Clinical Trials Of Major Depressive Disorder Research Articles

Desvenlafaxine in the treatment of major depression: an updated overview

ABSTRACT Introduction: Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages. Areas covered: This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed. Expert opinion: Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug–drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

Early improvement in HAMD-17 and HAMD-7 scores predict response and remission in depressed patients treated with fluoxetine or electroconvulsive therapy

BackgroundCompared to the 17-Item Hamilton Rating Scale for Depression (HAMD-17), the 7-Item Hamilton Rating Scale for Depression (HAMD-7) would be more practical for use in busy clinical settings. Herein, we aim to evaluate (1) whether the HAMD-7 is a reliable and valid measure that is sensitive to changes in depressive symptoms, and (2) whether early improvement of depressive symptoms, as measured by the HAMD-7, is capable of predicting response and remission in patients with major depressive disorder (MDD) during acute treatment with fluoxetine or electroconvulsive therapy (ECT). MethodsThis is a post-hoc analysis of two clinical trials in MDD. Internal consistency, validity, and sensitivity-to-change of the HAMD-17 and HAMD-7 were compared during acute treatment and at 3-month follow-up. Receiver operating characteristic analyses were used to evaluate the discriminative capacity of the HAMD-17 and HAMD-7. ResultsThe HAMD-7 is a reliable and valid measure that is sensitive to changes in depressive symptoms. Early improvement, as measured by either the HAMD-17 or HAMD-7, was capable of predicting response and remission to acute treatment with fluoxetine or ECT with good discriminative capacity. LimitationsThis is a post-hoc analysis of two open-label clinical trials with limited sample sizes. All patients were Taiwanese, which limits the generalizability of our results. ConclusionsHAMD-7 is a clinically useful measure that is capable of detecting early improvement of depressive symptoms. The HAMD-7 may have the potential to inform clinical assessment as part of measurement-based care.

Does the frequency of follow-up assessments affect clinical trial outcome? A meta-analysis and meta-regression of placebo-controlled randomized trials

The number and temporal distribution of follow-up assessments during a clinical trial is a critical factor which may influence the outcome as well as the overall cost of a trial. Therefore, we aimed to examine whether the overall and differential frequency of study observations during the course of a clinical trial affects the risk ratio (RR) of responding to antidepressants vs. placebo, specifically in trials for major depressive disorder (MDD). Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD (1 January 1980-11 May 2010). A total of 142 manuscripts involving 256 drug-placebo comparison were pooled (n=38 860). We found that higher overall frequency (OF, frequency of assessments during the entire trial) and higher late frequency (LF, frequency of assessments after the first 3 wk of the trial), but not higher early frequency (EF, frequency of assessments during the first 3 wk of the trial), of follow-up visits predicted a significantly greater RR of responding to antidepressant vs. placebo (coefficient=0.213, p=0.014; coefficient=0.238, p=0.003; and coefficient=0.021, p=0.755, respectively, for OF, LF and EF). None of the measures of frequency examined (OF, EF, LF) significantly predicted the RR of discontinuing antidepressant vs. placebo. These findings suggest that increasing the number of follow-up visits, specifically after the third week rather than within the first 3 wk of the trial, may be an effective approach to improve the likelihood of success in placebo-controlled clinical trials for MDD.

Clinical effectiveness: The importance of psychosocial functioning outcomes

Major depressive disorder (MDD) is associated with significant impairment in quality of life and psychosocial functioning, including social and occupational/role functioning. Evaluation of clinical effectiveness of treatments for depression must include improvement in these important functional outcomes. However, clinical trials for depression have primarily focused on reduction in symptoms, as measured by symptom severity scales such as the HDRS and MADRS or by standard definitions of response and remission. The rationale and necessity for accessing both symptom and functional outcomes in clinical trials for MDD are reviewed, and examples of validated scales for measuring QoL and social and occupational functioning are provided. Emerging data suggest that treatment effects assessed with functioning scales may differ from those captured by symptoms scales. Many validated scales are available to measure global and specific aspects of functional outcomes, including QoL, psychosocial functioning and occupational functioning. Nevertheless, systematic reviews have shown that functional outcome scales are used in fewer than 5% of trials. Given the importance of psychosocial functioning for the individual with MDD as well as for society, greater attention must be focused on the assessment of functional outcomes in clinical trials for MDD, as well as in the clinical management of people with depression.

Escitalopram versus serotonin noradrenaline reuptake inhibitors as second step treatment for patients with major depressive disorder: a pooled analysis

The objective of this study was to evaluate the efficacy and tolerability of escitalopram versus serotonin and noradrenaline reuptake inhibitors (SNRIs) as second step treatment (defined operationally as poor response or intolerability to an antidepressant) for major depressive disorder (MDD). Results from all eligible head-to-head clinical trials of MDD (which excluded patients who earlier failed two or more antidepressants) sponsored by Lundbeck or Forest comparing escitalopram and SNRIs (venlafaxine and duloxetine) were pooled. A second step treatment subgroup was identified, defined as patients treated earlier with any antidepressant in the 6-month period before baseline. Data from three clinical trials were included in the analysis; 132 patients were identified in the second step treatment subgroup (66 in each of the escitalopram and SNRI groups). The primary efficacy analysis showed that the patients subsequently treated with escitalopram had significantly lower Montgomery Asberg Depression Rating Scale total scores after 8 weeks compared with those subsequently treated with SNRIs (difference = -6.4, P<0.0001). Escitalopram treatment was also associated with higher clinical response (73 vs. 44%, P=0.0004) and remission rates (62 vs. 41%, P=0.0083) compared with subsequent treatment with SNRIs. Escitalopram showed a better tolerability profile with lower all-cause withdrawals from study (9 vs. 23%, P<0.04) and lower withdrawals because of adverse events (2 vs. 17%, P<0.003). In conclusion, escitalopram is associated with a better efficacy and tolerability profile than SNRIs (duloxetine and venlafaxine) when used as a second step treatment in patients with MDD. These results should be confirmed in prospective randomized clinical trials.

Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD

Substantial and highly variable placebo response rates represent a major obstacle to antidepressant development in major depressive disorder (MDD). However, whether the likelihood of receiving active treatment or placebo, a proxy of the degree of expectation of improvement, may itself influence clinical trial outcome is unclear. The goal of this work was to examine whether the probability of receiving placebo influences clinical trial outcome antidepressant MDD trials. Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD. 146 manuscripts involving 182 clinical trials were pooled ( n = 36,385). Pooled response rates for drug and placebo were 53.8% and 37.3%. A meta-regression (random-effects) established that the probability of receiving placebo, year of publication, and baseline severity were independent predictors of the risk ratio of responding to antidepressants versus placebo. Specifically, a greater probability of receiving placebo, greater baseline severity and an earlier year of publication predicted greater antidepressant-placebo “efficacy separation”. Fixed versus flexible dose design, trial duration and population age did not influence clinical trial outcome.

Desvenlafaxine succinate for the treatment of major depressive disorder

Major depressive disorder (MDD) remains one of the most common psychiatric disorders with high morbidity and mortality. Effective treatment is limited and response/remission to antidepressant pharmacotherapy remains poor and unpredictable. The development of new antidepressants is thus of great importance to the field. Desvenlafaxine succinate (DVS) is the active metabolite of the serotonin and noradrenaline re-uptake inhibitor venlafaxine and was recently FDA approved for the treatment of MDD. DVS showed efficacy in clinical trials in MDD with doses ranging from 50 – 400 mg. Advantages compared to other antidepressants include once daily dosing at effective doses, no CYP450 metabolism and low drug–drug interactions. Concerns include side effect profile and moderate efficacy. DVS might be a useful addition to the arsenal of antidepressants available to the clinician. Additional studies, in particular head-to-head comparison to other antidepressants and long-term treatment studies, will be necessary to comprehensively evaluate DVS safety and efficacy for clinical practice.

Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis

In general, antidepressant drugs are regarded as too slow acting. Most patients who benefit from treatment require more than 2 weeks of therapy to respond to treatment. An efficacious and well-tolerated antidepressant drug with an earlier onset of effect would be of greater interest to clinicians and patients. To study the onset of effect of escitalopram, a selective serotonin reuptake inhibitor (SSRI), data were pooled from controlled randomized clinical double-blind trials comparing this drug with other antidepressant drugs (SSRIs and venlafaxine XR) in major depressive disorder (MDD), with assessments of the primary efficacy parameter [mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline, using last observation carried forward]. The mean change in MADRS total scores was significantly higher for escitalopram-treated patients than for patients treated with the comparators on day 7 (-3.9 versus -3.4, respectively, P = 0.029). This difference remained significant and in favour of escitalopram at all subsequent assessments. Using secondary outcomes (Clinical Global Impression of Improvement and Severity scales and early improvement), the results consistently showed a statistically significantly faster onset of effect of escitalopram compared to other antidepressants. In conclusion, by using the MADRS scale and pooling data from the escitalopram clinical trials in MDD comparing escitalopram with other active antidepressant drugs, escitalopram was shown to be a fast-acting antidepressant with a more rapid onset of effect than the comparators, particularly other SSRIs.