Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial

Background

Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the treatment of depressed patients. Looking for new medications that can potentiate the effects of current antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in resistant major depressive disorder (MDD).

Method

This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in the study. Patients were randomized to receive a flexible dose of topiramate (100-200 mg/day) or placebo beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton Depression Scale (HAM-D) and Clinical Global Impression (CGI).

Results

42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups, respectively. The topiramate group demonstrated significant improvement over the study period based on mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms were significantly improved in the topiramate group.

Conclusion

Our double-blind placebo-controlled study demonstrated that topiramate augmentation potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to confirm the results.     

Paroxetine controlled-release formulation in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled study in Japan and Korea

Aim: The main purpose of this study was to evaluate the efficacy of paroxetine controlled‐release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective‐serotonin‐reuptake‐inhibitors‐induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate‐release (IR) formulation. Methods: We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end‐point was the adjusted mean change from baseline in the 17‐item Hamilton Rating Scale for Depression total score at Week 8. Results: A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17‐item Hamilton Rating Scale for Depression was ?12.8 in the CR group, ?12.5 in the IR group, and ?10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR (P < 0.001) and IR (P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). Conclusion: Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period.     

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.     

Vortioxetine: a meta-analysis of 12 short-term,randomized, placebo-controlled clinical trials for the treatment of major depressive disorder

BackgroundVortioxetine was approved by the U.S. Food and Drug Administration (FDA) in September 2013 for treating major depressive disorder (MDD). Thus far, a number of randomized, double-blind, placebo-controlled clinical trials (RCTs) of vortioxetine have been conducted in patients with MDD. We performed a meta-analysis to increase the statistical power of these studies and enhance our current understanding of the role of vortioxetine in the treatment of MDD.MethodsWe performed an extensive search of databases and the clinical trial registry. The mean change in total scores on the 24-item Hamilton Rating Scale for Depression (HAM-D) and the Montgomery–Åsberg Depression Rating Scale (MADRS) from the baseline were the primary outcome measures. The secondary efficacy measures were the response and remission rates, as defined by a 50% or greater reduction in HAM-D/MADRS total scores and as a score of 10 or less in the MADRS and 7 or less in the HAM-D total scores at the end of treatment.ResultsWe included 7 published and 5 unpublished short-term (6–12 wk) RCTs in our meta-analysis. Vortioxetine was significantly more effective than placebo, with an effect size (standardized mean difference [SMD]) of −0.217 (95% confidence interval [CI] −0.313 to −0.122) and with odds ratios (ORs) for response and remission of 1.652 (95% CI 1.321 to 2.067) and 1.399 (95% CI 1.104 to 1.773), respectively. Those treated with vortioxetine did not differ significantly from those treated with selective norepinephrine reuptake inhibitors/agomelatine with regard to the SMD of the primary outcome measure (0.081, −0.062 to 0.223) or for response (OR 0.815, 95% CI 0.585 to 1.135) and remission (OR 0.843, 95% CI 0.575 to 1.238) rates. Discontinuation owing to lack of efficacy (OR 0.541, 95% CI 0.308 to 0.950) was significantly less common among those treated with vortioxetine than among those who received placebo, whereas discontinuation owing to adverse events (AEs; OR 1.530, 95% CI 1.144 to 2.047) was significantly more common among those treated with vortioxetine than among those receiving placebo. There was no significant difference in discontinuation rates between vortioxetine and comparators owing to inefficacy (OR 0.983, 95% CI 0.585 to 1.650), whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group (OR 0.728, 95% CI 0.554 to 0.957).LimitationsStudies examining the role of vortioxetine in the treatment of MDD are limited.ConclusionAlthough our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs.     

Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study

OBJECTIVE: Aripiprazole is a relatively new atypical antipsychotic agent that has been successfully employed in therapy for schizophrenia and schizoaffective disorders. A few neuroleptics have been used in therapy for patients with borderline personality disorder, which is associated with severe psychopathological symptoms. Aripiprazole, however, has not yet been tested for this disorder, and the goal of this study was to determine whether aripiprazole is effective in the treatment of several domains of symptoms of borderline personality disorder. METHOD: Subjects meeting criteria for the Structured Clinical Interview for DSM-III-R Personality Disorders for borderline personality disorder (43 women and 9 men) were randomly assigned in a 1:1 ratio to 15 mg/day of aripiprazole (N=26) or placebo (N=26) for 8 weeks. Primary outcome measures were changes in scores on the symptom checklist (SCL-90-R), the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), and the State-Trait Anger Expression Inventory and were assessed weekly. Side effects and self-injury were assessed with a nonvalidated questionnaire. RESULTS: According to the intent-to-treat principle, significant changes in scores on most scales of the SCL-90-R, the HAM-D, the HAM-A, and all scales of the State-Trait Anger Expression Inventory were observed in the subjects treated with aripiprazole after 8 weeks. Self-injury occurred in the groups. The reported side effects were headache, insomnia, nausea, numbness, constipation, and anxiety. CONCLUSIONS: Aripiprazole appears to be a safe and effective agent in the treatment of patients with borderline personality disorder.     

Duloxetine, 60 mg once daily,for major depressive disorder: a randomized double-blind placebo-controlled trial

BACKGROUND: Despite treatment advances, major depressive disorder (MDD) is still a significant cause of morbidity and mortality. Current therapies frequently fall short of providing full remission. In addition, physical symptoms are commonly seen in MDD patients, increasing overall morbidity and health care utilization. Duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, was evaluated for efficacy and tolerability/safety in the treatment of MDD and associated physical symptoms. METHOD: In this multicenter, double-blind, parallel-group study, adult patients with DSM-IV MDD were randomly assigned to receive placebo (N = 122) or duloxetine (60 mg/day, N = 123) for 9 weeks. The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score. Painful physical symptoms were assessed using visual analog scales, and global illness and quality of life were evaluated using the Clinical Global Impressions-Severity scale, the Patient Global Impressions-Improvement scale, and the Quality of Life in Depression Scale. Safety and tolerability were determined by monitoring discontinuation rates, adverse events, vital signs, and laboratory results. RESULTS: Duloxetine was significantly superior to placebo (p < .001) in reducing HAM-D-17 total scores, starting at week 2. The estimated probability of remission for duloxetine-treated patients (44%) was almost 3 times that of placebo patients (16%). Duloxetine significantly reduced painful physical symptoms in comparison with placebo. Discontinuation due to adverse events for duloxetine-treated patients (13.8%) compared favorably with the rates reported for SSRIs in other studies. Nausea, dry mouth, and somnolence were the most common adverse events; no significant incidence of hypertension was seen. CONCLUSION: Duloxetine, 60 mg/day, is a well-tolerated and effective treatment for MDD that reduces painful physical symptoms. These findings suggest that duloxetine may be a first-line treatment for patients with MDD and associated painful physical symptoms.     

Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial

Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor with a relative potency to inhibit serotonin, norepinephrine, and dopamine uptake of ～1:2:8, respectively. This 6-week, multicenter, randomized, double-blind, parallel, placebo-controlled study evaluated the efficacy and tolerability of amitifadine in 63 patients with major depressive disorder. Eligible patients (17-item Hamilton Depression Rating Scale [HAMD-17] ≥ 22 at baseline) were randomized to amitifadine 25 mg twice daily (BID) for 2 weeks, then 50 mg BID for 4 weeks or placebo. Mean baseline scores in the modified intent-to-treat population (n = 56) were 31.4 for the Montgomery-Åsberg Depression Rating Scale (MADRS), 29.6 for the HAMD-17, and 25.4 for the Derogatis Interview for Sexual Functioning – Self Report (DISF-SR). At the end of the 6-week double-blind treatment, estimated least squares mean change from baseline (mixed-model repeated measures [MMRM]) in MADRS total score was statistically significantly superior for amitifadine compared to placebo (18.2 vs. 22.0; p = 0.028), with an overall statistical effect size of ?0.601 (Cohen’s d). Amitifadine also was statistically significantly superior to placebo (p = 0.03) for the Clinical Global Impression of Change – Improvement. An anhedonia factor score grouping of MADRS Items 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel) demonstrated a statistically significant difference in favor of amitifadine compared to placebo (p = 0.049). No differences were observed between treatments in DISF-SR scores. Amitifadine was well-tolerated. Two patients on each treatment discontinued the study early due to adverse events; however, no serious adverse events were reported. This initial clinical trial in patients with severe major depression demonstrated significant antidepressant activity with amitifadine, including attenuating symptoms of anhedonia, and a tolerability profile that was comparable to placebo. The efficacy and tolerability of amitifadine for major depressive disorder are being investigated in additional clinical trials.     

Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III,randomized, double-blind,fixed-dose,placebo-controlled study

Background

Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults.

Methods

This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18–75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.

Results

The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%–83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (–3.3 [−5.5 to −1.1], p = 0.003) and 80 mg/day (−3.1, [−5.3 to −1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (−1.8, 95% [−3.6 to 0], p = 0.046) and 80 mg/day (−2.7 [−4.5 to −0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction.

Limitations

Limitations to our study included short treatment duration and lack of an active control arm.

Conclusion

Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population.

Clinical trial registration

{"type":"clinical-trial","attrs":{"text":"NCT01377194","term_id":"NCT01377194"}}NCT01377194.     

Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial

Thiazolidinediones have shown antidepressant effect in animal studies, as well as in some uncontrolled studies evaluating human subjects with concurrent major depressive disorder (MDD) and metabolic syndrome. Although these drugs are insulin sensitizers, they also have important anti-inflammatory, neuroprotective, and anti-excitotoxic properties. Thus, we hypothesized that they would show antidepressant effect in patients with MDD even if it was not accompanied by metabolic disturbances. In this double-blind placebo-controlled study, 40 patients with MDD (DSM-IV-TR) and Hamilton depression rating scale-17 (Ham-D) score ≥ 22 were randomized to citalopram plus pioglitazone (15 mg every 12 h) (n=20) or citalopram plus placebo (n=20) for 6 weeks. Patients were evaluated using Ham-D (weeks 0, 2, 4, 6). Repeated-measure analysis of variance (ANOVA) and analysis of covariance were used for comparison of scores between the two groups. Treatment response (≥ 50% reduction in Ham-D score), remission (Ham-D score ≤ 7), and early improvement (≥ 20% reduction in Ham-D score within the first 2 weeks) were compared between the two groups using Fisher's exact test. Pioglitazone showed superiority over placebo during the course of the trial (F(1, 38)=9.483, p=0.004). Patients in the pioglitazone group had significantly lower scores at all time points than the placebo group (P<0.01). Frequency of early improvement, response (week 6), and remission was significantly higher in the pioglitazone group (95%, 95%, 45%, respectively) than in the placebo (30%, 40%, 15% respectively) group (P<0.001, <0.001, 0.04, respectively). Frequency of side effects was similar between the two groups. Pioglitazone is a safe and effective adjunctive short-term treatment in patients with moderate-to-severe MDD even in the absence of metabolic syndrome and diabetes.     

Riluzole combination therapy for moderate-to-severe major depressive disorder: A randomized,double-blind,placebo-controlled trial

Recent evidences suggest that glutamatergic dysregulation implicated in neural plasticity and cellular resilience may contribute to the pathophysiology of Major Depressive Disorder (MDD). Riluzole, which exerts its effect by targeting glutamate neurotransmission, has shown antidepressant effect in recent preclinical, observational and open label studies. This study aimed to assess the efficacy and tolerability of riluzole in patients with MDD. Sixty-four inpatients with diagnosis of moderate to severe major depressive disorder participated in a parallel, randomized, controlled trial, and sixty patients underwent 6 weeks treatment with either riluzole (50 mg/bid) plus citalopram (40 mg/day) or placebo plus citalopram (40 mg/day). All participants were inpatients for the whole duration of the study. Patients were assessed using Hamilton depression rating scale (HDRS) at baseline and weeks 2, 4 and 6. The primary outcome measure was to assess the efficacy of riluzole compared to placebo in improving the depressive symptoms. General linear model repeated measures demonstrated significant effect for time × treatment interaction on HDRS [F (1.86, 107.82) = 8.63, p < 0.001]. Significantly greater improvement was observed in HDRS scores in the riluzole group compared to the placebo group from baseline HDRS score at weeks 2, 4 and 6 (p < 0.001, p = 0.001, p = 0.002, respectively). Significantly greater response with greater speed to treatment was observed in the riluzole group than the placebo group. No serious adverse event occurred. This study showed a favorable safety and efficacy profile in patients with major depressive disorder. Larger controlled studies with longer treatment periods are needed to investigate long term safety, efficacy and optimal dosing.     

Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial

BACKGROUND: Duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, was evaluated for therapeutic efficacy and safety/tolerability in the treatment of major depression. METHOD: In an 8-week multicenter, double-blind, placebo-controlled study, 173 patients (aged 18-65 years) with DSM-IV major depressive disorder were randomly allocated to receive placebo (N = 70), duloxetine (N = 70), or fluoxetine, 20 mg q.d. (N = 33). Duloxetine dose was titrated in the first 3 weeks in a forced-titration regimen from 40 mg (20 mg b.i.d.) to 120 mg/day (60 mg b.i.d.). Patients were required to have a Clinical Global Impressions (CGI)-Severity of Illness scale score of at least moderate severity (> or = 4) and a 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score of at least 15. Patients could not have had any current primary DSM-IV Axis I diagnosis other than major depressive disorder, or any anxiety disorder as a primary diagnosis within the past year, excluding specific phobias. The primary efficacy measurement was the HAM-D-17 total score, and secondary measures included the Montgomery-Asberg Depression Rating Scale, CGI-Severity of Illness and CGI-Improvement, and Patient Global Impression of Improvement. Safety was evaluated by recording the occurrence of discontinuation rates and treatment-emergent adverse events and by measurement of vital signs and laboratory analytes. RESULTS: Duloxetine was superior to placebo in change on the HAM-D-17 (p = .009). Estimated probabilities of response and remission were 64% and 56%, respectively, for duloxetine, compared with 52% and 30% for fluoxetine and 48% and 32% for placebo. Duloxetine was numerically superior to fluoxetine on the primary and most of the secondary outcome measures. In general, duloxetine was well tolerated; 76% of patients achieved the maximum dose, and insomnia and asthenia were the only adverse events reported statistically significantly (p < .05) more frequently by duloxetine-treated patients compared with placebo-treated patients. CONCLUSION: These data indicate that duloxetine is efficacious for the treatment of major depressive disorder and is well tolerated and safe.