The RESTORE-LIFE study (ClinicalTrials.govNCT03320304) is a global, prospective, multi-center, observational study, which assesses the long-term effectiveness and safety of vagus nerve stimulation (VNS) as an adjunctive treatment in difficult-to-treat depression (DTD). Data on the impact of stimulation parameters on clinical outcome are limited.

The study is ongoing, however titration of stimulation parameters and their association with clinical response was analyzed in the first 100 patients (mean age 50.0, range 22-79) reaching 12 months follow-up. Daily charge delivered was compared in 12-month responders vs. non-responders to VNS. Regression models were employed to investigate the relationship between VNS dosing parameters and mean MADRS reduction.

The probability of reaching an output current of 1.0 mA and 1.5 mA was 93 % and 70 % at 6 months and 95 % and 81 % at 12 months respectively. By month 12, there was a trend towards higher daily charge delivered in non-responders than in responders (p = 0.0798 for median). Older age (>65, p = 0.001) as well as high baseline MADRS (p < 0.001) were significantly predictive for mean MADRS reduction, whereas stimulation parameters at 12 months were not.

The majority of patients reached a current output of at least 1.5 mA, which is considered to be well within the therapeutic range. The daily charge delivered was higher in non-responders, possibly because physicians tended to increase the duty cycle in those who did not respond. Demographics typically associated with difficulty to treat (older age and higher baseline MADRS) were associated with greater MADRS reduction.

New pathogenesis-based therapeutics and evidence-based consensus treatment recommendations, often with predefined treatment goals, have remarkably improved outcomes across many chronic diseases. However, a clinically significant subgroup of patients responds poorly to interventions and show a progressive decline in the disease trajectory, which poses an increasing health-care challenge. Difficult-to-treat approaches exist in several areas of medicine and the need for similar definitions has recently also emerged in rheumatology. The term difficult-to-treat refers not only to patients with pathology-driven, treatment-refractory disease, but also implicates multiple other factors that can contribute to patients being in this state, including having few treatment options, misdiagnosis, and coincident psychosocial factors. Therefore, the difficult-to-treat state requires a comprehensive, holistic, multidisciplinary approach that considers the specific characteristics of each disease and the personalised needs of the patient. In this Personal View, we provide an overview of the different aspects of the concept of difficult-to-treat disease, highlight its advantages, and propose the importance of incorporating this concept more widely in the design of rheumatological treatment strategies.

Suicide attempts are a major concern in major depressive disorder (MDD), especially for those with multiple prior unsuccessful treatment trials. This report compares baseline demographic, clinical features, and treatment history of participants with marked treatment-resistant, nonpsychotic MDD based on lifetime history of suicide attempt (SA vs NSA).

RECOVER is a randomized, sham-controlled trial of vagus nerve stimulation and the largest such trial of a psychiatric neuromodulation intervention. Baseline data were analyzed. Univariate analyses (SA vs NSA) and logistic regression with backward selection (variables with univariate p <0.1) were performed.

SA group (N = 196) was more likely than NSA group (N = 297) to be female (72.4% vs 61.6%), <65 years of age (73.5% vs 61.6%), have earlier onset of depressive symptoms (mean, 19.1 vs 22.5 years), earlier diagnosis of MDD (mean, 25.0 vs 29.2 years), higher percentage of lifetime in depressive episodes (mean, 56.0% vs 51.0%), more failed antidepressants (mean, 15.0 vs 12.1), and greater lifetime use of electroconvulsive therapy (ECT; 55.1% vs 40.1%). Female sex, age at MDD diagnosis, number of failed antidepressants, number of psychiatric hospitalizations, and baseline suicide score retained association with logistic regression analysis.

Information on medical morbidity of suicide attempts was not collected and timing of suicide attempts relative to treatment exposures was unknown.

For marked treatment-resistant MDD, those with prior suicide attempts have more complex course of illness with earlier onset of depressive symptoms, earlier diagnosis of MDD, more lifetime spent in depressive illness, more failed antidepressant medication trials, and greater use of ECT.

ClinicalTrials.gov Identifier NCT03887715.

The RECOVER trial randomized 493 patients with markedly treatment-resistant major depressive disorder to treatment-as-usual with or without active vagus nerve stimulation (VNS Therapy). While the primary outcome measure did not statistically separate the treatment conditions, the field may lack optimal metrics for quantifying symptom improvement in markedly treatment-resistant patients.

This study examined the impact of three factors on sensitivity to clinical improvement across the total RECOVER sample and to differences in the effectiveness of the randomized conditions, systematically varying outcome classification (remission, response, and partial response), observation period (3-12 months, 6-12 months, 10-12 months and last observation), and depression rating scale.

Effect sizes for detecting therapeutic change across the total sample and the difference in effectiveness between the randomized groups were markedly higher for partial response than response or remission classifications. Longer observation periods produced larger therapeutic effects across the sample, but the effect sizes for the randomized treatment differences were substantially higher in the final 10-12 month period. The MADRS showed the least sensitivity to change across the sample and between the treatment groups. Using the partial response classification and the 10-12 month observation period, a significant difference between the groups was obtained for 3 of 4 depression scales.

The findings derive from a retrospective assessment of alternative outcome metrics.

In a large randomized controlled trial of VNS for markedly treatment-resistant depression, the magnitude of therapeutic effects and separation of treatment groups differed as a function of outcome classification, measurement period, and rating scale.

Ketamine is an N-methyl-D-aspartate receptor antagonist that has shown effectiveness as a rapidly acting treatment for depression. Although advances have been made in understanding ketamine's antidepressant pharmacological and molecular mechanisms of action, the large-scale neurocognitive mechanisms driving its therapeutic effects are less clearly understood. To help provide such a framework, we provide a synthesis of current evidence linking ketamine treatment to the modulation of brain systems supporting reward processing, interoception, and self-related cognition. We suggest that ketamine's antidepressant effects are, at least in part, driven by dynamic multi-level influences across these key functional domains.

Major depressive disorder affects more than 50 million people in the world. However, 50% of patients don't respond to two or more drugs or psychotherapeutic treatments, named treatment-resistant depression (TRD). In this work, we propose a new augmentation treatment against TRD based on combining Fluoxetine (FLX) and the N-terminal fragment Galanin, GAL(1-15). In Wistar Kyoto (WKY) rats, akin to endogenous depression genetically, we evaluate GAL(1-15)'s impact on FLX-induced behaviours on tests measuring despair and anhedonia. We explored GALR2 involvement using the antagonist M871 and an in vivo model with siRNA 5-HT1A knockdown. Also, the 5-HT1AR was analyzed by autoradiography binding in several brain regions. We analyze the corticosterone levels and a dexamethasone-suppressed corticotropin-releasing hormone stimulation to study the HPA axis regulation. Our results shows that only the combination of FLX + GAL(1-15) induced antidepressant effects in the WKY animals in Behavioural tests related to despair. This combination also reduced corticosterone levels in the WKY animals and modulated the functional characteristics of the serotoninergic receptor 5-HT1A in the prefrontal cortex. These novel results suggest combining GAL(1-15) with FLX is a new potentiation strategy in TRD cases. It shows the innovative potential of the interactions between the galaninergic and serotonergic systems to find new strategies and drugs against resistant depression.

High adherence to the Mediterranean diet (MD) has been associated with a reduced risk of depression in prospective cohort studies, but whether MD interventions are effective among adults with depression is uncertain.

This study aimed to synthesize findings on the effects of MD interventions on the severity of depressive symptoms in adults with depression.

PubMed, Cochrane CENTRAL, PsycINFO, Scopus, and Web of Science were systematically searched from database inception to March 2023. The Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines and the Cochrane recommendations were followed. We included randomized controlled trials (RCTs) comparing outcomes after MD interventions with outcomes for control conditions in adults with depressive disorders or depressive symptoms.

Two authors extracted the data independently. The Sidik-Jonkman estimator, the I2 metric, and the prediction interval were used to estimate between-study heterogeneity. To determine the risk of bias and the certainty of evidence from RCTs, we used the Cochrane Collaboration's Risk of Bias 2 and Grades of Recommendation, Assessment, Development, and Evaluation tools, respectively.

In total, 1507 participants (mean age range: 22.0 years-53.3 years) with depression were initially included in the 5 RCTs of this review. Compared with control conditions, MD interventions significantly reduced depressive symptoms among young and middle-aged adults with major depression or mild to moderate depressive symptoms (standardized mean difference: -0.53; 95% confidence interval: -0.90 to -0.16; I2 = 87.1%). The prediction interval ranged from -1.86 to 0.81. The overall risk of bias was within the range of "some concerns" to "high," while the certainty of evidence was low.

MD interventions appear to have substantial potential for alleviating depressive symptoms in people experiencing major or mild depression. However, to establish robust recommendations, there remains a need for high-quality, large-scale, and long-term RCTs.

PROSPERO registration no. CRD42022341895.

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.

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.

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).

Definition of TRD lacks consensus. We used routine data to define TRD.

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.

Process-based therapy (PBT) is a new framework to intervention planning, based on the use of ecological momentary assessment (EMA) data and dynamic and idiographic network analyses. Support for its applicability has been reported from a single-case studies. Here, we examine the feasibility and effectiveness of PBT in a larger clinical sample. We have translated a training manual of PBT and modified for delivery of CBT in mental health service. The aim of this study is to test the relative efficacy of PBT compared to traditional CBT delivered in routine practice (r-CBT) for difficult-to-treat mood and anxiety disorders.

The study is a randomized controlled trial (RCT) of PBT vs r-CBT for difficult-to-treat unipolar depression and anxiety disorders. In total, 80 patients are recruited at an outpatient clinic and included in two intervention arms. Primary outcome is emotional distress; secondary outcomes include psychological well-being and quality of life, adaptive behavior, psychological flexibility, and reflective functioning. Assessments of outcome variables are conducted before and after therapy and at 6 months follow-up. Weekly patient-rated outcomes are collected for every session to investigate process of change. Outcome assessors, blind to treatment allocation, will perform the observer-based symptom ratings, and adherence with manual will be monitored using self-report.

The current study will be the first RCT of PBT in a health care setting. The planned moderator and mediator analyses will clarify the mechanisms of change in psychotherapy and the association between personalized assessment based on dynamic network analysis and treatment effect.

ClinicalTrials.gov NCT06517589. Registered 24 July 2024.

Few treatments are available for individuals with marked treatment-resistant depression (TRD).

Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD.

This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3-12, with response defined as a ≥50 % change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated.

Overall, 88.4 % of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory-Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology-Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology-Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P = 0.004) and QIDS-SR (P = 0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30 %) on the CGI-I (P < 0.001) and QIDS-C (P = 0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P = 0.035), a known side effect of VNS. No new adverse events were identified.

Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD.

Depression treatments aim to minimize symptom burden and optimize quality of life (QoL) and psychosocial function.

Compare the effects of adjunctive versus sham vagus nerve stimulation (VNS) on QoL and function in markedly treatment-resistant depression (TRD).

In this multicenter, double-blind, sham-controlled trial, 493 adults with TRD and ≥4 adequate but unsuccessful antidepressant treatment trials (current episode) were randomized to active (n = 249) or sham (n = 244) VNS (plus treatment as usual) over a 12-month observation period. Quarterly outcomes included QoL with the Q-LES-Q, Mini-Q-LES-Q, and EQ-5D-5L, and function with the WHODAS 2.0 and Work Productivity and Activity Impairment Questionnaire (WPAI) item 6. Differences between treatment groups in change in scores from baseline and percentage of time with a meaningful response in Q-LES-Q, Mini-Q-LES-Q, and WPAI item 6 scores were analyzed.

Active VNS was superior to sham in mean change in scores from baseline in the Mini-Q-LES-Q (P = 0.050) and WPAI item 6 (health condition's effect on regular activities [P = 0.050]) used as continuous variables, with a similar trend for Q-LES-Q (P = 0.061). Active VNS was superior to sham in time spent in clinically meaningful benefit (categorical analyses) using the Q-LES-Q (P = 0.029), Mini-Q-LES-Q (P = 0.011), and WPAI item 6 (P = 0.039). The WHODAS 2.0 (P = 0.304) and EQ-5D visual analog scale (P = 0.125) failed to reveal between-group differences.

Active VNS was superior to sham VNS in improving QoL and psychosocial function in patients with TRD. VNS has a broader therapeutic impact than symptom improvement alone in patients with marked psychosocial impairment.

Recent evidence syntheses have supported the protective role of daily steps in decreasing the risk of cardiovascular disease and all-cause mortality. However, step count-based recommendations should cover additional health outcomes.

To synthesize the associations between objectively measured daily step counts and depression in the general adult population.

In this systematic review and meta-analysis, a systematic search of the PubMed, PsycINFO, Scopus, SPORTDiscus, and Web of Science databases was conducted from inception until May 18, 2024, to identify observational studies using search terms related to physical activity, measures of daily steps, and depression, among others. Supplementary search methods were also applied.

All identified studies were uploaded to an online review system and were considered without restrictions on publication date or language. Included studies had objectively measured daily step counts and depression data.

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted the published data.

Pooled effect sizes (correlation coefficient, standardized mean difference [SMD], and risk ratio [RR]) with 95% CIs were estimated using the Sidik-Jonkman random-effects method.

Thirty-three studies (27 cross-sectional and 6 longitudinal [3 panel and 3 prospective cohort]) involving 96 173 adults aged 18 years or older (range of mean [SD] ages: 18.6 [0.6] to 91.2 [1.6] years) were included. Daily steps were inversely correlated with depressive symptoms in both cross-sectional and panel studies. Compared with fewer than 5000 steps/d, pooled SMDs from cross-sectional studies revealed that 10 000 or more steps/d (SMD, -0.26; 95% CI, -0.38 to -0.14), 7500 to 9999 steps/d (SMD, -0.27; 95% CI, -0.43 to -0.11), and 5000 to 7499 steps/d (SMD, -0.17; 95% CI, -0.30 to -0.04) were significantly associated with fewer depressive symptoms. Pooled estimates from prospective cohort studies indicated that participants with 7000 or more steps/d had reduced risk of depression compared with their counterparts with fewer than 7000 steps/d (RR, 0.69; 95% CI, 0.62-0.77). An increase of 1000 steps/d was associated with a lower risk of depression (RR, 0.91; 95% CI, 0.87-0.94).

In this systematic review and meta-analysis of 33 observational studies involving 96 173 adults, higher daily step counts were associated with fewer depressive symptoms in cross-sectional and longitudinal studies in the general adult population. Further prospective cohort studies are needed to clarify the potential protective role of daily steps in mitigating the risk of depression during adulthood.

A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use will increase success rates in the treatment of TRD. There is a growing literature on the precision use of ketamine in TRD, and the body of evidence on esketamine is still relatively small. The identification of reliable predictors of response to ketamine/esketamine that are easily translatable to clinical practice is urgently needed. Potential clinical predictors of a robust response to ketamine include a pre-treatment positive family history of alcohol use disorder and a pre-treatment positive history of clinically significant childhood trauma. Pre-treatment versus post-treatment increases in gamma power in frontoparietal brain regions, observed in electroencephalogram (EEG) studies, is a promising brain-based biomarker of response to ketamine, given its time of onset and general applicability. Blood-based biomarkers have shown limited usefulness, with small-effect increases in brain-derived neurotrophic factor (BDNF) being the most consistent indicator of ketamine response. The severity of treatment-emergent dissociative symptoms is typically not associated with a response either to ketamine or esketamine. Future studies should ensure that biomarkers and clinical variables are obtained in a similar manner across studies to allow appropriate comparison across trials and to reduce the signal-to-noise ratio. Most predictors of response to ketamine/esketamine have modest effect sizes; therefore, the use of multivariate predictive models will be needed.

Little research is available to provide practical guidance to health care providers for exercise preparticipation screening and referral of patients with interstitial lung diseases (ILDs), including lymphangioleiomyomatosis (LAM), to participate in remote, unsupervised exercise programs.

What exercise preparticipation screening steps are essential to determine whether a patient with LAM is medically appropriate to participate in a remote, unsupervised exercise program?

Sixteen experts in LAM and ILD participated in a two-round modified Delphi study, ranking their level of agreement for 10 statements related to unsupervised exercise training in LAM, with an a priori definition of consensus. Additionally, 60 patients with LAM completed a survey of the perceived risks and benefits of remote exercise training in LAM.

Seven of the 10 statements reached consensus among experts. Experts agreed that an in-person clinical exercise test is indicated to screen for exercise-induced hypoxemia and prescribe supplemental oxygen therapy as indicated prior to initiating a remote exercise program. Patients with recent pneumothorax should wait to start an exercise program for at least 4 weeks until after resolution of pneumothorax and clearance by a physician. Patients with high cardiovascular risk for event during exercise, severe resting pulmonary hypertension, or risk for falls may be more appropriate for referral to a rehabilitation center. A LAM-specific remote exercise preparticipation screening tool was developed from the consensus statements and agreed upon by the panelists.

A modified Delphi study approach was useful to develop disease-specific recommendations for safety and preparticipation screening prior to unsupervised, remotely administered exercise in LAM. The primary product of this study is a clinical decision aid for providers to use when medically screening patients prior to participation in the newly launched LAMFit remote exercise program.

As treatment-resistant depression (TRD) is linked to suicidal behaviors and suicidal risk is a predictor of TRD, depression with current suicidal ideation (SI) may lead to TRD. Early identification of TRD risk factors in patients with depression and current SI is crucial. The aims of our study were: i) to identify risk factors for depression non-remission and TRD in patients with depression and current SI; ii) to assess if SI at baseline mediated the relationship between depression severity at baseline and depression remission at week 6. We analyzed data from two large, prospective, naturalistic French cohorts of adult outpatients with depression (DSM-IV criteria) followed for 6 weeks after starting or changing antidepressants (LUEUR and GENESE). Sociodemographic and clinical characteristics, along with early symptom improvement, were compared between patients with and without current SI using logistic regression models (univariate and multivariate). Patients with antidepressant change or initiation were analyzed separately. Those without depression remission at week 6 after an antidepressant change were considered TRD cases. In patients with antidepressant change, the major predictor of non-remission was poorer early improvement (at week 2) of anxiety. For patients with treatment initiation, SI at baseline mediated the relation between depression severity at baseline and depression remission. Depression severity at baseline alone did not explain depression remission. Clinicians should systematically target with specific pharmacological and non-pharmacological treatments anxiety and SI and assess their changes in the short term to increase the chance of depression remission in depressed patients with current SI.

Background and Objectives: Observational studies with data from real-world clinical practice with patients with difficult-to-treat depression (DTD) are rare. This study aims to collect observational data from the real-world clinical practice of a Portuguese community mental health team (CMHT) on the prevalence of DTD and to explore differences between DTD and non-DTD groups. Materials and Methods: We conducted a retrospective chart review study using data from Electronic Health Records (EHRs) of adult patients with psychiatric disorders followed by a CMHT from the Department of Psychiatry of the Coimbra Local Health Unit (between 1 December 2020-31 December 2022). The Dutch Measure for quantification of Treatment Resistance in Depression (DM-TRD) was used to assess the degree of treatment resistance and the Charlson Comorbidity Index (CCI) to measure medical comorbidity. Results: A quantity of 473 patients were referred to Cantanhede CMHT for a first assessment. Of these, 219 patients met the criteria for a primary diagnosis of any depressive disorder. Assistant psychiatrists identified 57 patients with DTD during follow-up (approximately 26%). The DTD group had higher rates of depressive episodes, greater depression severity, increased service use, higher DM-TRD scores, and a higher prevalence of comorbid anxiety symptoms, personality disorders, and severe medical comorbidities. The DTD group also had a higher prescription rate of antidepressants. Differences were observed in the use of antidepressant augmentation strategies and in the prescription of anticoagulant/antiplatelet drugs and analgesics, with higher prescription rates in the DTD group. We found correlations between DM-TRD and CCI scores, and between DM-TRD scores and all service use variables. Conclusions: Our results are consistent with a similar study in the United Kingdom, highlighting the need for a different approach to the management of DTD patients, who continue to live with a significant burden despite usual pharmacological and non-pharmacological treatments.

Major depression (MD) is a prevalent and disabling condition in Chile, with most cases being treated at the primary care level. In Chilean primary care, the authors have identified key factors associated with more complex presentations of MD and a poorer prognosis, such as a history of childhood trauma, suicidality, and comorbidities. These findings underscore the need for a multidimensional, trauma-informed, and interprofessional approach to the treatment of depression.

This protocol is a two-arm, single-blinded, cluster RCT to compare the effectiveness of a collaborative multidimensional approach for depression (CMAD) versus usual care to treat MD in primary care clinics in Chile. In total, 394 depressed adults from 18 to 65 years of age in twelve clinics located in Chile's Maule Region will be consented to participate in the study. Patients and care teams from each clinic will be randomized to the intervention or to the control arm.Interprofessional teams in the intervention arm will attend 27 hours of didactic and active learning sessions focused on clinical competences to effectively engage, treat and follow up patients with the factors associated to the complex presentation of MD. Team in the control arm will receive 27 didactic sessions on current clinical guidelines for MD.Patients of both arms will be blindly assessed at baseline, three months, and six months. The primary outcome will be the reduction in depressive symptoms, with secondary outcomes including improvements in anxiety symptoms, interpersonal and social functioning, and treatment adherence.

This protocol proposes the evaluation of an intervention designed to improve depression symptoms by enhancing the clinical competencies of primary care teams. These competencies are structured around collaborative care and trauma-informed practices.

NCT05016388, registered on 16 August 2021 at ClinicalTrials.gov.

Accumulating evidence suggests that early life trauma (ELT) initiates and perpetuates a cycle of depression, leading to challenges in management and achieving remission. This scoping review aimed to examine the intricate relationship between ELT and difficult-to-treat depression (DTD). An extensive literature search from 1 January 2013 to 21 October 2023 was conducted using the Cochrane Library, PubMed, Scopus, PsycINFO and OpenGrey.

Our review identified scientific literature illustrating the multifaceted link between ELT and DTD, highlighting the dual impact of ELT on therapeutic resistance and clinical complexity.

This complexity hampers management of patients with DTD, who are characterised by limited pharmacological responsiveness and heightened relapse risk. While exploring the ELT-DTD nexus, the review revealed a paucity of literature on the impact of ELT within DTD. Findings underscore the profound link between ELT and DTD, which is essential for comprehensive understanding and effective management. Tailoring treatments to address ELT could enhance therapeutic outcomes for patients with DTD. Future studies should use larger samples and well-defined diagnostic criteria and explore varied therapeutic approaches.

In the United States (US), prescription drug coverage is subject to prior authorization (PA) criteria, which may vary between health plans and may exceed drug label requirements. This study aimed to characterize profiles and treatment history of patients with treatment-resistant depression (TRD) who initiated esketamine nasal spray, by stringency of their health plans' PA criteria relative to the esketamine label.

Adults with evidence of TRD (≥2 antidepressant courses of adequate dose and duration) prior to initiating esketamine were identified using US insurance claims data (03/2016-02/2022). Based on health plan PA criteria for esketamine obtained from Managed Markets Insight & Technology data (05/2020-02/2022), patients were grouped into stringent (PA criteria exceeds label) and non-stringent (PA criteria less stringent or equal to label) cohorts. Patient treatment history before esketamine initiation was compared using Wilcoxon rank sum and Fisher's exact tests.

The stringent cohort included 168 patients (mean age: 45 years, 63% female) and the non-stringent cohort included 400 patients (mean age: 45 years, 70% female). During the ongoing major depressive episode before esketamine initiation, the stringent versus non-stringent cohort completed 3.9 versus 3.8 antidepressant treatment courses, on average (p = 0.217); 94.6% versus 96.8% used augmentation therapy (p = 0.240), including 59.3% versus 58.1% with an antipsychotic (p = 0.844), respectively.

Regardless of health plan stringency, on average, patients exceeded US label-mandated number of antidepressant trials before esketamine initiation, which questions the need for health insurance plans PA criteria above label.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults.

CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process.

The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted.

The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Difficult-to-treat depression (DTD) represents a broad spectrum of patients with persistent depression where standard treatment modalities are insufficient, yet specific characteristics of this group remain insufficiently understood. This investigation aims to delineate the sociodemographic and clinical profiles of suspected DTD patients in real-world clinical settings.

We conducted a retrospective analysis of data from patients comprehensively evaluated for suspected DTD at Kyorin University Hospital, Tokyo, Japan, between October 2014 and September 2018. The study participants consisted of individuals with persistent depression unresponsive to conventional antidepressant treatments during the current episode. Diagnoses adhered to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Additional evaluations included the Montgomery-Åsberg Depression Rating Scale (MADRS) and other pertinent measures. The analysis focused on comparing demographic and clinical characteristics across diagnosed groups.

The analysis encompassed 122 patients, with diagnoses of major depressive disorder (MDD) in 41.8%, bipolar disorder (BD) in 28.7%, and subthreshold depression in 29.5%. Notably, high incidences of psychiatric comorbidities were present across all groups, with anxiety disorders exceeding 30% and personality disorders surpassing 50%. The only significant distinction among the three groups was observed in the MADRS scores, with the MDD group exhibiting the highest values (20.9 ± 9.7 vs. 18.6 ± 9.3 vs. 11.3 ± 7.4, p<0.01).

This study sheds light on the intricate nature of suspected DTD, emphasizing the coexistence of MDD, BD, and subthreshold depression within this category. Our findings underscore the necessity for thorough evaluations and tailored treatment approaches for managing suspected DTD.

An estimated 30 % of Major Depressive Disorder (MDD) patients exhibit resistance to conventional antidepressant treatments. Identifying reliable biomarkers of treatment-resistant depression (TRD) represents a major goal of precision psychiatry, which is hampered by the clinical and biological heterogeneity. To uncover biologically-driven subtypes of MDD, we applied an unsupervised data-driven framework to stratify 102 MDD patients on their neuroimaging signature, including extracted measures of cortical thickness, grey matter volumes, and white matter fractional anisotropy. Our novel analytical pipeline integrated different machine learning algorithms to harmonize data, perform data dimensionality reduction, and provide a stability-based relative clustering validation. The obtained clusters were characterized for immune-inflammatory peripheral biomarkers, TRD, history of childhood trauma and depressive symptoms. Our results indicated two different clusters of patients, differentiable with 67 % of accuracy: one cluster (n = 59) was associated with a higher proportion of TRD, and higher scores of energy-related depressive symptoms, history of childhood abuse and emotional neglect; this cluster showed a widespread reduction in cortical thickness (d = 0.43-1.80) and volumes (d = 0.45-1.05), along with fractional anisotropy in the fronto-occipital fasciculus, stria terminalis, and corpus callosum (d = 0.46-0.52); the second cluster (n = 43) was associated with cognitive and affective depressive symptoms, thicker cortices and wider volumes. Multivariate analyses revealed distinct brain-inflammation relationships between the two clusters, with increase in pro-inflammatory markers being associated with decreased cortical thickness and volumes. Our stratification of MDD patients based on structural neuroimaging identified clinically-relevant subgroups of MDD with specific symptomatic and immune-inflammatory profiles, which can contribute to the development of tailored personalized interventions for MDD.

Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD.

Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item).

We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels.

We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Approximately 15-25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT).

We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19.

DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups.

Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 - F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.

The antidepressant effect of N-methyl-D-aspartate antagonists is often short lasting, raising the question of the best maintenance strategy, which has remained unanswered. Vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need for maintenance treatment sessions in patients receiving electroconvulsive therapy. To our knowledge, there are no published data on the combination of VNS and esketamine in the literature.

This is a naturalistic prospective and retrospective observational study in patients treated with long-term VNS owing to difficult-to-treat depression. These patients also have received esketamine maintenance sessions in addition to short-term treatment. We have investigated the need for maintenance esketamine sessions per month after VNS implantation (number of sessions/number of months between visits), the change in depression severity (mean Montgomery-Asberg Depression Rating Scale [MADRS] score), and the number of hospitalizations per month (number of hospitalizations/number of postoperative observation months). Follow-up visits have been scheduled every three months after VNS implantation (follow-up period 12-24 months, mean 17).

All patients (n = 8, mean age 53.1 years) had severe difficult-to-treat depression (DTD) (mean MADRS at baseline 30.9). Mean number of hospitalizations per month decreased from 0.17 to 0.11 after VNS implantation (p = 0.041, T = 2.030, df = 7). Mean MADRS at 12 months was 18.3 (40.8% MADRS reduction, p = 0.008, T = 3.146, df = 7). Six of eight patients were offered maintenance esketamine treatment. Mean number of esketamine treatment sessions per month and case decreased from 2.3 at the six-month visit to 0.8 at 12 months (p = 0.076, T = 1,690, df = 5) after VNS implantation. Termination of maintenance esketamine was possible in four cases after a mean of 11.5 months.

Combination of esketamine and VNS was effective in patients with DTD to relieve disease severity and reduce hospitalizations. The need for esketamine treatment sessions decreased after 6 months of VNS. No safety concerns arose in this study regarding the combination treatment.

The Clinicaltrials.gov registration number for the study is NCT03320304.

One in five people will likely suffer from major depressive disorder (MDD) during their life. Thirty percent of those with MDD will experience Treatment Resistant Depression (TRD), which is characterized by a failure to respond to two adequately administered trials of antidepressants. Esketamine is a rapidly acting intranasal antidepressant. Present-day Esketamine research has limited data in real-world populations. This study aimed to assess Esketamine treatment in a real-world community-based population. This naturalistic retrospective study included 94 individuals age 18 and above diagnosed with TRD, treated with Esketamine in an outpatient setting. The treatment was given in a single clinic, from January 2021 to January 2023, following approval of the Institutional Internal Review Board. The treatment included an acute phase (biweekly treatment, continuing 4-8 weeks), followed by a maintenance phase (once a week to once a month, for 6-12 months). Dosing ranged from 28 mg to 84 mg. Demographic and clinical data were retrospectively gathered. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology, at baseline and during each treatment phase. All patients completed the acute phase. About 60% completed the maintenance phase. Linear improvement of depressive symptoms was revealed in both phases. A sub-analysis of patients with comorbid personality disorder revealed a similar improvement pattern in the acute phase with milder improvement during the maintenance phase, compared to the other patients. This study supports the use of Esketamine for TRD, including patients with comorbid personality disorder and previous electroconvulsive therapy.

Online psychological interventions have emerged as a treatment alternative because they are accessible, flexible, personalized, and available to large populations. The number of Internet interventions in Latin America is limited, as are Randomized Controlled Trials (RCTs) of their effectiveness and a few studies comparing their effectiveness in multiple countries at the same time. We have developed an online intervention, Well-being Online, which will be available to the public free of charge in 7 countries: Mexico, Ecuador, Peru, Chile, Brazil, Spain, and the Netherlands. We expect a reduction in depression and anxiety symptoms and an increase in well-being of the participants.

A multi-country, randomized controlled trial will be conducted. The intervention is multicomponent (Cognitive Behavioral Therapy, Behavioral Activation Therapy, Mindfulness, Acceptance and Commitment Therapy, and Positive Psychology), with 10 sessions. In each country, eligible participants will be randomized to one of three groups: Enriched Intervention (interactive web design with videos, infographics, text, audio, and forum), Text Intervention (text on the website), and Wait List (control group). Repeated measures will be obtained at 5-time points. Our primary outcomes will be anxiety symptomatology, depressive symptomatology, and mental well-being. MANOVA analysis will be used for our main analysis.

This protocol describes the design of a randomized trial to evaluate the efficacy of a web-based intervention to reduce anxiety and depression symptomatology and increase subjective well-being. The intervention will be made available in four languages (Spanish, Portuguese, Dutch, and English). Its results will contribute to the evidence of effectiveness in terms of randomized trials and Internet interventions, mainly in Latin America and Europe.

About one third of patients with depression are in a condition that can be termed as "difficult-to-treat". Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector.

In this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed.

This trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group.

ClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE).

The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE.

The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals.

German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.