Depression Rating Scale Total Score Research Articles

Efficacy of aripiprazole augmentation in Japanese patients with major depressive disorder: a subgroup analysis and Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression item analyses of the Aripiprazole Depression Multicenter Efficacy study.

Results from this randomized, placebo-controlled study of aripiprazole augmentation to antidepressant therapy (ADT) in Japanese patients with major depressive disorder (MDD) (the Aripiprazole Depression Multicenter Efficacy [ADMIRE] study) revealed that aripiprazole augmentation was superior to ADT alone and was well tolerated. In subgroup analyses, we investigated the influence of demographic- and disease-related factors on the observed responses. We also examined how individual symptom improvement was related to overall improvement in MDD. Data from the ADMIRE study were analyzed. Subgroup analyses were performed on the primary outcome measures: the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) treatment to the end of the randomized treatment. Changes in the MADRS total scores were consistently greater with aripiprazole than placebo in each of the subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of the current episode, age at first depressive episode, time since the first depressive episode, type of SSRI/SNRI, or severity at the end of SSRI/SNRI treatment phase. Compared to placebo, aripiprazole resulted in significant and rapid improvement on seven of the 10 MADRS items, including sadness. These post-hoc analyses indicated that aripiprazole was effective for a variety of Japanese patients with MDD who had exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improved the core depressive symptoms.

The effectiveness of prefrontal theta cordance and early reduction of depressive symptoms in the prediction of antidepressant treatment outcome in patients with resistant depression: analysis of naturalistic data.

Current studies suggest that an early improvement of depressive symptoms and the reduction of prefrontal theta cordance value predict the subsequent response to antidepressants. The aim of our study was (1) to compare the predictive abilities of early clinical improvement defined as ≥ 20 % reduction in Montgomery and Åsberg Depression Rating Scale (MADRS) total score at week 1 and 2, and the decrease of prefrontal theta cordance at week 1 in resistant depressive patients and (2) to assess whether the combination of individual predictors yields more robust predictive power than either predictor alone. Eighty-seven subjects were treated (≥ 4 weeks) with various antidepressants chosen according to the judgment of attending psychiatrists. Areas under curve (AUC) were calculated to compare predictive effect of defined single predictors (≥ 20 % reduction in MADRS total score at week 1 and 2, and the decrease of cordance at week 1) and combined prediction models. AUCs of all three predictors were not statistically different (pair-wise comparison). The model combining all predictors yielded an AUC value 0.91 that was significantly higher than AUCs of each individual predictor. The results indicate that the combined predictor model may be a useful and clinically meaningful tool for the prediction of antidepressant response in patients with resistant depression.

Efficacy of olanzapine monotherapy in the treatment of bipolar depression with mixed features

BackgroundThis analysis investigated the correlations between the efficacy of olanzapine monotherapy and the number of concurrent manic symptoms in patients treated for bipolar depression. MethodsPooled data from 2 placebo-controlled olanzapine studies in patients with bipolar I depression were analyzed (total 1214 patients; 690 olanzapine monotherapy patients and 524 placebo patients). Patients were categorized for mixed features by the number of concurrent manic symptoms at baseline (0, 1 or 2, and ≥3, respectively, as measured by a Young Mania Rating Scale item score ≥1). Efficacy was evaluated by change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score from baseline to 6 weeks. ResultsLeast-squares mean differences between olanzapine and placebo in the change of MADRS total scores were −3.76 (p=0.002), −3.20 (p<0.001), and −3.44 (p=0.002) for mixed features 0, 1 or 2, and ≥3, respectively. The response rates for olanzapine versus (vs.) placebo were 52.6% vs. 39.8%, 50.3% vs. 40.0%, and 42.2% vs. 33.7% for mixed features 0, 1 or 2, and ≥3, respectively. The remission rates for olanzapine vs. placebo group were 46.1% vs. 34.3%, 39.5% vs. 32.0%, and 34.8% vs. 24.1% for mixed features 0, 1 or 2, and ≥3, respectively. No significant interaction between mixed features and treatment was seen in the MADRS changes or response and remission rates. LimitationsPost hoc analyses of the data from 2 previous randomized clinical studies. ConclusionsOlanzapine monotherapy was shown to be effective in the treatment of bipolar depression irrespective of the presence of concurrent manic symptoms.

Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder.

This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery–Åsberg Depression Rating Scale (MADRS) total score≥26 and Clinical Global Impression – Severity score≥4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression – Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale ≥20; remission (MADRS≤10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n=158) of −5.5 (vortioxetine 15 mg, P<0.0001, n=149) and −7.1 MADRS points (vortioxetine 20 mg, P<0.0001, n=151). Duloxetine (n=146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence≥5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder.

Effect of symptom severity on efficacy and safety of aripiprazole adjunctive to antidepressant monotherapy in major depressive disorder: A pooled analysis

BackgroundThere is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. MethodsData from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25–30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. ResultsAripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, −2.5 [−4.0 to −1.1]; moderate, −3.2 [−4.9 to −1.6]; severe, −4.5 [−6.8 to −2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. LimitationsThe original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. ConclusionsIn patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. Clinical trial registrationClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758.

Safety and efficacy of olanzapine in the long‐term treatment of Japanese patients with bipolar I disorder, depression: An integrated analysis

Safety and efficacy of long-term olanzapine treatment in Japanese patients with bipolar depression were assessed. An integrated analysis of data from two studies was performed in olanzapine-treated patients (n = 165) with bipolar depression. Study 1 was a 6-week, double-blind, global study. Patients were randomly assigned to olanzapine or placebo followed by 18 weeks of open-label treatment. Study 2 was an open-label extension of Study 1 involving only Japanese patients. Patients assigned to Pre-olanzapine and Pre-placebo in Study 1 were treated for 24 weeks (total olanzapine exposure 42 or 48 weeks) and newly recruited patients (New-olanzapine) were treated for 48 weeks. Safety outcomes included treatment-emergent adverse events and changes in metabolic parameters. Efficacy outcome was assessed with Montgomery-Åsberg Depression Rating Scale score. Forty-three percent of patients completed the 42- or 48-week olanzapine treatment period. The most common treatment-emergent adverse event was weight increased (47.9%). Significant increases were seen in weight (3.5 kg), and in fasting glucose (3.5 mg/dL), fasting total cholesterol (8.1 mg/dL), and fasting triglycerides (35.1 mg/dL). Remission rates (Montgomery-Åsberg Depression Rating Scale total score ≤12 at any time) were 79.8% for the Pre-olanzapine group, 90.2% for the Pre-placebo group, and 85.0% for the New-olanzapine group. No patents developed mania during treatment. Long-term use of olanzapine in a Japanese population with bipolar depression is associated with increases in weight and fasting metabolic measures, and also with improved depressive symptoms with avoidance of mania. Clinicians must carefully consider the benefits and risks of long-term therapy with olanzapine.

Debunking the placebo effect in depression

In approximately half of the major depressive disorder (MDD) antidepressant trials published in the last decade, 30% or more of the patients assigned to the placebo arm showed clinically significant improvements. Attempts to reduce the placebo effect in a variety of ways have proven mostly unsuccessful. The aim of this study was to determine whether trial design has an effect on the efficacy outcome in a mock placebo versus escitalopram treatment of adult outpatients with MDD. An 8-week study was designed to evaluate the placebo effect on the response to fixed doses of escitalopram (10 and 20 mg/day) in patients with MDD. The variables affecting placebo response evaluated were as follows: patient expectation, rater expectation, three different outcome measures and the number of visits during the study. Investigators were blinded to the inclusion and exclusion criteria. Forty patients were randomized to receive what they and their treating physicians conceived of as double-blind treatment. The mean age of the patients in the group was 45.1 years, 19 women (47.5%) and 21 men. The mean change from baseline to week 8 in the Montgomery-Åsberg Depression Rating Scale total score was -13.7 for participants with 'monthly' visits and -12.9 for the 'fortnightly' group (P=0.75). In each group, 14/16 responders and their physicians thought that they were receiving active treatment. Of 22 nonresponsive patients, 17 thought that they had been receiving placebo. The pharmacological effect of escitalopram observed in the present study is almost identical to that observed in open-label studies, even when patients and clinicians are misled by the study design, placebo presence or raters' blindability.

Seizure threshold variations in ECT-treated chronic patients with schizophrenia: a brief report.

Seizure threshold (ST) is a parameter that differs in each person and can be modified both spontaneously and because of drug intake and/or other exogenous factors. A rise in ST during a course of electroconvulsive therapy (ECT) has been demonstrated in patients with depression and mania, but little information has been available as to whether the same result occurs in schizophrenia (SCZ). 11 male patients underwent estimation of the seizure threshold over a bilateral ECT course. Mean ST changed not significantly. No correlations were found between baseline ST and Positive and Negative Syndrome Scale (PANSS) scores. A significant positive correlation emerged between baseline ST and the variation of Hamilton Depression Rating Scale (HDRS) total and cognitive scores. The results suggest that ST in SCZ patients is not related to baseline psychopathological features, it is not related to clinical improvements of negative or positive SCZ symptoms and it does not change during the ECT course but it appears predictive of the improvement of affective and cognitive symptmos.

Abstract T P121: A Comparative Study of Duloxetine and Paroxetine in Japanese Patients With Post-Stroke Depression

Background and methods: Patients with stroke may suffer from post-stroke depression and concomitant pain symptoms. A double-blind, parallel-group, controlled study was performed to investigate if duloxetine was superior to paroxetine in terms of improvement in symptoms of depression and pain in Japanese patients with post-stroke depression in a fixed-dose design. The efficacy and safety of duloxetine 60 mg/day were also assessed in comparison with those at the standard dose of 40 mg/day. Results: Changes in 17-item Hamilton depression rating scale (HAM-D) total score (mean ± standard deviation) for group D1 (duloxetine 40 mg/day), group M2 (duloxetine 60 mg/day), and group PX (paroxetine 20 mg/day) were –14.9 ± 5.6, –15.6 ± 6.4, and –11.4 ± 6.2, respectively, and the estimated differences in total score for group PX (Dunnett’s 95% simultaneous confidence interval) were 3.8 (3.2 to 4.4) for group D1 and 4.2 (3.6 to 4.8) for group D2. The superiority of groups M1 and M2 to group PX was thus confirmed, because the upper confidence limit of differences between groups D1 and PX and between groups D2 and PX was more than 3.2. The groups M1 and M2 presented a reduction in the pain, which was not observed in the group PX. The incidence of treatment-related adverse events was 21% for group D1, 28% for group D2, and 30% for group PX, indicating no significant difference between the three groups. Conclusion: These results demonstrate that duloxetine 40 mg/day and 60 mg/day is superior to paroxetine in terms of efficacy on post-stroke depression and central pain.

A randomized, double-blind, placebo-controlled study of flexible doses of levomilnacipran ER (40–120 mg/day) in patients with major depressive disorder

Objective:Levomilnacipran ER is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). Efficacy and safety have been evaluated in five Phase II/III studies, four of which met the pre-specified primary efficacy outcome. Results of the negative trial (ClinicalTrials.gov NCT00969150) are reported here.Methods:A Phase III randomized, double-blind, placebo-controlled trial comparing flexible-dose levomilnacipran ER 40–120 mg/day with placebo was conducted in outpatients with MDD. Patients met the DSM-IV-TR criteria for MDD, had a current episode of depression of at least 4 weeks’ duration, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥30. The study comprised a 1-week, single-blind, placebo lead-in, 8-week double-blind treatment, and a 2-week down-taper. The primary and secondary efficacy measures were change from baseline to Week 8 in MADRS and Sheehan Disability Scale (SDS) total scores, respectively, analyzed using a mixed-effects model for repeated measures approach. Safety outcomes included adverse events (AEs), laboratory and vital sign measures, the Columbia-Suicide Severity Rating Scale, and the Arizona Sexual Experiences Scale (ASEX).Results:Three hundred and fifty-five patients received the study drug and had ≥1 post-baseline MADRS total score assessment (ITT Population); 81.9% of placebo and 77.1% of levomilnacipran ER patients completed the study. For levomilnacipran ER vs placebo, MADRS (−15.7 vs −14.2) and SDS (−8.8 vs −8.2) total score improvements, and rates of MADRS response (38.5% vs 34.8%) and remission (25.3% vs 23.8%) were numerically greater but differences were not statistically significant. Levomilnacipran ER was generally well tolerated. More levomilnacipran ER patients vs placebo reported AEs; the most common AEs for levomilnacipran ER were nausea (17%) and headache (16%). Mean changes in most safety measures were small and similar between groups. There were no meaningful differences in total ASEX scores between groups.Limitations:Short duration of treatment, inclusion and exclusion criteria, and lack of an active comparator.Conclusion:Numerical improvements for levomilnacipran ER vs placebo were detected in this study, but the differences were not statistically significant; levomilnacipran ER was generally well tolerated.

Pooled analysis of adjunct extended-release quetiapine fumarate in patients with major depressive disorder according to ongoing SSRI or SNRI treatment

This pooled analysis evaluated the efficacy of extended-release quetiapine fumarate (quetiapine XR) adjunct to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). Pooled data were analyzed from two 6-week, double-blind, randomized, placebo-controlled trials of adjunct quetiapine XR (150 and 300 mg/day) in patients with MDD and inadequate response to initial antidepressant monotherapy. This post-hoc analysis included evaluation of change from randomization at week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total scores (primary endpoint), and week 6 MADRS response and remission rates for quetiapine XR as an adjunct to ongoing SSRI or SNRI. In total, 189, 178, and 202 patients received quetiapine XR 150 mg/day+SSRI, 300 mg/day+SSRI, and placebo+SSRI, respectively, whereas 82, 90, and 76 patients, respectively, received quetiapine XR 150 mg/day+SNRI, 300 mg/day+SNRI, and placebo+SNRI. At week 6, quetiapine XR 150 mg/day+SSRI and 300 mg/day+SSRI reduced the MADRS total score from randomization versus placebo+SSRI [least squares mean (LSM) change, -14.70 (P<0.05) -14.72 (P<0.05) vs. -12.59, respectively]. Quetiapine XR 150 mg/day+SNRI (LSM change, -14.68, P<0.01) and 300 mg/day+SNRI (LSM change, -14.99, P<0.01) also reduced the MADRS total score from randomization at week 6 versus placebo+SNRI (-10.77). In conclusion, in patients with MDD and inadequate response to ongoing antidepressant, adjunct quetiapine XR (150 and 300 mg/day) was effective in both SSRI and SNRI subgroups.

Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant

This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1–4mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1–4mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies.

Vortioxetine: Atypical antidepressant

Although its mechanism of action is not fully understood, vortioxetine is an inhibitor of serotonin (5-hydroxytryptamine [5-HT]) reuptake and an agonist at 5-HT1A receptors; a partial agonist at 5-HT1B receptors; and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. According to Takeda, it is the fi rst and only antidepressant that increases the availability of serotonin by this unique combination of pharmacodynamic activity. The contribution of each of these mechanisms of action to vortioxetine’s antidepressant effect has not been established; however, they may represent an improvement over other antidepressants currently on the market, said Takeda.

Aripiprazole augmentation for treatment of patients with chronic or recurrent major depressive disorder

Patients with chronic or recurrent major depressive disorder (MDD) have faced a dearth of treatment options. The present study evaluated the effectiveness and tolerability of aripiprazole augmentation for the treatment of chronic or recurrent MDD. This was the first 12-week prospective, multicentre, open-label study of the effectiveness and tolerability of flexibly dosed aripiprazole as an augmentation to ongoing antidepressant treatment in patients with chronic or recurrent MDD. The primary outcome measure for effectiveness was changes between baseline and endpoint (week 12) in total scores on the Montgomery-Asberg Depression Rating Scale. Adverse events (AEs) occurring throughout the trial are also reported. The Montgomery-Asberg Depression Rating Scale total scores decreased significantly between the baseline and the endpoint (magnitude of difference=-11.6, P<0.0001). At the endpoint, the response rate was 55.2% and the remission rate was 41.3%. Adjunctive aripiprazole treatment administered from week 1 through the endpoint was associated with remission and significant treatment responses. More than half (55.8%) of those taking adjunctive aripiprazole completed the study and relatively few patients discontinued participation because of AEs. None of the patients discontinued participation in the study because of an inadequate therapeutic response. Common AEs included headache, akathisia, insomnia and constipation. The mean dose of aripiprazole at the endpoint was 6.6 mg/day. Adjunctive aripiprazole may be effective and tolerable for patients with chronic or recurrent MDD. Adequately powered and controlled clinical trials should be conducted to confirm our open-label study findings.

Relationship between major depressive disorder and associated painful physical symptoms

The aim of this study was to evaluate the relationship between painful physical symptoms (PPS) and outcomes in major depressive disorder (MDD). Post-hoc analysis of two identically designed 8-week trials compared the efficacy of 60 mg/day duloxetine (N=523) with that of placebo (N=532) in treating PPS associated with MDD. The Montgomery-Åsberg Depression Rating Scale (MADRS) total score, the Brief Pain Inventory (BPI) average pain score, and the Sheehan Disability Scale global functional impairment score assessed depression symptoms, pain, and functioning, respectively. Remission was defined as a MADRS score of 10 or less, and the BPI response subgroup was defined as a 50% or greater reduction from baseline. Path analyses assessed relationships among variables. Duloxetine-treated patients who had a 50% or greater reduction in BPI score at endpoint had higher rates of remission. Path analysis indicated that 16% of likelihood of remission in depression symptoms was because of the direct effect of treatment, 41% because of pain reduction, and 43% because of functional improvement. Path analysis also indicated that 51% of improvement in functioning was attributed to pain improvement and 43% to mood improvement. Results demonstrate that improvement in pain and mood contributes to functional improvement, and pain reduction and functional improvement increase the likelihood of remission of depressive symptoms with duloxetine treatment in patients with both MDD and PPS at baseline.

Efficacy and Safety of Desvenlafaxine 50 mg/d in a Randomized, Placebo-Controlled Study of Perimenopausal and Postmenopausal Women With Major Depressive Disorder

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

Augmentation of Aripiprazole for Depressed Patients With an Inadequate Response to Antidepressant Treatment

Nonresponse or a partial response to 1 or more antidepressants is a common and significant problem in clinical practice. Adjunctive therapy with atypical antipsychotics is considered as 1 of the next treatment options for such inadequate responses. The present trial evaluated the efficacy and the safety of aripiprazole as an augmentation to ongoing antidepressant monotherapy for patients with major depressive disorder (MDD) who have previously exhibited an inadequate clinical response. This was a 6-week prospective, multicenter, open-label study with flexibly dosed adjunctive aripiprazole. The 86 participants with MDD showed inadequate responses to more than 8 weeks of standard antidepressant treatment. The primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale total score from baseline to the end point (week 6). The mean daily dose of aripiprazole at the end point was 6.9 mg. The Montgomery-Asberg Depression Rating Scale total score was significantly decreased with adjunctive aripiprazole during the study period (by 14.0 points, P = 0.000). At the end point, the response rate was 52.3% and the remission rate was 39.8%. Adjunctive aripiprazole produced a significant response and remission from week 1 through the end point. The study completion rate was 73.9%, and adverse events included sedation (n = 11), akathisia (n = 9), headache (n = 6), tremor (n = 6), and increased appetite (n = 5). Of the discontinuations, only 5.7% were due to adverse events. Adjunctive aripiprazole in patients with MDD who had previously exhibited an inadequate response to standard antidepressant therapy was efficacious and well tolerated. A low daily dose of aripiprazole would be more acceptable in the clinical setting.

The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder

We primarily sought to determine the effect of adjunctive lisdexamfetamine dimesylate (LDX) on anthropometric and metabolic parameters. Our secondary aim was to evaluate the effect of LDX on attention deficit hyperactivity disorder (ADHD) symptom severity in adults with bipolar I/II disorder. Forty-five stable adults (i.e., non-rapid cycling, absence of clinically significant hypo/manic symptoms) with bipolar I/II disorder and comorbid ADHD were enrolled in a phase IV, 4-week, flexible dose, open-label study of adjunctive LDX. All subjects were initiated at 30 mg/day of adjunctive LDX for the first week with flexible dosing (i.e., 30-70 mg/day) between weeks 2 and 4. Of the 45 subjects enrolled, 40 received adjunctive LDX (mean dose = 60 ± 10 mg/day). A statistically significant decrease from baseline to endpoint was evident in weight (p < 0.001), body mass index (p < 0.001), fasting total cholesterol (p = 0.011), low density lipoprotein cholesterol (p = 0.044), high density lipoprotein cholesterol (p = 0.015) but not triglycerides, or blood glucose. Significant reductions were also observed in leptin (p = 0.047), but not in ghrelin, adiponectin, or resistin levels. Diastolic blood pressure and pulse increased significantly over time but on average remained within the normal range (p < 0.001). There was a significant reduction from baseline to endpoint in the total score of the ADHD Self-Report Scale. Significant improvement from baseline to endpoint was also observed in the Montgomery-Åsberg Depression Rating Scale total score as well as the Clinical Global Impression Severity and Improvement score. Short-term adjunctive LDX treatment was well tolerated by this sample of adults with stable bipolar I/II disorder. Lisdexamfetamine dimesylate offered beneficial effects on body weight, body mass index and several metabolic parameters. In addition to demonstrating short-term (i.e., 4 weeks) safety and tolerability, beneficial effects of LDX were also observed in mitigating depressive and ADHD symptom severity.

Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: A randomized, double-blind, placebo-controlled study (ADMIRE study)

ObjectiveThis randomized, placebo-controlled study evaluated the efficacy and safety of a fixed dose (3mg/day) and flexible dose (3–15mg/day) schedule of aripiprazole as augmentation therapy in Japanese patients with inadequate response to antidepressant therapy (ADT). MethodDuring an 8-week prospective treatment phase, patients experiencing a major depressive episode received clinicians' choice of ADT. Subjects with inadequate response to ADT were randomized to receive adjunctive treatment with placebo (n=195), fixed dose aripiprazole (n=197) or flexible dose aripiprazole (n=194) for 6 weeks. The primary efficacy endpoint was mean change in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score from the end of prospective treatment (baseline) to the end of randomized treatment. ResultsMore than 90% of patients in all treatment groups completed the 6-week double-blind treatment phase. Mean MADRS total score was improved to a significantly greater extent with fixed dose aripiprazole and flexible dose aripiprazole (−10.5 and −9.6, respectively) than with placebo (−7.4). Aripiprazole was well tolerated. The incidence of akathisia observed in the flexible dose group may relate to a higher prevalence of the CYP2D6*10 allele in Asian populations. LimitationsSix weeks of adjunctive treatment is insufficient to draw conclusions about the long-term benefits of aripiprazole. Exclusion of patients with established medical comorbidities does not reflect real-world practice. ConclusionsAripiprazole augmentation at a fixed or flexible dose was superior to ADT alone and was reasonably well tolerated in Japanese patients with inadequate response to ADT. Clinical trials registrationClinicalTrials.gov identifier NCT00876343.

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.