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.

Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan.

Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March 2020 and October 2023 were extracted from the registry.

All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response, and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence.

This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2 years. Further validation with a randomized controlled trial design with a larger sample size is warranted.

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.

Electroconvulsive therapy (ECT) is one of the most studied and validated available treatments for severe or treatment-resistant depression. However, little is known about the neural mechanisms underlying ECT. This systematic review aims to critically review all structural magnetic resonance imaging studies investigating longitudinal cortical thickness (CT) changes after ECT in patients with unipolar or bipolar depression.

We performed a search on PubMed, Medline, and Embase to identify all available studies published before April 20, 2023. A total of 10 studies were included.

The investigations showed widespread increases in CT after ECT in depressed patients, involving mainly the temporal, insular, and frontal regions. In five studies, CT increases in a non-overlapping set of brain areas correlated with the clinical efficacy of ECT. The small sample size, heterogeneity in terms of populations, comorbidities, and ECT protocols, and the lack of a control group in some investigations limit the generalisability of the results.

Our findings support the idea that ECT can increase CT in patients with unipolar and bipolar depression. It remains unclear whether these changes are related to the clinical response. Future larger studies with longer follow-up are warranted to thoroughly address the potential role of CT as a biomarker of clinical response after ECT.

Despite the availability of effective therapies, many patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD).

To evaluate and compare prescribing patterns, contact with specialist services and treatment outcomes in patients with MDD and TRD.

This was a retrospective analysis of linked primary and secondary care National Health Service data in the north-west London Discover-NOW data-set. Eligible patients were adults who had diagnostic codes for depression and had been prescribed at least one antidepressant between 2015 and 2020.

A total of 110 406 patients were included, comprising 101 333 (92%) with MDD and 9073 (8%) with TRD. Patients with TRD had significantly higher risks of suicidal behaviour and comorbidities such as anxiety, asthma, and alcohol or substance misuse (all P < 0.0001). Citalopram, sertraline, fluoxetine and mirtazapine accounted for 83% of MDD and 71% of TRD prescriptions. Use of antidepressant switching (1% MDD, 7% TRD) and combination therapy (1%, 5%) was rare, whereas augmentation occurred more frequently in the TRD group (4%, 35%). Remission was recorded in 42 348 (42%) patients with MDD and 1188 (13%) with TRD (P < 0.0001), whereas relapse was seen in 20 970 (21%) and 4923 (54%), respectively (P < 0.0001). Mean times from diagnosis to first contact with mental health services were 38.9 (s.d. 33.6) months for MDD and 41.5 (s.d. 32.0) months for TRD (P < 0.0001).

There appears to be a considerable difference between treatment guidelines for depression and TRD and the reality of clinical practice. Long-term treatment with single antidepressants, poor remission, and high relapse rates among patients in primary care highlight the need to optimise treatment pathways and access to newer therapies.

Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone.

To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone).

In a 4-week, three-arm, ‘double dummy’ trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure.

This trial will advance the understanding of psilocybin's mechanism of antidepressant action.

This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.

Treatment-resistant depression (TRD) is an important clinical challenge and may present differently between age groups.

A total of 893 depressed patients recruited within the framework of the European research consortium “Group for the Studies of Resistant Depression” were assessed by generalized linear models regarding age effects (both as numerical and factorial predictors) on treatment outcome, number of lifetime depressive episodes, hospitalization time, and duration of the current episode. Effects of age as numerical predictor on the severity of common depressive symptoms, measured with Montgomery–Åsberg Depression Rating Scale (MADRS) for two-time points, were assessed by linear mixed models, respectively, for patients showing TRD and treatment response. A corrected p threshold of 0.001 was applied.

Overall symptom load reflected by MADRS (p < 0.0001) and lifetime hospitalization time (p < 0.0001) increased with age in TRD patients but not treatment responders. In TRD, higher age was predicting symptom severity of inner tension, reduced appetite, concentrations difficulties, and lassitude (all p ≤ 0.001). Regarding clinical significance, older TRD patients were more likely to report severe symptoms (item score > 4) for these items both before and after treatment (all p ≤ 0.001).

In this naturalistic sample of severely ill depressed patients, antidepressant treatment protocols were equally effective in addressing TRD in old age. However, specific symptoms such as sadness, appetite, and concentration showed an age-dependent presentation, impacting residual symptoms in severely affected TRD patients and calling for a precision approach by a better integration of age profiles in treatment recommendations.

In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD.

Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores.

Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores.

Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

Irremediability is a key requirement for euthanasia and assisted suicide for psychiatric disorders (psychiatric EAS). Countries like the Netherlands and Belgium ask clinicians to assess irremediability in light of the patient's diagnosis and prognosis and ‘according to current medical understanding’. Clarifying the relevance of a default objective standard for irremediability when applied to psychiatric EAS is crucial for solid policymaking. Yet so far, a thorough examination of this standard is lacking.

Using treatment-resistant depression (TRD) as a test case, through a scoping review in PubMed, we analyzed the state-of-the-art evidence for whether clinicians can accurately predict individual long-term outcome and single out irremediable cases, by examining the following questions: (1) What is the definition of TRD; (2) What are group-level long-term outcomes of TRD; and (3) Can clinicians make accurate individual outcome predictions in TRD?

A uniform definition of TRD is lacking, with over 150 existing definitions, mostly focused on psychopharmacological research. Available yet limited studies about long-term outcomes indicate that a majority of patients with long-term TRD show significant improvement over time. Finally, evidence about individual predictions in TRD using precision medicine is growing, but methodological shortcomings and varying predictive accuracies pose important challenges for its implementation in clinical practice.

Our findings support the claim that, as per available evidence, clinicians cannot accurately predict long-term chances of recovery in a particular patient with TRD. This means that the objective standard for irremediability cannot be met, with implications for policy and practice of psychiatric EAS.

Previous Electronic Health Records (EHR) based studies adopted various definitions in identifying Treatment-Resistant Depression (TRD) patients. There is a lack of similar attempts among Chinese population which limits the understanding of TRD in China.

Assess TRD identification using EHR from a major psychiatric hospital in China.

This study utilized a retrospective Major Depressive Disorder (MDD) cohort of patients who newly initiated pharmaceutical treatment (2010-2018); follow-up was ended upon 1-year or treatment discontinuation (≥120d without treatment). TRD was first identified based on common clinical definition of two prior regimen failures (change of regimen) with 4-week as regimen adequacy threshold (Def1). Alternative adequacy thresholds of 2-week and 6-week were applied. Based on Def1 (4-week), at least 3 distinctive regimens were additionally required in TRD identification (Def2). Further, a data-driven definition (Def3) based on drug count as having ≥3 antidepressants or ≥1 antipsychotic within 1 year was considered (Cepeda et al., 2018).

From 12257 MDD patients included in the cohort, Def1 identified 633 (5.2%) TRD cases, whereas regimen adequacy thresholds of 2-week and 6-week identified 1772 (14.5%) and 61 (0.5%) cases, respectively. Further, Def2 identified 261 (2.4%) TRD cases. Finally, Def3 yielded 2449 (20.0%) TRD cases, including 1966 exclusive cases that were not identified by Def1.

This study showed different definitions for TRD identification had considerable impact on the number of patients identified among Chinese population, obscuring the comparability among EHR-based TRD studies. As first step, we found the criteria of regimen adequacy as major contributor to the observed variability in China.

No significant relationships.

Major depressive disorder (MDD) is a highly prevalent clinical condition with a leading cause of disability worldwide. The currently available therapeutic agents have important limitations regarding side effects, partial or non-responsiveness. Patients are considered to have treatment-resistant depression (TRD) if there is no effect or minimal effectiveness after receiving adequate dose-duration use of antidepressants from two different categories. For this patients, electroconvulsive therapy (ECT) can be a treatment option and new therapies appear to tackle TRD like ketamine, a dissociative anesthetic and analgesic.

The authors elaborate a narrative literature review to understand if ketamine might enhance the antidepressant efficacy of ECT.

PubMed database searched using the terms “Electroconvulsive therapy”, “ketamine” and “treatment-resistant depression”.

ECT is currently recommended as an end-line therapy for TRD. Memory impairment after ECT could be a consequence of indiscriminate activation or saturation of glutamate receptors during the treatment, disrupting hippocampal plasticity involved in memory. Ketamine inhibits N-methyl-d-aspartate (NMDA) receptors, while stimulating glutamate release and was proposed as an ECT adjuvant, might reduce cognitive adverse effects, time until response/ remission and inclusively improve response rates to ECT.

However, response and remission rates of ketamine in ECT showed no significant difference from the comparator groups and was associated with higher rates of psychiatric and cardiovascular adverse events.

The results did not support the use the combination of ketamine and propofol as anesthetic agents for ECT in patients with MDD. However, further studies are needed to investigate the beneficial clinical and cognitive effects of ketamine alone in ECT settings.

No significant relationships.

The compassionate use of intranasal esketamine is approved in Spain for treatment-resistant depression (TRD).

The objective of the study is to assess the clinical stability in the medium-term follow-up of patients with TRD after esketamine use.

Descriptive, retrospective and multicenter study carried out in Spain. Patients with TRD who had received esketamine treatment, and for whom there were clinical data of subsequent evolution, were included. The scores on the MADRS and Hamilton scales were changed into scores on the CGI scale according to the studies by Leucht et al. The Student’s t test was performed to assess differences in the CGI.

Eleven patients were included: 72.7% were women and the mean age was 56 (SD: 12.9). The maximum dose of esketamine used was 84mg in 63.7%. The onset of antidepressant action was observed from the 1st dose in 72.6% of the patients. The mean time in treatment was 6.6 months (SD: 2.3) and 90.9% reached remission criteria. After 7.4 months (SD: 3.0) from the end of the treatment, 90.9% remained in remission and without visits to the emergency room or hospitalization for psychiatric reasons. The mean baseline score on the CGI-SI was 5.7 points, at the end of the treatment was 1.2 points and after longitudinal follow-up it was 1. Statistically significant differences were observed (p<0.001) both at the end of the treatment and in the post-esketamine follow-up compared with baseline score.

In our sample, the use of esketamine in TRD shows clinical stability in the medium-term follow-up.

Daniel Hernández has participated in medical meetings and/or received payment for presentations from Otsuka, Lundbeck, Janssen, Angelini, Casen Recordati, and Ferrer.

Depression is a leading cause of disability affecting over 300 million indivuals worldwide. About 1/3 of patients with depression fail to achive remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). In view of such facts, vagus nerve stimulation (VNS) therapy was approved as an adjunctive long-term treatment for TRD.

The authors elaborate a narrative literature review about de effectiveness of VNS in treatment for TRD.

PubMed database searched using the terms “treatment-resistant depression”, “vagus nerve stimulation”

The pathophysiology of depression is complex and includes social environmental stress factors, genetic and biological processes, inflammation, and disturbances in monoamine neurotransmission. The overdrive of the HPA axis is most consistently seen in subjects with more severe depression, when the cortisol feedback inhibitory mechanisms are impaired, contributing to cytokine oversecretion. It has been shown that chronic exposure to elevated inflammatory cytokines can lead to depression. The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood and imune response. VNS therapy has a demonstrated anti-inflammatory effect which might be a significant reason for its efficacy in patients who did not respond to antidepressants. Treatments thar target the vagus nerve increase the vagal tone and inhibit cytokine production and the stimulation of vagal aferente fibers in the gut influences monaminergic brain systems.

The mecanismos by which VNS may benefit patients nonresponsive to conventional antidepressants is unclear, with further research need to clarify this.

No significant relationships.