment-resistant MDD. Primary efficacy measure: change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomisation to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS. ResultsAt week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229); least squares means (LSM) differences (97.5% CI) in MADRS total score changes were −2.32 (−4.6, −0.05) and −0.97 (−3.24, 1.31), respectively. LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; p<0.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (≥50% reduction in total score), MADRS remission (total score ≤10, add-on quetiapine XR only) and Clinical Global Impressions (‘much’/‘very much’ improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments. LimitationsLimitations included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase. ConclusionsAdd-on quetiapine XR (300mg/day) and quetiapine XR monotherapy (300mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD.

Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study

The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests. With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test. Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.

Efficacy and safety of olanzapine for treatment of patients with bipolar depression: Japanese subpopulation analysis of a randomized, double-blind, placebo-controlled study

BackgroundThe efficacy and safety of olanzapine monotherapy are evaluated in Japanese patients from a large, global study of bipolar depression.MethodsThis is an analysis of Japanese patients from a 6-week, global (Japan, China, Korea, Taiwan, and the United States), randomized, double-blind, placebo-controlled, Phase 3 study of patients with a depressive episode of bipolar I disorder. The primary outcome was baseline-to-endpoint change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcome measures included the Clinical Global Impressions-Bipolar Version Severity of Illness Scale (CGI-BP), the 17-item Hamilton Depression Rating Scale (HAMD-17) total score, the Young Mania Rating Scale (YMRS) total score, and rates of response (≥50% baseline-to-endpoint reduction in MADRS total score), recovery, and remission.ResultsOf the 156 Japanese patients, 104 had been allocated to olanzapine and 52 to placebo. All results are baseline-to-endpoint change. Compared to placebo, patients in the olanzapine group experienced greater improvement in the primary outcome measure, MADRS total score (−14.9 vs. −10.7; p = .01). They also had greater reductions in the following secondary measures: CGI- BP Depression (−1.41 vs. -0.89; p = .008), CGI-BP Bipolar (−1.31 vs. −0.83; p = .01), HAMD-17 (−11.7 vs. −7.9; p < .01), and YMRS (-0.32 vs. 0.34; p = .03). Differences in rates of response, recovery, and remission were not statistically significant. A greater proportion of olanzapine-treated patients reported treatment- emergent adverse events (87.5% vs. 59.6%; p < .001). Patients treated with olanzapine had greater increases in weight (p < .001) and fasting total cholesterol (p = .008); fasting triglycerides (p = .02), and fasting low-density lipoprotein (p = .01). There was a greater reduction in fasting high-density lipoprotein in olanzapine-treated patients (p = .01). Compared with placebo-group patients, more olanzapine-group patients shifted from borderline to high cholesterol (25.0% vs. 0.0%; p = .007) and had clinically significant weight gain (≥7% body weight) (20.2% vs. 1.9%; p = .001).ConclusionsResults of this analysis support the efficacy and tolerability of olanzapine for the treatment of bipolar depression in Japanese patients. Results in this population were consistent with those seen in the more ethnically diverse parent study. In making treatment decisions for individual patients, clinicians should carefully consider the risks and benefits of olanzapine treatment.Trial RegistrationClinicatrials.gov ID NCT00510146 Olanzapine Treatment of Patients with Bipolar I Disorder

Quetiapine XR monotherapy in major depressive disorder

The efficacy of quetiapine XR was investigated in patients with major depressive disorder and differing levels of baseline severity. Pooled data from four placebo-controlled monotherapy studies of quetiapine XR (50-300 mg/day) were analyzed. Post-hoc analyses were carried out to assess change from baseline in the Montgomery Åsberg Depression Rating Scale (MADRS) total score at endpoint (week 6 or 8) to week 1, and response (≥50% reduction in MADRS total score) and remission (MADRS total score≤10) rates at endpoint for all patients and six baseline severity cohorts (MADRS total score ≥24, ≥26, ≥28, ≥30, ≥32, and ≥34). In total, 1752 patients (all patients) were evaluated (MADRS score at baseline: ≥24, n=1601; ≥26, n=1467; ≥28, n=1269; ≥30, n=1038; ≥32, n=745; and ≥34, n=500). At endpoint, quetiapine XR reduced MADRS total score in all patients (P<0.001) and each severity cohort (≥24, ≥26, ≥28, ≥30, and ≥32, P<0.001; ≥34, P<0.01) versus placebo. Quetiapine XR also improved MADRS total score at week 1, response rates for each severity cohort, and remission rates in five out of six severity cohorts, versus placebo. Quetiapine XR monotherapy showed antidepressant effects in patients with major depressive disorder across different levels of baseline severity.

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.

Efficacy of olanzapine monotherapy in acute bipolar depression: A pooled analysis of controlled studies

BackgroundThe efficacy and safety of olanzapine monotherapy in bipolar depression has been evaluated in 2 placebo-controlled studies. MethodsWe pooled data from 2 previously published studies examining olanzapine monotherapy in patients with bipolar I depression. Changes from baseline to 6 weeks in Montgomery–Åsberg Depression Rating Scale (MADRS) total score, MADRS-6 (included items: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts) score, and individual MADRS item scores were assessed with an analysis of variance (ANOVA) model. Influence of patient baseline characteristics (age, gender, MADRS total score, age at onset of bipolar disorder, psychotic features, melancholic feature, mixed features [≥2 on ≥3 Young Mania Rating Scale items], and racial origin) on the efficacy of olanzapine monotherapy was examined with an ANOVA model for each factor and stepwise multiple regression analysis. ResultsIncluded were a total of 690 olanzapine-group and 524 placebo-group patients. MADRS total, MADRS-6, and all individual MADRS item scores (except concentration difficulties and suicidal thoughts) showed significantly (P≤0.05) greater decreases from baseline to 6 weeks in olanzapine-treated patients than those on placebo. The only baseline characteristic associated with response to olanzapine was melancholic feature. LimitationsThe study was limited by omission of patients with bipolar II disorder, post hoc analysis of data from only two clinical trials, and exclusion of suicidal patients. ConclusionsOlanzapine monotherapy improved core symptoms of depression in patients with bipolar I depression. Additionally, we identified melancholic feature as a baseline factor associated with improved treatment response to olanzapine.

Efficacy and Safety of Desvenlafaxine 50 mg/d for Prevention of Relapse in Major Depressive Disorder

To evaluate the long-term (11-month) efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) at the recommended 50-mg/d dose in preventing relapse in patients with major depressive disorder (MDD). Adult outpatients (age ≥ 18 years) with MDD (DSM-IV criteria) and a 17-item Hamilton Depression Rating Scale (HDRS17) total score ≥ 20 at screening and baseline were enrolled in a multicenter, double-blind, placebo-controlled, randomized withdrawal trial conducted between June 2009 and March 2011. Patients who responded to 8-week open-label treatment with desvenlafaxine 50 mg/d with continuing stable response through week 20 were randomly assigned to receive placebo or desvenlafaxine 50 mg/d in a 6-month, double-blind, randomized withdrawal period. The primary efficacy endpoint was time to relapse following randomization to double-blind treatment, which was compared between groups using the log-rank test. Relapse was defined as HDRS17 total score ≥ 16, discontinuation for unsatisfactory response, hospitalization for depression, suicide attempt, or suicide. Safety and tolerability data were collected throughout the trial. A total of 874 patients were enrolled; 548 patients were randomly assigned to receive placebo (n = 276) or desvenlafaxine 50 mg/d (n = 272) in the double-blind withdrawal period. Time to relapse was significantly shorter for placebo versus desvenlafaxine (P < .001). At the end of the 6-month double-blind treatment, the estimated probability of relapse was 30.2% for placebo versus 14.3% for desvenlafaxine 50 mg/d. Safety and tolerability results were generally consistent with those in short-term studies of desvenlafaxine 50 mg/d. Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment. ClinicalTrials.gov identifier: NCT00887224.

Acute and Long-term Treatment of Late-Life Major Depressive Disorder: Duloxetine Versus Placebo

To compare the efficacy of duloxetine with placebo on depression in elderly patients with major depressive disorder. Multicenter, 24-week (12-week short-term and 12-week continuation), randomized, placebo-controlled, double-blind trial. United States, France, Mexico, Puerto Rico. Age 65 years or more with major depressive disorder diagnosis (one or more previous episode); Mini-Mental State Examination score≥20; Montgomery-Asberg Depression Rating Scale total score≥20. Duloxetine 60 or 120 mg/day or placebo; placebo rescue possible. Primary-Maier subscale of the 17-item Hamilton Depression Rating Scale (HAMD-17) at week 12. Secondary-Geriatric Depression Scale, HAMD-17 total score, cognitive measures, Brief Pain Inventory (BPI), Numeric Rating Scales (NRS) for pain, Clinical Global Impression-Severity scale, Patient Global Impression of Improvement in acute phase and acute plus continuation phase of treatment. Compared with placebo, duloxetine did not show significantly greater improvement from baseline on Maier subscale at 12 weeks, but did show significantly greater improvement at weeks 4, 8, 16, and 20. Similar patterns for Geriatric Depression Scale and Clinical Global Impression-Severity scale emerged, with significance also seen at week 24. There was a significant treatment effect for all BPI items and 4 of 6 NRS pain measures in the acute phase, most BPI items and half of the NRS measures in the continuation phase. More duloxetine-treated patients completed the study (63% versus 55%). A significantly higher percentage of duloxetine-treated patients versus placebo discontinued due to adverse event (15.3% versus 5.8%). Although the antidepressant efficacy of duloxetine was not confirmed by the primary outcome, several secondary measures at multiple time points suggested efficacy. Duloxetine had significant and meaningful beneficial effects on pain.

Randomized, Double-Blind Study of the Efficacy and Tolerability of Extended Release Quetiapine Fumarate (Quetiapine XR) Monotherapy in Elderly Patients with Major Depressive Disorder

This study assessed the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD). An 11-week (9-week randomized; 2-week posttreatment phase), double-blind, placebo-controlled, Phase III study (D1448C00014). A total of 53 centers in Argentina, Estonia, Finland, Russia, Ukraine, and the United States. A total of 338 patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, age≥66 years, Hamilton Rating Scale for Depression [HAM-D] total score≥22, HAM-D Item 1 [depressed mood] score≥2) were randomized (mean age: 71.3 years). Patients were randomized to quetiapine XR (n= 166; flexible-dosing 50-300 mg/day) or placebo (n= 172). Primary outcome was Montgomery Åsberg Depression Rating Scale (MADRS) total score change from randomization at Week9. At Week 9, quetiapine XR (least squares [LS] means:-16.33, standard error [SE]: 0.95; mean change:-16.0, standard deviation [SD]: 9.3) significantly reduced MADRS total score from randomization versus placebo (LS means [SE]:-8.79 [0.94]; mean [SD]:-9.0 [9.9]); significant improvements were also seen at Week 1 (LS means [SE]:-4.65 [0.53] versus-2.56 [0.53], respectively; mean [SD]:-4.3 [5.1] versus-2.4 [3.7], respectively). At Week 9, secondary outcome variables significantly improved with quetiapine XR versus placebo, including MADRS response (≥50% reduction in total score); MADRS remission (total score≤8); HAM-D total, HAM-A total, HAM-A psychic and somatic cluster, and Clinical Global Impressions-Severity of Illness (CGI-S) total scores; proportion of patients with CGI-Improvement score of 2 or less; Q-LES-Q-SF% maximum total, Pittsburgh Sleep Quality Index global, and pain Visual Analog Scale scores. Common adverse events (>10% patients with quetiapine XR) were somnolence, headache, dry mouth, and dizziness. In elderly patients with MDD, quetiapine XR monotherapy (50-300 mg/day, flexibly dosed) is effective at improving depressive symptoms, with symptom improvement observed as early as Week 1. Overall tolerability and safety were consistent with the known profile of quetiapine.

Lurasidone as a potential therapy for bipolar disorder

Lurasidone is a benzisothiazol derivative and an atypical antipsychotic approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia (October 2010) and bipolar 1 depression (June 2013). Lurasidone has a strong antagonistic property at the D2, serotonin (5-HT)2A, and 5-HT7 receptors, and partial agonistic property at the 5-HT1A receptor. Lurasidone also has lower binding affinity for the α2C and 5-HT2C receptor. Lurasidone is rapidly absorbed (time to maximum plasma concentration: 1–3 hours), metabolized mainly by CYP3A4 and eliminated by hepatic metabolism. In two large, well-designed, 6-week trials in adult patients with bipolar 1 depression, lurasidone monotherapy and adjunctive therapy with mood stabilizers were significantly more effective than placebo at improving depressive symptoms assessed using the Montgomery–Åsberg Depression Rating Scale total score. In both trials, lurasidone also reduced the Clinical Global Impression–Bipolar Severity depression score to a greater extent than placebo. In these two trials, discontinuation rates due to adverse events in the lurasidone group were small (<7%) and were not different from those of the placebo group. The most common adverse events in the lurasidone group were headache, nausea, somnolence, and akathisia. The changes in lipid profiles, weight, and parameters of glycemic control were minimal, and these findings were in line with those observed in schizophrenia trials. Further active comparator trials and long-term tolerability and safety data in bipolar patients are required. Lurasidone may be an option for the management of depressive symptoms in patients with bipolar 1 disorder, and it may be considered as a treatment alternative for patients who are at high risk for metabolic abnormalities.

The efficacy and safety of bupropion sustained-release formulation for the treatment of major depressive disorder: a multi-center, randomized, double-blind, placebo-controlled study in Asian patients

This study was conducted to compare the efficacy and safety of bupropion sustained-release (SR) formulation orally administered at daily doses of 150 mg/day (once daily) and 300 mg/day (150 mg twice daily) for 8 weeks versus placebo in Asian patients with major depressive disorder. The mean change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 8 was compared between each of the bupropion SR dose groups and the placebo group using an analysis of covariance with the multiplicity adjustment by Dunnett’s step-down procedure. A total of 569 subjects met all of the inclusion criteria and proceeded to the treatment phase. The subjects proceeding to the treatment phase included 454 Japanese patients and 115 Korean patients. There was no statistically significant difference between each of the bupropion SR dose groups and the placebo group in the primary efficacy endpoint of change from baseline in MADRS total score at week 8. Similar results were generally obtained for all of the secondary efficacy endpoints. The secondary analysis and the other subgroup analysis did not show a statistically significant difference in efficacy. There was no substantial difference in the type, severity, and incidence of adverse events (AEs) between the bupropion SR dose groups and the placebo group, which indicates a favorable safety profile for bupropion SR. There were no significant findings in subjects treated with bupropion SR in regard to sexual dysfunction, weight change, and withdrawal syndrome, which are frequently recognized as clinical concerns associated with selective serotonin reuptake inhibitors, widely used for the treatment of depression.

Double-blind, comparative study of milnacipran and paroxetine in Japanese patients with major depression

Background and methodsA double-blind, parallel-group, controlled study was performed to investigate if milnacipran was noninferior to paroxetine in terms of improvement in symptoms of depression in Japanese patients with major depressive disorders in a fixed-dose design. The efficacy and safety of milnacipran 200 mg/day were also assessed in comparison with those at the standard dose of 100 mg/day.ResultsChanges in 17-item Hamilton depression rating scale (HAM-D) total score (mean ± standard deviation) for group M1 (milnacipran 100 mg/day), group M2 (milnacipran 200 mg/day), and group PX (paroxetine 30 or 40 mg/day) were −12.9 ± 5.8, −12.8 ± 6.1, and −13.1 ± 6.2, respectively, and the estimated differences in total score for group PX (Dunnett’s 95% simultaneous confidence interval) were 0.1 (−1.1 to 1.3) for group M1 and 0.3 (−0.9 to 1.5) for group M2. The noninferiority of groups M1 and M2 to group PX was thus confirmed, because the upper confidence limit of differences between groups M1 and PX and between groups M2 and PX was less than 2.0. The estimated mean difference of change in HAM-D total score (95% confidence interval) between groups M2 and M1 was 0.2 (−0.9 to 1.2), indicating a comparable change in total score for both groups. The incidence of treatment-related adverse events was 71.7% for group M1, 68.8% for group M2, and 69.3% for group PX, indicating no significant difference between the three groups.ConclusionThese results demonstrate that milnacipran 100 mg/day and 200 mg/day is not inferior to paroxetine in terms of efficacy and safety.

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary

Objective:Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS).Design:A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials.Setting:Placebo-controlled, active-comparator, short- and long-term studies were reviewed.Participants:Adult (≥18 years) patients with MDD.Measurements:Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery–Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures.Results:Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p≤0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite.Conclusion:These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.

Naltrexone/Bupropion Combination Therapy in Overweight or Obese Patients With Major Depressive Disorder

Objective: To evaluate the effect of 32-mg/d naltrexone sustained release and 360-mg/d bupropion sustained release (NB32) in overweight and obese patients with major depressive disorder (MDD).Method: Twenty-five female patients with a DSM-IV diagnosis of MDD, an Inventory of Depressive Symptomatology—Self-Report score > 26, and a body mass index ≥ 27 and ≤ 43 kg/m2 received up to 24 weeks of open-label treatment with NB32 with dietary and behavioral counseling (data collection: March 2008–July 2009). The primary endpoint was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 12 weeks; secondary endpoints included MADRS total score at week 24, change in weight, and Clinical Global Impressions–Improvement scale responder status (CGI-I score ≤ 2) at weeks 12 and 24 (modified intent-to-treat [mITT]: patients with ≥ 1 postbaseline MADRS total score on study drug; N = 23).Results: MADRS scores showed significant reductions at weeks 12 and 24 (mITT–last observation carried forward [LOCF]: –13.1 ± 7.1 and –15.3 ± 8.1, respectively, P < .001 vs baseline for all). Mean ± SD weight loss was –4.0% ± 4.6% (mITT-LOCF) and –6.1% ± 4.7% (observed cases) at week 12 and –5.3% ± 6.5% (mITT-LOCF) and –9.2% ± 6.2% (observed cases) at week 24 (P < .001 vs baseline for all). By week 24, 95% of patients (mITT-LOCF) were responders (CGI-I score ≤ 2) and 70% were in remission (CGI-I score = 1). The safety/tolerability profile of NB32 was consistent with its individual components; the most common adverse events were nausea, constipation, headache, and insomnia, with no serious adverse events attributed to NB32.Conclusion: Twenty-four weeks of open-label NB32 therapy with dietary and behavioral counseling was associated with improvement in depressive symptoms and reduced body weight in overweight/obese women with MDD.Trial Registration: ClinicalTrials.gov Identifier: NCT00624858

Beneficial Effects of Adjunctive Aripiprazole in Major Depressive Disorder Are Not Dependent on Antidepressant Therapy History

To determine whether switching within or between antidepressant therapy (ADT) classes prior to the use of adjunctive antipsychotic treatment is associated with different outcomes in major depressive disorder (MDD). This was a post hoc analysis of pooled data from 3 similar, multicenter, randomized, double-blind, placebo-controlled registrational studies of aripiprazole adjunctive to ADT conducted between September 2004 and April 2008. The trials comprised the following 3 phases: a 7- to 28-day screening phase, an 8-week single-blind prospective treatment phase, and a 6-week double-blind, randomized phase. Patients were aged 18-65 years and met DSM-IV-TR criteria for MDD. Patients with an inadequate response to ADT during the screening phase entered the prospective treatment phase, during which they were switched to another ADT medication of either the same or a different class. Those patients with an inadequate response were then randomized to double-blind adjunctive aripiprazole or adjunctive placebo and followed for 6 weeks. Mean improvement in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole versus adjunctive placebo for both between-class (-9.2 vs -6.2, P < .001) and within-class (-9.8 vs -6.6, P < .001) switch groups. Relative risks for response were 1.6 (95% CI = 1.3-2.1) for those who switched between classes and 1.7 (95% CI = 1.2-2.2) for those who switched within class. Augmentation with aripiprazole, after either a between-class or within-class switch following initial ADT failure, is an effective option for patients with nonresponsive MDD. In contrast to current strategies employed in clinical practice, these results suggest that adjunctive aripiprazole is a logical strategy in patients unresponsive to ADT. ClinicalTrials.gov identifiers: NCT00105196, NCT00095758, NCT00095823.

Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression

Atypical antipsychotics are widely used in bipolar mania. However, the efficacy of atypical antipsychotics in bipolar depression has not been comprehensively explored. To evaluate olanzapine monotherapy in patients with bipolar depression. Patients with bipolar depression received olanzapine (5-20 mg/day, n = 343) or placebo (n = 171) for 6 weeks. The primary outcome was change from baseline to end-point in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included: Clinical Global Impression - Bipolar Version (CGI-BP) scale, 17-item Hamilton Rating Scale for Depression (HRSD-17) and Young Mania Rating Scale (YMRS) scores, and the rate of response (≥50% reduction in MADRS at end-point), recovery (MADRS ≤12 for ≥4 weeks plus treatment completion) and remission (MADRS ≤8). The trial was registered with ClinicalTrials.gov (NCT00510146). Olanzapine demonstrated: significantly greater (P<0.04) improvements on MADRS (least-squares mean change -13.82 v. -11.67), HRSD-17 and YMRS total scores and all CGI-BP subscale scores v. placebo; significantly (P≤0.05) more response and remission, but not recovery; significantly (P<0.01) greater mean increases in weight, fasting cholesterol and triglycerides; and significantly more (P<0.001) patients gained ≥7% body weight. Olanzapine monotherapy appears to be efficacious in bipolar depression. Additional long-term studies are warranted to confirm these results. Safety findings were consistent with the known safety profile of olanzapine.

Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder

A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex. During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis. During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was -8.5 ± 1.7 points for lamotrigine and -9.1 ± 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment.

The Vasopressin V1bReceptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) total scores were ≥ 24 and 18, respectively, and in the GAD trial baseline Hamilton Anxiety Rating Scale (HARS) score was ≥ 22. Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS, and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score (CGI-S). A 4-week, double-blind, placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal (HPA) axis in MDD patients was also conducted. In the GAD trial, SSR149415 did not separate from placebo on the primary (HARS-100 mg: P = .29; 250 mg: P = .21) and secondary (CGI-S-100 mg: P = .18; 250 mg: P = .24) outcome measures, while paroxetine demonstrated efficacy (HARS: P = .003; CGI-S: P = .01). In 2 MDD trials, SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients (HDRS-100 mg: P = .21 and .48, respectively; 250 mg: P = .22 and P = .46, respectively; CGI-S-100 mg: P = .64 and P = .82, respectively; 250 mg: P = .33 and P = .08, respectively). In the third MDD study, SSR149415 250 mg (P = .04), but not escitalopram (P = .15), demonstrated significant improvement compared to placebo on the HDRS total score at week 8. SSR149415 had no deleterious effects on the HPA axis. These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated. ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).

Double‐blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder

The objective of the study was to evaluate once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder (GAD). An 11-week (9-week treatment; 2-week posttreatment), randomized, double-blind, placebo-controlled study (D1448C00015) of flexibly-dosed quetiapine XR (50-300 mg/day) or placebo conducted at 47 sites (Estonia, Poland, Russia, Ukraine, and USA) between September 2006 and April 2008. Patients (≥66 years) with DSM-IV diagnosis of GAD, Hamilton Anxiety Rating Scale (HAM-A) total score of ≥20 with item 1 (anxious mood) and 2 (tension) scores of ≥2, Clinical Global Impressions-Severity of Illness (CGI-S) score of ≥4, and Montgomery Åsberg Depression Rating Scale (MADRS) total score of ≤16 were eligible for inclusion. Primary endpoint: week 9 change from randomization in HAM-A total score. Patients were randomized to quetiapine XR (n = 223) or placebo (n = 227). At week 9, quetiapine XR significantly reduced HAM-A total score versus placebo (least squares mean -14.97 versus -7.21; p < 0.001); symptom improvement with quetiapine XR versus placebo was significant at week 1 (p < 0.001). At week 9, quetiapine XR demonstrated significant benefits over placebo for HAM-A response and remission rates, HAM-A psychic and somatic cluster, MADRS total, CGI-S, Pittsburgh Sleep Quality Index global, pain visual analog scale, and Quality of Life, Enjoyment and Satisfaction Questionnaire short form % maximum total scores and Clinical Global Impressions-Improvement (% patients with a score of 1/2) (all p < 0.001). Adverse events (>5% in either treatment group) included somnolence, dry mouth, dizziness, headache, and nausea. Quetiapine XR (50-300 mg/day) monotherapy is effective in the short term in improving symptoms of anxiety in older patients with GAD, with symptom improvement seen as early as week 1. Tolerability findings were generally consistent with the known profile of quetiapine.

Multicenter Study on the Clinical Effectiveness, Pharmacokinetics, and Pharmacogenetics of Mirtazapine in Depression

Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.