Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023.

PURPOSE OF REVIEW: We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. RECENT FINDINGS: Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD. Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

Genetic factors and symptom dimensions associated with antidepressant treatment outcomes: clues for new potential therapeutic targets?

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Bilateral rTMS Shows No Advantage in Depression nor in Comorbid Depression and Anxiety: A Naturalistic Study.

The objective was to determine if adding low-frequency right-sided rTMS treatment to the standard high-frequency left-sided treatment (LUL), referred to as sequential bilateral treatment (SBT), confers additional benefit for depression or anxiety outcomes. A retrospective chart review from January 2015 through December 2018 yielded 275 patients, all of whom were treated with a figure-8 coil for a major depressive episode. Their protocol was either LUL or SBL. Outcome measures were the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9). There was no significant difference in GAD-7 change scores between patients who had LUL or SBL (4.2 vs 4.8). This was also true when the sample was restricted to only patients who started with high GAD-7 scores. There was likewise no significant difference in PHQ-9 change scores between patients who had LUL or SBL (6.8 vs 5.1). Patients switching from LUL to SBL mid-course had poorer overall outcomes as compared to patients who stayed with the same protocol throughout treatment. This large naturalistic study shows no advantage for SBL treatment any group or condition examined. The results of this study have clinical applicability and sound a cautionary note regarding the use of combination rTMS protocols.

Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model.

BACKGROUND: There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. METHODS: A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. RESULTS: The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. CONCLUSIONS: Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials.

BACKGROUND: Several meta-analyses demonstrated the efficacy of unilateral High-Frequency Left-sided (HFL) repetitive Transcranial Magnetic Stimulation (rTMS) for individuals with Major Depressive Disorder (MDD); however, results are contradictory due to heterogeneity of the included studies. METHODS: A systematic literature review (SLR) of English language articles published since 2000 was performed in March 2022 on PubMed and Scopus databases. Empirical evidence on the relative efficacy of rTMS treatment compared with standard pharmacotherapy in Treatment-Resistant Depression (TRD) were extracted. Random effects models were used to assess the effects of rTMS on response and remission rates. RESULTS: 19 randomized double-blinded sham-controlled studies were included for quantitative analysis for response (n = 854 patients) and 9 studies for remission (n = 551 patients). The risk ratio (RR) for response and remission are 2.25 and 2.78, respectively for patients after two treatment failures using rTMS as add-on treatment compared to standard pharmacotherapy. Cochrane's Q test showed no significant heterogeneity. No publication bias was detected. CONCLUSIONS: rTMS is significantly more effective than sham rTMS in TRD in response and remission outcomes and may be beneficial as an adjunctive treatment in patients with MDD after two treatment failures. This finding is consistent with previous meta-analyses; however, the effect size was smaller than in the formerly published literature.

The prevalence and economic burden of treatment-resistant depression in Thailand.

BACKGROUND: The objectives of this study were to investigate the proportion of treatment-resistant depression (TRD) among patients with diagnosed major depressive disorder (MDD) and undergoing antidepressant treatment, to estimate the economic cost of MDD, TRD, and non-treatment-resistant depression (non-TRD), and to examine the differences between TRD and non-TRD MDD in a Thai public tertiary hospital. METHODS: This was a combined study between retrospective review of medical records and a cross-sectional survey. The sample size was 500 dyads of antidepressant-treated MDD patients and their unpaid caregivers. MDD patients' medical records, the concept of healthcare resource utilization, the Work Productivity and Activity Impairment Questionnaire: depression and mood & mental state versions (WPAI: D, MM), the Class Impairment Questionnaire (CIQ), and the Family Experiences Interview Schedule (FEIS) were applied as the tools of the study. Pearson Chi's square, Fisher's Exact test, and independent T-test were employed for statistical analysis. RESULTS: The proportion of TRD was 19.6% among antidepressant-treated MDD patients in a Thai tertiary public hospital. The results of the study indicated that several factors showed a statistically significant association with TRD criteria. These factors included younger age of MDD patients, a younger age of onset of MDD, lower body mass index (BMI), a history of suicide attempts and self-harm, as well as frequent smoking behavior. The annualized economic cost of TRD was 276,059.97 baht per person ($7,668.33), which was significantly higher than that of cost of non-TRD (173,487.04 baht or $4,819.08). The aggregated economic costs of MDD were 96.8 million baht annually ($2.69 M) if calculated from 500 MDD patients and unpaid caregivers. This contributed to the economic cost of TRD 27.05 million baht (98 respondents) and the economic cost of non-TRD 69.74 million baht (402 respondents). CONCLUSIONS: The economic burden associated with TRD was significantly higher compared to non-TRD among antidepressant-treated MDD patients. Specifically, both direct medical costs and indirect costs were notably elevated in the TRD group.

Improving Patient-Centered Care for Veterans With Treatment-Resistant Depression Using Shared Decision-Making Tools.

INTRODUCTION: Treatment-resistant depression (TRD) exists when patient depression continues without remission or reduction despite treatment. There are no standardized guidelines for identifying TRD, but one failed antidepressant treatment at an adequate dose and duration can constitute TRD, especially in cases of severe depression or suicidality. TRD rates for depressed patients average approximately 50% to 60% of the general population. These numbers are higher in the military population and are often complicated by comorbidities. AIM: Chart audits revealed 68% of psychiatric clinic outpatient veterans met criteria for TRD. Only 25% of patients were being treated adequately for TRD, and 0% were offered other options for treatment. This project aimed to improve patient-centered TRD care at a veteran's hospital to 80% within 90 days. METHODS: This quality improvement project was implemented using plan-do-study-act (PDSA) cycles. Interventions were tested over four rapid-cycle phases with improvements for screening, handouts, surveys, and team meetings over 8 weeks. Four core interventions were followed throughout the project: screening for TRD, right-care case management tracking, patient engagement with shared decision-making (SDM), and team engagement. RESULTS: Starting from a baseline right-care score of 25%, the project attained an overall mean of 99.6% representing improved patient-centered TRD care and surpassing the 80% goal defined in the aim. CONCLUSION: Overall TRD care was improved using SDM options and inter-clinic teamwork and communication.

Efficacy of adjunctive intensive transcranial direct current stimulation of different cortices in treatment-resistant depression: a study protocol for a randomized double-blinded sham-controlled trial.

BACKGROUND: Treatment-resistant depression (TRD) carries a high economic burden worldwide. Transcranial direct current stimulation (tDCS) is advantageous for improving cognition and can be safely used in the treatment of depression. The effectiveness of tDCS of the left and right orbitofrontal cortex (OFC) as adjuvant treatment in patients with TRD has rarely been explored. Therefore, the objective of this trial is to evaluate the effectiveness there of when administering left dorsolateral prefrontal cortex (DLPFC) positive stimulation or OFC negative stimulation in patients with TRD. METHODS: Ninety eligible participants will be recruited to receive intervention at Shanghai Mental Health Center. Treatment will be randomly assigned in a double-blind fashion. Participants will receive either DLPFC (n = 30), OFC (n = 30), or sham (n = 30) tDCS, while continuing their usual pharmacotherapy at a stable dosage for at least 2 weeks before enrollment and throughout the stimulation period. All participants will receive 20 weekday stimulation sessions of 60 minutes duration each. Participants in the active group will be stimulated at 2 mA throughout the session, whereas the sham group will receive only a brief period of stimulation to mimic the sensation. After 20 stimulation sessions, no further treatment will be administered. Measurements will be conducted at regular points throughout and at 8 weeks after trial completion. The primary outcome is the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) score after 20 sessions. Secondary outcomes were defined as changes in other measurement scales, cognitive function, resting-state functional magnetic resonance imaging (rs-fMRI), and serum biomarkers. DISCUSSION: We hypothesize that, in contrast to the sham group, both the active DLPFC and OFC tDCS groups will show superiority in HAMD-17 score reduction after 5, 10, and 20 sessions. Moreover, associations of the improvement of depressive symptoms with variations in rs-fMRI and TRD-related biomarkers will be evaluated. Our study may suggest that adjunctive intensive tDCS with left DLPFC positive stimulation or right OFC negative stimulation may be effective as a novel method to relieve depressive symptoms in patients with TRD. The variation of rs-fMRI, biomarkers could be used as a potential prediction model of treatment efficacy in TRD. TRIAL REGISTRATION: The trial protocol is registered with www.chictr.org.cn under protocol registration number ChiCTR2200058030. Date of registration: March 27, 2022. Recruitment started in September 2022 and is ongoing.

Cervical muscle stiffness and parasympathetic nervous system improvements for treatment-resistant depression.

BACKGROUND: Although treatment-resistant depression (TRD) is a major public health problem that increases mortality due to suicides, a considerable percentage of patients do not respond adequately to variable treatments. Patients with TRD sometimes have comorbid cervical stiffness. This observational study aims to examine the association of local modulation of cervical muscles with TRD and to learn the involvement of the parasympathetic nervous system in the underlying mechanism. METHODS: A total of 1103 hospitalized patients with TRD who were resistant to outpatient care were enrolled between May 2006 and October 2021. All patients underwent local modulation of the cervical muscles by physical therapy during hospitalization. The presence or absence of TRD and whole-body disorders, such as headache, dazzling, cervical stiffness, and cardiovascular and gastrointestinal disorders, was determined by the patient's subjectivity using the self-rated medical interview sheet at admission and discharge. Pupil light reflex parameters were also measured at admission and discharge using a binocular infrared pupilometer. RESULTS: The improvement rate of TRD during hospitalization was 72.1%, and did not differ significantly by sex, age, and hospitalization period. The improvement of TRD showed a strong association with those of cervical stiffness and dazzling, a pupil light reflex disorder (p < 0.001: odds ratios = 12.76 and 6.39, respectively), but not with those of headache or cardiovascular and gastrointestinal disorders (p > 0.05). In the TRD-improved patients, the pupil light reflex parameters representative of the parasympathetic nervous system function ameliorated: pupil diameter decreased, while constriction rate and velocity increased during hospitalization. In contrast, little amelioration of the parameters was seen in the TRD-unimproved patients. CONCLUSIONS: Cervical muscle stiffness may be associated with TRD, possibly through dysfunction of the parasympathetic nervous system. TRIAL REGISTRATION: ID: UMIN000040590. First registration date: 30/05/2020.

Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression.

BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration. METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition.

BACKGROUND: Major depressive disorder (MDD) is highly heterogeneous and can be classified as treatment-resistant depression (TRD) or antidepressant-responsive depression (non-TRD) based on patients' responses to antidepressant treatment. Methods for distinguishing between TRD and non-TRD are critical clinical concerns. Deficits of cortical inhibition (CI) have been reported to play an influential role in the pathophysiology of MDD. Whether TRD patients' CI is more impaired than that of non-TRD patients remains unclear. METHODS: Paired-pulse transcranial magnetic stimulation (ppTMS) was used to measure cortical inhibitory function including GABAA- and GABAB-receptor-related CI and cortical excitatory function including glutamate-receptor-related intracortical facilitation (ICF). We recruited 36 healthy controls (HC) and 36 patients with MDD (non-TRD, n = 16; TRD, n = 20). All participants received evaluations for depression severity and ppTMS examinations. Non-TRD patients received an additional ppTMS examination after 3 months of treatment with the SSRI escitalopram. RESULTS: Patients with TRD exhibited reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), as shown by abnormally higher estimates, than those with non-TRD or HC (F = 11.030, p < 0.001; F = 10.309, p < 0.001, respectively). After an adequate trial of escitalopram treatment, the LICI of non-TRD reduced significantly (t = - 3.628, p < 0.001), whereas the ICF remained lower than that of HC and showed no difference from pretreatment non-TRD. CONCLUSIONS: TRD was characterized by relatively reduced CI, including both GABAA- and GABAB-receptor-mediated neurons while non-TRD preserved partial CI. In non-TRD, SSRIs may mainly modulate GABAB-receptor-related LICI. Our findings revealed distinguishable features of CI in antidepressant-resistant and responsive major depression.

Buprenorphine: prospective novel therapy for depression and PTSD.

BACKGROUND: Depression and post-traumatic stress disorder (PTSD) are leading causes of disability and loss of life by suicide. Currently, there are less than satisfactory medical solutions to treat these mental disorders. Here, we explore recent preclinical and clinical studies demonstrating the potential of using buprenorphine to treat major depressive disorder, treatment-resistant depression, and PTSD. METHOD: Bibliographic databases were searched to include preclinical and clinical studies demonstrating the therapeutic potential of buprenorphine and the involvement of the kappa opioid receptor (KOR) in mediating these effects. RESULTS: Original clinical studies examining the effectiveness of buprenorphine to treat depression were mixed. The majority of participants in the PTSD studies were males and suffer from chronic pain and/or substance use disorders. Nonetheless, these recent studies and analyses established proof of concept warranting farther investigations. Additionally, KOR likely mediates the antidepressant and some of the anxiolytic effects of buprenorphine. Still, it appears that the full spectrum of buprenorphine's beneficial effects might be due to activity at other opioid receptors as well. CONCLUSIONS: Pharmaceuticals' abilities to treat medical conditions directly relates to their ability to act upon the endogenous biological systems related to the conditions. Thus, these recent findings are likely a reflection of the central role that the endogenous opioid system has in these mental illnesses. Further studies are necessary to study the involvement of endogenous opioid systems, and specifically KOR, in mediating buprenorphine's beneficial effects and the ability to treat these medical conditions while minimizing risks for misuse and diversion.

Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy.

Modern electroconvulsive therapy (ECT) and the approval of nasal esketamine for clinical use have significantly improved the approach to treatment-resistant depression (TRD), which is defined as non-response to at least two different courses of antidepressants with verified adherence to treatment, adequate dosage, and duration of treatment. The goal of this literature review is to present the newest evidence regarding efficacy and safety. Furthermore, we aim to provide an overview of future perspectives in this field of research, for example, regarding structural and molecular effects. Both treatment methods will be critically evaluated for their individual advantages, disadvantages, and response rates. Firstly, we will discuss the well-established method of ECT and its different treatment modalities. Secondly, we will discuss the properties of ketamine, the discovery of its antidepressive effects and the route to clinical approval of the esketamine nasal spray. We will comment on research settings which have evaluated intravenous ketamine against ECT. The decision-making process between esketamine nasal spray or ECT should include the assessment of contraindications, age, severity of disease, presence of psychotic symptoms, patient preference and treatment accessibility. We conclude that both treatment options are highly effective in TRD. If both are indicated, pragmatically esketamine will be chosen before ECT; however, ECT studies in ketamine non-responders are missing.

Effects of ketamine on metabolic parameters in depressive disorders: A systematic review.

BACKGROUND: Persons with Major Depressive Disorder (MDD), notably treatment-resistant depression (TRD), are differentially affected by type 2 diabetes mellitus and associated morbidity. Ketamine is highly efficacious in the treatment of adults living with MDD, notably TRD. Herein, we sought to determine the effect of ketamine on metabolic parameters in animal stress paradigms and human studies. METHODS: We performed a comprehensive search on PubMed, OVID, and Scopus databases for primary research articles from inception to May 5, 2024. Study screening and data extraction were performed by two reviewers (S.W. and G.H.L.). Both preclinical and clinical studies were included in this review. RESULTS: Results from the preclinical studies indicate that in experimental diabetic conditions, ketamine does not disrupt glucose-insulin homeostasis. Within adults with MDD, ketamine is associated with GLUT3 transporter upregulation and differentially affects metabolomic signatures. In adults with TRD, ketamine induces increased brain glucose uptake in the prefrontal cortex. Available evidence suggests that ketamine does not adversely affect metabolic parameters. LIMITATIONS: There are a paucity of clinical studies evaluating the effects of ketamine on glucose-insulin homeostasis in adults with MDD. CONCLUSIONS: Our results indicate that ketamine is not associated with significant and/or persistent disruptions in metabolic parameters. Available evidence indicates that ketamine does not adversely affect glucose-insulin homeostasis. These results underscore ketamine's efficacy and safety as an antidepressant treatment that is not associated with metabolic disturbances commonly reported with current augmentation therapies.

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications.

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

Technical Report: Efficacy and Safety of Low-Intensity Transcranial Magnetic Stimulation in the Remission of Depressive Symptoms in Patients With Treatment-Resistant Depression in Mexico.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that induces action potentials in the stimulated cortical area and has been approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The prevalence of MDD in Mexico almost tripled after the COVID-19 pandemic. In this study, we evaluated the safety and therapeutic effects of low-intensity TMS (Li-TMS) - characterized by inducing electric currents below the action potential threshold on the cerebral cortex - in 41 subjects diagnosed with treatment-resistant depression (TRD). A Li-TMS device dispensed repetitive magnetic pulses at 30 mT for 60 minutes during 20 sessions (once daily from Monday to Saturday) with the theta burst pattern. Our results suggest that Li-TMS is a safe therapy with antidepressant effects, demonstrated by the decrease in Beck Depression Inventory (BDI) scores and lessening of depressive symptoms.

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

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To 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. METHODS: Medical, 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). RESULTS: Unipolar 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. CONCLUSIONS: RECOVER-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 REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Combination of Transcranial Magnetic Stimulation and Ketamine in Treatment-Resistant Depression: A Systematic Review.

Treatment-resistant depression (TRD) is a significant challenge in psychiatric practice, affecting a substantial proportion of patients with major depressive disorder (MDD). Traditional treatment modalities often fall short, necessitating the exploration of alternative therapies. This literature review examines the combined use of Transcranial Magnetic Stimulation (TMS) and ketamine in treating TRD. The objective of this study is to evaluate the efficacy, safety, and potential synergies of combining TMS and ketamine in the treatment of TRD. A comprehensive literature search was conducted using PubMed and Google Scholar databases from 2014 to 2024. The search terms included combinations of "Transcranial Magnetic Stimulation," "Ketamine," "Depression," "Major Depressive Disorder," "Treatment-Resistant Depression," and "Combination." After screening for relevance and applying inclusion and exclusion criteria, six studies were selected for review, including three case reports, a retrospective study, a pilot study, and a review study. The selected studies demonstrated that the combination of TMS and ketamine resulted in substantial and sustained improvement in depressive symptoms for patients with TRD. Case reports and retrospective studies highlighted significant reductions in depression severity and improvements in psychosocial functioning. The combination therapy showed a higher efficacy compared to monotherapies of either TMS or ketamine alone. Notably, adverse effects were generally mild and transient, with no severe adverse events reported in most studies. In conclusion, the combination of TMS and ketamine presents a promising treatment modality for patients with TRD, offering significant improvements in depressive symptoms and better outcomes compared to traditional monotherapies. However, the heterogeneity in study designs and small sample sizes underline the need for larger, randomized controlled trials to establish standardized protocols and further validate these findings.

A Retrospective Case-Control Study on the Differences in the Effectiveness of Theta-Burst Stimulation Therapy for Depression with and without Antidepressant Medication.

Transcranial magnetic stimulation (TMS) therapy has few side effects and comparable therapeutic effects to antidepressant treatment, but few studies have introduced TMS therapy as an initial treatment for MDD. The objective of this study was to retrospectively compare the clinical outcomes between 50 MDD patients without antidepressants (i.e., TMS monotherapy) and 50 MDD patients with antidepressants plus TMS therapy, matched for age, sex, and depression severity. The presence or absence of antidepressant therapy in first-line treatment was determined via a detailed interview by psychiatrists. The study design was a retrospective observational case-control study using the TMS registry data. The key inclusion criteria were adult patients who met the diagnosis of MDD and received 20-30 sessions of intermittent theta-burst stimulation (iTBS) therapy to the left dorsolateral prefrontal cortex (DLPFC). In this study, the Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary outcome measure. No significant group differences existed in the baseline MADRS total score between the unmedicated and medicated patient groups. Following TMS therapy, no significant group differences in response rate, remission rate, or relative total score change in the MADRS were observed. The main limitations were the retrospective design and the use of registry data as a source. Our findings suggest that TMS monotherapy may be as effective as TMS add-on therapy to antidepressants when used as the first-line therapy for MDD, but randomized controlled trials are needed.