Antidepressant effects of tDCS are associated with prefrontal gray matter volumes at baseline: Evidence from the ELECT-TDCS trial

BackgroundTranscranial direct current stimulation (tDCS) is a promising intervention for major depression. However, its clinical effects are heterogeneous. We investigated, in a subsample of the randomized, clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECT-TDCS), whether the volumes of left and right prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were associated with prefrontal tDCS response.MethodsBaseline structural T1 weighted MRI data were analyzed from 52 patients (15 males). Patients were randomized to the following conditions: escitalopram 20 mg/day, bifrontal tDCS (2 mA, 30min, 22 sessions), or placebo. Antidepressant outcomes were assessed over a treatment period of 10 weeks. Voxel-based gray matter volumes of PFC and ACC were determined using state-of-the-art parcellation approaches.ResultsAccording to our a priori hypothesis, in the left dorsal PFC, larger gray matter volumes were associated with depression improvement in the tDCS group (n = 15) compared to sham (n = 21) (Cohen's d = 0.3, 95% confidence interval [0.01; 0.6], p = 0.04). Neither right PFC nor ACC volumes were associated with depression improvement. Exploratory analyses of distinct PFC subregions were performed, but no area was associated with tDCS response after correction for multiple comparisons.ConclusionLeft PFC baseline gray matter volume was associated with tDCS antidepressant effects. This brain region and its subdivisions should be investigated further as a potential neurobiological predictor for prefrontal tDCS treatment in depression and might be correlated with tDCS antidepressant mechanisms of action.     

Relationship between depression severity entry criteria and antidepressant clinical trial outcomes.

BACKGROUND: We assessed whether increasing the minimum prerandomization Hamilton Depression Rating Scale (HAM-D) score to enrich the severity of the depressed sample affects antidepressant trial outcome. METHODS: Using the Food and Drug Administration Summary Basis of Approval reports, we examined outcome data from 51 clinical trials (11,270 depressed patients) evaluating 10 investigational antidepressants. RESULTS: Using four categories of trials with increasing minimum HAM-D entry trial criteria, we found no statistically significant relationship between prerandomization categories and trial outcome overall. Although there were minor differences in trial outcome among the three categories with the lowest entry criteria (mean 49%, range, 44.4%-50.0%), the antidepressant trials requiring the highest prerandomization HAM-D score (> or = 20 HAM-D 17) had the lowest frequency of positive outcomes (20%), chi(2) = 4.04, df =1, p = .04. Paradoxically, high entry criteria requirements failed to increase reliably actual mean total prerandomization HAM-D scores, although mean total prerandomization HAM-D scores and use of flexible dosing were associated with higher rates of positive outcome. A greater placebo response was seen in trials requiring higher prerandomization depressive symptoms. CONCLUSIONS: In summary, requiring higher prerandomization depressive symptoms was not associated with an increased rate of favorable outcomes among these 51 antidepressant trials.     

Comparison of blinding effectiveness between sham tDCS and placebo sertraline in a 6-week major depression randomized clinical trial

ObjectiveTo compare blinding integrity and associated factors for transcranial direct current stimulation (tDCS) vs. placebo-pill, the gold standard blinding method.MethodsParallel trial. Depressed participants were randomized to verum/placebo sertraline and active/sham tDCS (2 mA, 30-min 10-daily sessions and two additional, fortnight sessions) over 6 weeks. Blinding was assessed in completers (n = 102) and in a random subgroup (n = 35) of raters and participants, in which we also inquired to qualitatively describe their strongest guessing reason.ResultsParticipants and raters presented similar performance for predicting treatment assignment at endpoint, correctly guessing tDCS and sertraline beyond chance. Nevertheless, clinical response was associated with correct prediction and tDCS non-responders failed to predict the allocation group. For tDCS, “trouble concentrating” was inversely associated with correct prediction. “Skin redness” was more reported for active-tDCS, but did not predict the allocation group. The qualitative reasons for raters’ guessing were not associated with correct prediction, whereas for participants clinical response and adverse effects were directly and inversely associated with correct prediction, respectively.ConclusionBlinding integrity of tDCS and sertraline were comparable and mainly associated with efficacy rather than blinding failure.SignificanceTDCS blinding can be improved by adopting parallel designs and avoiding subjects’ awareness of skin redness.     

Interferon beta-1 a and depression in relapsing-remitting multiple sclerosis: an analysis of depression data from the PRISMS clinical trial

Depression is a suspected side effect of multiple sclerosis (MS) treatment with interferon beta-1a. However, this has not been confirmed by rigorous studies. Several psychological symptom rating scales were completed during the PRISMS clinical trial of subcutaneous interferon beta-1a (Rebif) for relapsing-remitting MS. We conducted an analysis of these data in order to determine whether symptom elevations were associated with treatment. The PRISMS clinical trial included 560 subjects from 22 centres in nine countries. There were two active treatment arms (44 mcg x 3 and 22 mcg x 3 subcutaneously three times per week) and a placebo group. Two hundred and sixty-seven of these subjects were enrolled at English speaking study centres, where psychiatric symptom ratings were obtained at baseline, 6, 12, 18 and 24 months using the Center for Epidemiological Studies Depression Rating Scale (CES-D), the General Health Questionnaire (GHQ) and the Beck Hopelessness Scale (BHS). After randomization, the groups completing these scales were similar in terms of age, gender, EDSS, duration of illness and employment status. Median CES-D scores in the high dose, low dose and placebo groups at baseline were also similar: 8.0, 7.0 and 8.0, respectively. After 6 months of treatment the median change in CES-D score was zero in all three groups. The proportion of subjects exceeding the traditional CES-D cut-point for clinically significant depression (> 15) after 6 months of treatment was strongly associated with pre-treatment depression (RR 2.9, 95% C.I.: 1.8-4.7), but not with treatment group (chi-square=1.64, d.f.=2, P=0.44). The results were comparable at 12, 18 and 24 months and when ratings from the other scales were evaluated. This analysis confirms that depression is common in persons with MS: the incidence of CES-D depression in the first 6 months of follow-up was 15.6%. However, no evidence of increased depressive symptomatology was observed in association with interferon beta-1a (Rebif).     

Prefrontal resting-state connectivity and antidepressant response: no associations in the ELECT-TDCS trial

European Archives of Psychiatry and Clinical Neuroscience - Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to...     

Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the ‘AX200 for ischemic stroke'' trial (AXIS 2 study {"type":"clinical-trial","attrs":{"text":"NCT00927836","term_id":"NCT00927836"}}NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.     

Using longitudinal data from a clinical trial in depression to assess the reliability of its outcome scales

Longitudinal studies are permeating clinical trials in psychiatry. Additionally, in the same field, rating scales are frequently used to evaluate the status of the patients and the efficacy of new therapeutic procedures. Therefore, it is of utmost importance to study the psychometric properties of these instruments within a longitudinal framework. In the area of depression, the Hamilton depression rating scale (HAMD) is regularly used for antidepressant treatment evaluation. However, the use of HAMD has not been exempted from criticism what has lead to the development of new scales that are expected to be more sensitive for change, such as the Montgomery-Åsberg depression rating scale (MADRS). In general, the reliability of these scales has been extensively studied by using classical methods for reliability estimation, developed for specifically designed reliability studies. Unfortunately, the settings customarily considered in these reliability studies are usually far from the practical conditions in which these scales are applied in clinical trials and practice. In the present paper, we assess the reliability of these instruments in a more realistic scenario thereby using longitudinal data coming from clinical studies. Nowadays, newly developed methodology based on an extended concept of reliability, allows us to use longitudinal data for reliability estimation. This new approach not only enables to avoid bias by offering a better control of disturbing factors but it also produces more precise estimates by taking advantage of the large sample taking sizes available in clinical trials. Further, it offers practical guidelines for an optimal use of a rating scale in order to achieve a particular level of reliability. The merits of this new approach are illustrated by applying it on two clinical trials in depression to assess the reliability of the three outcome scales, HAMD, MADRS, and the Hamilton anxiety rating scale (HAMA).     

Pro-inflammatory cytokines and psychotherapy in depression: Results from a randomized clinical trial

Depression is a serious condition that is associated with great psychic suffering and major impairments on the patient's general health, quality of life, and social and occupational activities. In some cases, it may lead to suicide. Regardless of the innumerous research works that have already addressed depression in wide and specific facets, there is still a lot to grasp in order to effectively help preventing and treating depression. This work presents data from a randomized clinical trial that sought to evaluate the effectiveness of two brief psychotherapeutic for Depression: Cognitive Behavioral Therapy (CBT) and Supportive-Expressive Dynamic Psychotherapy (SEDP). This was a convenience sample composed of 46 individuals that were evaluated using a structured diagnostic interview and then randomly allocated to the SEDP group. We examined baseline and post-intervention serum levels of the Interleukin-6 (IL-6) and the Tumor Necrosis Factor (TNF-α) in addition to the severity of depressive symptoms according to the Outcome Questionnaire - 45.2 (OQ-45.2) and the Beck Depression Inventory (BDI). Results show that serum IL-6 and TNF-α levels, as well as the scores from the OQ-45.2 and the BDI significantly decreased after 16 sessions of SEDP (p < 0.001), except for the Interpersonal Relationship domain from the OQ-45. Despite the reduction of serum cytokines levels and OQ-45 and BDI scores, they were only significantly correlated regarding the social role domain from the OQ-45. Nonetheless, our data suggests an effective role of brief psychodynamic psychotherapy in the reduction of depressive symptoms and serum inflammatory levels that are associated with depression.     

Transcranial direct current stimulation (tDCS) for depression in pregnancy: A pilot randomized controlled trial

BackgroundDepression in pregnancy negatively affects maternal-child health. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation treatment for depression, has not been evaluated in pregnancy.ObjectiveTo conduct a pilot randomized controlled trial (RCT) to evaluate tDCS for antenatal depression.MethodsIn this pilot RCT in Toronto, Ontario (October 2014 to December 2016), adult pregnant women 14–32 weeks gestation with major depressive disorder who had declined antidepressant medication were considered for inclusion. Participants were randomly assigned 1:1 to tDCS or sham-control. Active tDCS comprised 30-min sessions of 2 mAmp direct current delivered over the dorsolateral prefrontal cortex, 5 days per week, for 3 weeks. Sham was administered similarly, but with current turned off after 30 s. Main outcomes were feasibility, acceptability, and protocol adherence. Maternal Montgomery Asperg Depression Rating Scale (MADRS) was measured post-treatment and at 4 and 12 weeks postpartum.ResultsOf 20 women randomized, 16 completed treatment and provided data (124 tDCS, 122 sham sessions). Views of treatment were positive with no serious adverse events. Post-treatment estimated marginal mean MADRS scores were 11.8 (standard error, SE 2.66) for tDCS and 15.4 (SE 2.51) for sham (p = 0.34). At 4 weeks postpartum, 75.0% of tDCS women were remitted versus 12.5% sham-control (p = 0.04).ConclusionsResults support proceeding to a definitive RCT to evaluate tDCS for antenatal depression. The preliminary efficacy estimates immediately post-treatment and in the postpartum, are encouraging with respect to the potential use of tDCS to improve treatment rates in this population. The trial was registered at: clinical trials.gov (NCT02116127).     

Effects of transcranial Direct Current Stimulation (tDCS) on cortical activity: A computational modeling study

Although it is well-admitted that transcranial Direct Current Stimulation (tDCS) allows for interacting with brain endogenous rhythms, the exact mechanisms by which externally-applied fields modulate the activity of neurons remain elusive. In this study a novel computational model (a neural mass model including subpopulations of pyramidal cells and inhibitory interneurons mediating synaptic currents with either slow or fast kinetics) of the cerebral cortex was elaborated to investigate the local effects of tDCS on neuronal populations based on an in-vivo experimental study. Model parameters were adjusted to reproduce evoked potentials (EPs) recorded from the somatosensory cortex of the rabbit in response to air-puffs applied on the whiskers. EPs were simulated under control condition (no tDCS) as well as under anodal and cathodal tDCS fields. Results first revealed that a feed-forward inhibition mechanism must be included in the model for accurate simulation of actual EPs (peaks and latencies). Interestingly, results revealed that externally-applied fields are also likely to affect interneurons. Indeed, when interneurons get polarized then the characteristics of simulated EPs become closer to those of real EPs. In particular, under anodal tDCS condition, more realistic EPs could be obtained when pyramidal cells were depolarized and, simultaneously, slow (resp. fast) interneurons became de- (resp. hyper-) polarized. Geometrical characteristics of interneurons might provide some explanations for this effect.     

One extra month of depression: the effects of caregiving on depression outcomes in the IMPACT trial

BACKGROUND: Depression occurs in 5-10% of older adults and there are nearly 6 million informal caregivers aged 65 or older. Prior research has focused on vulnerability to psychological distress in caregivers. Research has not addressed the caregiving burden of depressed elderly patients or how that burden affects depression treatment outcomes. AIMS: To describe the self-reported caregiving burden in a large, representative cohort of depressed elderly patients and compare depression treatment outcomes between caregivers and non-caregivers. METHODS: Univariate and multiple regression analyses were performed comparing 24-month depression outcomes (measured as depression free days) in those providing care at any time over the 24-month trial to those who never reported a caregiving burden. RESULTS: At 3, 6, 12, 18, and 24 months, nearly 10% of cohabitating elderly depressed patients provided care for basic activities such as bathing or dressing while nearly 20% reported providing care for other activities such as making phone calls or taking medication. Over 24 months, after adjusting for marital status, intervention status, and number of medical comorbidities, those reporting any caregiving burden had over 30 more days with depression compared to those with no caregiving burden. The IMPACT collaborative care model did not modify the effect of caregiving on depression outcomes. CONCLUSION: Caregiving is common in depressed older adults and appears to affect response to depression treatment. In the future, interventions for depressed older adults should consider and specifically address caregiving activities in addition to specific depression treatment.     

Association between hemodynamics,morphology, and rupture risk of intracranial aneurysms: a computational fluid modeling study

The objective of the study was to examine the correlations between intracranial aneurysm morphology and wall shear stress (WSS) to identify reliable predictors of rupture risk. Seventy-two intracranial aneurysms (41 ruptured and 31 unruptured) from 63 patients were studied retrospectively. All aneurysms were divided into two categories: narrow (aspect ratio ≥1.4) and wide-necked (aspect ratio <1.4 or neck width ≥4 mm). Computational fluid dynamics was used to determine the distribution of WSS, which was analyzed between different morphological groups and between ruptured and unruptured aneurysms. Sections of the walls of clipped aneurysms were stained with hematoxylin–eosin, observed under a microscope, and photographed. Ruptured aneurysms were statistically more likely to have a greater low WSS area ratio (LSAR) (P = 0.001) and higher aneurysms parent WSS ratio (P = 0.026) than unruptured aneurysms. Narrow-necked aneurysms were statistically more likely to have a larger LSAR (P < 0.001) and lower values of MWSS (P < 0.001), mean aneurysm-parent WSS ratio (P < 0.001), HWSS (P = 0.012), and the highest aneurysm-parent WSS ratio (P < 0.001) than wide-necked aneurysms. The aneurysm wall showed two different pathological changes associated with high or low WSS in wide-necked aneurysms. Aneurysm morphology could affect the distribution and magnitude of WSS on the basis of differences in blood flow. Both high and low WSS could contribute to focal wall damage and rupture through different mechanisms associated with each morphological type.     

No association between anxiety and depression and adverse clinical outcome among patients with cardiovascular disease: findings from the DANREHAB trial

Objective

Anxiety and depression have been linked to adverse prognostic outcome in patients with cardiovascular disease (CVD) with mixed results. The timing of anxiety and depression measurement has received little attention so far.

Methods

The study sample consisted of 536 patients admitted to hospital for CVD and followed in a rehabilitation trial. Symptoms were assessed using the Hospital Anxiety and Depression Scale at baseline and after 1 year. Cox proportional hazards model was used to describe the association between anxiety and depression and adverse outcome (myocardial infarction (MI), heart failure (HF), stroke, death and a combined endpoint) after 5 years.

Results

Prevalence of anxiety and depression at baseline was 32% and 13%, respectively. There were 303 combined events; 140 deaths, 60 patients had MI, 177 patients were admitted to hospital with HF and 60 patients had a stroke. Neither anxiety nor depression at any time was associated with mortality or the combined endpoint. Anxiety in IHD patients at baseline and at 1 year was associated with increased risk of MI (HR 2.74; 95% CI: 1.10–6.83) but was attenuated after adjusting for other risk factors (HR 1.18; 95% CI: 0.39–3.55). Both anxiety and depression at 1 year were associated with increased risk of stroke: HR 2.25 (95% CI: 1.05–4.82) and 2.34 (95% CI: 0.99–5.50), respectively, but risk associated with anxiety was attenuated after adjustment. There were no gender differences.

Conclusions

Contrary to conclusions from recent meta-analyses, anxiety and depression measured at baseline and after 1 year were not associated with adverse outcome in CVD patients after multivariable adjustment.     

Association between psychotic experiences and depression in a clinical sample over 6 months

Psychotic-like experiences (PLEs) are used to identify individuals considered to be at Ultra High Risk (UHR) of, or prodromal for, psychotic disorder. They are also common in the general population and in clinical samples of non-psychotic individuals. Depression has been found to be an important factor in mediating outcome in those with PLEs in both community and UHR populations. It is associated with increased risk of transition to psychotic disorder in the UHR group, and with need for care in relation to PLEs in community samples. In this study we aimed to examine the 6-month outcome of PLEs in a sample of help-seeking young people aged 15 to 24 years in relation to their level of depression. Subjects (n=140) were assessed at baseline and 6 months for PLEs and depression. PLEs were measured by the Community Assessment of Psychic Experiences (CAPE). Depression was assessed as a continuous measure using the Mood and Anxiety Symptom Questionnaire (MASQ) and categorically according to DSM-IV diagnosis of mood disorder. PLEs reduced in conjunction with an improvement in depression level and with remission of diagnosis of mood disorder. It is important to assess depression in those with PLEs and consider the need for treatment of the comorbid depressive syndrome. This may reduce the risk of worsening of PLEs and transition to psychotic disorder.     

Association between obesity and depression: evidence from a longitudinal sample of the elderly in Taiwan

Objectives: Obesity has been identified as an epidemic worldwide. In Taiwan, the highest prevalence of obesity is observed in adults age ≥65. This article investigates the effects of body weight status on the likelihood of depression among the elderly in Taiwan.

Method: A longitudinal sample of the elderly (1351 males and 1165 females) interviewed in both the 1999 and 2003 Surveys of Health and Living Status of the Elderly in Taiwan is used. A random effect logit model is estimated to examine the effects of body weight status, lifestyle, and socio-demographic characteristics on the likelihood of depression.

Results: About 10.4% of the elderly men are overweight and 13.4% are obese in 2003. A higher prevalence of obesity is found among elderly women, with 19.3% being overweight and 26.4% obese. Elderly men who are underweight are more likely to be depressed (odds ratio; OR?=?2.36) than those from other weight categories, while overweight and obese women are less likely to be depressed (ORs?=?0.72 and 0.61) than elderly women of the normal weight category.

Conclusions: In contrast to most findings for the Western countries, a negative association between obesity and depression of the elderly is evident in Taiwan. The different findings between Western and Asian countries may be due to the cultural differences. Unlike the Western countries that stigmata are attached to excessive overweight, being overweight is not a symbol of unhealthiness because only the wealthy can afford to eat more and put on more weight in the Chinese society.