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.

Autonomic arousal elicited by subcallosal cingulate stimulation is explained by white matter connectivity.

BACKGROUND: Subcallosal cingulate deep brain stimulation (SCC DBS) is an experimental treatment for severe depression. Surgery is performed with awake patients and intraoperative stimulation produces acute behavioral responses in select contacts. While there have been reports on the relationship between acute intraoperative behaviors and their relation to the location of the contacts, there are no descriptions of the physiological changes that accompany them. OBJECTIVE: The present study sought to examine these physiological readouts, and their association with the anatomical substrates that generated them. METHODS: Nine patients with severe, treatment-resistant depression were tested intraoperatively. The stimulation protocol consisted of 12 three-minute, sham-controlled, double-blind trials. Changes in heart rate and skin conductance were recorded during each stimulation cycle. Probabilistic tractography between the stimulated contacts and predefined regions of the mood regulation network was performed. RESULTS: Acute intraoperative SCC stimulation produced increases in autonomic sympathetic response that correlated with the salience of the behavioral responses. The autonomic changes were observed within seconds of initiating acute stimulation and prior to verbalization of subjective experiences. The probabilistic tractography analysis suggested that structural connectivity between the stimulated area and the midcingulate cortex is the primary pathway that mediates autonomic responsivity to SCC DBS. CONCLUSIONS: These findings demonstrate that acute SCC stimulation produces autonomic and behavioral changes in the operating room that are explained by the modulation of networks associated with long term antidepressant response. Intraoperative autonomic recordings paired with careful behavioral observations and precise anatomical mapping aid in the identification and classification of the intraoperative phenomena.

Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin (IL)-6 predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment-resistant depression and to what extent this association differed between men and women. METHODS: In patients (N = 29) who had a current major depressive episode diagnosed using DSM-IV-TR criteria and were scheduled to undergo ECT at an academic referral center, levels of CRP, IL-6, IL-8, and tumor necrosis factor-α and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS]) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between December 2011 and December 2014. The primary outcome was end-of-treatment MADRS score. RESULTS: In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (P = .01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (P = .02) but not men (P = .1), and CRP emerged as a significant predictor for women (P = .04) but not men (P = .66). CRP and IL-6 increased from baseline to the second ECT session (P values < .01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. CONCLUSIONS: Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pretreatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment-resistant depression.

A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography 'connectome blueprint' to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Episodic memory following deep brain stimulation of the ventral anterior limb of the internal capsule and electroconvulsive therapy.

BACKGROUND: Electroconvulsive Therapy (ECT) and Deep Brain Stimulation (DBS) are effective treatments for patients with treatment-resistant depression (TRD). However, a common side effect of ECT is autobiographical memory loss (e.g., personal experiences), whereas the impact of DBS on autobiographical memories has never been established. OBJECTIVE: Comparing autobiographical memories following DBS and ECT. METHODS: In two hospitals in The Netherlands, we interviewed 25 TRD patients treated with DBS of the ventral anterior limb of the internal capsule (vALIC), 14 TRD patients treated with ECT and 22 healthy controls (HC) with the Autobiographical Memory Inventory - Short Form (AMI-SF) in a prospective, longitudinal study between March 2010 and August 2016. Patients treated with DBS were interviewed before surgery, after surgery, and twice during treatment over 122.7 (SD: ±22.2) weeks. Patients treated with ECT were tested before ECT, after six right unilateral (RUL) ECT sessions and twice following ECT over 65.1 (±9.3) weeks. Controls were tested four times over 81.5 (±15.6) weeks. RESULTS: Compared to HC, the AMI-SF score decreased faster in both TRD groups (P < 0.001). More specifically, AMI-SF score decreased in a comparable rate as HC after DBS surgery, but decreased more during treatment. The AMI-SF decrease in the ECT group was larger than both the DBS and HC groups. CONCLUSIONS: Both ECT and vALIC DBS result in a faster autobiographical memory decline compared to HC. DBS might have a negative impact on autobiographical memories, although less so than ECT. Future work should dissect whether DBS or characteristics of TRD cause this decline.

Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression.

BACKGROUND: The purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD). METHOD: This was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery-Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery. RESULTS: Patients improved on the clinical measure of depression after surgery by -21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred. CONCLUSIONS: With the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate.

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman's meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.

Effect of recombinant erythropoietin on inflammatory markers in patients with affective disorders: A randomised controlled study.

AIM: This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory. METHODS: In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (sub-study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS)⩽14) (sub-study 2). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were measured at week 1 (baseline) and weeks 5, 9 and 14. HDRS-17 and neuropsychological function was assessed at weeks 1, 9 and 14 using a test battery including the RAVLT Auditory Verbal Learning Test (primary depression and primary cognition outcomes in the original trial). RESULTS: EPO had no cumulative effect on plasma levels of IL-6 or IL-18 but increased hsCRP levels in patients with TRD (mean±SD change in ng/L: EPO: 0.43±1.64; Saline: -0.90±2.43; F(1,39)=4.78, p=0.04). EPO had no effects on inflammatory markers in BD. There was no correlation between change in inflammatory markers and change in verbal memory. CONCLUSIONS: Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory pathway is not a putative mechanism of the EPO-associated improvement of cognition in affective disorders.

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.

IMPORTANCE: Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. OBJECTIVE: To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS: Deep brain stimulation targeted to the vALIC. MAIN OUTCOMES AND MEASURES: The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS: Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). CONCLUSIONS AND RELEVANCE: Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2118.

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission?

Although accelerated repetitive Transcranial Magnetic Stimulation (rTMS) paradigms and intermittent Theta-burst Stimulation (iTBS) may have the potency to result in superior clinical outcomes in Treatment Resistant Depression (TRD), accelerated iTBS treatment has not yet been studied. In this registered randomized double-blind sham-controlled crossover study, spread over four successive days, 50 TRD patients received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). The accelerated iTBS treatment procedure was found to be safe and resulted in immediate statistically significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham). While only 28% of the patients showed a 50% reduction of their initial Hamilton Depression Rating Scale score at the end of the two-week procedure, this response rate increased to 38% when assessed two weeks after the end of the sham-controlled iTBS protocol, indicating delayed clinical effects. Importantly, 30% of the responders were considered in clinical remission. We found no demographic predictors for response. Our findings indicate that only four days of accelerated iTBS treatment applied to the left DLPFC in TRD may lead to meaningful clinical responses within two weeks post stimulation.

Deep brain stimulation of the posterior gyrus rectus region for treatment resistant depression.

BACKGROUND: Deep brain stimulation (DBS) represents an alternative symptomatic treatment for major depressive disorder in case of failure of pharmacotherapy. The sub-genual cingulate-Brodmann area 25 (CG-25), is one of the most widely used targets for electrode implantation. Given the diverging clinical outcome after DBS, there is a pressing need for in-depth study of brain anatomy and function allowing accurate and reliable prognosis before surgery. METHODS: We studied five treatment-resistant major depressive disorder patients planned to undergo DBS targeting the CG-25. Before surgery, we acquired high-resolution magnetic resonance (MR) diffusion-weighted images for each patient followed by post-surgery MRI for electrode localization. To estimate individual anatomical connectivity pattern of the active contact location we performed probabilistic diffusion tractography intra-individually. We then correlated connectivity patterns with outcome assessed with standardized clinical tests. Connectivity results were compared between DBS responders and non-responders. RESULTS: We observed in one patient an excellent clinical response after DBS of the bilateral posterior gyrus rectus rather than the initially targeted CG-25. The remaining four patients with DBS of the CG-25 were considered as non-responders. In the case patient, we demonstrate a strong connectivity of the stimulated regions to the medial prefrontal cortex (mPFC), which contrasted to the lower mPFC connectivity in non-responders. LIMITATIONS: Confirmation in larger cohorts is needed. CONCLUSIONS: We propose the posterior gyrus rectus as viable alternative new target for DBS in major depressive disorder. High connectivity between target and mPFC supports the pivotal role of this region in brain networks involved in mood processing.

Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation.

IMPORTANCE: The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown. OBJECTIVE: To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression. DESIGN, SETTING, AND PARTICIPANTS: Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015. MAIN OUTCOMES AND MEASURES: Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes. RESULTS: Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch." CONCLUSIONS AND RELEVANCE: This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

Determinants of brain SPECT perfusion and connectivity in treatment-resistant depression.

This study aims to characterize and compare functional brain single photon emission tomography (SPECT) perfusion and connectivity in treatment-resistant depression (TRD) according to distinct demographic or clinical profiles (male vs. female; old vs. young; unipolar vs. bipolar) and to study their relationship to the severity and the duration of episode/illness. We retrospectively included 127 consecutive patients who met DSM-IV criteria for a nonpsychotic major TRD episode. All patients were studied using (99m)Tc-ethyl cysteinate dimer SPECT. Whole-brain, voxel-based, between-groups analyses were performed according to demographic and clinical data and in comparison to 37 healthy subjects. Voxel-wise interregional correlation was also performed to compare functional SPECT connectivity. Finally, relationships were searched for regarding severity and duration of episode/illness. The whole group of patients exhibited significant hypoperfusion within bilateral fronto-temporal, insular, and anterior cingulate cortices, as well as within the left caudate. Functional connectivity between left frontal and left cerebellar regions was higher in patients than in healthy subjects. Gender, age, and type of mood disorder did not influence these SPECT patterns. A significant relationship was found between brain SPECT perfusion and either duration or global severity of illness in particular frontal areas. Our data support the hypothesis of a shared SPECT pattern, whatever the profile of TRD, involving fronto-temporal regions and the cerebellum.

Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: an exploratory study.

Deep brain stimulation (DBS) is being investigated as a therapeutic alternative for patients with treatment-resistant depression (TRD), but its cognitive safety has been scarcely explored. The aim of this exploratory study is to evaluate cognitive function of patients before and after deep brain stimulation of the subgenual cingulate gyrus (SCG). Eight treatment-resistant depressed patients were implanted in subgenual cingulate gyrus. A neuropsychological battery was used to evaluate patients before surgery and 1-year after. A matched group of eight first-episode patients was also assessed. A MANOVA was performed for each cognitive domain and those tests showing main time effects were then correlated with depressive symptoms and with medication load. There were significant group and time effects for memory and a group effect for language. No significant interactions between groups or cognitive domains were observed. Medication load was negatively correlated with memory at time 1, and clinical change negatively correlated with memory improvement. These findings support the cognitive safety of DBS of subgenual cingulate gyrus, as cognitive function did not worsen after chronic stimulation and memory performance even improved. The results, though, should be interpreted cautiously given the small sample size and the fact that some treatment-resistant patients received electroconvulsive therapy (ECT) before implantation.

Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP⩽5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation.

Stem cell therapy: a new approach to the treatment of refractory depression.

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.

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.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression.

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-µs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.