Major Depressive Disorder Trials Research Articles

The role of regulators, investigators, and patient participants in the rise of the placebo response in major depressive disorder.

The role of regulators, investigators, and patient participants in the rise of the placebo response in major depressive disorder.

New atypical antipsychotic approved

A new atypical antipsychotic, brexpiprazole (Rexulti—Otsuka), hasreceived FDA approval as an adjunct treatment to antidepressantsfor major depressive disorder (MDD) and for the treatment of schizophrenia.According to the National Alliance on Mental Illness, approximately6.7% of American adults−about 14.8 million people—live withMDD, and approximately 1.1% of American adults—about 2.4 millionpeople—live with schizophrenia. Therefore, there is a real need foreffective treatments for these conditions.

Antidepressant treatment history and drug-placebo separation in a placebo-controlled trial in major depressive disorder.

A history of antidepressant treatment may predispose subjects toward placebo nonresponse in randomized controlled trials (RCTs) in major depressive disorder (MDD). The objective of this study is to examine self-reported prior antidepressant treatment and response in relationship to clinical outcome in an 8-week randomized trial of reuptake inhibitor antidepressant medication (MED) versus placebo (PBO) administered along with limited supportive care. Chi-square and MMRM analyses examined MED vs. PBO outcomes in antidepressant-naïve vs. antidepressant-experienced subjects. Linear regression models examined treatment history along with covariates as predictors of clinical improvement. Among completers (n = 56), there was no significant difference in response rate between MED (53.3 %) and PBO (42.3 %) (χ (2) = 0.33, p = 0.28, 1-tailed). The antidepressant-experienced subgroup (n = 37), however, showed a significantly greater response rate to MED (52.4 %) than PBO (25.0 %) (χ (2) = 2.82, p = 0.047, 1-tailed). The full intent-to-treat (ITT) sample (n = 69) did not show a significant difference between MED and PBO group improvement over time, but in the treatment-experienced subgroup (n = 46), MED showed significantly greater improvement than PBO (coefficient = .39, SE = .23, p = .045, 1-tailed). A history of prior antidepressant treatment predicted poorer overall response independent of pretreatment symptom severity, number or length of previous episodes, subject expectations, or family history of MDD. Treatment history appears to constitute a factor that is distinct from other commonly studied illness characteristics or expectancy measures, and that impacts overall response as well as drug-placebo separation in RCTs.

Double blinding requirement for validity claims in cognitive-behavioral therapy intervention trials for major depressive disorder.Analysis of Hollon S, et al., Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial.

This paper will focus on problems in the inability to double-blind cognitive-behavioral therapy (CBT) studies for major depressive disorder (MDD), and provides an analysis of a recently published study to show how this problem can lead to faulty conclusions. A study by Hollon et al. published in JAMA Psychiatry that compared an antidepressant medication-only arm with a combined CBT/antidepressant arm concluded that the cognitive therapy/antidepressant combination enhanced the recovery rates compared with antidepressant alone, and that the magnitude of this increment nearly doubled for patients with more severe depression. We propose that for subjects with greater severity, there could have been both antidepressant efficacy as well as more hope and expectation in the group who knew they had received combined cognitive therapy/medication, leading to an erroneous conclusion of greater efficacy for the combined group.The large subject number in this study could easily lead to an erroneous finding on statistical testing as a small amount of bias in the subjects adds-up. We opine that the conclusions of unblind CBT outcome research in conditions with subjective endpoints such as MDD need to be given with great caution. The validity of CBT (and its derivatives such as dialectical behavioral therapy) for indications other than MDD is also part of a larger problem in the inability to blind outcome studies for these interventions.

Double-Blinding and Bias in Medication and Cognitive-Behavioral Therapy Trials for Major Depressive Disorder

While double-blinding is a crucial aspect of study design in an interventional clinical trial of medication for a disorder with subjective endpoints such as major depressive disorder, psychotherapy clinical trials, particularly cognitive-behavioral therapy trials, cannot be double-blinded. This paper highlights the evidence-based medicine problem of double-blinding in the outcome research of a psychotherapy and opines that psychotherapy clinical trials should be called, "partially-controlled clinical data" because they are not double-blinded. The implications for practice are, 1. For practitioners to be clear with patients the level of rigor to which interventions have been studied, 2. For authors of psychotherapy outcome studies to be clear that the problem in the inability to blind a psychotherapy trial severely restricts the validity of any conclusions that can be drawn, and 3. To petition National Health Insurance plans to use caution in approving interventions studied without double-blinded confirmatory trials as they may lead patients to avoid other treatments shown to be effective in double-blinded trials.

Summary of Findings From the FDA Regulatory Science Forum on Measuring Sexual Dysfunction in Depression Trials

Sexual dysfunction is a significant treatment-emergent adverse reaction to the serotonergic antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]). However, the rate of sexual dysfunction is often underestimated in registration trials, which have relied on unsolicited reports. We conducted a literature search to examine the rates of sexual dysfunction with SSRIs/SNRIs when these rates were ascertained by structured questionnaires or standardized instruments. Additionally, we conducted exploratory analyses of major depressive disorder (MDD) registration trial data. For the literature search, we used the PubMed and EMBASE databases, with a cutoff date of April 1, 2011. We included all the SSRIs and SNRIs that at the time had been approved for the treatment of MDD. For each of these drugs, a search was conducted with the following terms: sexual dysfunction, SD, sexual adverse effects, desire, arousal, excitement, and orgasm. For the exploratory analyses of US Food and Drug Administration in-house trial data, we searched our database for short-term (6-8 weeks), randomized, placebo-controlled MDD monotherapy trials of approved drugs included in New Drug Application submissions that used a standardized instrument to assess sexual function. For the literature search, we initially found a total of 123 nonduplicate articles, some of which included multiple studies. After screening based on our inclusion/exclusion criteria (and to remove duplicate trial-level data), we were left with 7 articles representing 11 unique studies in which sexual dysfunction was assessed with direct questioning or standardized instruments. The Changes in Sexual Functioning Questionnaire-Short-Form (CSFQ-14) and Arizona Sexual Experiences Scale (ASEX) were the only instruments represented. For the exploratory analyses of in-house MDD trial data, we found controlled studies using either the CSFQ-14 (6 trials) or ASEX (5 trials). For the literature search, we were able to pool the results for the studies that included direct questioning. For the studies that used standardized instruments to assess sexual function, we simply describe our findings. For the exploratory analyses of in-house MDD trial data, we constructed a dataset containing all subject-level CSFQ-14 or ASEX item scores for each of the trials as well as demographic and other relevant variables. For each treatment or placebo group, analyses were performed on pooled data, including multiple studies, and on individual studies. For our literature search, regardless of which method was used to assess sexual function, the data from these articles were informative and showed the expected effects on sexual function with SSRIs/SNRIs. However, for our exploratory analyses, no trend was observed in CSFQ-14 or ASEX results for individual drugs or drug classes. These results raise the question as to why the CSFQ-14 and ASEX appeared to perform well in the published studies but not in our exploratory analyses of in-house MDD trial data. We discuss possible reasons and solutions.

Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD). The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short-term weight gain appears modest; however, more outliers with an increase of ≥ 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident. Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed.

Lurasidone Effective in Major Depressive Disorder With Mixed Features: RESOLVE2

The first-ever placebo-controlled trial in major depressive disorder with mixed features demonstrated that lurasidone, an atypical antipsychotic agent, was efficacious in reducing depressive symptoms in these patients and was also well tolerated when compared with placebo.

Lifetime trauma victimization and PTSD in relation to psychopathy and antisocial personality disorder in a sample of incarcerated women and men.

Antisocial personality disorder (ASPD) and psychopathy are similar, but distinct, psychiatric conditions that are common in male and female inmates; a segment of the population with high rates of trauma exposure. It is unclear whether specific types of lifetime trauma are associated with ASPD and psychopathy in incarcerated women and men. Furthermore, the unique roles of post-traumatic stress disorder (PTSD) symptom severity and trauma victimization in antisocial personality disturbance are not well-understood. The paper aims to discuss these issues. This study investigated associations between trauma variables (different kinds of traumatic experiences and PTSD) and antisocial personality variables (ASPD and psychopathy) in a sample of incarcerated women and men who participated in a randomized clinical trial for major depressive disorder. In total, 88 incarcerated men and women were assessed for ASPD diagnosis, psychopathy severity, PTSD symptom severity, and history of physical, sexual, and crime-related trauma. Regression analyses predicted ASPD or psychopathy from trauma variables, controlling for gender. Physical trauma was the only form of trauma that was significantly related to psychopathy. Physical trauma and crime-related trauma were associated with ASPD. PTSD symptom severity was not associated with psychopathy or ASPD. There are associations between some kinds of lifetime trauma exposure and current ASPD/psychopathy in the target sample, but these associations do not appear to be mediated through current PTSD symptoms.

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for pediatric major depressive disorder (MDD). We conducted a meta-analysis to examine the following: the time-course of response to SSRIs in pediatric depression; whether higher doses of SSRIs are associated with an improved response in pediatric depression; differences in efficacy between SSRI agents; and whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD. We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo groups. The meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating that the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data (log[week]= 0.10, 95% CI= 0.06-0.15, p< .0001). There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD. Treatment gains in pediatric MDD are greatest early in treatment and are, on average, minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response (e.g., 2-4 weeks) to predict outcomes in short-term pharmacological trials.

P.2.b.009 Effects of levomilnacipran ER on measures of attention in a phase III trial of major depressive disorder

P.2.b.009 Effects of levomilnacipran ER on measures of attention in a phase III trial of major depressive disorder

Review of Maintenance Trials for Major Depressive Disorder

The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. Trial characteristics, relapse rates, and time to relapse in each study were examined. Relapse rates were significantly lower (P < .05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the double-blind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups.

Biological Markers in Noninvasive Brain Stimulation Trials in Major Depressive Disorder

The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients' likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was −0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (−0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (−0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (−0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy.

Does Early Improvement in Anxiety Symptoms in Patients with Major Depressive Disorder Affect Remission Rates? A Post-Hoc Analysis of Pooled Duloxetine Clinic Trials

Objectives: Patients with major depressive disorder (MDD) and a comorbid anxiety disorder or significant anxiety symptoms have decreased functioning, increased risk of suicidality, and worse post-treatment outcomes. This pooled analysis of 8 duloxetine MDD trials was designed to determine whether early improvement in anxiety symptoms predicts MDD remission. Methods: Eight trials were pooled. Patients with a baseline 17-item Hamilton Rating Scale for Depression (HA-MD17) anxiety/somatization factor score ≥7 were considered to have anxious depression. Early response on the HAMD17 total score was defined as a 20% reduction at weeks 2 or 4, a 30% reduction at weeks 2 or 4, or a 50% reduction at weeks 2 or 4 in the HAMD17 anxiety subscale. Each category was analyzed separately for all patients. MDD remission is a score of ≤7 on the HAMD17 total score at study endpoint. Results: The early responder group in each analysis showed greater numerical improvement at endpoint on the HAMD17 total score than the nonresponder group. Duloxetine showed statistically significantly greater improvement than placebo in most nonresponder and responder subgroups. There were no statistically significant interaction effects for the difference between duloxetine and placebo for any of the anxious categories. Conclusion: Although patients who responded in the various response categories had greater numerical improvement and greater remission rates than nonresponding patients, the response and nonresponse groups did not differ statistically regarding the treatment effect of duloxetine. Therefore, early improvement in anxiety symptoms was not a predictor of greater endpoint remission of depressive symptoms for duloxetine treatment.

A randomized controlled trial of venlafaxine XR for major depressive disorder after spinal cord injury: Methods and lessons learned

Context/objectiveWe describe the rationale, design, methods, and lessons learned conducting a treatment trial for major depressive disorder (MDD) or dysthymia in people with spinal cord injury (SCI).DesignA multi-site, double-blind, randomized (1:1) placebo controlled trial of venlafaxine XR for MDD or dysthymia. Subjects were block randomized and stratified by site, lifetime history of substance dependence, and prior history of MDD.SettingSix SCI centers throughout the United States.ParticipantsAcross participating centers, 2536 subjects were screened and 133 were enrolled into the trial. Subjects were 18–64 years old and at least 1 month post-SCI.InterventionsTwelve-week trial of venlafaxine XR versus placebo using a flexible titration schedule.Outcome measuresThe primary outcome was improvement in depression severity at 12 weeks. The secondary outcome was improvement in pain.ResultsThis article includes study methods, modifications prompted by a formative review process, preliminary data on the study sample and lessons learned. We describe common methodological and operational challenges conducting multi-site trials and how we addressed them. Challenges included study organization and decision making, staff training, obtaining human subjects approval, standardization of measurement and treatment, data and safety monitoring, subject screening and recruitment, unblinding and continuity of care, database management, and data analysis.ConclusionsThe methodological and operational challenges we faced and the lessons we learned may provide useful information for researchers who aim to conduct clinical trials, especially in the area of medical treatment of depression in people with SCI.

Which placebo to cure depression? A thought-provoking network meta-analysis

BackgroundAntidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation.MethodsPublished and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an “evidence network”: 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to-head RCTs.Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested.ResultsThe three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias.ConclusionThe presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy.

Are antidepressants effective in quality of life improvement among children and adolescents? A systematic review

There is some evidence indicating that psychotropic medications might lead to health-related quality of life (QOL) improvements among children and adolescents with psychiatric disorders. The aim of this systematic review is to assess evidence regarding whether antidepressant treatment improves QOL among children and adolescents with depressive or anxiety disorders. A comprehensive search resulted in 5 clinical trials to be included in this review: 4 trials with major depressive disorder (MDD) and 1 trial with social anxiety disorder (SAD). In one MDD trial, fluoxetine combined with cognitive behavior therapy (CBT) significantly improved QOL compared to fluoxetine or CBT alone (effect sizes were 0.53 and 0.69, respectively). In 2 combined trials, sertraline alone significantly improved QOL among adolescents with MDD (effect size was 0.29), but not among children with MDD. Essentially, it was observed that antidepressants in these trials had minor positive effects on QOL improvement, which were lower than their potential to improve depressive symptoms. Although fluoxetine with CBT or sertraline monotherapy were shown to have some potential to improve QOL, this systematic review found inconclusive evidence that antidepressant treatments improve QOL among children and adolescents with depressive or anxiety disorders. More research is required, considering that QOL is currently under-evaluated in clinical trials with antidepressants among children and adolescents and available trials have limited methodological quality when reporting QOL data.

Levomilnacipran Extended Release: First Global Approval

Pierre Fabre and Forest Laboratories are developing levomilnacipran extended release (ER) [FETZIMA™], an enantiomer of milnacipran, for the treatment of major depressive disorder (MDD). In addition, Pierre Fabre (the originator of the compound) is developing the drug to improve recovery in patients with ischaemic stroke. Levomilnacipran ER exerts its effects by selectively inhibiting the reuptake of norepinephrine and serotonin (two neurotransmitters known to play an essential role in regulating mood) without directly affecting the uptake of dopamine or other neurotransmitters. The agent is being developed as an extended-release capsule formulation for once-daily dosing. Levomilnacipran ER is approved and launched in the US for the treatment of MDD; phase III development in this indication was completed in the US and Canada. In Europe, a phase II trial for MDD was completed, and development is in progress for improving functional recovery of patients with ischaemic stroke. A completed phase II trial in the US investigated levomilnacipran ER for the treatment of fatigue associated with MDD. This article summarizes the milestones in the development of levomilnacipran ER leading to the first approval for major depressive disorder.

Less Is More in Antidepressant Clinical Trials

We investigated how the number of follow-up visits affects response rates and dropout among patients in antidepressant trials for major depressive disorder (MDD). MEDLINE, PsycINFO, and PubMed were searched to identify trials contrasting antidepressants to placebo or active comparator in adults with depression. The index terms depression-drug therapy, depressive disorder-drug therapy, and antidepressant agents, in addition to the classes and individual generic names of all antidepressants, were combined using the "or" operator. Results were limited to (1) English-language articles, (2) publication year 1985 or later, (3) age group ≥ 18 years, and (4) publication types including clinical trials, controlled clinical trials, meta-analysis, multicenter study, randomized controlled trial, or review. Included articles reported trials of approved antidepressant medications for MDD in outpatients aged 18-65 years, were 6-12 weeks in duration, and had response rates specified using a standardized measure. Trials were excluded for enrolling inpatients, pregnant women, psychotic subjects, or those with treatment-resistant depression. These criteria allowed 9,189 articles identified in the literature review to be narrowed to 111 reports. Demographic characteristics, the number of study visits planned in each treatment cell, duration of active treatment, attrition rates, and response rates to medication and placebo were entered into a database. In a multilevel meta-analysis, active medication versus placebo (OR = 1.96, P < .001), active comparator versus placebo-controlled study design (OR = 1.82, P < .001), and longer versus shorter duration (OR = 1.87, P < .001) were associated with significantly increased odds of treatment response. After controlling for these variables, the number of study visits did not significantly influence response rates (OR = 0.97, P = .877). The odds of dropout were significantly decreased for active comparator versus placebo-controlled trials (OR = 0.67, P = .002) and longer versus shorter duration trials (OR = 0.54, P = .035), while increasing numbers of study visits significantly increased the odds of participant dropout (OR = 2.77, P < .001). Visit schedules that are much more frequent than are commonly practiced in the community treatment of depression may increase the expense of clinical trials and make them less generalizable to standard clinical treatment.