Browsing by Author "Tondo, Leonardo"
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Item Antidepressant responses in direct comparisons of melancholic and non-melancholic depression(2020) Undurraga, Juan; Vázquez, Gustavo H.; Tondo, Leonardo; Baldessarini, Ross J.Background: Efforts to develop less heterogeneous, more clinically useful diagnostic categories for depressive disorders include renewed interest in the concept of melancholia (Mel). However, clinical or biological differentiation of Mel from other (nonMel) episodes of depression has been questioned, and it remains unclear whether pharmacological responses proposed to be characteristic of Mel are supported by available research. Methods: We carried out a systematic review seeking treatment trials reports comparing Mel and nonMel depressed subjects for meta-analyses of their differences in responses (a) to antidepressants overall, (b) to tricyclic (TCAs) or serotonin-enhancing agents (serotonin reuptake inhibitors/serotonin–norepinephrine reuptake inhibitors) and (c) with placebo treatment. Results: We identified 25 trials in 16 reports comparing 2597 Mel with 5016 nonMel subjects. Overall, responses to antidepressant treatment did not differ between Mel (39.4%) and nonMel (42.2%) subjects. However, all subjects responded better to TCAs (50.6%) than SRIs (30.0%; p<0.0001). Mel subjects also responded less well with placebo, but also were significantly more severely depressed at intake. Conclusions: Antidepressant responses were similar in Mel and nonMel depressed patients. Mel subjects responded 25% less with placebo but were more severely depressed initially, and there was preferential response to TCAs in both Mel and nonMel subjects. The findings provide little support for proposed differences in responses to particular treatments among Mel versus nonMel depressed patients, and underscore the need to match for illness severity in making such comparisons.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 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.Item Melancholia: Does This Ancient Concept Have Contemporary Utility?(2020) Sani, Gabriele; Tondo, Leonardo; Undurraga, Juan; Vázquez, Gustavo H.; Salvatore, Paola; Baldessarini, Ross J.Many efforts have been made to develop coherent and clinically useful categories of depressive illness, especially to facilitate prediction of morbidity and guide treatment-response. They include proposals to resurrect the ancient concept of melancholia, a form of severe depression with particular symptomatic and proposed psychobiological characteristics. However, modern research is inconsistent in supporting differences between melancholic and nonmelancholic depression. In our recent study of over 3200 patient-subjects with DSM-5 major depressive episodes with/without melancholic characteristics, and matched for illness severity, prevalence of melancholic features was 35.2% with remarkably few clinical differences between melancholic and nonmelancholic subjects. Also, our systematic review of trials comparing melancholic and nonmelancholic subjects found little difference in responses to antidepressant treatments. These findings indicate that the concept of melancholia may have limited value for clinical prediction and treatment-selection. Overlap of symptoms in melancholic and nonmelancholic depression, based on DSM criteria, may limit distinction of melancholia; alternative definitions can be sought, and psychomotor retardation is a particularly strong differentiating feature. For now, however, melancholia seems best considered a state-dependent depression-type strongly associated with greater symptomatic severity, rather than a distinct syndrome. Its current status as a depression-type specifier seems appropriate, and it is a logical target for genetic and other biomedical studies.Item Pharmacological treatment of bipolar depression(2014) Vázquez, Gustavo H.; Tondo, Leonardo; Undurraga, Juan; Zaratiegui, Rodolfo; Selle, Valerio; Baldessarini, Ross J.Bipolar depression remains a major challenge for psychiatric therapeutics. It is associated with disability and excess mortality, and accounts for three-quarters of the time spent in morbid states by treated patients with bipolar disorder. Major limitations of research on the treatment of depression in bipolar disorder include a paucity of short-term and lack of long-term trials, probably reflecting concern about inducing mania. In addition, polytherapy with multiple drugs appears to be widespread, but it is virtually untested for efficacy and safety. Here, we summarise the evidence concerning efficacy of treatment of bipolar depression with antidepressants, mood- stabilising anticonvulsants, lithium and second-generation antipsychotics.