Severe Treatment-resistant Depression Research Articles

Single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression – A first-in-kind open-label pilot study

BackgroundThe enduring and severe depression often suffered by Veterans causes immense suffering and is associated with high rates of suicide and disability. This is the first study to evaluate the efficacy and safety of psilocybin in Veterans with severe treatment-resistant depression (TRD). Methods15 Veterans with severe TRD (major depressive episode failing to respond to ≥5 treatments, or lasting >2 years) received 25 mg of psilocybin. Primary outcome was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Response was defined s ≥ 50 % reduction in MADRS, and remission as ≤10 MADRS score. Psychedelic experience was assessed using the Five-Dimensional Altered States of Consciousness scale (5D-ASC). Safety measures included assessment of suicidality and adverse events. Participants on antidepressants were tapered to avoid drug interactions. ResultsOf 15 participants, 60 % met response and 53 % met remission criteria at Week 3. At 12 weeks, 47 % maintained response, and 40 % remission. Co-morbid PTSD did not significantly influence study outcomes. The psychedelic experience reported in 5D-ASC did not correlate with response. Participants judged to need antidepressants were restarted and considered non-responders from that timepoint (n = 4). No unexpected adverse events occurred. LimitationsLimitations include the small sample size, and the uncontrolled and unblinded nature of the study. ConclusionsIn this first study on psilocybin for Veterans with severe TRD, a surprising response and remission was seen. Many Veterans had PTSD though no moderating impact of response was observed. The degree of psychedelic experience did not correlate with depression changes. Further study is warranted.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04433858.

Raynaud’s phenomenon on initiation of Lithium therapy: a case report

Lithium Carbonate is an effective treatment for affective disorders, but has a range of side effects. This case report highlights a rare side effect of Raynaud’s phenomenon following initiation of Lithium therapy in a patient with recurrent depressive disorder. He was commenced on Lithium therapy to treat severe treatment resistant depression with psychotic symptoms when alternative treatments trialled were ineffective. He had no other risk factors or known aetiological causes for development of Raynaud’s phenomenon. Symptoms resolved on discontinuation of Lithium and re-emerged on recommencement. Previous case series have shown Lithium effectively treating vasospastic disorders such as cluster headache and Raynaud’s phenomenon. However, a paradoxical reaction to those previously described was induced in this case.

Compassionate use of esketamine intranasal in patients with severe major depressive disorder resistant to the treatment.

Treatment-resistant depression (TRD) is defined as the failure of at least two antidepressants in adequate doses and timing during a major depressive episode. Esketamine intranasal (ESK-IN) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of TRD in combination with other antidepressants. To assess the effectiveness and tolerability of a sample of TRD patients who received treatment with ESK-IN as part of the compassionate use program. A retrospective, observational study was carried out on patients with a diagnosis of TRD enrolled in the early access program of ESK-IN in nine centers. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS) at four time points: baseline, 28, 90, and 180 days of treatment. The sample included 71 patients (70% women) with a mean baseline MADRS score of 38.27 ± 5.9 and total or partial work disability rates of 85%. ESK-IN treatment was associated with a statistically and clinically significant reduction in the severity of depressive symptoms at all time points assessed. The presence of side effects was common but the majority were mild in severity and resolved after the observation period. Those patients who received psychotherapy in combination with ESK-IN showed a significantly lower MADRS score at 90 and 180 days than those patients who did not undergo psychotherapy. ESK-IN has proven to be effective and safe in a clinical sample of patients with severe TRD. To optimize clinical outcomes, the pharmacological treatment for TRD should always be integrated into a comprehensive therapeutic plan that encompasses strategies such as psychotherapy, social support, and family interventions.

The Impact of Ketamine-Based Versus Non-Ketamine-Based ECT Anesthesia Regimens on the Severity of Patients’ Depression and Occurrence of Adverse Events: A Systematic Review with Meta-Analysis

Objective: To compare efficacy and safety outcomes for ketamine anesthesia + electroconvulsive therapy (ECT) versus nonketamine anesthesia + ECT in treatment-resistant depression (TRD) patients. Data Sources: PubMed and Embase were searched from the earliest date through November 27, 2023. Study Selection and Data Extraction: Relevant randomized controlled trials (RCTs) of ketamine + ECT versus nonketamine anesthesia + ECT that reported data on remission (odds ratio [OR]), defined as a Hamilton Depression Rating Scale (HAM-D) and Montgomery-Asburg Depression Rating Scale (MADRS) score <8-10) and mean differences (MDs) in HAM-D scores after several ECT sessions were compared using inverse variance methods. The risk of bias (RoB) was assessed using the Cochrane RoB tool. Data Synthesis: Seventeen RCTs (RoB: Low N = 12, Moderate N = 2, High N = 3) with 1181 total patients met inclusion criteria. Patients receiving ECT experienced greater clinical remission (OR: 1.78, [95% confidence interval (CI): 1.08-2.93], I2 = 11%, N = 9) and lower HAM-D scores after the third through sixth ECT sessions as well as the eighth ECT session when ketamine versus nonketamine anesthesia was used. Ketamine use with ECT significantly increased fear with hallucinations (OR: 1.99, [95% CI: 1.11-3.58], I2 = 0%, N = 7) than with nonketamine anesthesia. Relevance to Patient Care and Clinical Practice: Selecting ketamine-based anesthesia could more quickly and profoundly enhance the beneficial effects of ECT for patients with severe TRD, but the balance of benefits to harm is unclear as there may be additional adverse events. Conclusion: Ketamine is a promising anesthesia adjunct to ECT that may enhance antidepressant effects in exchange for more adverse events.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

How adults with treatment resistant depression experience their first esketamine nasal spray treatment? Preliminary results from a French qualitative study

IntroductionSpravato® (esketamine nasal spray- ENS) is a new adjunctive drug for Treatment Resistant Depression (TRD), i.e. patients with major depressive disorder that failed to adequately respond despite the use of two different antidepressants. In France, a real world non-interventional post-commercialization cohort study is being conducted aiming to describe the conditions of use of the esketamine, and to observe the outcomes.ObjectivesTo in-depth explore the lived experience of first administered ENS treatment among adults with TRD, we are conducting an ancillary qualitative study.MethodsThis qualitative study uses the IPSE approach (Sibeoni et al. BMC Medical Research Methodology 20.1(2020):1-21) and has been conducted in four French psychiatric departments. Design was based on the recruitment of patients through the Cohort study, all interviewed twice, the first time 3 to 5 weeks after the first administration of ENS, and the second time around 6 months after, whether treatment has been continued or not. Data analysis follows the IPSE analytic procedure and is conducted in two stages: three individual researchers carry out independent work and the group collectively pools data. These preliminary results are based on the sole analysis of the first interviews conducted from July 2022 to July 2023.ResultsEighteen participants with moderate to severe TRD, including 13 women, were interviewed and two axes of experience have been produced: (1) the overwhelming experiences of the treatment, perceived differently depending on patients, as a dissociative experience, both inside – described as a trip- and outside of them; (2) A discordant treatment experience with both solitude and relational support from medical team.ConclusionsThese results highlight the need to better prepare the patients for the initiation of the treatment and to take into consideration the settings in which the treatment is administered, as well as the importance of the support received from the nursing staff.Disclosure of InterestE. Manolios Grant / Research support from: have recieved financial support to conduct the study, J. Mathé Grant / Research support from: have recieved financial support to conduct the study, J. Sibeoni Grant / Research support from: have recieved financial support to conduct the study, M. Rotharmel Consultant of: Janssen, B. Astruc Consultant of: Janssen, B. Falissard Consultant of: Janssen, L. Mekaoui Consultant of: Janssen, A. Laurin Consultant of: Janssen, E. Gaudre-Wattinne Employee of: Janssen Cilag, J. Dupin Employee of: Janssen Cilag, A. Revah-Levy Grant / Research support from: have recieved financial support to conduct the study

Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report

BackgroundSevere forms of depression have been linked to hyperactivity of the subcallosal cingulate cortex. The ability to stimulate the subcallosal cingulate cortex or associated circuits noninvasively and directly would maximize the number of patients who could receive treatment. To this end, we have developed an ultrasound-based device for effective noninvasive modulation of deep brain circuits. Here we describe an application of this tool to an individual with treatment-resistant depression.Case presentationA 30-year-old Caucasian woman with severe treatment-resistant non-psychotic depression was recruited into a clinical study approved by the Institutional Review Board of the University of Utah. The patient had a history of electroconvulsive therapy with full remission but without sustained benefit. Magnetic resonance imaging was used to coregister the ultrasound device to the subject’s brain anatomy and to evaluate neural responses to stimulation. Brief, 30-millisecond pulses of low-intensity ultrasound delivered into the subcallosal cingulate cortex target every 4 seconds caused a robust decrease in functional magnetic resonance imaging blood-oxygen-level-dependent activity within the target. Following repeated stimulation of three anterior cingulate targets, the patient’s depressive symptoms resolved within 24 hours of the stimulation. The patient remained in remission for at least 44 days afterwards.ConclusionsThis case illustrates the potential for ultrasonic neuromodulation to precisely engage deep neural circuits and to trigger a durable therapeutic reset of those circuits.Trial registration ClinicalTrials.gov, NCT05301036. Registered 29 March 2022, https://clinicaltrials.gov/ct2/show/NCT05301036

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression.

Subanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine's mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties. This article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives' strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model's various components, which are presented in detail. The Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support. Our integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model's effectiveness and hypothesized psychological mechanisms.

Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report

We present the first evidence that sub-anesthetic ketamine infusions for treatment resistant depression (TRD) may facilitate deprescription of long-term benzodiazepine/z-drugs (BZDRs). Long-term BZDR prescriptions are potentially harmful yet common, partly because of challenging withdrawal symptoms. Few pharmacological interventions have evidence for facilitating BZDR discontinuation, and none in patients actively suffering from TRD. In this ambi-directional cohort study, discontinuation of long-term (>6 month) BZDRs was attempted in 22 patients with severe unipolar or bipolar TRD receiving a course of six subanesthetic ketamine infusions over four weeks. We investigated the rates of successful BZDRs deprescription, trajectories of acute psychological withdrawal symptoms, and subsequent BZDRs abstinence during a mean follow-up of 1 year (primary outcome). Clinically significant deteriorations in depression, anxiety, sleep, and/or suicidality during the acute BZDR discontinuation phase were measured by repeated standardized scales and analyzed by latent growth curve models and percent correct classification analysis. Of the 22 eligible patients, all enrolled in this study and 91% (20/22) successfully discontinued all BZDRs by the end of the 4-week intervention, confirmed by urinary analyses. Less than 25% of discontinuers experienced any significant worsening of anxiety, depression, sleep difficulties, or suicidality during treatment. During follow-up (mean [range] duration, 12 [3–24] months), 64% (14/22) of patients remained abstinent from any BZDRs. These preliminary results suggest that ketamine infusions for TRD may facilitate the deprescription of BZDRs, even in patients with active depressive symptoms and significant comorbidity. Further investigation is warranted into this potential novel application of ketamine.

Psilocybin therapy: A novel approach to treating depression

Psilocybin therapy: A novel approach to treating depression

Subanesthetic Ketamine Infusion Reducing Symptoms of Depression in a Patient With End-Stage Heart Failure Enrolled in Hospice Care: A Case Report.

Background: The development of major depressive disorder in patients at end of life often goes undiagnosed, as it is difficult to distinguish from preparatory grief and/or hypoactive delirium in this unique patient population. If this preliminary barrier of appropriate diagnosis is overcome, it can be quite difficult to properly select and adjust pharmacological therapy. Many well-established antidepressants take four to five weeks for maximal effectiveness (which may be far too long of a titration period for patients at end of life), have various contraindications to patients' comorbid chronic conditions (particularly patients with cardiovascular disease), or may simply be ineffective. Case: We present a case report of severe treatment-resistant depression in an end-stage heart failure patient enrolled in hospice care. Discussion: We discuss the potential use of a single low-dose intravenous racemic ketamine infusion to reduce end-of-life suffering related to depression, despite the theoretical contraindication of ketamine use in such patients, in part, due to its sympathomimetic secondary effect.

A Prospective, Multi-center Randomized, Controlled, Blinded Trial of Vagus Verve Stimulation for Difficult to Treat Depression: the RECOVER Trial

Abstract Introduction: Therapeutic Vagus Nerve Stimulation (VNS) has been FDA-approved for treatment-resistant depression (TRD). In 2007, the US Centers for Medicare and Medicaid Services (CMS) issued a non-coverage decision, making access difficult for patients. In 2019, CMS requested a “coverage with evidence development trial” to determine potential VNS efficacy in the US Medicare TRD population. This trial, RECOVER, is co-sponsored by CMS and the device maker (LivaNova) to assess VNS efficacy over 12 months is large, multi-centered (N=71, US sites), randomized, and placebo-controlled. Methods: Inclusion criteria include: ≥18 years old, diagnosis of Major Depressive Disorder (MDD) or Major Depressive Episode (MDE) in bipolar disorder, chronic (2 years) or recurrent (≥ 4 MDEs), failure of four medical record-verified AD treatments in the current MDE, a score of ≥ 22 on the Montgomery Asberg Depression Rating Scale (MADRS). Exclusion criteria include: substance use and psychotic disorders, acute suicidal ideation/intention, severe personality disorder. All subjects undergo VNS implantation then randomized to active treatment (device on) or sham (implanted, not activated) for 12 months. Depression ratings are performed by blinded, offsite raters. The trial’s primary measure is number of months in response (active –vs- placebo). Results: 480 patients enrolled; subject mean age is 54.0, 34.6 mean MADRS, mean age of onset is 20.9, and 20.4 years of lifetime MDE. Average failed lifetime ADs is 14.1, with many receiving aggressive treatments: ECT (41.9%), TMS (46.7%), and ketamine (21.3%). Many report psychiatric hospitalizations (64.0%); attempted suicide (43.8%). To date, 222 patients (including 40 early terminated) have completed the trial’s first year. Conclusions: RECOVER is the largest prospective, randomized, device-based, placebo-controlled MDD trial ever undertaken; enrolling severe TRD patients not studied in most MDD clinical trials. It will provide a thorough understanding of the nature of VNS response (e.g., onset of response and potential baseline outcome predictors). Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Treatment-Resistant Depression, Vagus Nerve Stimulation, Difficult to Treat Depression, Major Depressive Disorder

Fronto-medial electrode placement for electroconvulsive treatment of depression.

Electroconvulsive therapy (ECT) is the most effective treatment for severe treatment-resistant depression but concern about cognitive side-effects, particularly memory loss, limits its use. Recent observational studies on large groups of patients who have received ECT report that cognitive side-effects were associated with electric field (EF) induced increases in hippocampal volume, whereas therapeutic efficacy was associated with EF induced increases in sagittal brain structures. The aim in the present study was to determine whether a novel fronto-medial (FM) ECT electrode placement would minimize electric fields in bilateral hippocampi (HIP) whilst maximizing electric fields in dorsal sagittal cortical regions. An anatomically detailed computational head model was used with finite element analysis, to calculate ECT-induced electric fields in specific brain regions identified by translational neuroimaging studies of treatment-resistant depressive illness, for a range of electrode placements. As hypothesized, compared to traditional bitemporal (BT) electrode placement, a specific FM electrode placement reduced bilateral hippocampal electric fields two-to-three-fold, whilst the electric fields in the dorsal anterior cingulate (dAC) were increased by approximately the same amount. We highlight the clinical relevance of this specific FM electrode placement for ECT, which may significantly reduce cognitive and non-cognitive side-effects and suggest a clinical trial is indicated.

Association of intranasal esketamine, a novel ‘standard of care’ treatment and outcomes in the management of patients with treatment-resistant depression: protocol of a prospective cohort observational study of naturalistic clinical practice

IntroductionEsketamine is the S-enantiomer of racemic ketamine and has been approved by the Food and Drug Administration for the management of treatment resistant depression, demonstrating effective and long-lasting benefits. The...

Outcomes of TMS treatments for Montana Medicaid patients

Background: Our practice began treating Medicaid patients with TMS in 2020 following Montana Medicaid’s approval for TMS treatment in those with treatment-resistant depression. In Montana, 37% of Medicaid enrollees have a behavioral health diagnosis. We report on the response of these patients to encourage other states’ Medicaid programs also to cover TMS for these patients. Objectives: This study aimed to assess the clinical efficacy of Transcranial Magnetic Stimulation in a Medicaid population subset. All patients recorded PHQ-9, BDI-II, and GAD-7 scores before beginning treatment, at weekly intervals, and the conclusion of treatment. Methods: From 2020 to 2022, we prescribed and treated 12 (n=12) Medicaid patients who had a history of severe treatment-resistant depression with a complete course of 36 TMS therapy treatments. Each patient met the Montana Medicaid TMS criteria of failure of at least four different optimized or intolerable antidepressants from two distinctly different medication classes. Treatments were delivered using the Magventure MagVita device over nine weeks. Patients receive five treatments per week in the first six weeks, then six in the standard taper protocol over three weeks (3,2,1). Overall Results: Patients included eight females and four males with an average age of 31 years old. The average baseline PHQ-9 score was 22.7, BDI-II baseline score of 47.6, and GAD-7 baseline score of 17.4. These scores indicate a patient population with severe depression and severe anxiety. The PHQ-9 showed a response rate of 42% (n=5) and a remission rate of 17% (n=2). BDI-II response rate was 58% (n=7), and the remission rate of 42% (n=5). The GAD-7 response rate was 42% (n=5) and remission was 33% (N=4). 1 of 12 patients withdrew before completing the entire treatment course due to medical issues unrelated to the TMS treatment. The most common side effects were headaches and fatigue. No adverse events were seen. Results of males: Based on the PHQ-9 and the BDI-II, males (n=4) achieved a response rate of 100% and a remission rate of 50% (n=2). Results of females: Based on the BDI-II, females (n=8) achieved a response rate of 50% (n=4) and a remission rate of 25% (n=2). Conclusions: Our study demonstrated that TMS is a highly effective treatment option for the Medicaid population. Although TMS was slightly less effective than results published in non-Medicaid patients, we attribute this to three significant facts. First, the patients had severe symptoms reported on the PHQ-9 and BDI-II scores. Second, our female patients had prevalent trauma histories and a high incidence of comorbid personality disorders. Lastly, our rural state posed a significant challenge. For example, two male patients came from rural areas and rented housing to receive nine weeks of treatments. We are optimistic about offering TMS treatments for Medicaid patients as over half the participants achieved response criteria (n=7), and 42% (n=5) achieved remission criteria based on the BDI-II. We encourage other state Medicaid programs to offer this to their Medicaid patients. Conflicts: of Interest: None. Funding: No external funding

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Efficacy and Tolerability of Two Novel “Standard of Care” Treatments—Intranasal Esketamine Versus Intravenous Ketamine—for Treatment-Resistant Depression in Naturalistic Clinical Practice: Protocol for a Pilot Observational Study

BackgroundIntravenous (IV) ketamine and intranasal (IN) esketamine have been studied as novel alternatives to manage treatment-resistant depression (TRD). The objective of this observational pilot study is to compare the real-world effectiveness and tolerability of IV ketamine and IN esketamine in the management of unipolar TRD.ObjectiveTo compare the effectiveness (primary outcome measure) and tolerability (secondary outcome measure) of racemic ketamine and esketamine in the management of TRD in adults and provide an expert qualitative commentary on the application of IV ketamine and IN esketamine in clinical practice (exploratory objective), focusing on the recruitment process, patient retention, effectiveness, and tolerability of the treatments.MethodsThis is a multicenter prospective observational study of naturalistic clinical practice. We expect to recruit 10 patients per treatment arm—IV ketamine or IN esketamine per center (2 centers, total 40 subjects). Patients experiencing moderate to severe TRD and who are candidates for receiving low-dose IV ketamine treatments or IN esketamine as part of their standard-of-care treatments will be recruited. We will measure the effectiveness of each treatment arm by measuring the severity of depression symptoms using the Montgomery and Åsberg Depression Rating Scale; tolerability, side effects, and the appearance of dissociation symptoms using the simplified 6-item version of the Clinician Administered Dissociative Symptom Scale (CADSS-6); and potential for abuse using a Likeability and Craving Questionnaire. Logistic regression will examine odds ratios, number needed to treat for response and remission, number needed to harm, and likelihood to be helped or harmed of each treatment. Covariate analysis will assess the impact of site and demographic variables on treatment efficacy.ResultsThis observational trial was approved by the Queen’s University Health Science and Affiliated Teaching Hospital’s Research Ethics Board in February 2021. The two research centers involved have started patient recruitment. Our research center (Providence Care Hospital, Kingston, Ontario) has recruited 9 patients so far. We expect to finalize data gathering by August 2022. The manuscript is expected to be published by December 2022.ConclusionsWe hypothesize that both treatments will have comparable rapid and robust antidepressant effects and similar tolerability profiles in a real-world setting for the management of TRD.International Registered Report Identifier (IRRID)DERR1-10.2196/34711

Ten Sessions of 30 Min tDCS over 5 Days to Achieve Remission in Depression: A Randomized Pilot Study.

Although transcranial Direct Current stimulation (tDCS) shows promise in the treatment of major depressive episodes, the optimal parameters and population to target remain unclear. We investigated the clinical interest of a 10 session tDCS regimen in patients with mild to severe treatment-resistant depression, in a pilot double-blind, randomized sham-controlled trial. tDCS was delivered over 5 consecutive days (two 30 min sessions per day separated by at least 2 h, 2 mA). The anode and cathode were placed over the left and the right dorsolateral prefrontal cortex, respectively. One month after tDCS, we observed significantly fewer patients who achieved remission (MADRS10 < 10) in the sham group (0 out of 18 patients) than in the active group (5 out of 21 patients; p = 0.05). However, no significant difference was observed between the groups regarding the mean scores of severity changes throughout the study period. Bifrontal add-on tDCS delivered twice per day over 5 days, in combination with antidepressant medication, can be a safe and suitable approach to achieve remission in patients with mild to severe treatment-resistant major depressive disorder. However, in regards to the pilot nature and limitations of the present study, further studies are needed before any frank conclusions can be made regarding the use of tDCS with the proposed parameters in clinical settings.

Serum Mature BDNF Level Is Associated with Remission Following ECT in Treatment-Resistant Depression.

The search for a biological marker predicting the future failure or success of electroconvulsive therapy (ECT) remains highly challenging for patients with treatment-resistant depression. Evidence suggests that Brain-Derived Neurotrophic Factor (BDNF), a protein known to be involved in brain plasticity mechanisms, can play a key role in both the clinical efficacy of ECT and the pathophysiology of depressive disorders. We hypothesized that mature BDNF (mBDNF), an isoform of BDNF involved in the neural plasticity and survival of neural networks, might be a good candidate for predicting the efficacy of ECT. Total BDNF (tBDNF) and mBDNF levels were measured in 23 patients with severe treatment-resistant depression before (baseline) they received a course of ECT. More precisely, tBDNF and mBDNF measured before ECT were compared between patients who achieved the criteria of remission after the ECT course (remitters, n = 7) and those who did not (non-remitters, n = 16). We found that at baseline, future remitters displayed significantly higher mBDNF levels than future non-remitters (p = 0.04). No differences were observed regarding tBDNF levels at baseline. The multiple logistic regression model controlled for age and sex revealed that having a higher baseline mBDNF level was significantly associated with future remission after ECT sessions (odd ratio = 1.38; 95% confidence interval = 1.07–2.02, p = 0.04). Despite the limitations of the study, current findings provide additional elements regarding the major role of BDNF and especially the mBDNF isoform in the clinical response to ECT in major depression.

Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study.

Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium. To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine. Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed. Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission. These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.