Treatment-resistant Major Depressive Disorder Research Articles

Rapid and sustained antidepressant effects of intravenous ketamine in treatment-resistant major depressive disorder and suicidal ideation: a randomized clinical trial

BackgroundMajor depressive disorder (MDD) is the most disabling and burdensome mental disorder, negatively affecting an individual’s quality of life and daily functioning. the current study was conducted with the aim of investigating the clinical effects of intravenous ketamine on symptoms of MDD and suicidal ideation.MethodsThe current randomized clinical trial was carried out on 64 patients diagnosed with treatment-resistant major depressive disorder between April and August 2022. The participants were randomly assigned to two groups: the intervention group received a dose of 0.5 mg/kg of ketamine, while the control group received normal saline. The Montgomery-Asberg Depression Scale and Beck’s Suicidal Ideation Scale were utilized to assess depression and suicidal ideation, respectively.ResultsOne hour after the administration of ketamine treatment, there was a notable and significant improvement in both depression symptoms (35.16 ± 8.13 vs. 14.90 ± 10.09) and suicidal ideation (6.74 ± 6.67 vs. 0.42 ± 1.52). Moreover, there were statistically significant differences in depression scores between the two groups at one hour, four hours, one day, three days, one week, one month, and two months after the administration of ketamine (p-value < 0.001). However, ketamine recipients frequently experienced side effects such as increased heart rate, headache, dizziness, and dissociative syndrome symptoms.ConclusionThe observed rapid onset of action and sustained effect demonstrate the potential of ketamine to provide relief from depressive symptoms in a shorter timeframe compared to traditional treatment approaches. These findings contribute to the growing body of evidence supporting the use of ketamine as a valuable therapeutic option for patients with treatment-resistant depression.IRCT registrationIRCT registration number: IRCT20210806052096N1; IRCT URL: https://www.irct.ir/trial/62243; Ethical code: IR.ZUMS.REC.1400.150; Registration date: 2022-04-09.

Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community

IntroductionAlthough short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral...

Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.

To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD). We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events. Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies. A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.

Synergistic use of deep TMS therapy with IV ketamine infusions for major depressive disorder: a pilot study.

Major Depressive Disorder (MDD) is a pervasive psychiatric condition effecting approximately 21 million adults in the U.S. (8.4%). An estimated 30-60% of patients are resistant to traditional treatment approaches (medications and talk-therapy), alluding to the need for additional options. Two promising treatment modalities include transcranial magnetic stimulation (TMS) and ketamine infusions; both have shown efficacy in standalone studies but have scarcely been investigated synergistically in the same group of participants. In the current study, 169 participants with treatment-resistant MDD received 36 treatments of Deep TMS-only (H1 + H7 protocols), while 66 received 36 treatments of Deep TMS (H1 + H7 protocols) and 6 IV infusions of ketamine over the course of 9weeks. Depressive symptoms were compared pre- and -post treatment in both conditions using the PHQ-9. In both treatment groups, depressive symptoms were significantly reduced from pre-to-post and there were no significant differences in response between the TMS + ketamine condition and the TMS-only condition. The TMS + ketamine condition had an 80.30% response rate (53 out of 66) and 43.42% remission rate (28 out of 66) compared to a 76.92% response (130 out of 169) and 39.64% remission (67 out of 16) in the TMS-only condition. These results support the notion that TMS treatments yield high response rates in treatment-resistant cases; however, in this investigation there was no added benefit for including 6 sessions of IV ketamine in conjunction with TMS. Future investigations using randomized-control designs and robust outcome measures are warranted.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report

BackgroundRECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. ObjectiveTo describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. MethodsMedical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). ResultsUnipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. ConclusionsRECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. Trial registrationClinicalTrials.gov Identifier NCT03887715.

How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS)

BackgroundDue to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). MethodsIn this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5–0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. ResultsResults showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LimitationsThe study included two Cohorts with different dosing regimes. ConclusionsThe findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Multimodal Neuroimaging of the Effect of Serotonergic Psychedelics on the Brain.

The neurobiological mechanisms underpinning psychiatric disorders such as treatment-resistant major depression, post-traumatic stress disorder, and substance use disorders, remain unknown. Psychedelic compounds, such as psilocybin, lysergic acid diethylamide, and N,N-dimethyltryptamine, have emerged as potential therapies for these disorders because of their hypothesized ability to induce neuroplastic effects and alter functional networks in the brain. Yet, the mechanisms underpinning the neurobiological treatment response remain obscure. Quantitative neuroimaging is uniquely positioned to provide insight into the neurobiological mechanisms of these emerging therapies and quantify the patient treatment response. This review aims to synthesize our current state-of-the-art understanding of the functional changes occurring in the brain following psilocybin, lysergic acid diethylamide, or N,N-dimethyltryptamine administration in human participants with fMRI and PET. We further aim to disseminate our understanding of psychedelic compounds as they relate to neuroimaging with the goal of improved diagnostics and treatment of neuropsychiatric illness.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters,mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indicationsof TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, andimpact on cognition. An overview ofthe drug'sorigins,pharmacology, and standard treatment regimen are provided. Theoutcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlinedto demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative toketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD,propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, includingketamine, esketamine, treatment-resistant depression, and biomarkers,using automation toolsalong with selective search engine results.After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

Do benzodiazepines reduce the efficacy of transcranial magnetic stimulation?

To investigate the effect of concomitant use of benzodiazepines on the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant major depressive disorder (TR-MDD). This is a retrospective study comparing rTMS treatment outcomes between patients taking benzodiazepines (n = 59) and those who were not (n = 136). Participants completed the HAM-A, HAM-D17, MADRS and ZUNG at baseline and at the end of treatment. Patients taking benzodiazepines during rTMS treatment did not show any difference in partial response, response or remission rates compared to patients not treated with benzodiazepines. There was a significant decrease (p < .0001) in depression and anxiety scores from baseline to post-treatment among both groups. Concomitant benzodiazepine treatment had no effect on the efficacy of rTMS treatment of TRD, contrary to previous research.

The Efficacy and Safety of Intranasal Formulations of Ketamine and Esketamine for the Treatment of Major Depressive Disorder: A Systematic Review.

Ketamine and its enantiomers represent an innovative glutamatergic agent as a treatment for individuals with treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal ideation and behavior. Intranasal (IN) formulations could allow for quick onset of action on depressive symptoms as well as a reduction in side effects by bypassing the blood-brain barrier compared with administration via the intravenous route. The aim of this review was to provide an up-to-date analysis of the data on the efficacy and safety of IN ketamine and IN esketamine for the treatment of MDD. A systematic review following PRISMA guidelines was conducted. Databases (PubMed, Embase, MEDLINE, PsycINFO, and Google Scholar) were searched to capture articles about IN ketamine or IN esketamine for MDD. This systematic review highlighted the interest in IN routes of ketamine and esketamine for MDD patients with TRD or active suicidal ideation. They provide a rapid onset of antidepressant action within the first hours after administration. Nevertheless, the evidence of efficacy is stronger for IN esketamine than for IN ketamine in MDD patients. The safety profile appears to be acceptable for IN esketamine but requires further studies, and a more accurate IN delivery device is required for ketamine.

Magnetic seizure therapy and electroconvulsive therapy increase aperiodic activity

Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical “slowing” of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.

73 Sleep Onset Latency and Duration in rTMS Treatment in Veterans with Treatment-Resistant Major Depressive Disorder

Objective:This study builds on the work by Rehman et al (2022) who argued that transcranial magnetic stimulation (TMS) treatment not only helps treat depression but also decreases sleep problems such as difficulty falling asleep,staying asleep, and waking too early. The present study further explores differences in sleep onset latency, meaning the time it takes to fall asleep, and duration of sleep per night in the pre and post treatment phases of rTMS. The information regarding major attributes of sleep is critical because recent research shows that about 90% of patients with major depressive disorder (MDD) also struggle with sleep disorders (Li et al., 2022), and sleeping for less than seven hours may eventually lead to sleep deprivation (Hirshkowitz et al., 2015), with increased risk of physical and mental health problems (Sheehan et al, 2019). Sleep onset latency estimates vary from individual to individual but typical sleep latency is considered between 10 to 20 minutes (Jung et al, 2013). As it has been shown that overall sleep problems improve with rTMS, we hypothesized that self-reported sleep onset latency will decrease, and sleep duration will increase.Participants and Methods:All participants met inclusion criteria for MDD diagnosis and completed a full course of TMS treatment (N=470; Mean age=53.45, SD=13.73). The sample was mostly male (81%) and ethnically diverse: 77.7% non-Hispanic White, 13.3% Black Americans, 1.9% Asian, 0.2 % Asian Indian, and 1.9% other ethnicities. Sleep problems were assessed using the following questions at the pre and post treatment stages: the number of minutes it takes to fall asleep and duration of sleep each night.Results:A Wilcoxon matched-pairs signed-rank test was conducted to determine whether there was a difference in sleep onset latency and hours of sleep per night between pre and post intervention. The results indicated a significant difference in time to fall asleep between pre and post treatment (pre-treatment M = 1.19, SD = 0.99, post-treatment M = 0.93, SD = 0.91; z = -5.01, p &lt; .001. In addition, there was a significant increase in the minutes of sleep per night in pre (M = 6.11, SD = 2.07) compared to the post treatment (M = 6.32, SD = 1.77), z = -2.56, p = .010.Conclusions:Reduced sleep is known to negatively impact mood, cognitive ability, work performance, and immune function (Besedovsky et al., 2012; Killgore, 2010; Massar et al, 2019; Vandekerckhove &amp; Wang, 2018). Similarly, longer sleep onset latency can cause an individual to enter the first sleep stage later than expected and complete fewer sleep cycles. The results of the present study show the effectiveness of rTMS in decreasing sleep onset latency and increasing the duration of sleep. Given the comorbidity and bidirectionality between sleep disturbances and mood disorders (Fang et al., 2019; Palagini et al., 2019), further researching treatments such as rTMS to improve sleep as a means to also improve mood is crucial. We propose acquiring knowledge about sleep attributes as an essential part of clinicians’ work early on in the rTMS treatment in order to monitor an individual’s global functioning level in light of improved sleep.

Financement de la psychiatrie en France, la question des médicaments onéreux : exemple de l’Esketamine dans l’épisode dépressif caractérisé résistant

In France, the funding of mental health institutions relies on an annual budget allocation. Esketamine, a non-competitive NMDA glutamate receptor antagonist, has been approved for adults with treatment-resistant major depressive disorder since 2019. However, due to its high cost (€200 per 28 mg device, excluding tax), the aim of this work was to evaluate whether the income received by an institution for the management of a patient treated with Esketamine could cover the purchase of devices, based on real clinical data. Within our institution, seven patients underwent treatment with Esketamine during the study period resulting in a total usage of 714 devices, amounting to a purchase cost of €142,800. Over the course of the follow-up period, the institution received €149,054 in revenue for the treatment of these patients. Our analysis reveals that the expense associated with Esketamine constitutes 95.8 % of the income generated from caring for these patients. This not only raises questions about the pricing of this drug but also highlights the lack of a funding system for costly psychiatric drugs. This concern extends to somatic treatments associated with psychiatric care.

Multidisciplinary development of guidelines for ketamine treatment for treatment-resistant major depression disorder for use by adult specialist mental health services in New Zealand.

The evidence base for racemic ketamine treatment for treatment-resistant major depressive disorder (TRD) continues to expand, but there are major challenges translating this evidence base into routine clinical care. To prepare guidelines for ketamine treatment of TRD that are suitable for routine use by publicly funded specialist mental health services. We consulted with senior leadership, clinical pharmacy, psychiatrists, nursing, service users and Māori mental health workers on issues relating to ketamine treatment. We prepared treatment guidelines taking the evidence base for ketamine treatment and the consultation into account. Ketamine treatment guidance is reported. This offers two treatment pathways, including a test of ketamine responsiveness with intramuscular ketamine and the dominant use of oral ketamine for a 3-month course to maximise the opportunity for the short-term benefits of ketamine to accumulate. We have responded to the challenges of translating the evidence base for ketamine treatment into a form suitable for routine care.

A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression – the U-B-D study protocol

BackgroundMajor depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD.MethodsIn this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4–6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals.DiscussionComprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD.Trial registrationThe trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

53.2 Improvement in Depression and Fluid Cognition Following Accelerated Theta Burst Stimulation for Treatment-Resistant MDD in ASD

53.2 Improvement in Depression and Fluid Cognition Following Accelerated Theta Burst Stimulation for Treatment-Resistant MDD in ASD

Baseline levels of miR-223-3p correlate with the effectiveness of electroconvulsive therapy in patients with major depression

There is a strong medical need to develop suitable biomarkers to improve the diagnosis and treatment of depression, particularly in predicting response to certain therapeutic approaches such as electroconvulsive therapy (ECT). MicroRNAs are small non-coding RNAs that have the ability to influence the transcriptome as well as proteostasis at the systems level. Here, we investigate the role of circulating microRNAs in depression and response prediction towards ECT. Of the 64 patients with treatment-resistant major depression (MDD) who received ECT treatment, 62.5% showed a response, defined as a reduction of ≥50% in the MADRS total score from baseline. We performed smallRNA sequencing in blood samples that were taken before the first ECT, after the first and the last ECT. The microRNAome was compared between responders and non-responders. Co-expression network analysis identified three significant microRNA modules with reverse correlation between ECT- responders and non-responders, that were amongst other biological processes linked to inflammation. A candidate microRNA, namely miR-223-3p was down-regulated in ECT responders when compared to non-responders at baseline. In line with data suggesting a role of miR-223-3p in inflammatory processes we observed higher expression levels of proinflammatory factors Il-6, Il-1b, Nlrp3 and Tnf-α in ECT responders at baseline when compared to non-responders. ROC analysis of confirmed the diagnostic power of miR-223-3p demarcating ECT-responders from non-responder subjects (AUC = 0.76, p = 0.0031). Our data suggest that miR-223-3p expression and related cytokine levels could serve as predictors of response to ECT in individuals with treatment-resistant depressive disorders.

Rumination symptoms in treatment-resistant major depressive disorder, and outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) treatment

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.