Small Effects, Questionable Outcomes: Bremelanotide for Hypoactive Sexual Desire Disorder.

Efficacy outcomes are only informative to the extent that they are validated. We examined the measurement properties of efficacy measures from the phase III ("RECONNECT") bremelanotide trials for hypoactive sexual desire disorder (HSDD) in women. Continuous efficacy outcomes, including a) the Female Sexual Function Index (FSFI) and its Desire domain (FSFI-D) and b) the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) and its item assessing distress due to low desire (FSDS-DAO #13) have questionable, at best, validity evidence for women with HSDD. We found no validity evidence for previously published categorical treatment response outcomes from the RECONNECT trials. All efficacy results should be reported, but results on 8 of the 11 clinicaltrials.gov-specified efficacy outcomes were heretofore unpublished (including FSDS-DAO total score, FSFI total score, FSFI arousal domain, and items from the Female Sexual Encounter Profile-Revised). We analyzed these outcomes, upon which effect sizes ranged from nil to small. Several other continuous and categorical outcomes generated modest apparent benefits, though nearly all of these outcomes were likely derived post-hoc. Across RECONNECT trial data from two prior publications and the current study, bremelanotide's benefits are statistically modest and limited to outcomes for which scant evidence of validity among women with HSDD exists.

Corrigendum Compounds Errors and Again Fails to Support the Specificity of Acupoint Tapping.

ABSTRACT: In a prior article (Spielmans, Rosen, Spence-Sing J Nerv Ment Dis 208:628-631, 2020), we demonstrated that Church, Stapleton, Yang, and Gallo's (J Nerv Ment Dis 206:783-793, 2018) meta-analytic finding that acupoint tapping had specific therapeutic benefit was highly flawed, both statistically and methodologically. Our analysis based on corrected effect sizes found no significant benefit for acupoint tapping at study endpoint. Church, Stapleton, Kip, and Gallo (J Nerv Ment Dis 208:632-635, 2020) issued a corrigendum in which they reported a new post hoc analysis using follow-up (rather than study endpoint) measures. Shifting to a post hoc outcome while pooling highly disparate follow-up endpoints is problematic; it ignored the nonsignificant result of the a priori analysis. Here, we clarify these issues and address Church, Stapleton, Kip, and Gallo's (J Nerv Ment Dis 208:632-635, 2020) often irrelevant or confusing responses to our methodological concerns. Considering this recent exchange of articles, and absent meaningful correction to the original incorrect findings, we remain concerned that emotional freedom technique proponents will continue to advance unfounded claims regarding the purported benefits of acupoint tapping.

Re-Analyzing Phase III Bremelanotide Trials for "Hypoactive Sexual Desire Disorder" in Women.

Kingsberg et al. described results from two 24-week Phase III trials of bremelanotide for treating hypoactive sexual desire disorder (HSDD) in women. 72.72% of protocol-listed outcomes were not reported by Kingsberg et al., who provided results of 15 secondary measures which were not listed in the study protocols. None of their efficacy outcomes were reported in line with CONSORT data reporting standards and no secondary outcome had a stated rationale or cited evidence of validity. My meta-analysis of the trials' data, based on the FDA New Drug Application, found similar results to Kingsberg et al. However, Kingsberg et al. did not report that a) adverse event-induced study discontinuation was substantially higher on bremelanotide: OR = 11.98, 95% CI = 3.74-38.37, NNH: 6 or b) participants preferred placebo, measured by the combination of both 1) completing a clinical trial and 2) electing to participate in the follow-up open-label study (OR = 0.30, 95% CI = .24-.38, NNH: 4). Bremelanotide's modest benefits on incompletely reported post-hoc measures of questionable validity in combination with participants substantially preferring to take placebo suggest that the drug is generally not useful. Kingsberg et al.'s data reporting and measurement practices were incomplete and lacked transparency.

Tapping Away at a Misleading Meta-analysis: No Evidence for Specificity of Acupoint Tapping.

Church et al.'s meta-analysis of three studies claimed to support the specificity of acupoint tapping as a therapeutic technique in the treatment of mental health problems. However, our critical analysis found substantial methodological problems and inaccurate statistical analyses, which render their results invalid. Specifically, 1) two included studies did not include participants with documented mental health problems; 2) two included studies did not specifically isolate the effect of acupoint tapping; 3) clear rationales for selected measures were not provided; 4) comparison groups were not bona fide therapies; 5) researcher and therapist allegiances were not controlled; and 6) selection of included studies may have been biased. Further, our attempt to replicate their results failed; we found that acupoint tapping fared no better than comparison groups: k = 3 studies, d = -0.38 (95% confidence interval, 0.10 to -0.87), p = 0.12. We conclude that the Church et al.'s meta-analysis actually found no specific mental health benefits for acupoint tapping.

Duty to Warn: Antidepressant Black Box Suicidality Warning Is Empirically Justified.

The United States Food and Drug Administration issued a Black Box warning in October 2004 after placebo-controlled trials of antidepressant medications found an increased risk of suicidal thoughts and behaviors among children and adolescents taking antidepressant medications relative to placebo. Subsequently, some researchers have concluded that the Black Box warning caused severe unintended consequences; specifically, they have argued that the warning led to reduced use of antidepressants among youth, which led to more suicides. In this paper, we critically examine research regarding the Black Box warning's alleged deleterious consequences. One study claimed that controlled trials did not actually find an increased risk of suicidality among youth taking fluoxetine relative to those taking placebo, but its measure of suicidality is likely invalid. We found that ecological time series studies claiming that decreasing antidepressant prescriptions are linked to higher rates of suicide attempts or actual suicides among youth were methodologically weak. These studies exhibited shortcomings including: selective use of time points, use of only a short-term time series, lack of performing statistical analysis, not examining level of severity/impairment among participants, inability to control confounding variables, and/or use of questionable measures of suicide attempts. Further, while some time-series studies claim that increased antidepressant prescriptions are related to fewer youth suicides, more recent data suggests that increasing antidepressant prescriptions are related to more youth suicide attempts and more completed suicides among American children and adolescents. We also note that case-control studies show increased risk of suicide attempts and suicide among youth taking antidepressants, even after controlling for some relevant confounds. As clinical trials have the greatest ability to control relevant confounds, it is important to remember such trials demonstrated increased risk of suicidality adverse events among youth taking antidepressants. The Black Box warning is firmly rooted in solid data whereas attempts to claim the warning has caused harm are based on quite weak evidence.

Editorial: Room for Improvement in the Treatment of Youth Depression.

Psychotherapy has been studied for decades and is often used to treat youths with depression. How well does it work? Eckshtain et al.1 answered this question with a thoughtful, complex meta-analysis of 53 psychotherapy trials. Psychotherapy was significantly superior relative to control groups. More revealingly, treatment effects were small to moderate (g = .49) compared with no treatment, small (g = .29) compared with a broad range of usual care interventions, and middling and statistically insignificant (g = .16) relative to placebo interventions (nearly all placebo psychotherapies merely controlling for therapist attention; only one study used pill placebo). I describe these findings in the context of research on both psychotherapy and antidepressant medications. The current meta-analysis and a wider body of research provide guidance for both clinicians and researchers.

Moderators in psychotherapy meta-analysis.

Psychotherapy meta-analyses sometimes generate heterogeneous results, partially due to key methodological characteristics which vary between studies (e.g., psychotherapy conditions are contrasted with structurally different control conditions). Examining these potential moderator variables can help explain heterogeneous results within and between psychotherapy meta-analyses. The present manuscript provides an overview of moderators that are highly relevant to test the generalizability of effects across psychotherapy trials. These moderators mainly fall into one of the following groups: (a) structural equivalence of interventions, (b) preferences/allegiances, (c) therapist effects, and (d) sample representativeness. Individual moderators include: Bona fide psychotherapy, proximity to psychological interventions, psychotherapy orientation, pre-training of therapists, supervision, caseload of therapists, dosage, homework, patient preferences, researcher and therapist allegiance, therapist effects in nested designs, aspects of sample representativeness, multiple outcomes, and time of assessment. Our analysis of 15 psychotherapy meta-analyses published in 2016 suggests that the structural equivalence of psychotherapeutic conditions, patient and therapist preferences/allegiances, therapist effects and nested data structures as well as sample representativeness were often neglected and little-discussed as potential moderators. The manuscript describes further conceptual and methodological challenges when conducting moderator analyses such as the categorization of psychological treatments and the importance of interrater coding. We encourage meta-analysts to consider moderators which have previously shown utility in explaining heterogeneous results in the psychotherapy literature. Clinical or methodological significance of this article: Relevant moderator variables help explain heterogeneous results in psychotherapy meta-analyses. Though these variables are often overlooked, they should be regularly incorporated in meta-analyses.

Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes.

(Reprinted with permission from PLoS Med 2013; 10(3): e1001403).

The efficacy of antidepressants on overall well-being and self-reported depression symptom severity in youth: a meta-analysis.

BACKGROUND: Recent meta-analyses of the efficacy of second-generation antidepressants for youth have concluded that such drugs possess a statistically significant advantage over placebo in terms of clinician-rated depressive symptoms. However, no meta-analysis has included measures of quality of life, global mental health, self-esteem, or autonomy. Further, prior meta-analyses have not included self-reports of depressive symptoms. METHODS: Studies were selected through searching Medline, PsycINFO, and the Cochrane Central Register for Controlled Trials databases as well as GlaxoSmithKline's online trial registry. We included self-reports of depressive symptoms and pooled measures of quality of life, global mental health, self-esteem, and autonomous functioning as a proxy for overall well-being. RESULTS: We found a nonsignificant difference between second-generation antidepressants and placebo in terms of self-reported depressive symptoms (k = 6 trials, g = 0.06, p = 0.36). Further, pooled across measures of quality of life, global mental health, self-esteem, and autonomy, antidepressants yielded no significant advantage over placebo (k = 3 trials, g = 0.11, p = 0.13). DISCUSSION: Though limited by a small number of trials, our analyses suggest that antidepressants offer little to no benefit in improving overall well-being among depressed children and adolescents.

Drug approval and drug effectiveness.

Data on the efficacy and safety of psychiatric medicines should form the foundation of evidence-based treatment practices. The US Food and Drug Administration (FDA) reviews such data in determining whether to approve new treatments, and the published literature serves as a repository for evidence on treatment benefits and harms. We describe the FDA review of clinical trials, examining the underlying logic and legal guidelines. Several FDA reviews provide evidence that the agency requires only minimal efficacy for psychiatric drugs. Further, in some instances, the FDA has relied on secondary rather than primary outcomes and has discounted the findings of negative studies in its review of antidepressant and antipsychotic medications. The published literature provides another lens into the safety and efficacy of treatments. We describe how treatment efficacy is systematically overstated and treatment-related harms are understated in the scientific literature. Suggestions are provided to improve public access to underlying safety and efficacy data and for the FDA to potentially improve its review process.

Efficacy of new generation antidepressants: differences seem illusory.

BACKGROUND: Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani's analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted. MATERIALS AND METHODS: A Monte Carlo simulation was conducted which involved replicating Cipriani's network meta-analysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated. FINDINGS: Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed. INTERPRETATION: Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.'s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses.

Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes.

BACKGROUND: Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk-benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. METHODS AND FINDINGS: We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48-2.73), OFC (OR, 1.42; 95% CI, 1.01-2.0), quetiapine (OR, 1.79; 95% CI, 1.33-2.42), and risperidone (OR, 2.37; 95% CI, 1.31-4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58-2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87-1.93), quetiapine (OR, 1.53, 95% CI, 1.17-2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16-2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery-Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. CONCLUSIONS: Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm. Please see later in the article for the Editors' Summary.

Specificity of psychological treatments for bulimia nervosa and binge eating disorder? A meta-analysis of direct comparisons.

Treatment guidelines state that cognitive-behavioral therapy (CBT) and interpersonal therapy are the best-supported psychotherapies for bulimia nervosa (BN) and that CBT is the preferred psychological treatment for binge eating disorder (BED). However, no meta-analysis which both examined direct comparisons between psychological treatments for BN and BED and considered the role of moderating variables, such as the degree to which psychotherapy was bona fide, has previously been conducted Thus, such an analysis was undertaken. We included 77 comparisons reported in 53 studies. The results indicated that: (a) bona fide therapies outperformed non-bona fide treatments, (b) bona fide CBT outperformed bona fide non-CBT interventions by a statistically significant margin (only approaching statistical significance for BN and BED when examined individually), but many of these trials had confounds which limited their internal validity, (c) full CBT treatments offered no benefit over their components, and (d) the distribution of effect size differences between bona fide CBT treatments was homogeneously distributed around zero. These findings provide little support for treatment specificity in psychotherapy for BN and BED.