Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

The effectiveness of mindfulness-based cognitive therapy for reducing rumination and improving mindfulness and self-compassion in patients with treatment-resistant depression.

Introduction Depression is one of the most important psychiatric disorders, and the rate of recurrence is high. The heavy cost burden of depression is probably due to treatment-resistant depression. The purpose of this study was to determine the effectiveness of mindfulness-based cognitive therapy (MBCT) in patients with treatment-resistant depression (TRD). Method The present study was a quasi-experimental study conducted with twenty-four patients with treatment-resistant depression. Participants were selected by purposive sampling and randomly assigned to two groups, an experimental group and a control group. The experimental group received MBCT and antidepressants, while the control group received antidepressants only. The Hamilton and Beck Depression Inventory, Self-Compassion Scale, Thought Rumination Scale, and Mindfulness Scale were administered. The treatment program was conducted in eight sessions; with a follow-up period of one month subsequent to treatment termination. Data were analyzed using descriptive statistics (mean and standard deviation) and inferential statistics (analysis of variance for repeated measures and Bonferroni's post-hoc test). Results The results showed that MBCT significantly reduced depression and ruminative thinking in the experimental group and also improved mediators such as mindfulness and self-compassion. Patients maintained gains over the one month follow-up period (p < 0.01). Conclusion The present study provides additional evidence for the effectiveness of MBCT for TRD.

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca.

BACKGROUND: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45). AIMS: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. RESULTS: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. CONCLUSIONS: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

The effectiveness of mindfulness-based cognitive therapy for reducing rumination and improving mindfulness and self-compassion in patients with treatment-resistant depression

Abstract Introduction Depression is one of the most important psychiatric disorders, and the rate of recurrence is high. The heavy cost burden of depression is probably due to treatment-resistant depression. The purpose of this study was to determine the effectiveness of mindfulness-based cognitive therapy (MBCT) in patients with treatment-resistant depression (TRD). Method The present study was a quasi-experimental study conducted with twenty-four patients with treatment-resistant depression. Participants were selected by purposive sampling and randomly assigned to two groups, an experimental group and a control group. The experimental group received MBCT and antidepressants, while the control group received antidepressants only. The Hamilton and Beck Depression Inventory, Self-Compassion Scale, Thought Rumination Scale, and Mindfulness Scale were administered. The treatment program was conducted in eight sessions; with a follow-up period of one month subsequent to treatment termination. Data were analyzed using descriptive statistics (mean and standard deviation) and inferential statistics (analysis of variance for repeated measures and Bonferroni's post-hoc test). Results The results showed that MBCT significantly reduced depression and ruminative thinking in the experimental group and also improved mediators such as mindfulness and self-compassion. Patients maintained gains over the one month follow-up period (p < 0.01). Conclusion The present study provides additional evidence for the effectiveness of MBCT for TRD.

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans.

BACKGROUND: The breakthrough discovery has been made that a single dose of ketamine, an N-methyl-D-aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated. OBJECTIVES: This study protocol was designed to test the main hypothesis that ketamine could rapidly reverse depression- and stress-associated synaptic loss and deficits in resting-state functional connectivity and that this action could be affected by circadian rhythm, in patients with treatment-resistant depression. METHODS/STUDY DESIGN: In this clinical study, adults (aged 18-65 years) with treatment-resistant depression will be randomized to intravenous administration of placebo (control group) or ketamine (0.5 mg/kg body weight) at 11 a.m. (daytime group), or 6 p.m. (nighttime group) for 24 weeks. The primary outcome will be the change from baseline to 24 weeks in the total Montgomery-Asberg Depression Rating Scale score. Brain imaging, sleep, and genetic studies, including functional magnetic resonance imaging, positron emission tomography, polysomnography, and genetic analyses, will be performed to examine whether and how ketamine can rapidly reverse deficits in synaptic function and to identify objective markers for the assessment of ketamine infusion therapy for treatment-resistant depression. CONCLUSIONS: This clinical study protocol is the first, to our knowledge, to describe the prospective testing of the hypothesis that daytime and nighttime administrations of ketamine would have different antidepressant effects. The brain imaging, sleep, and genetic findings from patients with treatment-resistant depression are expected to shed new light on the mechanisms of ketamine and its interaction with target sites in the brain, which can be used for objective evaluation of the efficacy of ketamine.

Updates on Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder.

Transcranial magnetic stimulation has emerged as a treatment option for treatment-resistant depression. While existing data largely support efficacy of transcranial magnetic stimulation for major depressive disorder, ongoing research aims to optimize treatment parameters and identify biomarkers of treatment response. In this article, the authors describe data from controlled trials and ongoing efforts to enhance transcranial magnetic stimulation outcomes for major depressive disorder. Findings from preliminary research aimed at identifying neuroimaging and neurophysiological biomarkers of transcranial magnetic stimulation effects are discussed.

Adjunctive low-dose docosahexaenoic acid (DHA) for major depression: An open-label pilot trial.

OVERVIEW: Whilst the majority of evidence supports the adjunctive use of eicosapentaenoic acid (EPA) in improving mood, to date no study exists using low-dose docosahexaenoic acid (DHA) alone as an adjunctive treatment in patients with mild to moderate major depressive disorder (MDD). METHODS: A naturalistic 8-week open-label pilot trial of low-dose DHA, (260 mg or 520 mg/day) in 28 patients with MDD who were non-responsive to medication or psychotherapy, with a Hamilton Depression Rating Scale (HAM-D) score of greater than 17, was conducted. Primary outcomes of depression, clinical severity, and daytime sleepiness were measured. RESULTS: After 8 weeks, 54% of patients had a ≥50% reduction on the HAM-D, and 45% were in remission (HAM-D ≤ 7). The eta-squared statistic (0.59) indicated a large effect size for the reduction of depression (equivalent to Cohen's d of 2.4). However confidence in this effect size is tempered due to the lack of a placebo. The mean score for the Clinical Global Impression Severity Scale was significantly improved by 1.28 points (P < 0.05). Despite a significant reduction in the HAM-D score for middle insomnia (P = 0.02), the reduction in excessive daytime somnolence on the total Epworth Sleepiness Scale (ESS) did not reach significance. No significant adverse reactions to DHA were found. CONCLUSION: Within the major limits of this open-label pilot study, the results suggest that DHA may provide additional adjunctive benefits in patients with mild- to -moderate depression.

Blunted amygdala activity is associated with depression severity in treatment-resistant depression.

Up to 50% of individuals with major depressive disorder (MDD) do not recover after two antidepressant medication trials, and therefore meet the criteria for treatment-resistant depression (TRD). Mindfulness-based cognitive therapy (MBCT) is one promising treatment; however, the extent to which MBCT influences clinical outcomes relative to baseline neural activation remains unknown. In the present study we investigated baseline differences in amygdala activation between TRD patients and healthy controls (HCs), related amygdala activation to depression symptoms, and examined the impacts of MBCT and amygdala activation on longitudinal depression outcomes. At baseline, TRD patients (n = 80) and HCs (n = 37) participated in a functional magnetic resonance imaging task in which they identified either the emotion (affect labeling) or the gender (gender labeling) of faces, or passively viewed faces (observing). The TRD participants then completed eight weeks of MBCT or a health enhancement program (HEP). Relative to HCs, the TRD patients demonstrated less amygdala activation during affect labeling, and marginally less during gender labeling. Blunted amygdala activation in TRD patients during affect labeling was associated with greater depression severity. MBCT was associated with greater depression reductions than was HEP directly following treatment; however, at 52 weeks the treatment effect was not significant, and baseline amygdala activation across the task conditions predicted depression severity in both groups. TRD patients have blunted amygdala responses during affect labeling that are associated with greater concurrent depression. Furthermore, although MBCT produced greater short-term improvements in depression than did HEP, overall baseline amygdala reactivity was predictive of long-term clinical outcomes in both groups.

Association of thalamic hyperactivity with treatment-resistant depression and poor response in early treatment for major depression: a resting-state fMRI study using fractional amplitude of low-frequency fluctuations.

Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low-frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD.

Target-based biomarker selection - Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression.

Aldosterone and mineralocorticoid receptor (MR)-function have been related to depression. We examined central and peripheral parameters of MR-function in order to characterize their relationship to clinical treatment outcome after six weeks in patients with acute depression. 30 patients with a diagnosis of major depression were examined 3 times over a 6 week period. Aldosterone and cortisol salvia samples were taken at 7.00 a.m. before patients got out of bed. Easy to use e-devices were used to measure markers of central MR function, i.e. slow wave sleep (SWS) and heart-rate variability (HRV). Salt-taste intensity (STI) and salt pleasantness (SP) of a 0.9% salt solution were determined by a newly developed scale. In addition, systolic blood pressure (SBP) and plasma electrolytes were determined as markers for peripheral MR activity. The relationship between the levels of these biomarkers at baseline and the change in clinical outcome parameters (Hamilton depression rating scale (HDRS)-21, anxiety, QIDS and BDI) after 6 weeks of treatment was investigated. A higher aldosterone/cortisol ratio (Aldo/Cort) (n = 17 due to missing values; p < 0.05) and lower SBP (n = 24; p < 0.05) at baseline predicted poor outcome, as measured with the HDRS, independent of gender. Only in male patients higher STI, lower SP, lower SWS (all n = 13) and higher HRV (n = 11) at baseline predicted good outcome p < 0.05). Likewise, in male patients low baseline sodium appears to be predictive for a poor outcome (n = 12; p = 0.05; based on HDRS-6). In conclusion, correlates of higher central MR-activation are associated with poorer clinical improvement, particularly in men. This contrasts with the finding of a peripheral MR-desensitization in more refractory patients. As one potential mechanism to consider, sodium loss on the basis of dysfunctional peripheral MR function and additional environmental factors may trigger increased aldosterone secretion and consequently worse outcome. These markers deserve further study as potential biological correlates for therapy refractory depression.

Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Folates and S-adenosylmethionine for major depressive disorder.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.