Showing papers on "Treatment-resistant depression published in 2017"

The History and Future of Ablative Neurosurgery for Major Depressive Disorder

Abstract: Background: There is an urgent need to develop safe and effective treatments for patients with treatment-resistant depression (TRD). Several neurosurgical procedu

Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial

Abstract: Importance Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Results Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84 mg: −9.0 [2.13], P P Conclusions and Relevance In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration clinicaltrials.gov identifier:NCT01998958

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

Abstract: Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression:

Abstract: Objective: To identify patients’ perceptions of the value of psilocybin as a treatment for depression. Method: Twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. Thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. Results: Two main change processes were identified in relation to the treatment. The first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. A third theme concerned comparison between psilocybin and conventional treatments. Patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. Conclusions: These results suggest that psilocybin treatment for depression may wor...

A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality

Abstract: Objective:The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only.Method:This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years’ duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Asberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission.Results:Patients had chronic moderate to severe depression at b...

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy:

Abstract: Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30-50%. Historically, the monoamine depletion hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants. Stimuli like inflammation and infection can trigger the activation of microglia to release pro-inflammatory cytokines, acting on two main pathways: (1) activation of the hypothalamic-pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits; (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels and the production of quinolinic acid. If this hypothesis is proven true, the subgroup of MDD patients with increased levels of pro-inflammatory cytokines, mainly IL-6, TNF-α and IL-1β, might benefit from an anti-inflammatory intervention. Here, we discuss the pre-clinical and clinical studies that have provided support for treatment with non-steroidal anti-inflammatory drugs in depressed patients with inflammatory comorbidities or an elevated immune profile, as well as evidences for anti-inflammatory properties of standard antidepressants.

Association of Microvascular Dysfunction With Late-Life Depression: A Systematic Review and Meta-analysis

Abstract: Importance The etiologic factors of late-life depression are still poorly understood Recent evidence suggests that microvascular dysfunction is associated with depression, which may have implications for prevention and treatment However, this association has not been systematically reviewed Objective To examine the associations of peripheral and cerebral microvascular dysfunction with late-life depression Data Sources A systematic literature search was conducted in MEDLINE and EMBASE for and longitudinal studies published since inception to October 16, 2016, that assessed the associations between microvascular dysfunction and depression Study Selection Three independent researchers performed the study selection based on consensus Inclusion criteria were a study population 40 years of age or older, a validated method of detecting depression, and validated measures of microvascular function Data Extraction and Synthesis This systematic review and meta-analysis has been registered at PROSPERO (CRD42016049158) and is reported in accordance with the PRISMA and MOOSE guidelines Data extraction was performed by an independent researcher Main Outcomes and Measures The following 5 estimates of microvascular dysfunction were considered in participants with or without depression: plasma markers of endothelial function, albuminuria, measurements of skin and muscle microcirculation, retinal arteriolar and venular diameter, and markers for cerebral small vessel disease Data are reported as pooled odds ratios (ORs) by use of the generic inverse variance method with the use of random-effects models Results A total of 712 studies were identified; 48 were included in the meta-analysis, of which 8 described longitudinal data Data from 43 600 participants, 9203 individuals with depression, and 72 441 person-years (mean follow-up, 37 years) were available Higher levels of plasma endothelial biomarkers (soluble intercellular adhesion molecule–1: OR, 158; 95% CI, 128-196), white matter hyperintensities (OR, 129; 95% CI, 119-139), cerebral microbleeds (OR, 118; 95% CI, 103-134), and cerebral (micro)infarctions (OR, 130; 95% CI, 121-139) were associated with depression Among the studies available, no significant associations of albuminuria and retinal vessel diameters with depression were reported Longitudinal data showed a significant association of white matter hyperintensities with incident depression (OR, 119; 95% CI, 109-130) Conclusions and Relevance This meta-analysis shows that both the peripheral and cerebral forms of microvascular dysfunction are associated with higher odds of (incident) late-life depression This finding may have clinical implications because microvascular dysfunction might provide a potential target for the prevention and treatment of depression

Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome

Abstract: A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.

Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression

Abstract: Introduction: Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine's antidepressant effects. Methods: Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol. Results: Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT. Conclusions: CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine's antidepressant effects.

Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation:

Abstract: Objective:Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies ar...

Refining Prediction in Treatment-Resistant Depression: Results of Machine Learning Analyses in the TRD III Sample

Abstract: Objective The study objective was to generate a prediction model for treatment-resistant depression (TRD) using machine learning featuring a large set of 47 clinical and sociodemographic predictors of treatment outcome. Method 552 Patients diagnosed with major depressive disorder (MDD) according to DSM-IV criteria were enrolled between 2011 and 2016. TRD was defined as failure to reach response to antidepressant treatment, characterized by a Montgomery-Asberg Depression Rating Scale (MADRS) score below 22 after at least 2 antidepressant trials of adequate length and dosage were administered. RandomForest (RF) was used for predicting treatment outcome phenotypes in a 10-fold cross-validation. Results The full model with 47 predictors yielded an accuracy of 75.0%. When the number of predictors was reduced to 15, accuracies between 67.6% and 71.0% were attained for different test sets. The most informative predictors of treatment outcome were baseline MADRS score for the current episode; impairment of family, social, and work life; the timespan between first and last depressive episode; severity; suicidal risk; age; body mass index; and the number of lifetime depressive episodes as well as lifetime duration of hospitalization. Conclusions With the application of the machine learning algorithm RF, an efficient prediction model with an accuracy of 75.0% for forecasting treatment outcome could be generated, thus surpassing the predictive capabilities of clinical evaluation. We also supply a simplified algorithm of 15 easily collected clinical and sociodemographic predictors that can be obtained within approximately 10 minutes, which reached an accuracy of 70.6%. Thus, we are confident that our model will be validated within other samples to advance an accurate prediction model fit for clinical usage in TRD.

A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression.

Abstract: Background Deep brain stimulation (DBS) has been applied in treatment-resistant depression (TRD) as a putative intervention targeting different brain regions. However, the antidepressant effects of DBS for TRD in recent clinical trials remain controversial. Methods We searched Scopus, EMBASE, the Cochrane Library, PubMed, and PsycINFO for all published studies investigating the efficacy of DBS in TRD up to Feb 2017. Hamilton depression rating scale (HDRS) scores and Montgomery–Asberg depression rating scale (MARDS) scores were compared between baseline levels and those after DBS using the standardized mean difference (SMD) with 95% confidence intervals (CIs). The pooled response and remission rates were described using Risk Difference with 95% CIs. Results We identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB), and nucleus accumbens (NAcc). The overall effect sizes showed a significant reduction in HDRS after DBS stimulation in these four regions, with a standardized mean difference of − 3.02 (95% CI = − 4.28 to − 1.77, p Conclusions DBS significantly alleviates depressive symptoms in TRD patients by targeting the SCG, VC/VS, MFB, and NAcc. Several adverse events might occur during DBS therapy, although it is uncertain whether some AEs can be linked to DBS treatment. Further confirmatory trials are required involving larger sample sizes.

Investigational drugs in recent clinical trials for treatment-resistant depression.

Abstract: Introduction: The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future.Areas covered: Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV-101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to ...

A New Prediction Model for Evaluating Treatment-Resistant Depression

Abstract: OBJECTIVE Despite a broad arsenal of antidepressants, about a third of patients suffering from major depressive disorder (MDD) do not respond sufficiently to adequate treatment. Using the data pool of the Group for the Study of Resistant Depression and machine learning, we intended to draw new insights featuring 48 clinical, sociodemographic, and psychosocial predictors for treatment outcome. METHOD Patients were enrolled starting from January 2000 and diagnosed according to DSM-IV. Treatment-resistant depression (TRD) was defined by a 17-item Hamilton Depression Rating Scale (HDRS) score ≥ 17 after at least 2 antidepressant trials of adequate dosage and length. Remission was defined by an HDRS score < 8. Stepwise predictor reduction using randomForest was performed to find the optimal number for classification of treatment outcome. After importance values were generated, prediction for remission and resistance was performed in a training sample of 400 patients. For prediction, we used a set of 80 patients not featured in the training sample and computed receiver operating characteristics. RESULTS The most useful predictors for treatment outcome were the timespan between first and last depressive episode, age at first antidepressant treatment, response to first antidepressant treatment, severity, suicidality, melancholia, number of lifetime depressive episodes, patients' admittance type, education, occupation, and comorbid diabetes, panic, and thyroid disorder. While single predictors could not reach a prediction accuracy much different from random guessing, by combining all predictors, we could detect resistance with an accuracy of 0.737 and remission with an accuracy of 0.850. Consequently, 65.5% of predictions for TRD and 77.7% for remission can be expected to be accurate. CONCLUSIONS Using machine learning algorithms, we could demonstrate success rates of 0.737 for predicting TRD and 0.850 for predicting remission, surpassing predictive capabilities of clinicians. Our results strengthen data mining and suggest the benefit of focus on interaction-based statistics. Considering that all predictors can easily be obtained in a clinical setting, we hope that our model can be tested by other research groups.

Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis

Abstract: Objective: Major depressive disorder (MDD) affects about 10–15% of the general population in a lifetime. A considerable number of patients fail to achieve full symptom remission despite adequate tr...

Association between habenula dysfunction and motivational symptoms in unmedicated major depressive disorder.

Abstract: The lateral habenula plays a central role in reward and punishment processing and has been suggested to drive the cardinal symptom of anhedonia in depression. This hypothesis is largely based on observations of habenula hypermetabolism in animal models of depression, but the activity of habenula and its relationship with clinical symptoms in patients with depression remains unclear. High-resolution functional magnetic resonance imaging (fMRI) and computational modelling were used to investigate the activity of the habenula during a probabilistic reinforcement learning task with rewarding and punishing outcomes in 21 unmedicated patients with major depression and 17 healthy participants. High-resolution anatomical scans were also acquired to assess group differences in habenula volume. Healthy individuals displayed the expected activation in the left habenula during receipt of punishment and this pattern was confirmed in the computational analysis of prediction error processing. In depressed patients, there was a trend towards attenuated left habenula activation to punishment, while greater left habenula activation was associated with more severe depressive symptoms and anhedonia. We also identified greater habenula volume in patients with depression, which was associated with anhedonic symptoms. Habenula dysfunction may contribute to abnormal response to punishment in patients with depression, and symptoms such as anhedonia.

A combination of probiotics and magnesium orotate attenuate depression in a small SSRI resistant cohort: an intestinal anti-inflammatory response is suggested.

Abstract: Approximately, one-third of those who develop major depression will have a poor response to treatment and over time can become treatment resistant. Intestinal dysbiosis has been implicated in depression with systemic inflammation and vagal and enteric nerve impairment. We report on a sequel pilot study (n = 12) with a combination probiotics/magnesium orotate formulation adjuvant administered with SSRIs for treatment resistant depression. At the end of an 8-week intervention mean changes for depression scores and quality of life in the group was clinically significantly improved (p < 0.001) with all but 4 participants experiencing a benefit. An intestinal anti-inflammatory response was suggested. At 16-weeks follow-up while still on SSRI medications, the group had relapsed after cessation of the test intervention.

Major Depressive Disorder: Pathophysiology and Clinical Management.

Abstract: Depression is a chronic mental disorder that causes changes in mood, thoughts, behavior and physical health. According to the World Health Organization (WHO) 350 people worldwide are said to suffer from this mental disorder. The lifetime prevalence for major depression is reported to be as high as 14-17% and the one-year prevalence is 4-8%. The lifetime prevalence rates of major depressive disorders among women are 10-25%, and for men 5-12%. There are various forms of depression that range from mild to extremely severe conditions like psychotic depression in which the patients show symptoms such as hallucinations and delusions. There are diverse theories on the pathogenesis of depression most based on measurement of indirect markers, post-mortem studies and neuro-imaging techniques. Furthermore, an array of treatment options has been developed to combat depression over the decades. The various approaches include pharmacotherapy, psychotherapy and somatic therapy often employed for treatment resistant depression. Medicinal plants around the world have been used to treat disorders of the body and the mind since antiquity. Herbal medicine has also been a reasonable alternative for the management of mental disorders such as anxiety, depression and dementia among plenty others. Medicinal plants most widely used to treatment depression around the world are Hypericum perforatum, Centella asiatica, Rhodiola rosea, Pfaffia paniculata, Rauwolfia serpentina, Rhododendron molle, Schizandra chin, Thea sinensis, Uncaria tome, Valeriana officinalis and Withania somnifera.

A Review of the Conceptualisation and Risk Factors Associated with Treatment-Resistant Depression

Abstract: Major depression does not always remit. Difficult-to-treat depression is thought to contribute to the large disease burden posed by depression. Treatment-resistant depression (TRD) is the conventional term for nonresponse to treatment in individuals with major depression. Indicators of the phenomenon are the poor response rates to antidepressants in clinical practice and the overestimation of the efficacy of antidepressants in medical scientific literature. Current TRD staging models are based on anecdotal evidence without an empirical rationale to rank one treatment strategy above another. Many factors have been associated with TRD such as inflammatory system activation, abnormal neural activity, neurotransmitter dysfunction, melancholic clinical features, bipolarity, and a higher traumatic load. This narrative review provides an overview of this complex clinical problem and discusses the reconceptualization of depression using an illness staging model in line with other medical fields such as oncology.

Updated Review on the Clinical Use of Repetitive Transcranial Magnetic Stimulation in Psychiatric Disorders.

Abstract: With the ability to modulate cortical activity, repetitive transcranial magnetic stimulation (rTMS) is becoming increasingly important in clinical applications for psychiatric disorders. Previous studies have demonstrated its promising efficacy in depression and schizophrenia, and emerging evidence has also been found in patients with anxiety disorder, obsessive–compulsive disorder, and substance or food craving. However, the overall literature features some conflicting results, varied quality of studies, and a lack of consensus on optimal rTMS parameters. Besides, the efficacy of rTMS in patients with medication-resistant symptoms has drawn most attention from clinicians. Here we review multi-site studies and double-blind randomized controlled trials (RCTs) in single sites, as well as meta-analyses of RCTs in the last three years, in order to update evidence on efficacy and the optimal protocol of rTMS in psychiatric disorders, especially for medication-resistant symptoms.