Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

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.

Antidepressants in children and adolescents with major depressive disorder and the influence of placebo response: A meta-analysis.

BACKGROUND: There are few available antidepressants for pediatric Major Depressive Disorder (MDD). The objective of this systematic review and meta-analysis was to review industry-funded studies of antidepressants in children and adolescents with MDD, and to better understand the contribution of study design and placebo response to the findings of these studies. METHODS: Randomized, double-blind, placebo-controlled clinical trials that compared antidepressant with placebo for the acute treatment of MDD in children and/or adolescents were selected. Estimates of the standardized mean difference (SMD) in change in Children's Depression Rating Scale-Revised scores were pooled, after examining for heterogeneity. A random-effects meta-analysis was completed. RESULTS: Thirty-four antidepressant-placebo comparisons, involving 6161 subjects, were included. The SMD among all studies was 0.12 (CI 0.08, 0.17; p < 0.001), a very small effect size, lower than that seen in studies of adults with MDD. When the meta-analysis was limited to studies with a low mean placebo response, the SMD increased to 0.19 and further increased to 0.22 when studies with at least a 50% chance of receiving placebo were included. LIMITATIONS: Many studies focused on older children and younger adolescents. Our findings may not reflect antidepressant efficacy in older adolescents. CONCLUSIONS: The modest SMD identified in this analysis may reflect study design factors and the application of antidepressants developed for adults to pediatric patients. Given the urgent clinical need for more pediatric MDD treatments, the influence of placebo response and the need for drug development tailored to this population should be considered in pediatric MDD trial design.

Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Objective: Rapid-acting treatment options are needed for major depressive disorder (MDD). The objective of this systematic review and meta-analysis was to estimate the magnitude of the treatment effect for intranasal esketamine over placebo at 24 hours after the first dose and at endpoint.Data Sources: PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing the term intranasal with esketamine and randomized.Study Selection: Of 27 studies reviewed, 8 articles, with a total of 1,437 patients with MDD, met study criteria and were included in the meta-analysis.Data Extraction: Randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with intranasal esketamine for MDD, using intranasal placebo augmentation as a comparator, were selected.Results: Estimates of the standardized mean difference (SMD) in change scores were pooled after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. Findings of the random effects model were presented. Augmentation of standard antidepressants with intranasal esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI = 0.11 to 0.46, P < .0001) with a 2.9-point greater mean MADRS score reduction following intranasal esketamine versus active control plus intranasal saline. A similar finding was evident at endpoint.Conclusions: This updated systematic review and meta-analysis found that augmentation of antidepressants with intranasal esketamine was statistically and clinically more effective in reducing depression severity than augmentation with placebo, at both 24 hours and study endpoint. Future studies are needed to evaluate dose-response relationship for esketamine.

Treatment of major depressive disorder and dysthymic disorder with antidepressants in patients with comorbid opiate use disorders enrolled in methadone maintenance therapy: a meta-analysis.

Depression and opiate-use disorders (abuse, dependence) often co-occur, each condition complicating the course and outcome of the other. It has been recommended that clinicians prescribe antidepressant therapy for mood symptoms in patients with active substance-use disorders, but whether antidepressants are effective in this specific population is not entirely clear. Therefore, the aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder (DD) with comorbid opiate-use disorders currently in methadone maintenance treatment (MMT). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the treatment of MDD/DD in patients with comorbid opiate-use disorders currently in MMT. The search was limited to articles published between January 1, 1980, and June 30, 2010 (inclusive). Four manuscripts were found eligible for inclusion in our analysis (n = 317 patients). We found no statistically significant difference in response rates between antidepressant and placebo therapy in trials of MDD/DD patients with comorbid opiate-use disorders currently in MMT (risk ratio for response, 1.182; 95% CI: 0.822-1.700; P = 0.366). These results show no difference in the depressive outcome of patients with comorbid opiate-use disorders on MMT whether they are on medication or placebo. Future studies examining the effectiveness of antidepressants while controlling for several variables such as psychosocial treatment and assessing the specific classes of antidepressants are needed.

Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse.

BACKGROUND: Many patients with major depressive disorder (MDD) who achieve full remission after antidepressant treatment still have residual depressive symptoms. In this study, we assess the type and frequency of residual symptoms and their relationship to subsequent depressive relapses after remission of major depression with fluoxetine. METHOD: Five hundred seventy-six patients with MDD were openly treated with fluoxetine for 12 weeks. Those who responded underwent random assignment, under double-blind conditions, to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse. The presence of residual symptoms in patients who achieved remission at the end of the acute phase (N=203) was assessed using the 28-item Hamilton Depression Rating Scale. Survival analysis was used to examine the effect of residual symptoms on relapse in remitters. RESULTS: More than 90% of patients who met criteria for remission had at least one residual depressive symptom (median=4). The most common were sleep disturbances (insomnia 48.2%, hypersomnia 35.9%) and anxiety (52.7%). The most common individual symptom was middle insomnia (33.5%). No statistically or clinically significant differences in baseline variables were found between remitters with and without residual symptoms. The presence of residual symptoms, the presence of residual insomnia and the global number of residual symptoms did not predict relapse during the continuation phase of the study. CONCLUSION: The great majority of patients with remission of MDD after treatment with fluoxetine continue to experience selected residual depressive symptoms. The presence of residual symptoms is not significantly associated with an increased risk of relapse.

Vortioxetine Versus Placebo for Major Depressive Disorder: A Comprehensive Analysis of the Clinical Trial Dataset.

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD).Data Sources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. No language or publication year restrictions were used.Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD.Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST).Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate.Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect.

Efficacy of Ziprasidone Augmentation of Escitalopram for Cognitive Symptoms of Major Depressive Disorder.

OBJECTIVE: To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. METHODS: This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. RESULTS: Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. CONCLUSIONS: In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.

Demographic variables, design characteristics, and effect sizes of randomized, placebo-controlled, monotherapy trials of major depressive disorder and bipolar depression.

OBJECTIVE: The aim of this work is to compare the efficacy of pharmacologic agents for the treatment of major depressive disorder (MDD) and bipolar depression. DATA SOURCES: MEDLINE/PubMed databases were searched for studies published in English between January 1980 and September 2014 by cross-referencing the search term placebo with each of the antidepressant agents identified and with bipolar. The search was supplemented by manual bibliography review. STUDY SELECTION: We selected double-blind, randomized, placebo-controlled trials of antidepressant monotherapies for the treatment of MDD and of oral drug monotherapies for the treatment of bipolar depression. 196 trials in MDD and 19 trials in bipolar depression were found eligible for inclusion in our analysis. DATA EXTRACTION: Data were extracted by one of the authors and checked for accuracy by a second one. Data extracted included year of publication, number of patients randomized, probability of receiving placebo, duration of the trial, baseline symptom severity, dosing schedule, study completion rates, and clinical response rates. RESULTS: Response rates for drug versus placebo in trials of MDD and bipolar depression were 52.7% versus 37.5% and 54.7% versus 40.5%, respectively. The random-effects meta-analysis indicated that drug therapy was more effective than placebo in both MDD (risk ratio for response = 1.373; P < .001) and bipolar depression (risk ratio = 1.257; P < .001) trials. The meta-regression analysis suggested a statistically significant difference in the risk ratio of responding to drug versus placebo between MDD and bipolar depression trials in favor of MDD (P = .008). CONCLUSIONS: Although a statistically significantly greater treatment effect size was noted in MDD relative to bipolar depression studies, the absolute magnitude of the difference was numerically small. Therefore, the present study suggests no clinically significant differences in the overall short-term efficacy of pharmacologic monotherapies for MDD and bipolar depression.

Relationship between placebo response rate and clinical trial outcome in bipolar depression.

The aim of this work is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in Bipolar Depression (BPD). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of oral drugs used as monotherapy for the treatment of BPD. The search was limited to articles published between January 1980 and September 2015. Data extracted from 12 manuscripts and one poster with yet unpublished results, representing a total of 17 clinical trials were pooled (n = 6578). Pooled response rates for drug and placebo were 55.1% and 39.2%, corresponding to a risk ratio (RR) for responding to active treatment versus placebo of 1.29 (p < 0.001). Clinical response was defined as a 50% or greater reduction in depression scores, baseline to endpoint. A higher placebo response rate correlated with a significantly lower RR of responding to pharmacotherapy versus placebo (p = 0.002). The pooled drug and placebo response rates for studies with a placebo response rate ≤ 30% were 50.5% versus 26.6%, while corresponding values from studies with a placebo response rate >30 were 55.0% versus 41.6%. These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for BPD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates >30%. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in BPD.

The nature of placebo response in clinical studies of major depressive disorder.

OBJECTIVE: To review factors influencing placebo response and clinical trial outcome in depression, and suggest ways to optimize trial success in mood disorders. DATA SOURCES: PubMed searches were conducted by cross-referencing the terms depression, depressive with placebo, clinical trial, and clinical trials for studies published in English between 1970 and September 2013. STUDY SELECTION: Relevant abstracts were identified in PubMed, including clinical trials, quantitative studies, and qualitative research. We obtained and reviewed relevant articles and utilized their information to synthesize the present review. DATA EXTRACTION: Included articles were grouped in the following areas of relevance: (1) biological validity of illness, (2) baseline severity of illness, (3) chronicity of the index episode of depression, (4) age of participants, (5) medical and psychiatric comorbidity, (6) probability of receiving placebo, (7) use of prospective treatment phases (lead-in) (8) dosing schedule, (9) trial duration, (10) frequency of follow-up assessments, and (11) study outcome measure. RESULTS: Several key elements emerge as critical to the ultimate success of a clinical trial, including the probability of receiving placebo, study duration, dosing schedule, visit frequency, the use of blinded lead-in phases, the use of centralized raters, illness severity and duration, and comorbid anxiety. CONCLUSIONS: Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a, gradually, more predictable phenomenon and, hopefully, to one that becomes lesser in magnitude and variability. Several elements have emerged that seem to play a critical role in trial success, gradually reshaping the design of clinical, translational, as well as mechanistic studies in depression.

Binge eating disorder: from clinical research to clinical practice.

This case report describes the clinical course of a young woman suffering from binge eating disorder (BED) associated with obesity. It illustrates the efficacy of different medications in the treatment of BED and related conditions and is followed by the comments and clinical observations of 2 practicing psychiatrists. The issues described in this paper have important clinical implications and are topical, given that BED is now recognized as a specific disorder in the new Diagnostic and Statistical Manual of Mental Disorders, fifth edition classification system, but neither the US Food and Drug Administration nor any other regulatory agency has yet approved a drug for treatment of this disease, despite its very prevalent and disabling nature. Growing evidence from the fields of psychopathology and neurobiology, including preclinical and clinical studies, converges to support the idea that "overeating" has much in common with other behavioral addictions, and substance abuse treatment agents may show promise for the treatment of BED.

Predictors of placebo response in bipolar depression.

The aim of this work is to investigate placebo response rates in placebo-controlled randomized clinical trials (RCTs) of pharmacological therapy in bipolar depression (BPD) and to identify predictors of placebo response and clinical trial outcome in BPD. Medline/PubMed publication databases were searched for RCTs of oral drugs used as monotherapy for the treatment of BPD, published between January 1980 and September 2013. Data extracted from 12 manuscripts and one poster, representing a total of 17 clinical trials, were pooled. Pooled response rates for drug and placebo were 55.1 and 39.2%, corresponding to a risk ratio for responding to active treatment versus placebo of 1.29 (P<0.001). The probability of receiving placebo and trial duration correlated with the response rate to placebo. A meta-regression showed that trial duration and baseline severity correlated with the risk ratio of responding to drug versus placebo. There was a trend toward statistical significance for a greater probability of receiving placebo to predict greater drug-placebo 'separation'. In conclusion, several modifiable factors, specifically the probability of receiving placebo, baseline illness severity, and trial duration, correlate with placebo response rates and/or clinical trial outcome in RCTs of pharmacotherapy for BPD, and should be taken into account when designing studies for BPD.

A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder.

BACKGROUND: Multiple treatments for patients with major depressive disorder (MDD) have demonstrated efficacy, but up to one-third of individuals with MDD do not achieve symptomatic remission despite various interventions. Existing augmentation or combination strategies can have substantial safety concerns that may limit their application. METHOD: This study investigated the antidepressant efficacy of a flexible dose of the dopamine agonist pramipexole as an adjunct to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial conducted in a tertiary-level depression center. We randomized 60 outpatients (aged 18 to 75 years) with treatment-resistant nonpsychotic MDD (diagnosed according to DSM-IV) to either pramipexole (n = 30) or placebo (n = 30). Treatment resistance was defined as continued depression (Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 18) despite treatment with at least 1 prior antidepressant in the current depressive episode. Patients were recruited between September 2005 and April 2008. The primary outcome measure was the MADRS score. RESULTS: The analyses that used a mixed-effects linear regression model indicated a modest but statistically significant benefit for pramipexole (P = .038). The last-observation-carried-forward analyses indicated that 40% and 33% of patients randomized to augmentation with pramipexole achieved response (χ(2) = 1.2, P = .27) and remission (χ(2) = 0.74, P = .61), respectively, compared to 27% and 23% with placebo; however, those differences were not statistically significant. Augmentation with pramipexole was well-tolerated, with no serious adverse effects identified. CONCLUSION: For patients who have failed to respond to standard antidepressant therapies, pramipexole is a safe and potentially efficacious augmentation strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00231959.

Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis.

OBJECTIVE: To investigate the relationship between specific levels of placebo response rates and the drug response rate and the relative risk of response to drug versus placebo in clinical trials of antidepressant monotherapy and adjunctive polypharmacy for MDD. DATA SOURCES: MEDLINE/PubMed databases were searched for studies published in the English language between January 1980 and March 2011 by using the search terms depression, placebo, augmentation, adjunct, adjunctive, and each of the antidepressant agents identified. The search was supplemented by manual bibliographic review and examination of relevant review articles. STUDY SELECTION: The analysis included randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for MDD, 4 weeks or longer, and of augmentation/combination treatments for antidepressant partial responders/nonresponders with MDD, 1 week or longer. 169 antidepressant monotherapy studies and 35 adjunctive polypharmacy studies were found eligible for inclusion in our analysis. DATA EXTRACTION: Data extracted included number of patients enrolled, patient characteristics, drug dosages and scheme (fixed vs flexible dosing), duration of the trial, and response rates. RESULTS: In antidepressant monotherapy studies, a higher placebo response rate correlated with a lower risk ratio of responding to antidepressant versus placebo (P < .001) and correlated with higher antidepressant response rates (P < .001); the number needed to treat (NNT) for response was approximately 4, 6, and 9 in trials with placebo response rates < 30%, ≥ 30% and < 40%, and ≥ 40%, respectively. In adjunctive trials, a higher placebo response rate correlated with a lower risk ratio of responding to the adjunctive drug versus placebo (P < .001) and correlated with a trend toward statistical significance with higher response rates to the adjunctive drug (P = .050); the NNT was approximately 6, 7, 11, and 17 in trials with placebo response rates < 20%, ≥ 20% and < 30%, ≥ 30% and < 40%, and ≥ 40%, respectively. CONCLUSIONS: These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for MDD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates ≥ 30% and ≥ 40%, respectively, for monotherapy and adjunctive trials. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in MDD.

Does the presence of an open-label antidepressant treatment period influence study outcome in clinical trials examining augmentation/combination strategies in treatment partial responders/nonresponders with major depressive disorder?

OBJECTIVE: The authors sought to determine study design factors that may influence clinical trial outcome in augmentation/combination trials for antidepressant partial responders/nonresponders with major depressive disorder (MDD) and to examine whether the use of a prospective treatment phase (lead-in) to assess antidepressant nonresponse may result in a better chance to detect a drug-placebo separation in such trials. DATA SOURCES: MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of adjunctive pharmacologic strategies for antidepressant partial responders/nonresponders with MDD. The search term depression was successively cross-referenced with the terms augmentation, adjunct, and adjunctive to identify pertinent trials. (The search was limited to articles published between January 1980 and October 2010.) STUDY SELECTION: Thirty-five articles involving 40 adjunctive drug versus placebo comparisons were pooled (n = 4,676). Final inclusion of articles was determined by consensus between the authors. DATA EXTRACTION: Data extracted included whether there was a lead-in phase and, if so, the drugs, the doses, and the total duration of the lead-in phase. Additional data extracted included the number of patients enrolled, patient characteristics, methods used to define treatment resistance, drug dosages, duration of the adjunctive trial, response and remission rates, and rates of discontinuation for any reason and for adverse events. RESULTS: The risk ratio of responding to the adjunctive drug versus placebo was not influenced by any of the study design factors analyzed (probability of receiving placebo, year of publication, severity of depression at baseline). Meta-regression analysis yielded no significant difference in the risk ratio of responding and remitting to the adjunctive drug versus placebo between studies that did versus did not include an antidepressant lead-in phase. However, pooled response/remission rates for adjunctive drug and placebo were statistically significantly lower in trials that did versus did not include a lead-in phase (response rates: for adjunctive drug, 42.6% vs 47.4%, respectively, P = .014; for adjunctive placebo, 29.7% vs 36.2%, respectively, P = .002; remission rates: for adjunctive drug, 31.0% vs 37.3%, respectively, P = .003; and adjunctive placebo, 18.1% vs 24.7%, respectively, P = .001). CONCLUSIONS: These results suggest that the choice to use historical data only to define treatment resistance prior to patient enrollment and randomization rather than requiring patients to first undergo a prospective lead-in phase can be a reasonable and evidence-supported approach to design effective clinical trials on augmentation/combination strategies for partial responders/nonresponders with MDD.

Folates and S-adenosylmethionine for major depressive disorder.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.

Second-tier natural antidepressants: review and critique.

The use of Complementary and Alternative Medicine (CAM) for physical and mental problems has increased significantly in the US over the past two decades, and depression is one of the leading indications for the use of CAM. This article reviews some of the lesser-known natural products with potential psychiatric applications that are starting to emerge with some scientific and clinical evidence and may constitute a next wave of natural antidepressants: Rhodiola rosea, chromium, 5-Hydroxytryptophan (5-HTP) and inositol. Background information, efficacy data, proposed mechanisms of action, recommended doses, side effects, and precautions are reviewed. We found some encouraging data for the use of these natural products in specific populations of depressed patients. R. rosea is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects. Chromium has a beneficial effect on eating-related atypical symptoms of depression, and may be a valuable agent in treating atypical depression and seasonal affective disorder. Inositol may be useful in the treatment of bipolar depression when combined with mood stabilizers. Evidence for the clinical efficacy of 5-HTP is also promising but still preliminary. Although more well-designed and larger controlled studies are needed before any substantive conclusions can be drawn, the available evidence is compelling and these natural products deserve further investigation as a possibly significant addition to the antidepressant armamentarium.

Antidepressants for major depressive disorder in patients with a co-morbid axis-III disorder: a meta-analysis of patient characteristics and placebo response rates in randomized controlled trials.

The objective of this study is to assess whether the antidepressants are effective in treating major depressive disorder (MDD) in patients with a co-morbid axis-III disorder, and to compare the relative efficacy (vs. placebo) of antidepressants between these patients and those enrolled in general MDD trials. Medline/Pubmed publication databases were searched. We selected for randomized, double-blind, placebo-controlled trials of antidepressants for MDD, whether conducted in a general population, or in populations with an axis-III disorder. Antidepressants were more effective than placebo in patients with axis-III disorders overall [risk ratio for response (RR)=1.42, P<0.0001], as well as specifically for post-stroke (RR=1.43, P=0.04), human-immunodeficiency virus positive or acquired immunodeficiency syndrome (RR=1.66, P=0.005), but not cancer patients (RR=1.26, P=0.19). There was a trend for higher placebo response rates in studies, which did (41.2%) versus those which did not (37.7%) select for axis-III disorders (P=0.06), and significantly higher antidepressant response rates in studies which did (57.4%) versus those which did not (53.5%) select for axis-III disorders (P=0.01). Antidepressants are effective for MDD in patients who present with co-morbid axis-III disorders and as effective (vs. placebo) in this population as they are in the general MDD population. Higher general response rates observed in the co-morbid MDD population are intriguing, and require replication.