Reduction In Montgomery-Asberg Depression Rating Scale Scores Research Articles

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD).Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures.Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04019704.

Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial.

Objective:Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone.Methods:Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment.Results:A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported.Conclusion:Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use.Clinical trial registration:ClinicalTrials.gov, NCT02579642

Prediction of residual cognitive disturbances by early response of depressive symptoms to antidepressant treatments in patients with major depressive disorder

BackgroundPatients with major depressive disorder (MDD) frequently retain cognitive disturbances after recovery from mood symptoms. We investigated the relationship between early response of mood symptoms and/or remission, and residual cognitive disturbances after 6 months of antidepressant treatment. Methods518 patients with MDD were followed up for 6 months after antidepressant treatment initiation (first-line or switch from a previous drug). Subjective and objective cognitive disturbances were assessed by the Perceived Deficits Questionnaire – Depression (PDQ-D) and digit symbol substitution test (DSST), respectively. Depressive symptoms, as well as remission and early response to treatment, were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Multivariable linear and logistic regression models were used to adjust for confounders. ResultsEarly response of depressive mood (≥50% reduction in MADRS score at month 1) was related with fewer residual subjective cognitive symptoms, as evaluated by the PDQ-D at month 6 (p<0.001). Likewise, early remission status at month 2 was inversely associated with PDQ-D scores at month 6 (p<0.001). Among patients with baseline DSST scores of ≥1 standard deviation below the norm, early response/remission was associated with better performance on the DSST at month 6 (p<0.05). LimitationsThe cohort may not be representative of the general MDD patient population, and the possible influence of concomitant medications was not evaluated. ConclusionsThese findings suggest that early improvements in depressive symptoms predict better cognitive outcomes in patients with MDD. Grouping of patients by mood and cognition status in early stages of antidepressant treatments may facilitate efforts to improve long-term functional outcomes.

Depression treatment in women and men with bipolar affective disorder: a comparative study

Objective: to compare depression treatment efficacy with and without antidepressants (ADs) in men and women with bipolar affective disorder (BAD).Patients and methods. We enrolled 100 patients with BAD (F31.3–F31.5 according to ICD-10), including 50 women aged 33.0 [23.0; 50.2] years and 50 men aged 37.5 [29.5; 47.2] years using prospective and retrospective methods. Various antidepressants, normothymics, antipsychotics combinations were used to treat depression. We performed a comparative analysis of treatment efficacy with and without antidepressants in men and women subgroups. Clinical assessment at the baseline and the end of 1, 2, 4, 6-th week of therapy (or at discharge) included a specially developed clinical examination chart and the following psychometric scales: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression – Severity of illness (CGI-S), Clinical Global Impression – Improvement (CGI-I).Results and discussion. Women tended to have a slower improvement in the condition compared to men. Maximum reduction in MADRS score and a CGI-I, CGI-S higher frequency of clinical improvement and remission was observed in men and women who did not receive antidepressants than patients who did not receive antidepressants. When BAD type was included in the analysis, in patients treated with antidepressants, transient symptoms of the opposite pole occurred in 24.7% of patients of both sexes with bipolar affective I disorder (BAD I) and in 16.8% with bipolar affective II disorder (BAD II). There were no significant gender differences in patients with BAD I, while women predominated in BAD II group (22.5% compared to 7.8% men). No significant treatment-emergent affective switch was observed with tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors in both groups (21; 16.7; 16.7% in men and 28; 21.8; 12.5% in women, respectively). The assessment of intermission revealed that women were significantly more likely to have shorter periods between phases (42% compared to 22% in men). In addition, women were significantly more likely to have shorter periods between phases (42% compared to 22% in men) when the intermission duration was included in the analysis. In some patients with severe depression and infective first-line therapy (anticonvulsants and atypical antipsychotics), antidepressants prescription can increase treatment effectiveness. However, several factors should be considered, such as BAD type and variant, depression severity, treatment-emergent affective switch in history, and gender.Conclusion. A decision about antidepressants' dosage and treatment duration requires a dynamic follow-up of the patient in order to discontinue the antidepressants as fast as possible and decrease the risk of treatment-emergent affective switch and shortening of remission period.

Improvement after two sessions of electroconvulsive therapy predicts final remission in in-patients with major depression.

ObjectiveTo investigate whether early improvement, measured after two electroconvulsive therapy (ECT) sessions, is a good predictor of eventual remission in severely depressed in‐patients receiving ECT.MethodA prospective cohort study was performed that included 89 major depressive disorder in‐patients treated with bilateral ECT. Sensitivity, specificity, and predictive values were computed for various definitions of early improvement (15%, 20%, 25%, and 30% reduction on the Montgomery Asberg depression rating scale (MADRS) score) after 1 week (i.e. two sessions) of ECT regarding prediction of remission (final MADRS score ≤ 9).ResultsA 15% reduction in MADRS score appeared to be the best definition of early improvement, with modest sensitivity (51%) and relatively good specificity (79%). Kaplan–Meier analysis showed a more than 2‐week shorter time to remission in patients with early improvement compared with patients lacking early improvement.ConclusionEarly improvement during an ECT course may be assessed after two ECT sessions. Such improvement, defined as a 15% reduction in the MADRS score, is a moderately sensitive predictor for eventual remission in an in‐patient population with severe major depression.

A Double-Blind, Randomized, Placebo-Controlled Study of Aspirin and N-Acetylcysteine as Adjunctive Treatments for Bipolar Depression.

Neuroinflammation has been implicated in the pathophysiology of bipolar disorder. Some evidence shows that nonsteroidal anti-inflammatory drugs (NSAIDs) have promising antidepressant effects. The antioxidant N-acetylcysteine (NAC) may enhance the effects of NSAIDs. No study has, however, tested the adjunctive therapeutic benefits of an NSAID and NAC in bipolar disorder. The sample included 24 medicated patients diagnosed with DSM-IV-TR bipolar disorder who were aged 18-65 years and had a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20. Participants were randomly assigned to receive either aspirin (1,000 mg), NAC (1,000 mg), combined aspirin and NAC (1,000 mg each), or placebo. Data were collected between 2013 and 2017. The primary outcome was a ≥ 50% reduction in MADRS scores. Participants completed mood and global functioning questionnaires. They also underwent blood tests prior to and following 8 and 16 weeks of treatment. A Bayesian analytic method was adopted, and posterior probability distributions were calculated to determine the probability of treatment response. Following the first 8-week treatment phase, individuals on treatment with placebo and NAC + aspirin had a similar probability for successful treatment response (about 70%). Following a 16-week treatment period, NAC + aspirin was associated with higher probability of treatment response (67%) compared to placebo (55%), NAC (57%), and aspirin (33%). There was no treatment effect on interleukin-6 and C-reactive protein levels at either 8 or 16 weeks. The coadministration of NAC and aspirin during a period of 16 weeks was associated with a reduction in depressive symptoms. The adverse effects were minimal. These preliminary findings may serve as a starting point for future studies assessing the efficacy, tolerability, and safety of anti-inflammatory and antioxidant agents in the treatment of bipolar depression. ClinicalTrials.gov identifier: NCT01797575.

The Impact of Repetitive Transcranial Magnetic Stimulation on Oxidative Stress in Subjects With Medication-Resistant Depression.

Recent studies have shown that oxidative stress is involved in the neurobiology of depression. We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on a novel oxidative stress marker, thiol-disulfide homeostasis, in subjects with medication-resistant major depression (MRD). Twenty-six subjects with MRD underwent 15 rTMS sessions. Sociodemographic and baseline and post-rTMS Montgomery-Asberg Depression Rating Scale (MADRS) data were collected. Serum levels of native thiol, total thiol, and disulfide and their pairwise ratios were measured in baseline and post-rTMS blood samples. Serum levels of native and total thiol were significantly decreased after rTMS treatment (P < 0.05). Serum levels of thiol-disulfide and their ratios did not significantly differ (P > 0.05) between rTMS treatment responders (>50% reduction in MADRS score, n = 11) and rTMS treatment nonresponders (n = 15). The percentage MADRS score changes did not correlate with the changes in the levels of serum thiol-disulfide from baseline to post-rTMS treatment in any subject (P > 0.05). Our results showed that rTMS treatment was effective in subjects with MRD and was associated with changes in serum thiol levels regardless of improvement in depression severity. Thus, the results did not support a possible therapeutic relationship between rTMS and thiol-disulfide homeostasis in subjects with MRD.

A pilot study of minocycline for the treatment of bipolar depression: Effects on cortical glutathione and oxidative stress in vivo

BackgroundThe antibiotic minocycline appears to promote neuroprotection through antioxidant and other mechanisms that may be relevant to the pathophysiology of bipolar disorder. The present study assessed the efficacy of minocycline in bipolar depression and examined the association between minocycline treatment and brain glutathione (GSH), an essential regulator of oxidative stress. MethodTwenty patients with bipolar disorder experiencing acute depressive symptoms enrolled in an 8-week, open-label trial of adjuvant minocycline. Depression was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and proton magnetic resonance spectroscopy (1H MRS) measures of cortical GSH within a voxel prescribed in the precuneus and aspects of the occipital cortex were obtained from a subset of patients (n=12) before and after treatment. ResultsThe daily dose of minocycline at study end was 256mg (SD: 71mg). Treatment was associated with improvements in depression severity [MADRS score change: –14.6 (95% CI: –7.8 to –21.3)]. Ten patients (50%) were classified as responders based on a ≥50% reduction in MADRS score and 8 patients (40%) were classified as remitters (MADRS score ≤ 9). Higher baseline GSH levels were associated with greater improvement in MADRS score following treatment (ρ=0.51, p=0.05). Increases in GSH levels at study end were higher in non-responders than in responders (p=0.04). LimitationsSmall sample size, lack of a placebo group. ConclusionMinocycline may be an effective adjuvant treatment for bipolar depression, particularly in patients with high baseline GSH levels. Further research is needed to evaluate the potential of minocycline in this population.

An 8-Week Randomized, Double-Blind Trial Comparing Efficacy, Safety, and Tolerability of 3 Vilazodone Dose-Initiation Strategies Following Switch From SSRIs and SNRIs in Major Depressive Disorder.

Vilazodone, a selective and potent 5-HT1A partial agonist and 5-HT reuptake inhibitor, has been approved for treatment of major depressive disorder (MDD) in adults. The primary objective of the study was to compare the efficacy and tolerability of switching to 3 different doses of vilazodone from an equivalent dose range of generic selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in adult subjects with MDD. This was an 8-week, randomized, double-blind, parallel-group, 3-arm trial to compare vilazodone 10 mg/d, 20 mg/d, and 40 mg/d as starting doses. Data were collected from December 2012 to December 2013. There was no washout phase, prior medications were stopped at the baseline visit, and vilazodone was started the next day in adults with MDD (DSM-IV criteria). The 10-mg/d and 20-mg/d dose was increased to 40 mg/d by week 3 and week 1, respectively, and the 40-mg/d initiation dose continued unchanged. The primary efficacy measure was change in Montgomery-Asberg Depression Rating Scale (MADRS) score between the 3 dose groups. The secondary efficacy measures were changes in Clinical Global Impressions-Severity (CGI-S), CGI-Improvement (CGI-I), and Hamilton Anxiety Rating Scale (HARS) scores. Safety measures were obtained by spontaneously reported adverse events, vital signs recording, and laboratory tests. Multivariate tests were used for statistical analysis. Seventy subjects were randomized, and 60 subjects completed the study (n = 20 in each group). Overall, there was a significant reduction in MADRS score from baseline (26.08 ± 1.1) to week 8 (9.86 ± 1.2) in the entire sample (P < .001). Similarly, there was a significant improvement in CGI-S (P < .001), CGI-I (P < .001) and HDRS (P < .001) scores from baseline to the end of the trial. There were no significant differences between the 3 vilazodone dose-initiation groups in changes in MADRS scores (P = .95) or changes in CGI-S (P = .83), CGI-I (P = .51), or HARS scores (P = .61). Dry mouth (n = 55), nausea (n = 10), and diarrhea (n = 5) were the most common side effects, with diarrhea reported in 5 subjects in the 40-mg/d initiation group. No serious adverse events were reported. The present study indicates the potential benefit of switching to vilazodone in patients with MDD who are inadequate responders to SSRIs or SNRIs. There were no meaningful differences in efficacy or tolerability between the 3 different dose-initiation strategies with vilazodone; however, diarrhea appeared to be more frequently reported with the 40-mg/d dose. Given the modest sample size, larger studies are required to confirm our findings. ClinicalTrials.gov identifiers: NCT02015546 and NCT01473381.

A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder

The efficacy, tolerability, and safety of LY2216684, a highly selective norepinephrine reuptake inhibitor, were studied in adult patients with major depressive disorder (MDD). This randomized, double-blind study compared flexible-dose LY2216684 6–18 mg once daily (N = 250) with placebo (N = 245) for 10 weeks acute therapy followed by 1 year LY2216684 treatment (results not reported here). Primary inclusion criteria consisted of GRID 17-item Hamilton Rating Scale for Depression total score ≥18 and Clinical Global Impressions-Severity score ≥4. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Response was defined as a ≥50% reduction in MADRS score and remission as MADRS total score ≤10. Global functioning was assessed using the Sheehan Disability Scale (SDS). LY2216684-treated patients showed significant improvement from baseline on the MADRS total score compared with placebo-treated patients (−13.3 vs. −9.8, p < .001), and they had a significantly higher probability of achieving response (49.5%) and remission (29.7%) compared with placebo-treated patients (29.3% and 18.8%, respectively). For the SDS global functional impairment score, LY2216684 treatment resulted in significantly greater improvement compared with placebo treatment (p < .001). More LY2216684-treated than placebo-treated patients discontinued from the study because of an adverse event or death (9.6% vs. 1.6%, p ≤ .001). LY2216684 was associated with significant increases (p < .01) from baseline in systolic (3 mm Hg) and diastolic (4 mm Hg) blood pressure and pulse (10 bpm) compared with placebo. LY2216684 6–18 mg demonstrated significant efficacy and was tolerated in the treatment of MDD.

A Pilot, 8-Week, Placebo Lead-In Trial of Quetiapine Extended Release for Depression in Midlife Women

Perimenopausal and early postmenopausal women have shown an increased risk for developing depression (new onset or recurrent); concomitant vasomotor and other menopause-related complaints significantly affect quality of life and overall functioning. This study examined the effects of quetiapine extended release (XR) in midlife women with major depressive disorder who also reported significant menopause-related symptoms. Forty eligible women with major depressive disorder entered a 2-week, placebo lead-in phase, followed by an 8-week open trial with quetiapine XR, flexible dose, 150-300 mg/d. The primary outcome measure (depressive symptoms) was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) scores. Other measures included menopause symptoms (Greene Climacteric Scale total scores and subscores) and the impact of hot flashes on functioning (Hot Flash-Related Daily Interference Scale). Weight, cholesterol, triglycerides, and glucose levels were monitored. Data from 24 subjects (modified intent-to-treat, last observation carried forward; quetiapine XR mean dose, 191 [SD, 55] mg/d) showed improvement in depressive and menopause-related symptoms, that is, reduction in MADRS, GCS, and Hot Flash-Related Daily Interference Scale scores (P < 0.01 for all comparisons). Seventeen subjects were considered responders (>50% reduction in MADRS scores); 15 achieved remission (MADRS<10). Main adverse effects included drowsiness and dry mouth. Based on these preliminary results, quetiapine XR should be further examined in larger, controlled trials for the management of depressed, symptomatic midlife women.

Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial

We previously reported that intravenous (IV) scopolamine administration produced rapid and robust antidepressant effects in a sample consisting of both unipolar and bipolar depressives. The present study aimed to replicate this finding in an independent sample limited to unipolar depressives. Outpatients with major depressive disorder (MDD; n = 23; 22 were included in analyses) participated in a double-blind, placebo-controlled, crossover trial. Subjects were randomized into either a P/S or S/P sequence (P = block of three placebo sessions; S = block of three scopolamine sessions; [4.0 microg/kg IV]). Sessions occurred 3 to 5 days apart, such that time spent in each block lasted 1.5 to 2 weeks and the interval between blocks was 3 to 5 days. The Montgomery-Asberg Depression Rating Scale (MADRS) served as the primary outcome measure. Following the initial block, the group receiving scopolamine first (S/P) showed a 32% reduction in MADRS scores (p < .001), which exceeded the corresponding change of 6.5% under placebo (P/S; p = .009), confirming the a-priori hypothesis. Improvement was significant at the first evaluation that followed scopolamine administration (p = .011). In Block 2, the P/S group showed a 53% reduction in MADRS scores (p = .001) following scopolamine versus placebo, whereas the reduction seen in S/P subjects who received scopolamine during Block 1 persisted as they received placebo during Block 2. Scopolamine induced drowsiness, blurred vision, dry mouth, light-headedness, and reduced blood pressure, which were sufficiently well tolerated that no subject dropped out because of side effects. These results replicate previous finding that scopolamine produces a rapid and robust antidepressant response.

Escitalopram Versus SNRI Antidepressants in the Acute Treatment of Major Depressive Disorder: Integrative Analysis of Four Double-Blind, Randomized Clinical Trials

Recent data suggest that escitalopram may be more effective in severe depression than other selective serotonin reuptake inhibitors. Individual patient data from four randomized, double-blind comparative trials of escitalopram versus a serotonin/norepinephrine reuptake inhibitor (SNRI) (two trials with duloxetine and two with venlafaxine extended release) in outpatients (18-85 years of age) with moderate-to-severe major depressive disorder were pooled. The primary efficacy parameter in all four trials was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. Significantly fewer escitalopram (82/524) than SNRI (114/527) patients prematurely withdrew from treatment due to all causes (15.6% vs. 21.6%, Fisher Exact: P=.014) and adverse events (5.3% vs. 12.0%, Fisher Exact: P<.0001). Mean reduction in MADRS score from baseline to Week 8 was significantly greater for the escitalopram group versus the SNRI group using the last observation carried forward (LOCF) approach [mean treatment difference at Week 8 of 1.7 points (P<.01)]. Similar results were observed in the severely depressed (baseline MADRS score >or= 30) patient subset (mean treatment difference at Week 8 of 2.9 points [P<.001, LOCF]). Observed cases analyses yielded no significant differences in efficacy parameters. This pooled analysis indicates that escitalopram is at least as effective as the SNRIs (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment was better tolerated.

Transcranial Magnetic Stimulation in the Acute Treatment of Major Depressive Disorder

This report describes the results of an open-label extension study of active trans-cranial magnetic stimulation (TMS) in medication-resistant patients with major depressive disorder who did not benefit from an initial course of therapy in a previously reported 6-week, randomized controlled study of active versus sham TMS. Patients with DSM-IV-defined major depressive disorder were actively enrolled in the study from February 2004 through September 2005 and treated with left prefrontal TMS administered 5 times per week at 10 pulses per second, at 120% of motor threshold, for a total of 3000 pulses/session. The primary outcome was the baseline to endpoint change score on the Montgomery-Asberg Depression Rating Scale (MADRS). In those patients who received sham in the preceding randomized controlled trial (N = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0 (95% CI = -14.0 to -19.9). Further, at 6 weeks, 36 (42.4%) of these patients achieved response on the MADRS, and 17 patients (20.0%) remitted (MADRS score < 10). For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (N = 73), the mean reduction in MADRS scores was -12.5 (95% CI = -9.7 to -15.4), and response and remission rates were 26.0% and 11.0%, respectively, after 6 weeks of additional open-label TMS treatment. This open-label study provides further evidence that TMS is a safe and effective treatment of major depressive disorder. Furthermore, continued active TMS provided additional benefit to some patients who failed to respond to 4 weeks of treatment, suggesting that longer courses of treatment may confer additional therapeutic benefit. clinicaltrials.gov Identifier: NCT00104611.

Augmentation with olanzapine in TCA‐refractory depression with melancholic features: a consecutive case series

Using an 8-week, open label study design, we report the effect of augmentation strategy with olanzapine in hospitalized depressive patients with melancholic features who had insufficient response to a tricyclic antidepressant (TCA), amitriptyline. Subjects were hospitalized patients meeting the criteria of DSM-IV major depressive disorder with melancholic features who had been suffering from residual symptoms after treatment of amitriptyline. After study entry, olanzapine was added to amitriptyline and the dose was adjusted according to patients' clinical condition. Data were analyzed using an intent-to-treat methodology, with last observation carried forward. Paired t-test was adopted to assess the data from baseline to endpoint. Of 26 patients who enrolled in this study, 23 patients completed the trial and 3 patients dropped out. The mean dose of olanzapine was 6.5 (SD = 2.4) mg/day. The mean score of Montgomery-Asberg Depression Rating Scale (MADRS) was significantly decreased from 33.6 (SD = 3.5) to 20.8 (SD = 9.1) during this study (37.9% from baseline) (p < 0.001). Ten patients (38.5%) were considered as responders (50% or greater reduction in MADRS scores from baseline). These results suggest that augmentation with olanzapine in TCAs-resistant melancholia may be effective and well tolerated. We cannot draw any conclusion with certainty from the open-label, uncontrolled clinical trial. Double blind, controlled trial is needed to confirm this preliminary finding.

Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study.

To determine the efficacy of divalproex (extended release) in the treatment of acute nonrefractory bipolar depression. In a stratified, double-blind, randomized, placebo-controlled trial, 18 acutely depressed bipolar outpatients (DSM-IV criteria) received either divalproex monotherapy (target dose level, 70-90 ng/dL) (N = 9) or placebo (N = 9) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale (MADRS) determined primary efficacy. The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo (group x time interaction, p = .0078). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo (p = .003, linear growth curve model). Standardized effect size was large (Cohen d = 0.81). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group (r = 0.29, df = 51, p = .03), but not in the placebo group (r = -0.15, df = 35, p = .36). Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small randomized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger randomized clinical trials is warranted. ClinicalTrials.gov identifier NCT00226343.

Paroxetine for prevention of depressive symptoms induced by interferon‐alpha and ribavirin for hepatitis C

Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established. To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication. Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS). Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate. This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.

A 7-Week, Randomized, Double-Blind Trial of Olanzapine/Fluoxetine Combination Versus Lamotrigine in the Treatment of Bipolar I Depression

Determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) for treatment of acute bipolar I depression compared with lamotrigine. The 7-week, acute phase of a randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/day; N = 205) with lamotrigine ([LMG] titrated to 200 mg/day; N = 205) in patients with DSM-IV-diagnosed bipolar I disorder, depressed. The study was conducted from November 2003 to August 2004. Completion rates were similar between treatments (OFC, 66.8% vs. LMG, 65.4%; p = .835). OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale (primary outcome) (p = .002, effect size = 0.26), Montgomery-Asberg Depression Rating Scale (MADRS) (p = .002, effect size = 0.24), and Young Mania Rating Scale total scores (p = .001, effect size = 0.24). Response rates did not significantly differ between groups when defined as > or = 50% reduction in MADRS score (OFC, 68.8% vs. LMG, 59.7%; p = .073). Time to response was significantly shorter for OFC-treated patients (median days [95% CI] = OFC, 17 [14 to 22] vs. LMG, 23 [21 to 34]; p = .010). There was a significant difference in incidence of "suicidal and self-injurious behavior" adverse events (OFC, 0.5% vs. LMG, 3.4%; p = .037). Somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor occurred more frequently (p < .05) in OFC-treated patients than lamotrigine-treated patients. Weight, total cholesterol, and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients (all p < or = .001). Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms, more treatment-emergent adverse events, greater weight gain, and some elevated metabolic factors with OFC than lamotrigine. Treatment differences were of modest size.