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There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes.
We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model.
Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches.
Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.
Suicidal behavior results from a complex interplay between stressful events and vulnerability factors, including cognitive deficits. However, it is not clear which cognitive tests may best reveal this vulnerability. The objective was to identify neuropsychological tests of vulnerability to suicidal acts in patients with mood disorders.
A search was made of Medline, EMBASE and PsycINFO databases, and article references. A total of 25 studies (2323 participants) met the selection criteria. A total of seven neuropsychological tests [Iowa gambling task (IGT), Stroop test, trail making test part B, Wisconsin card sorting test, category and semantic verbal fluencies, and continuous performance test] were used in at least three studies to be analysed.
IGT and category verbal fluency performances were lower in suicide attempters than in patient controls [respectively, g = –0.47, 95% confidence interval (CI) –0.65 to –0.29 and g = –0.32, 95% CI –0.60 to –0.04] and healthy controls, with no difference between the last two groups. Stroop performance was lower in suicide attempters than in patient controls (g = 0.37, 95% CI 0.10–0.63) and healthy controls, with patient controls scoring lower than healthy controls. The four other tests were altered in both patient groups versus healthy controls but did not differ between patient groups.
Deficits in decision-making, category verbal fluency and the Stroop interference test were associated with histories of suicidal behavior in patients with mood disorders. Altered value-based and cognitive control processes may be important factors of suicidal vulnerability. These tests may also have the potential of guiding therapeutic interventions and becoming part of future systematic assessment of suicide risk.
Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs).
We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT).
Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant.
HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.
Bilateral repetitive magnetic stimulation (rTMS) is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting evidence concerning its overall efficacy, which might have resulted from low statistical power. Thus, meta-analytical approaches could be useful in examining this issue by allowing the integration of findings from multiple studies and thus producing more accurate estimates of the treatment effect.
We searched the literature for randomized, double-blind and sham-controlled trials (RCTs) on bilateral rTMS for treating MD from 1995 to July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations and Theses, and from October 2008 until May 2012 using Medline. The main outcome measures were response and remission rates. We used a random-effects model, odds ratios (ORs) and the number needed to treat.
Data were obtained from seven RCTs, totaling 279 subjects with MD. After an average of 12.9 (s.d. = 2.7) sessions, 24.7% (40/162) and 6.8% (8/117) of subjects receiving active bilateral rTMS and sham rTMS were classified as responders [OR 4.3, 95% confidence interval (CI) 1.95–9.52, p < 0.0001]. Also, 19% (23/121) and 2.6% (2/77) of subjects were remitters following active bilateral rTMS and sham rTMS, respectively (OR 6.0, 95% CI 1.65–21.8, p = 0.006). No difference between baseline mean depression scores for the bilateral and sham rTMS groups was found, and the former was comparable with the latter in terms of drop-out rates at study end. Furthermore, we did not find significant differences efficacy- and acceptability-wise between active bilateral and unilateral rTMS at study end. Finally, heterogeneity between the included RCTs was not significant, and the risk of publication bias was found to be low.
Bilateral rTMS is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with those of standard antidepressants and unilateral rTMS. Furthermore, bilateral rTMS seems to be an acceptable treatment for depressed subjects.
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