Marcelo T. Berlim

Four Studies on How Past and Current Suicidality Relate Even When "Everything But the Kitchen Sink" Is Covaried.

T. E. Joiners (2004, in press) theory of suicidal behavior suggests that past suicidal behavior plays an important role in future suicidality. However, the mechanism by which this risk is transferred and the causal implications have not been well studied. The current study provides evaluation of the nature and limits of this relationship across 4 populations, with varying degrees of suicidal behavior. Across settings, age groups, and impairment levels, the association between past suicidal behavior and current suicidal symptoms held, even when controlling for strong covariates like hopelessness and symptoms of various Axis I and II syndromes. Results provide additional support for the importance of past suicidality as a substantive risk factor for later suicidal behavior.

Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods.

Objective: Up to 15% of depression patients eventually present with treatment-resistant or refractory depression (TRD), a condition that causes significant social and economic burdens. Our paper aims to summarize the current medical literature on the conceptual and methodologic issues involved in the definition, assessment, and staging of TRD. Method: We reviewed the recently published medical literature to identify papers that specifically discuss TRD. For this, we searched MEDLINE, EMBASE, and PsycINFO for potentially relevant English-language articles published between January 1996 and June 2006. Results: Recent methodologic and conceptual advances have contributed to the achievement of an acceptable level of theoretical consensus on the general meaning of TRD. Accordingly, depression is usually considered resistant or refractory when at least 2 trials with antidepressants from different pharmacologic classes (adequate in terms of dosage, duration, and compliance) fail to produce a significant clinical improvement. Regarding diagnostic assessments, an accurate and systematic evaluation should be made to elicit the potential role of several contributing factors, such as medical and psychiatric comorbidity. Conclusion: Recently, 3 staging methods for TRD have been described, but they currently require extensive empirical support. Future research on TRD should include prospective studies addressing the validity of the proposed criteria, the impact of depression comorbid with other psychiatric disorders and (or) physical conditions, and the possible predictors of treatment outcome. There is an important and clear need for studies that empirically test current definitions, assessment strategies, and staging methods of TRD.

A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes

BACKGROUND 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. METHOD 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. RESULTS 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. CONCLUSION 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.

Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: A systematic review and meta-analysis of randomized, double-blind and sham-controlled trials

OBJECTIVE tDCS is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting results concerning its efficacy, which likely resulted from low statistical power. Thus, we carried out a systematic review and meta-analysis on randomized, double-blind and controlled trials of tDCS in MD with a focus on clinically relevant outcomes, namely response and remission rates. METHOD We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on tDCS for treating MD from 1998 through July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and SCOPUS. We also consulted the Web of Sciences Citations Index Expanded for the selected RCTs up to July 2012. The main outcome measures were response and remission rates. We used a random-effects model and Odds Ratios (OR). RESULTS Data were obtained from 6 RCTs that included a total of 200 subjects with MD. After an average of 10.8 ± 3.76 tDCS sessions, no significant difference was found between active and sham tDCS in terms of both response (23.3% [24/103] vs. 12.4% [12/97], respectively; OR = 1.97; 95% CI = 0.85-4.57; p = 0.11) and remission (12.2% [12/98] vs. 5.4% [5/92], respectively; OR = 2.13; 95% CI = 0.64-7.06; p = 0.22). Also, no differences between mean baseline depression scores and dropout rates in the active and sham tDCS groups were found. Furthermore, sensitivity analyses excluding RCTs that involved less than 10 treatment sessions or stimulus intensity of less than 2 mA did not alter the findings. However, tDCS used as monotherapy was associated with higher response rates when compared to sham tDCS (p = 0.043). Finally, the risk of publication bias in this meta-analysis was found to be low. CONCLUSIONS The clinical utility of tDCS as a treatment for MD remains unclear when clinically relevant outcomes such as response and remission rates are considered. Future studies should include larger and more representative samples, investigate how tDCS compares to other therapeutic neuromodulation techniques, as well as identify optimal stimulation parameters.

What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials ☆

OBJECTIVE To summarize and discuss the conceptual and operational definitions of treatment resistant/refractory depression (TRD) by systematically reviewing randomized controlled trials (RCTs) on its somatic treatment. DATA SOURCES We searched the MEDLINE, Cochrane Library, PsycINFO, and EMBASE for potentially relevant RCTs on the somatic treatment of TRD published from January 1996 to June 2006. STUDY SELECTION Studies were included if they: (a) enrolled patients at least 18 years old with a primary diagnosis of unipolar major depression considered resistant/refractory to treatment at baseline, (b) had a randomized design, (c) were published in peer-reviewed journals, and (d) were written in English. Trials that enrolled patients with secondary depression were excluded from our review. Finally, the bibliographies of relevant articles were hand-searched for additional references. In total, 233 full electronic references were retrieved, from which 47 meet the inclusion criteria. DATA EXTRACTION Through a standardized form, we collected data describing the diagnostic procedure, the terminology and definition of TRD employed, the methodology for assessing the adequacy of previous treatments (in terms of type of ascertainment, dose, and duration), and the minimum required depressive symptoms at baseline. DATA SYNTHESIS Overall, RCTs diverged regarding the majority of the conceptual and methodological issues involved in the ascertainment of TRD. For example, eleven terms were used to describe resistance/refractoriness in depression, and six different criteria were employed to define the categorical presence of TRD (ranging form non-response to one antidepressant to non-response to two or more antidepressants from different pharmacological classes). Regarding the evaluation of previous treatments, the majority of RCTs did not use systematic methods to gather data, and diverge substantially on the minimum acceptable medication doses and trial durations. CONCLUSIONS There is a clear need for an internationally shared framework of concepts and methods for the investigation of TRD that could reduce current idiosyncrasies and provide a reference system. Such a foundation is essential for the interpretation of research findings and for their translation to clinical practice.

Clinically Meaningful Efficacy and Acceptability of Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) for Treating Primary Major Depression: A Meta-Analysis of Randomized, Double-Blind and Sham-Controlled Trials

Clinical trials on low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the right dorsolateral prefrontal cortex have yielded conflicting evidence concerning its overall efficacy for treating major depression (MD). As this may have been the result of limited statistical power of individual trials, we have carried the present systematic review and meta-analysis to examine this issue. We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on LF-rTMS for treating MD from 1995 through July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses, and from October 2008 until July 2012 using MEDLINE. The main outcome measures were response and remission rates as well as overall dropout rates at study end. We used a random-effects model, odds ratios (ORs) and number needed to treat (NNT). Data were obtained from eight RCTs, totaling 263 subjects with MD. After an average of 12.6±3.9 rTMS sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rTMS were classified as responders (OR=3.35; 95% CI=1.4–8.02; p=0.007). Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rTMS were classified as remitters (OR=4.76; 95% CI=2.13–10.64; p<0.0001). The associated NNT for both response and remission rates was 5. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rTMS as a monotherapy for MD were associated with higher rates of response to treatment. No differences on mean baseline depression scores and dropout rates for active and sham rTMS groups were found. Finally, the risk of publication bias was low. In conclusion, LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rTMS. Furthermore, LF-rTMS seems to be an acceptable intervention for depressed subjects.

A meta-analysis of neuropsychological markers of vulnerability to suicidal behavior in mood disorders.

BACKGROUND 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. METHOD 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. RESULTS 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. CONCLUSIONS 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.

Structural magnetic resonance imaging in eating disorders: a systematic review of voxel-based morphometry studies.

This systematic review summarises and critically appraises the literature on structural magnetic resonance imaging in people with a current or past eating disorder. Studies using voxel-based morphometry image analysis were included. Ten studies reported on a total of 236 people with a current or past eating disorder and 257 healthy controls. Sample heterogeneity prohibited a meta-analytic approach. The findings do not unequivocally indicate grey or white matter volume abnormalities in people with an eating disorder. Nevertheless, these preliminary data suggest that, compared with healthy controls, people with anorexia nervosa have decreased grey matter in a range of brain regions and that those with bulimia nervosa have increased grey matter volumes in frontal and ventral striatal areas. Research in the recovery phase and longitudinal studies suggest that potential brain tissue abnormalities may recover with clinical improvement. Overall, as the available data are inconclusive, further efforts in this field are warranted.

Reliability and validity of the WHOQOL BREF in a sample of brazilian outpatients with major depression

The present study assessed the psychometric properties of the Brazilian version of the World Health Organization’s Quality of Life Instrument – Short Version (WHOQOL BREF) in a sample of 89 adult outpatients with major depression. After analyses, the WHOQOL BREF showed good internal consistency, and was sensitive to improvement after treatment with antidepressants. Convergent validity between the WHOQOL BREF and the Beck Depression Inventory was statistically significant, as well as WHOQOL BREF’s ability to discriminate between outpatients on the basis of their level of depression. In conclusion, the WHOQOL BREF seems to be a psychometrically valid and reliable instrument that it is suitable for evaluating the quality of life of Brazilian-speaking depressed outpatients.

Epigenetic regulation of BDNF expression according to antidepressant response

Several lines of evidence support the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology and pharmacotherapy of depression.1 The neurotrophin hypothesis of depression postulates that stress and depression are associated with decreased BDNF expression, which can be reversed by antidepressant treatment.2 The goal of the present study was to investigate the effect of antidepressant treatment on the epigenetic regulation of BDNF in major depressive disorder (MDD).