Treatment-refractory Depression Research Articles

Serum BDNF Levels are Not Associated with the Antidepressant Effects of Nonconvulsive Electrotherapy.

ObjectiveBrain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and in the antidepressant response. This study examined whether changes in serum BDNF levels are associated with the antidepressant effects of nonconvulsive electrotherapy (NET).MethodsFor BDNF analyses, serum samples were collected from 20 patients with treatment-refractory depression (TRD) and from 20 healthy controls. Serum samples were also collected from patients following a course of NET.ResultsAlthough significantly lower baseline serum BDNF levels were observed in TRD patients than in healthy controls, no changes in serum BDNF levels were found in TRD patients after a course of NET compared to baseline. No significant association was found between serum BDNF levels and depression severity.ConclusionSerum BDNF levels appear to have no clinical utility in the prediction of the antidepressant effects of NET in patients with TRD. Future studies of higher quality and with larger sample sizes are needed to confirm these findings.

T207. METABOLIC ADVERSE EFFECTS OF OFF-LABEL USE OF SECOND-GENERATION ANTIPSYCHOTICS IN THE ADULT POPULATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

BackgroundSecond generation antipsychotics (SGAs) are approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia, bipolar disorder and treatment refractory depression. Since the late 1990’s, prescription of antipsychotics has more than doubled and off-label use (i.e. use for indications other than those approved by the FDA) has disproportionately contributed to this increase. These drugs, when used “on-label’, have very significant metabolic adverse effects. Currently, there is no existing literature systematically investigating the metabolic adverse effects of ‘off-label’ use to guide clinical decision making practices.MethodsA systematic review was conducted and MEDLINE, EMBASE, CENTRAL, PsycINFO, and CINAHL were searched for all randomized controlled trials (RCTs) that reported off-label use of SGAs in the adult population. A grey literature search was also completed on ClinicalTrials.gov and the ICTRP Search Portal. The Cochrane Risk of Bias tool was used for the assessment of potential biases. Meta-analyses of the reported metabolic outcomes were completed based on psychiatric diagnosis and subgroup analyses were conducted based on the individual prescribed SGA. Metabolic adverse events analyzed include weight, fasting plasma glucose, HbA1C, total cholesterol, HDL, LDL, and triglycerides. Sensitivity analyses were performed where studies of low quality were excluded.ResultsThe search strategy identified 9309 references, for which 47 randomized control trials (RCTS) were included in the meta-analysis. These studies were published from 1984 to 2019 and came from North America (n=27), Europe (n=9), Asia (n=4), and other (n=7). Participants with generalized anxiety disorder (n=9 studies) treated with quetiapine gained on average 0.53kg (CI 0.22 to 0.84, p= 0.008), had increases in triglyceride levels by 0.17mmol/L (CI 0.052 to 0.29, p=0.005), and decreases in HDL levels by 0.038mmol/L (CI -0.065 to -0.011 p=0.005). Similar results were found in patients with borderline personality disorder (BPD), where olanzapine was associated with a mean weight increase of 2.67kg (CI 2.23 to 3.11, p<0.00001), and increases in triglyceride levels by 0.0029mmol/L (CI 0.0015to 0.0045, p = 0.002). In a single study in patients with trichotillomania, olanzapine was associated with a weight gain of 4.90kg (CI 3.04 to 6.76). Participants with OCD (n=8 studies) receiving quetiapine gained on average 3.40kg (CI 3.17 to 3.63). In studies examining PTSD treatment (n=7 studies), quetiapine was associated with a mean 23kg weight increase (CI 4.85 to 41.15), and olanzapine with a 6.63kg mean weight increase (CI 4.87 to 8.39, p<0.0001). The degree of weight gain associated with quetiapine could partly be attributable to the report of endpoint mean weights only between groups (rather than change data). Participants with cocaine-related substance use disorder (n= 4 studies) on risperidone gained on average 4.70kg (CI 1.78 to 7.62). Where applicable, sensitivity analyses removing low quality studies, did not affect the significance of findings.DiscussionBased on the limited data available, there is a significant association between off-label antipsychotic use and weight gain. This was most commonly reported in association with quetiapine and olanzapine, which may be due to the fact they were the most widely studied agents (n =12, and 16 studies, respectively). Although other metabolic adverse events have been documented, there is not yet enough data available to draw conclusions. Our findings raise concern given the widespread use of SGAs in off-label indications, highlighting the need for raising clinical awareness, ensuring regular metabolic monitoring, and further study of these adverse effects.

Age Affects Temporal Response, but Not Durability, to Serial Ketamine Infusions in Veterans With Treatment Refractory Depression

Age Affects Temporal Response, but Not Durability, to Serial Ketamine Infusions in Veterans With Treatment Refractory Depression

Distance to white matter trajectories is associated with treatment response to internal capsule deep brain stimulation in treatment-refractory depression

BackgroundDeep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). Objective/HypothesisOur aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. MethodsWe performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. ResultsStimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. ConclusionsOur results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

P.660 A unique model to predict patient favourable outcomes in treatment refractory depression using ketamine infusion

P.660 A unique model to predict patient favourable outcomes in treatment refractory depression using ketamine infusion

Safety of Electroconvulsive Therapy in Treatment-Refractory Depression in the Setting of Multiple Sclerosis: Erratum.

Safety of Electroconvulsive Therapy in Treatment-Refractory Depression in the Setting of Multiple Sclerosis: Erratum.

The role of acetyl-L-carnitine (LAC) in the treatment of mental disorders

Abstract Introduction: Currently, there are no fully reliable biomarkers to identify individuals suffering from depression, and conventional antidepressant treatment has its limitations. The potential influence of acetyl-L-carnitine (LAC) on the treatment of mental disorders, including depressive disorders, was noted already in the 1980s. Goal and method: The literature on the role of LAC in the treatment of mental disorders, in particular depressive disorders, was reviewed using the Google Scholar and Pub Med databases. Two lines of research were considered: 1 the role of LAC in the therapy of various mental disorders and 2 the role of LAC in the treatment of depression and dysthymia Conclusions: Because LAC is safe to use and has a very good tolerance profile, authors have explored its role in the treatment of many neurological and psychiatric diseases. There are studies showing that LAC supplementation has a positive effect on ADHD treatment outcomes in boys diagnosed with fragile X syndrome and plays a role in the treatment of dementia. Research has also been conducted on the impact of LAC on the treatment of depressive and dysthymic disorders. Positive outcomes of such therapy have been reported. An important correlation has been observed between LAC concentrations and the severity and onset of depressive symptoms. For instance, reduced levels of LAC have been found in people with treatment-refractory depression. It has also been proposed that LAC could decrease vulnerability to depression.

Clinical Study on the Safety and Effectiveness of Vagus Nerve Stimulation in the Treatment of Refractory Depression

Clinical Study on the Safety and Effectiveness of Vagus Nerve Stimulation in the Treatment of Refractory Depression

Rapid and sustained improvement in treatment-refractory depression through use of acute intravenous ketamine and concurrent transdermal selegiline: A case series

BackgroundTreatment resistant depression is a significant source of morbidity and mortality. For patients having failed or unable to undergo the electroconvulsive therapy procedure few effective alternative treatments exist. MethodsA case series is presented where six patients with treatment resistant depression failing both electroconvulsive therapy and oral antidepressants are concomitantly treated with short course intravenous ketamine and longer term selegiline transdermal system. ResultsAll six patients experienced clinical improvement with intravenous ketamine, with resolution of suicidality, increased food intake, and commitment to treatment adherence. Five patients showed sustained improvement with the selegiline transdermal system. One patient discontinued selegiline after developing peripheral edema and palpitations. LimitationsThis case series included only patients experiencing moderate to severe treatment resistant depression. Availability of long-term follow-up data not available in some cases. ConclusionIntravenous ketamine with simultaneous administration of the selegiline transdermal system is one strategy for treating treatment resistant depression in patients having failed or unable to undergo the electroconvulsive therapy procedure.

A New Adjunctive Approach for Patients with Treatment-Refractory Depression

Augmenting antidepressants with atypical antipsychotics often works in patients with nonresponsive depression, although metabolic and other adverse

Psychiatric polypharmacy and electroconvulsive therapy in treatment-resistant depression

Despite its relevant medical risks, polypharmacy is common particularly among difficult to treat conditions, e.g. treatment refractory depression (TRD). According to numerous guidelines, electroconvulsive therapy (ECT) is the treatment of choice in severe and treatment-resistant major depression due to the high effectiveness; however, to date limited data are available concerning the effects of ECT on the concomitant prescription of psychiatric medication. For aretrospective explorative analysis of psychiatric polypharmacy (MED) in TRD, data from 58inpatient treatments were collected. Due to depressive episodes, all patients received psychopharmacological treatment and cognitive behavioral therapy (MED group). Of the patients 29 also underwent ECT (ECT group). Using a modified drug burden index (mod-DBI), the psychiatric medication was quantified at admission (TP0), start (TP1) and termination of ECT (TP2) and discharge in the ECT group or in comparable periods in the MED group (TP3). Differences in distribution were tested with the t-test and alterations in measurements were tested by means of variance analysis (F-test). Patients treated with ECT showed higher mod-DBI values at TP0, mainly due to more frequent prescription of benzodiazepines (BZD), mood stabilizers (MS) and antipsychotic drugs (AP). At the beginning of the inpatient treatment (TP0-TP1) there was an increase in BZD use (in both groups); in the ECT group MS were reduced and AP increased. In the time interval TP1-TP3, BZD (in both groups) and AP (ECT group) were again less frequently prescribed and MS (ECT and MED group) were increased again. Excluding BZD, there was asignificant increase in mod-DBI in both groups, whereas the mod-DBI no longer showed significant differences at TP2 and TP3. The data possibly indicate that patients with TRD who receive ECT during inpatient treatment already have a more extensive psychiatric medication at admission. Also, psychiatric medication appears to be increased less prominently when ECT is performed. These findings and the possibly associated long-term benefits should be addressed in future research.

Creatine for the Treatment of Depression.

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.

Attitudes toward assisted suicide requests in the context of severe and persistent mental illness: A survey of psychiatrists in Switzerland.

Switzerland is among the few countries worldwide where a request for assisted suicide (AS) can be granted on the basis of a primary psychiatric diagnosis. Psychiatrists play an increasingly important role in this regard, especially when the request for AS arises in the context of suffering caused by severe and persistent mental illness (SPMI). The objective of the survey was to assess general attitudes among psychiatrists in Switzerland regarding AS requests from patients with SPMI. In a cross-sectional survey of 1,311 German-speaking psychiatrists in Switzerland, participants were asked about their attitude to AS for patients with SPMI, based on three case vignettes of patients diagnosed with anorexia nervosa, treatment-refractory depression, or severe persistent schizophrenia. From a final sample of 457 psychiatrists (a response rate of 34.9%) whose mean age was 57.8 years, 48.6% of respondents did not support access to AS for persons diagnosed with SPMI, 21.2% were neutral, and 29.3% indicated some degree of support for access. In relation to the case vignettes, a slightly higher percentage of respondents supported the patient's wish to seek AS: 35.4% for those diagnosed with anorexia nervosa, 32.1% for those diagnosed with depression, and 31.4% for those diagnosed with schizophrenia. Although a majority of the responding psychiatrists did not support AS for SPMI patients, about one-third would have supported the wishes of patients in the case vignettes. In light of the increasing number of psychiatric patients seeking AS and the continuing liberalization of AS practices, it is important to understand and take account of psychiatrists' perspectives.

Focused ultrasound as a potential means of facilitated exosome delivery to brodmann area 25 in the treatment of refractory depression

Focused ultrasound as a potential means of facilitated exosome delivery to brodmann area 25 in the treatment of refractory depression

Resting-state fMRI biomarkers and effects of transcranial magnetic stimulation in treatment-refractory depression

Background: Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising predictor of transcranial magnetic stimulation (rTMS) treatment response in major depressive disorder. However, the underlying working mechanism is still poorly understood due to the large variety of treatment protocols and often small sample sizes. The aims of this study were identifying biomarkers of rTMS treatment response and examining changes in the brain associated with antidepressant treatment response.

Structural correlates of accelerated intermittent theta-burst stimulation for treatment-refractory depression

Structural correlates of accelerated intermittent theta-burst stimulation for treatment-refractory depression

Mindfulness as an Intervention for Depression

Mindfulness-based interventions (MBIs) for depression have become a frequent focus of research and clinical practice in recent decades. This article summarizes evidence regarding the use of MBIs in the prevention of depressive episodes and relief of depressive symptoms across different phases of depression. Much of the review is focused on evidence for mindfulness-based cognitive therapy (MBCT), a widely studied MBI for depression. There is strong evidence for MBCT in preventing depressive relapse among people with recurrent depression in remission. The evidence is less robust and consistent with respect to MBCT as a treatment for acute depression and treatment refractory depression. For some populations of people who are depressed, particularly those who prefer alternatives to antidepressant medications, MBIs may provide an adjunctive treatment option. Emerging work on MBIs suggests that online and other mobile health strategies may be used in the future. [ Psychiatr Ann. 2019;49(1):16–20.]

Accidental chronic lithium toxicity

Lithium is an effective first-line mood stabiliser for bipolar disorder, treatment-refractory depression and suicide prevention. Studies have demonstrated its ability to produce neuroprotective benefits. Despite this, Lithium can cause neurotoxicity, cardiotoxicity and endocrine derangement resulting in severe (and potentially permanent) side effects. Lithium toxicity can be precipitated by illness, salt restriction diets, dehydration, nephrogenic diabetes insipidus, impaired creatinine clearance, concomitant drugs. This is particularly true in older patients with altered pharmacodynamics and pharmacokinetics. We present a 52-year-old female who presented with prolonged signs of lithium toxicity post-diarrhoea. Lack of monitoring due to her nomadic life-style resulted in the combination of long-lasting neurotoxicity and thyroid dysfunction. Our patient displayed neurotoxicity that was not present on imaging. This highlights the importance of regular monitoring of renal function, lithium serum levels and neuro-endocrine function to reduce complications associated with lithium toxicity.

Decrease in frequency of ketamine infusions after dTMS in a 19 year old patient with treatment resistant depression: Case report

Objective: Describe treatment and durability with deep repetitive transcranial magnetic stimulation (dTMS) in a highly treatment refractory depression patient allowing decreased frequency of ketamine infusions.

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines.

Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1β, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.