Nitrous oxide may possess antidepressant effects; however, limited data exist on repeated administrations and active placebo-controlled studies in treatment-resistant depression (TRD).

We aimed to test the feasibility of a randomised controlled trial examining a 4-week course of nitrous oxide or midazolam, an active placebo.

In this randomised, active, placebo-controlled pilot trial, 40 participants with TRD were assigned either a 1-h inhalation of 50% nitrous oxide plus intravenous saline (n = 20) or a 1-h inhalation of 50% oxygen plus intravenous midazolam (0.02 mg/kg, up to 2 mg; n = 20) once weekly, for 4 weeks. Feasibility was assessed by examining rates of recruitment, withdrawal, adherence, missing data and adverse events. The main measure of clinical efficacy was the change in depression severity (Montgomery–Åsberg Depression Rating Scale (MADRS)) score from baseline to day 42.

The recruitment rate was 22.3% (95% CI 16.9–29.0). Withdrawal rates were 10% (95% CI 2.8–30.1) in both groups and adherence rates were 100.0% (95% CI 82.4–100) in the nitrous oxide group and 94.4% (95% CI 74.2–99.0) in the placebo group. There were no missing primary clinical outcome data in either group (0.0%, 95% CI 0.0–17.6). MADRS score changed by −20.5% (95% CI −39.6 to −1.3) in the nitrous oxide group and −9.0% (95% CI −22.6 to 4.6) in the placebo group. Nearly all adverse events were mild to moderate and transient.

The findings support the feasibility and necessity of conducting a full-scale trial comparing nitrous oxide and midazolam in patients with TRD.

Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.

Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.

We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (N = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10.

Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement (b = −1.6, t = −2.1, P = 0.033, 95% CI [−3.0, −0.1], where b is the coefficient of the relationship (i.e. effect size), and t is the t-statistic for that coefficient associated with the P-value). The effect was similar across all augmentation strategies. No other putative moderators were significant.

Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.

Ketamine exerts potent but transient antidepressant effects in treatment-resistant depression (TRD). Combinations of ketamine and psychotherapy have attracted interest, but no trial has investigated a psychedelic model of ketamine–psychotherapy for TRD to our knowledge.

This secondary analysis of a randomised clinical trial (RCT) explores the therapeutic effects and experiential mechanisms of the Montreal Model of ketamine–psychotherapy for TRD, with or without music.

A two-centre, single-blinded, RCT conducted in Montreal, Canada, between January 2021 and August 2022 (NCT04701866). Participants received ketamine–psychotherapy for TRD – six subanaesthetic infusions over 4 weeks and psychological support – with either music or matched non-music support during ketamine doses, as per random group assignments. The primary therapeutic outcome was the Montgomery–Åsberg Depression Rating Scale, assessed by blinded raters. Psychedelic-like experiences, evaluated by the Mystical Experience Questionnaire and Emotional Breakthrough Inventory, and their session-by-session relationships with depression were explored with multilevel, time-lagged covariate models with autoregressive residuals.

Thirty-two participants with severe and highly comorbid TRD, including high rates of personality disorder and suicidality, received 181 ketamine infusions. Therapeutic outcomes and psychedelic experiences did not differ between music (n = 15) and non-music (n = 17) interventions. Both groups experienced significant reductions in clinician-rated and self-reported depression (d = 1.2 and d = 0.87, respectively; p < 0.001), anxiety (d = 0.8, p < 0.001) and suicidality (d = 0.4, p < 0.05) at 4 weeks, fully maintained at 8-week follow-up. Ketamine experiences were highly emotional and mystical. Converging analyses supported mystical-like ketamine experiences as mechanisms of its antidepressant effects.

This trial found large and notably sustained benefits of ketamine–psychotherapy for severe TRD, with or without music, and psychedelic experiences of comparable intensity to those observed with psilocybin. Mystical-like experiences may particularly contribute to ketamine’s immediate and persistent psychiatric benefits.

Heterogeneous symptoms in major depression contribute to unsuccessful antidepressant treatment, termed treatment-resistant depression (TRD). Psychometric network modeling conceptualizes depression as interplay of symptoms with potential benefits for treatment; however, a knowledge gap exists regarding networks in TRD.

Symptoms from 1,385 depressed patients, assessed by the Montgomery-Åsberg-depression rating scale (MADRS) as part of the “TRD-III” cohort of the multinational research consortium “Group for the Studies of Resistant Depression,” were used for Gaussian graphical network modeling. Networks were estimated for two timepoints, pretreatment and posttreatment, after the establishment of outcomes response, non-response, and TRD. Applying the network-comparison test, edge weights, and symptom centrality was assessed by bootstrapping. Applying the network-comparison test, outcome groups were compared cross-sectionally and longitudinally regarding the networks’ global strength, invariance, and centrality.

Pretreatment networks did not differ in global strength, but outcome groups showed distinct symptom connections. For both response and TRD, global strength was reduced posttreatment, leading to significant differences between each pair of networks posttreatment. Sadness, lassitude, inability-to-feel, and pessimistic thoughts ranked most centrally in unfavorable outcomes, while reduced-appetite and suicidal thoughts were more densely connected in response. Connections between central symptoms increased in strength following unsuccessful treatment, particularly regarding links involving pessimistic thoughts in TRD.

Treatment reduced global network strength across outcome groups. However, distinct symptom networks were found in patients showing response to treatment, non-response, and TRD. More easily targetable symptoms such as reduced-appetite were central to networks in patients with response, while pessimistic thoughts may be a key symptom upholding disease burden in TRD.

Previous studies investigating the effectiveness of augmentation therapy have been limited.

To evaluate the effectiveness of antipsychotic augmentation therapies among patients with treatment-resistant depression.

We included patients diagnosed with depression receiving two antidepressant courses within 1 year between 2009 and 2020 and used the clone-censor-weight approach to address time-lag bias. Participants were assigned to either an antipsychotic or a third-line antidepressant. Primary outcomes were suicide attempt and suicide death. Cardiovascular death and all-cause mortality were considered as safety outcomes. Weighted pooled logistic regression and non-parametric bootstrapping were used to estimate approximate hazard ratios and 95% confidence intervals.

The cohort included 39 949 patients receiving antipsychotics and the same number of matched antidepressant patients. The mean age was 51.2 (standard deviation 16.0) years, and 37.3% of participants were male. Compared with patients who received third-line antidepressants, those receiving antipsychotics had reduced risk of suicide attempt (sub-distribution hazard ratio 0.77; 95% CI 0.72–0.83) but not suicide death (adjusted hazard ratio 1.08; 95% CI 0.93–1.27). After applying the clone-censor-weight approach, there was no association between antipsychotic augmentation and reduced risk of suicide attempt (hazard ratio 1.06; 95% CI 0.89–1.29) or suicide death (hazard ratio 1.22; 95% CI 0.91–1.71). However, antipsychotic users had increased risk of all-cause mortality (hazard ratio 1.21; 95% CI 1.07–1.33).

Antipsychotic augmentation was not associated with reduced risk of suicide-related outcomes when time-lag bias was addressed; however, it was associated with increased all-cause mortality. These findings do not support the use of antipsychotic augmentation in patients with treatment-resistant depression.

Evidence suggests the crucial role of dysfunctional default mode (DMN), salience and frontoparietal (FPN) networks, collectively termed the triple network model, in the pathophysiology of treatment-resistant depression (TRD).

Using the graph theory- and seed-based functional connectivity analyses, we attempted to elucidate the role of low-dose ketamine in the triple networks, namely the DMN, salience and FPN.

Resting-state functional connectivity magnetic resonance imaging (rs–fcMRI) data derived from two previous clinical trials of a single, low-dose ketamine infusion were analysed. In clinical trial 1 (Trial 1), patients with TRD were randomised to either a ketamine or normal saline group, while in clinical trial 2 (Trial 2) those patients with TRD and pronounced suicidal symptoms received a single infusion of either 0.05 mg/kg ketamine or 0.045 mg/kg midazolam. All participants underwent rs–fcMRI pre and post infusion at Day 3. Both graph theory- and seed-based functional connectivity analyses were performed independently.

Trial 1 demonstrated significant group-by-time effects on the degree centrality and cluster coefficient in the right posterior cingulate cortex (PCC) cortex ventral 23a and b (DMN) and the cluster coefficient in the right supramarginal gyrus perisylvian language (salience). Trial 2 found a significant group-by-time effect on the characteristic path length in the left PCC 7Am (DMN). In addition, both ketamine and normal saline infusions exerted a time effect on the cluster coefficient in the right dorsolateral prefrontal cortex a9-46v (FPN) in Trial 1.

These findings may support the utility of the triple-network model in elucidating ketamine’s antidepressant effect. Alterations in DMN, salience and FPN function may underlie this effect.

A substantial subset of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD), typically defined as failure to respond to at least two sequential antidepressant trials at adequate dose and length.

To examine clinical and service-level associations of TRD, and the experiences of people with TRD and clinicians involved in their care within a large, diverse National Health Service trust in the UK.

This mixed-methods study integrated quantitative analysis of electronic health records with thematic analysis of semi-structured interviews. Chi-squared tests and one-way analysis of variance were used to assess associations between lines of antidepressant treatments and sociodemographic and clinical variables, and binary logistic regression was used to identify associations of TRD status.

Nearly half (48%) of MDD patients met TRD criteria, with 36.9% having trialled ≥4 antidepressant treatments. People with TRD had higher rates of recurrent depression (odds ratio = 1.24, 95% CI: 1.05–1.45, P = 0.008), comorbid anxiety disorders (odds ratio = 1.21, 95% CI: 1.03–1.41, P = 0.019), personality disorders (odds ratio=1.35, 95% CI: 1.10–1.65, P = 0.003), self-harm (odds ratio = 1.76, 95% CI: 1.06–2.93, P = 0.029) and cardiovascular diseases (odds ratio = 1.46, 95% CI: 1.02–2.07, P = 0.0374). Greater treatment resistance was linked to increased economic inactivity and functional loss. Qualitative findings revealed severe emotional distress and frustration with existing treatments, as well as organisational and illness-related barriers to effective care.

TRD is characterised by increasing mental and physical morbidity and functional decline, with individuals experiencing barriers to effective care. Improved pathways, service structures and more effective biological and psychological interventions are needed.

Increasing attention has been recently devoted to treatment-resistant depression (TRD); however, its clinical characteristics, potential risk factors, and course are still debated. Most recently, childhood trauma exposure has been correlated to TRD, but systematic investigation on the role of lifetime trauma is still lacking. The aim of this paper was to revise current evidence on early and recent trauma exposure in TRD.

A systematic search was conducted from the 1st of June to the 20th of February 2024 in accordance with the PRISMA 2020 guidelines and using the electronic databases PubMed, Web of Science, and Embase.

The primary database search produced a total of 1998 record, and finally, the search yielded a total of 22 publications, including 18 clinical studies, 3 case reports, and 1 case series, all from the period 2014 to 2024.

Limitations include a small sample size of some studies and the lack of homogeneity in the definition of TRD. Furthermore, we only considered articles in English, we excluded preprints or abstracts, and we included case reports.

This review highlights the role of early and recent trauma in TRD, even in the absence of a full-blown post-traumatic stress disorder (PTSD), highlighting the need for a thorough assessment of trauma in patients with TRD and of its role as a therapeutic target.

Treatment-resistant depression (TRD) affects 10–30% of patients with major depressive disorder, leading to increased comorbidities, higher mortality, and significant economic and social burdens. This study aimed to compare the efficacy and safety of bupropion and aripiprazole as augmentation therapies for TRD.

This population-based, retrospective cohort study included adults aged ≥18 years with a diagnosis of depressive disorder who met the criteria for TRD. Data were collected from a nationwide claims database in South Korea. Patients prescribed bupropion were matched 1:1 with those prescribed aripiprazole. Subgroup analyses were performed according to age. An as-treated analysis was performed as the primary analysis, and an intention-to-treat analysis was performed to identify different risk windows. The primary outcome was depression-related hospitalization, and the secondary outcomes were first-time diagnoses of movement disorder and seizure.

A total of 5,619 patients (bupropion: n = 1,568; aripiprazole: n = 4,051) were included in this study. Bupropion was associated with lower risks of hospitalization (hazard ratio [HR]: 0.51; 95% confidence interval [CI] 0.29–0.86) and movement disorders (HR: 0.56; 95% CI 0.36–0.85) than aripiprazole. No significant difference in seizure risk (HR: 0.65; 95% CI 0.30–1.31) was observed between the two treatments. The subgroup analysis of participants aged ≥60 years revealed no significant differences in the three outcomes between the two medications.

Bupropion augmentation is associated with a significantly lower risk of depression-related re-hospitalization and movement disorders in patients with TRD. Therefore, bupropion augmentation can be a comprehensive treatment strategy for TRD.

Esketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and quetiapine extended-release (XR) in patients with TRD treated in accordance with US prescribing information (USPI).

ESCAPE-TRD (NCT04338321) was a randomized, open-label, rater-blinded phase 3b trial investigating ESK versus quetiapine XR for acute and maintenance treatment of patients with TRD. This secondary analysis included patients aged 18–64 years who were treated/dosed according to USPI. The primary endpoint was remission, defined as Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤ 10. Treatment-emergent adverse events (TEAEs) leading to discontinuation were summarized descriptively.

Among 636 patients in this secondary analysis (ESK, n = 316; quetiapine XR, n = 320), significantly more ESK-treated patients achieved remission starting at week 8 (28.3% versus 18.6%; P = 0.005) through week 32 (55.7% versus 36.3%; P < 0.001), compared with quetiapine XR–treated patients. There were clinically and statistically significant improvements in MADRS scores with ESK versus quetiapine XR at each visit from day 8 onwards. Fewer patients discontinued treatment because of TEAEs with ESK (4.5%) versus quetiapine XR (10.1%).

Consistent with the primary analysis, this secondary analysis demonstrated that ESK improves short- and long-term outcomes compared with quetiapine XR in patients with TRD treated according to USPI.

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.