Efficacy and safety of esketamine versus propofol in electroconvulsive therapy for treatment-resistant depression: A randomized, double-blind, controlled, non-inferiority trial.

BACKGROUND: Electroconvulsive therapy (ECT) is a commonly used alternative for treatment-resistant depression (TRD). Although esketamine has a rapid pharmacological antidepressant action, it has not been studied as an ECT anesthetic. The objective of this study was to compare the efficacy and safety of esketamine with propofol when both are used as ECT anesthetic agents. METHODS: Forty patients with TRD were assigned to one of two arms in a double-blind, randomized controlled trial: esketamine or propofol anesthesia for a series of eight ECT sessions. Using a non-inferiority design, the primary outcome was the reduction in HAMD-17 depressive symptoms. The other outcomes were: rates of response and remission, anxiety, suicidal ideation, cognitive function, and adverse events. These were compared in an intention-to-treat analysis. RESULTS: Esketamine-ECT was non-inferior to propofol-ECT for reducing TRD symptoms after 8 sessions (adjusted Δ = 2.0, 95 % CI: -1.2-5.1). Compared to propofol-ECT, esketamine-ECT also had higher depression response (80 % vs. 70 %; p = .06) and remission (65 % vs. 55 %; p = .11) rates but non-inferiority was not established. In four components of cognitive function (speed of processing, working memory, visual learning, and verbal learning) esketamine-ECT was non-inferior to propofol-ECT. The results for anxiety, suicidal ideation, and adverse events (all p's > .05) were inconclusive. CONCLUSION: Esketamine was non-inferior to propofol when both are used as anesthetics for TRD patients undergoing ECT. Replication studies with larger samples are needed to examine the inconclusive results. REGISTRATION NUMBER: ChiCTR2000033715.

Cause-specific mortality in treatment-resistant major depression: Population-based cohort study.

BACKGROUND: Limited evidence-base on long-term prognosis of treatment-resistant major depression (TRD) is a barrier to clinical decision-making. Therefore, the purpose of this study was to establish cause-specific mortality in TRD compared to non-TRD major depression. METHOD: We identified all individuals with a diagnosis of major depression (MDD) who were treated with an antidepressant aged 15 to 65 years during 2004-2016 in Finland. Persons with over two treatment trials were defined to have TRD. Data were analysed with Cox proportional hazard models. RESULTS: 176,942 individuals with MDD (63 % women, median age at index diagnosis 40 years), of whom 11 % (n = 19,305) fulfilled the TRD criteria, were followed-up for 1,525,646 person-years (median 8.9 years). There were 959 deaths (6.1 deaths/1000 person-years) in TRD and 7662 deaths (5.6/1000 person-years) in non-TRD. All-cause mortality was 17 % higher (adjusted hazard ratio (aHR), 1.17; 95 % confidence interval (CI), 1.09-1.25) in TRD compared to non-TRD, when sex and age at index antidepressant prescription were controlled for. In TRD, increased mortality was observed for suicides (aHR, 1.90; 95%CI, 1.64-2.20) and for accidental poisonings (aHR, 1.81; 95%CI, 1.48-2.22), but not for natural causes (aHR, 0.98; 95%CI, 0.90-1.07). A higher proportion of accidental drug overdoses was observed in TRD than in non-TRD (62 % vs 42 %, respectively). LIMITATIONS: Definition of TRD lacks consensus. We used routine data to define TRD. CONCLUSIONS: The markedly increased mortality due to suicides and accidental overdoses suggests that persons with TRD may experience higher intensity symptoms and more severe suicidal ideation than persons with non-TRD major depression.

The Efficacy of Renal Denervation in Treating Resistant Hypertension: A Systematic Review.

Resistant hypertension is blood pressure (BP) that is persistently above target in spite of the maximally tolerated usage of at least three anti-hypertensives simultaneously. The sympathetic nervous system is instrumental in blood pressure (BP) regulation. Renal (sympathetic) denervation involves using ablative energy to disrupt the sympathetic nerves in renal arteries. This systematic review examines the efficacy of this treatment modality. Abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, we conducted an extensive literature search in five databases, Cochrane Library, Google Scholar, PubMed, PubMed Central (PMC), and ScienceDirect, to retrieve studies that are free, open access, and published in English done within the past four years. Nineteen articles passed critical appraisal. These articles were randomized controlled trials (RCT), a case report, a cross-sectional study, a cohort study, and previous reviews. Renal denervation (RDN) was generally superior to sham control in patients with resistant hypertension for reducing various systolic blood pressure (SBP) measures, including 24-hour ambulatory, daytime, and nighttime SBP. The efficacy was highest in patients whose baseline SBP was higher. BP reduction was sustained for years post-procedure. The procedure had a good safety profile with no severe complications. Future studies should compare the efficacy of different types of renal denervation, such as ethanol ablation versus radiofrequency ablation, and renal denervation against other procedure-based treatment modalities, such as carotid baroreceptor stimulation and transcranial direct current stimulation.

Ketamine for refractory depression: Save the best for last?

Ketamine has recently been shown to be non-inferior to electroconvulsive therapy (ECT), one of psychiatry's most effective treatments for depression. Given the novelty of ketamine as well as its interventional nature, ketamine is currently viewed as an alternative to ECT and as such, considered a third-line agent for treatment-refractory depression. However, available data suggest that ketamine carries a low side-effect burden and is better tolerated than many second-line augmentation strategies for depression. With this combination of higher efficacy and lower side-effect burden in conjunction with what is known about treatment outcomes in relation to the duration of untreated illness, it is in the best interest of patients for the field of psychiatry to evaluate ketamine as a second-line augmentation strategy for refractory depression.

Brain structural changes underlying clinical symptom improvement following fast-acting treatments in treatment resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT), ketamine infusion (KI), and total sleep deprivation (TSD) are effective and fast in treating patients with treatment-resistant depression (TRD). However, it remains unclear whether the three treatments have the same effect on clinical symptom improvement and have common brain structural mechanisms. METHODS: The current study included 127 TRD patients and 37 healthy controls, which were obtained from the Perturbation of the Treatment Resistant Depression Connectome Project. We aimed to investigate the shared and distinct brain structural changes underlying clinical symptom improvement among ECT, KI, and TSD treatments. RESULTS: All of the three treatments significantly reduced the depressive symptoms in TRD patients, but they differently affected other clinical measurements. Neuroimaging results also revealed that all of ECT, KI, and TSD treatments significantly increased gray matter volume of left caudate after treatment in TRD patients. However, the gray matter volume of other brain regions including hippocampus, parahippocampus, amygdala, insula, fusiform gyrus, several occipital and temporal areas was increased only after ECT treatment. Still, the baseline or the change of gray matter volume did not correlate with the depressive symptom improvement for all of the three treatments. LIMITATIONS: A higher sample size would be required to further validate our findings. CONCLUSIONS: The results observed in the current study suggested that the ECT, KI, and TSD treatments differently affected clinical measurements and brain structures in TRD patients, though all of them were effective in depressive symptom improvement, which might facilitate the development of personalized treatment protocol for this disease.

Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition.

Introduction: Predictors of functioning are well-studied in schizophrenia, but much less so in treatment-resistant schizophrenia (TRS). In this study, we aim to investigate contributions of schizophrenia symptom domains and neurocognition to predict functioning in a TRS population (n = 146). Methods: Participants were assessed on the Positive and Negative Syndrome Scale (PANSS), to calculate scores for five symptom factors (Positive, Negative, Cognitive, Depressive and Hostility) and two negative symptom constructs (Diminished Expressivity (DE), and Social Anhedonia (SA) as part of the Motivation and Pleasure-related dimension), based on a previously validated model, modified in accordance with EPA guidelines on negative symptoms assessment. Neurocognition was assessed with symbol coding and digit sequencing tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). Functioning was assessed with the Social and Occupational Functioning Assessment Scale (SOFAS), employment status and World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Multiple regression analyses were performed on psychopathology scores and BACS scores against all three measures of functioning, controlling for age and sex. For WHODAS, regression with PANSS scores of significant symptom factors were also performed. Results: A lower severity of negative symptoms in the SA dimension was the strongest predictor of higher functioning across all three functioning measures. Neurocognition, in particular processing speed and attention assessed on the symbol coding task, predicted employment. A lower severity of somatic concerns and depressive symptoms was associated with lesser self-reported disability on WHODAS. Discussion: This study represents a first attempt at elucidating significant predictors of functioning in TRS. We highlight negative symptoms and neurocognition as important treatment targets to improve functioning in TRS, consistent with previous studies in general schizophrenia.

Real-world treatment outcomes of transcranial pulsating electromagnetic fields as augmentation therapy for treatment-resistant depression.

BACKGROUND: Treatment outcomes of patients who had received T-PEMF as an augmenting therapy at Aalborg University Hospital, Aalborg, Denmark, was evaluated. METHODS: Patients diagnosed with unipolar depression or bipolar disorder who had received a self-administered 8-week T-PEMF series between November 2019 and April 2023 were included. Data were retrieved from the patients' records. The primary outcome was the Hamilton Rating Scale for Depression 17-item version (HAMD17), both as a continuous measure and with proportions of response and remission reported. RESULTS: A total of 57 patients (65.1 % females, 86.0 % unipolar depression, mean age, 48 ± 14 years) were included. Duration of current depressive episode was almost equally divided for <2 years (38.6 %), 2-5 years (38.6 %) and > 5 years (22.8 %). HAM-D17 decreased significantly from baseline (20.8 (SD: 3.3)) to week 8 (14.5 (SD: 6.2), p < 0.001). An episode duration of 2-5 years was associated with lower odds of response on HAM-D6 (adjusted OR = 0.15, 95 % CI: 0.03; 0.96, p < 0.05) and self-rated HAM-D6 (adjusted OR = 0.09, 95 % CI: 0.01; 0.99, p = 0.05) when compared to an episode duration <2 years. LIMITATIONS: This study is limited by a lack of a control group, limited controlling of confounders, small sample sizes, and an attrition rate of 29.8 % for the primary outcome. CONCLUSION: T-PEMF reduced depressive symptoms in a real-world clinical setting including patients with both unipolar depression and bipolar disorder. Receiving T-PEMF within the first 2 years of the depressive episode was associated with an improved outcome.

Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression.

Background: Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by more accurate and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modeling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models are useful in predicting clinically meaningful change in symptom severity, i.e. categorical (non)response as opposed to continuous scores. Methods: We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression, across multiple coils and protocols. We then compared the predictive power of those models. Results: LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52 - 0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. Conclusions: In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

Deep Brain Stimulation (DBS) in Treatment-Resistant Depression (TRD): Hope and Concern.

In this chapter, we explore the historical evolution, current applications, and future directions of Deep Brain Stimulation (DBS) for Treatment-Resistant Depression (TRD). We begin by highlighting the early efforts of neurologists and neurosurgeons who laid the foundations for today's DBS techniques, moving from controversial lobotomies to the precision of stereotactic surgery. We focus on the advent of DBS, emphasizing its emergence as a significant breakthrough for movement disorders and its extension to psychiatric conditions, including TRD. We provide an overview of the neural networks implicated in depression, detailing the rationale for the choice of common DBS targets. We also cover the technical aspects of DBS, from electrode placement to programming and parameter selection. We then critically review the evidence from clinical trials and open-label studies, acknowledging the mixed outcomes and the challenges posed by placebo effects and trial design. Safety and ethical considerations are also discussed. Finally, we explore innovative directions for DBS research, including the potential of closed-loop systems, dual stimulation strategies, and noninvasive alternatives like ultrasound neuromodulation. In the last section, we outline recommendations for future DBS studies, including the use of alternative designs for placebo control, the collection of neural and behavioral recordings, and the application of machine-learning approaches.

Efficacy, Safety, and Tolerability of Psychedelics in Treatment-Resistant Depression (TRD).

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.

Major depressive disorder (MDD) is a psychiatric disorder with several effective therapeutic approaches, being antidepressants and psychotherapies the first-line treatments. Nonetheless, due to side effects, limited efficacy, and contraindications for these treatments, alternative treatment options are required. Neurostimulation is a non-pharmacological and non-psychotherapeutic approach that has been under study for diverse neuropsychiatric conditions in the form of electrical or magnetic stimulation of the brain. Repetitive transcranial magnetic stimulation (rTMS) is a neurostimulation method designed to generate magnetic fields and deliver magnetic pulses to stimulate the brain cortex. The magnetic pulses produce electrical currents in the brain which are not intense enough to provoke seizures, differentiating this method from other forms of neurostimulation that produce seizures. Although the exact rTMS mechanisms of action are not completely understood, rTMS seems to cause its beneficial effects through changes in neuroplasticity. Devices and protocols for rTMS are still evolving, becoming more efficient over time. There are still some challenges to be addressed, including further refinement of parameters (coil/device type, location, intensity, frequency, number of sessions, and duration of treatment); treatment cost and burden for patients; and treatment resistance. However, the efficacy, tolerability, and safety of some rTMS protocols have been demonstrated in different double-blind sham-controlled randomized controlled trials and meta-analyses for treatment-resistant depression.

The Importance of Psychotherapy for Treatment-Resistant Depression.

Many clinicians choose psychoanalytic psychotherapy or supportive psychotherapy as the primary method of treating depression with or without antidepressant medications. Despite new antidepressants, 20% or more patients showed inadequate responses to the medications, and remained in chronic courses, known as "treatment-resistant depression (TRD)."In this chapter, we described (1) the reasons for psychotherapy in treating TRD from the perspectives of the hazard of polypharmacy, resistance, and neural mechanisms. (2) Next, we focused on the importance of assessment with two clinical vignettes and the original modality of psychoanalysis, psychoanalytic psychotherapy, and supportive psychotherapy in brief. (3) Finally, we described specific considerations in undertaking psychotherapy for TRD patients in terms of transference, countertransference, and resistance. In addition, the efficacy of psychoanalytic psychotherapy in childhood, adolescent, and late-life depression has been depicted in this paper.

Interventional approaches to treatment resistant depression (DTR) in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. METHODS: Following PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10-24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. RESULTS: Meta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92-3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04-2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79-4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. CONCLUSIONS: This meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed.

Transformative Outcomes With Paliperidone Long-Acting Injection in Severe Treatment-Resistant Schizophrenia: A Case Report and Literature Review.

Treatment-resistant schizophrenia (TRS) presents considerable challenges in contemporary psychiatric practice due to inadequate response to conventional antipsychotic treatments. Paliperidone, the primary active metabolite of risperidone, particularly in its long-acting injectable (LAI) form, has emerged as a promising option for TRS due to its consistent medication delivery, reducing symptom exacerbation and relapse associated with oral dosing fluctuations. This case report presents the clinical journey of a 42-year-old female diagnosed with schizophrenia at age 15. Despite numerous hospital admissions and trials of various oral and injectable antipsychotics, including clozapine and electroconvulsive therapy (ECT), her symptoms persisted. During her last admission, her condition showed minimal improvement despite extensive pharmacological interventions. Introducing paliperidone LAI while tapering off other antipsychotics led to significant improvements within four weeks. The patient exhibited reduced hallucinatory behaviour, delusions, and disorganized behaviour. Follow-up assessments confirmed sustained progress, with the patient showing increased engagement in daily activities and reduced irritability and suspiciousness. This case underscores the potential efficacy of paliperidone LAI in managing TRS. The patient's notable improvement highlights the importance of personalized treatment plans and continuous monitoring in complex psychiatric conditions. Its favourable safety and tolerability profile further supports its use as a long-term treatment option for TRS, potentially leading to enhanced patient compliance and overall quality of life. The significant symptomatic relief and functional improvement observed advocate for the consideration of paliperidone LAI as a promising therapeutic option for TRS, with the potential to be considered in the future among the first-line treatments for TRS.

Real-world demographic and clinical profiles of patients with treatment-resistant depression initiated on esketamine nasal spray.

OBJECTIVE: ESKALE is a French, multicentre, observational study of adults with treatment-resistant depression (TRD) treated with esketamine. This interim analysis describes baseline demographic and clinical characteristic evolution in patients included and treated from early access program to post-marketing launch. METHODS: Data were collected from medical records and included patient characteristics, disease history at esketamine initiation, use of neurostimulation, the patient's care pathway, and the number of antidepressant treatment lines prescribed prior to esketamine initiation. Descriptive statistics were used for each cohort: the early access program 'Temporary Authorisation for Use' (ATU), post-ATU, and post-launch cohorts. RESULTS: The overall ESKALE cohort (N = 160 included; n = 157 treated with esketamine; average age 49.0 years; 66.2% female) demonstrated moderate-to-severe depression according to clinical assessment and a mean Montgomery-Åsberg Depression Rating Scale score of 32.6 (8.0); however, severity, subtype, and comorbidities were heterogeneous across the cohorts. Earlier use of esketamine and prior to alternative treatments occurred during the later cohorts. CONCLUSION: These findings demonstrated a high burden of TRD in these patients and that esketamine is used in TRD treatment regardless of their disease severity, subtype, or existing comorbidities. These results also suggest that esketamine is potentially a clinically useful alternative treatment, particularly with healthcare professionals gaining greater familiarity with and easier access to esketamine.

ESKALE is a long-term, French, multicentre, observational study based on secondary data in adult patients with treatment-resistant depression (TRD) who initiated esketamine treatment in one of three mutually exclusive cohorts: the Temporary Authorisation for Use (ATU), post-ATU, and post-launch cohorts.ESKALE is one of the largest European real-world studies investigating the profiles of more than 150 patients and their treatment with esketamine before and after marketing authorisation.A majority of patients had moderate to severe TRD, with multiple treatment failures with medications and/or neurostimulation prior to esketamine initiation.Esketamine nasal spray administration was undertaken more frequently in an outpatient setting, with the post-administration period monitoring being undertaken mostly by nurses.Esketamine was used in patients with TRD in real-world conditions regardless of their disease severity and subtype or existing comorbidities.These results highlight both the need for an effective treatment for TRD and the adoption of esketamine by multidisciplinary teams that are involved in esketamine prescription and administration.

Examination of a case of "treatment failure" in long-term psychoanalytic psychotherapy for treatment-resistant depression.

Randomized controlled trials have reported psychoanalytic psychotherapy to improve longer-term post-treatment outcomes in patients with treatment-resistant depression. In this case study, we examine the therapy process of a female trial participant diagnosed with treatment-resistant depression. Structured clinical assessments indicated that the patient's level of depression remained unchanged during and after treatment. Over the course of the therapy, she repeatedly broke away from important others and finally also from the therapy itself, which we linked to the impact of earlier experiences of abandonment on her internal world. In the discussion, we present a variety of reflections that were put forward by the authors during a series of case discussion meetings. Some of these reflections relate to how the inner world of this patient might have triggered a negative therapeutic reaction and a destructive pattern of repetition. The interpretative stance, in which the therapist interpreted this reaction as indicative of a psychic conflict and linked this conflict to the therapeutic relationship, seemed to be experienced by the patient as unhelpful and persecutory. Other elements that were brought up include basic distrust, lack of symbolization and trauma in the patient, as well as the constraints of the research context.

Predictors of response to accelerated rTMS in the treatment of treatment-resistant depression.

Accelerated repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for treatment-resistant depression (TRD). We aimed to investigate the existence of clinical predictive factors in response to accelerated rTMS in the treatment of TRD. In total, 119 TRD patients who received accelerated rTMS were included in this study. The stimulation protocol was 15 Hz stimulation over the the left dorsolateral prefrontal cortex. The protocol consisted of 25 sessions, each session lasting 30 min for a total of 3000 pulses. Five sessions were applied per day for 5 consecutive days. At baseline (T0), day 5 (immediately after treatment) (T1), 4 weeks after treatment (T2), depression severity was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD-17), cognitive function was evaluated using Wisconsin Card Sorting Test (WCST), the intensity of suicidal ideation was evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS). Systemic immune-inflammation index (SII) was calculated at T0 and T2. The HAMD-17 scores, WCST performance, the C-SSRS scores at T1 and T2 were improved from T0 (P < 0.01). The SII at T2 was lower than at T0 (P < 0.01). The response rates at T1 and T2 were 57.98% (69/119) and 48.74% (58/119), respectively. The results of binary logistic analysis showed that shorter course of depression, two failed antidepressant trials, no history of ECT treatment, and lower levels of SII were predictive factors for accelerated rTMS treatment response at T1 and T2 (P < 0.05), while not having a history of hospitalization was a predictive factor for response at T2 (P < 0.05) but not at T1 (P > 0.05). Based on ROC curve analysis, the optimal cut-off values of SII for discriminating responders from non-responders at T1 and T2 were < 478.56 and < 485.03, respectively. The AUC of SII at T0 predicting response for T1 and T2 were 0.729 and 0.797. We found several clinical predictors of better responses to the accelerated rTMS. Identifying clinical predictors of response is relevant to personalize and adapt rTMS protocols in TRD patients.

Optimizing antidepressant benefits: Effect of theta burst stimulation treatment in physically active people with treatment-resistant depression.

Theta burst stimulation (TBS) is a promising therapy for treatment-resistant major depressive disorder (MDD), but a significant proportion of individuals do not respond adequately, necessitating alternative approaches. This study explores whether individuals meeting minimum recommended physical activity levels demonstrate better responses to TBS compared to physically inactive individuals. Using data from a randomized controlled trial (n = 43), participants were categorized as physically active or inactive based on baseline International Physical Activity Questionnaire (IPAQ) scores. Depression scores (Hamilton Rating Scale for Depression, 17-item; HRSD-17) were assessed at baseline, 4, and 6 weeks of TBS treatment. A significant Time X Group effect adjusted for age and baseline depression was observed. Physically active individuals consistently exhibited lower depression scores across time points. At 4 and 6 weeks, there was a significant increase in between-group differences, indicating that the physically active group derived greater benefits from treatment. At 6 weeks, a significantly higher proportion of responders (≥50 % HRSD-17 reduction) were observed in the physically active compared to inactive group. Physical activity significantly contributed to regression and logistic models predicting treatment response. These findings support the potential role of baseline physical activity in enhancing TBS therapy for MDD.

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.