Browsing by Author "Baldessarini, Ross"
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Item Declining efficacy in controlled trials of antidepressants: effects of placebo dropout.(Oxford University Press, 2014) Schalkwijk, Stein; Undurraga, Juan; Tondo, Leonardo; Baldessarini, RossDrug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980–2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant–placebo contrasts in controlled treatment trials since the 1980s.Item Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-To-head trials in acute major depression: Systematic review and meta-Analysis(Sage Publications, 2017) Undurraga, Juan; Baldessarini, RossBACKGROUND: A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin-reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons. METHODS: We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings. RESULTS: In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent-improvement between TCAs and SSRIs. In addition to non-difference between drug-types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016. CONCLUSIONS: Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types.Item Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium(2021) Vázquez, Gustavo; Bahji, Anees; Undurraga, Juan; Tondo, Leonardo; Baldessarini, RossAbstract Background: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear. Methods: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes. Results: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT=11 [CI: 9–15]); esketamine (7 [5–10]) and lithium (5 [4–10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT<10) than quetiapine (NNT=13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most- frequently reported effects, among SGAs versus placebo was 5 [4–6] overall, and highest with quetiapine (NNH=3), lowest with brexpiprazole (19), 5 (4–6) for esketamine, and 9 (5–106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25–10.60) for lithium and much less favorable for esketamine (0.71 [0.60–0.80]) or SGAs (0.45 [0.17–0.77]). Conclusions: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated. Limitations: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.Item Lithium treatment for unipolar major depressive disorder: Systematic review(Sage, 2019-02) Undurraga, Juan; Kang, Sim; Tondo, Leonardo; Gorodischer, Ariel; Azua, Emilio; Tay, Kai; Tan, David; Baldessarini, RossBackground: The potential value of lithium treatment in particular aspects of unipolar major depressive disorder remains uncertain. Methods: With reports of controlled trials identified by systematic searching of Medline, Cochrane Library, and PsycINFO literature databases, we summarized responses with lithium and controls followed by selective random-effects meta-analyses. Results: We identified 36 reports with 39 randomized controlled trials: six for monotherapy and 12 for adding lithium to antidepressants for acute major depression, and 21 for long-term treatment. Data for monotherapy of acute depression were few and inconclusive. As an adjunct to antidepressants, lithium was much more effective than placebo ( p<0.0001). For long-term maintenance treatment, lithium was more effective than placebo in monotherapy ( p=0.011) and to supplement antidepressants ( p=0.038), and indistinguishable from antidepressant monotherapy. Conclusions: The findings indicate efficacy of lithium as a treatment for some aspects of major depressive disorder, especially as an add-on to antidepressants and for long-term prophylaxis. It remains uncertain whether some benefits of lithium treatment occur with many major depressive disorder patients, or if efficacy is particular to a subgroup with bipolar disorder-like characteristics or mixed-features.