Treatment Of Treatment-resistant Depression Research Articles

An Umbrella Review of Effectiveness of Intravenous Ketamine in Treatment-Resistant Depression

IntroductionMajor depressive disorder (MDD) is a tremendous global disease burden and the leading cause of disability worldwide. Unfortunately, individuals diagnosed with MDD typically experience a delayed response to traditional antidepressants and many do not adequately respond to pharmacotherapy, even after multiple trials. The critical need for novel antidepressant treatments has led to a recent resurgence in the clinical application of psychedelics, and intravenous ketamine, which has been investigated as a rapid-acting treatment for treatment resistant depression (TRD) as well acute suicidal ideation and behavior. However, variations in the type and quality of experimental design as well as a range of treatment outcomes in clinical trials of ketamine make interpretation of this large body of literature challenging.ObjectivesThis umbrella review aims to advance our understanding of the effectiveness of intravenous ketamine as a pharmacotherapy for TRD by providing a systematic, quantitative, large-scale synthesis of the empirical literature.MethodsWe performed a comprehensive PubMed search for peer-reviewed meta-analyses of primary studies of intravenous ketamine used in the treatment of TRD. Meta-analysis and primary studies were then screened by two independent coding teams according to pre-established inclusion criteria as well as PRISMA and METRICS guidelines. We then employed metaumbrella, a statistical package developed in R, to perform effect size calculations and conversions as well as statistical tests.ResultsIn a large-scale analysis of 1,182 participants across 51 primary studies, repeated-dose administration of intravenous ketamine demonstrated statistically significant effects (p<0.05) compared to placebo-controlled as well as other experimental conditions in patients with TRD, as measured by standardized clinician-administered and self-report depression symptom severity scales.ConclusionsThis study provides large-scale, quantitative support for the effectiveness of intravenous, repeated-dose ketamine as a therapy for TRD and a report of the relative effectiveness of several treatment parameters across a large and rapidly growing literature. Future investigations should use similar analytic tools to examine evidence-stratified conditions and the comparative effectiveness of other routes of administration and treatment schedules as well as the moderating influence of other clinical and demographic variables on the effectiveness of ketamine on TRD and suicidal ideation and behavior.Disclosure of InterestNone Declared

Intranasal esketamine efficacy as a treatment for treatment-resistant depression, case series

IntroductionIntranasal esketamine has been approved as a treatment for patients with treatment-resistant depression. We analyzed the results of its efficacy in 15 patients.ObjectivesTo evaluate the efficacy of intranasal Esketamine as a treatment in patients with treatment-resistant depressionMethodsCase seriesResultsFor the last 8 months, since the treatment with intranasal esketamine was approved for resistant depression, we have treated 14 patients with this drug. Through this process, we followed a standardized method consisting in the following steps:On the first esketamine session (DAY 1) the patient has to fill a CGI and a MADRS scale.On the second esketamine session (DAY 7) the patient has to fill a CGI, a MADRS scale, a form about the level of satisfaction with the drug and a last form in which they can include the secondary effects.On week 6 since the start of the treatment, the patient has to fill again a CGI, a MADRS scale, a form about the level of satisfaction with the drug and a last form in which they can include the secondary effects.In the 6th month since the start of the treatment, the patient has to fill again a CGI, a MADRS scale, a form about the level of satisfaction with the drug and a last form in which they can include the secondary effects they have perceived.We analyzed and compared all of the previous data and obtained the following results:At day 7: 64% of the patients had a response in the form of improvement, of which 66% were feeling “slightly better” and 33% were feeling “better”.At week 6: 71% of the patients had a response in the form of improvement, of which 50% were feeling “slightly better” and the other 50% were feeling “better”.At month 6: only 28% of the patients completed the treatment; of which 100% had a response in the form of improvement: 50% were feeling “slightly better”, 25% were feeling “better” and 25% were feeling “far better”.ConclusionsAlthough our data suggests that intranasal esketamine has been effective in short term depressive symptoms, we have yet no information about its medium and long-term efficacy or secondary effects. Nevertheless, other potential factors should be evaluated as they could affect the results in the long-term such as the difficulty in maintaining the treatment for more than 6 weeks.In addition, the patients who experienced the most improvement according to our data were patients with a TAB diagnosis, so this could be an interesting research focus.Disclosure of InterestNone Declared

Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness

BackgroundTranscranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. Objective/hypothesisThis pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. Methods15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). Results14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. LimitationsMain limitations include a small sample size and open-label design. ConclusionsThese findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression

BackgroundMajor depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. AimTo investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. MethodsACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. ResultsSub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. ConclusionThis study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Assessing the Efficacy of Methods for Treatment-Resistant Depression: A Review

Electroconvulsive Therapy (ECT), Transcranial Magnetic Stimulation (TMS), and Esketamine have all been proven to be effective against treatment-resistant depression (TRD). However, it is still unclear which method of treatment is the most effective both in general and in specific populations of patients exhibiting certain traits (i.e. psychosis) or with varied severities of TRD. ECT is the oldest form of treatment and has been proven effective, though not without significant side effects. TMS has also been shown to be effective, but without the side effects of ECT. Esketamine is the newest form of treatment for TRD, only having been approved by the FDA in 2019. Although current research demonstrates its efficacy, little research has been done on this modality because of its novelty. Trials from 2000-2019 were searched for and utilized to examine the efficacy of these three treatments in comparison to each other. The most recent and relevant studies were chosen. Studies completed before 2000 or utilizing patients without qualifying criteria for TRD were not included in our review. The data analyzed suggest that ECT is the most effective form of treatment overall, but TMS is noninferior in nonpsychotic patients and esketamine is effective for patients with TRD and no other chronic comorbidities.

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

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

Trend and geo-availability of somatic therapies for treatment resistant depression in the US

BackgroundHaving failed at least two pharmacotherapies, treatment-resistant depression (TRD) constitutes a major burden to healthcare in the US and globally, affecting close to a third of people diagnosed with depression in the US. Several studies have demonstrated the higher economic burden associated with TRD. This study sought to investigate changes in the availability of TRD somatic treatment options (Electroconvulsive therapy [ECT], Ketamine infusion therapy (KIT), and Transcranial Magnetic Stimulation [TMS]) in the US between 2014 and 2020 and the geographic variations in availability of TRD treatment options in the US as of 2020. MethodThis study is a cross-sectional study of US mental health facilities providing TRD treatment options between 2014 and 2020. We used the 2014 to 2020 National Mental Health Services Survey (N-MHSS) data from the Substance Abuse and Mental Health Service Administration (SAMHSA). We estimated service availability per 100,000 US adults, both nationally and regionally, and computed a random-effect logistic regression to calculate the changes in the availability of the services over the study period. ResultOverall, availability of any one of ECT, KIT, or TMS in US mental health facilities declined between 2014 and 2019 (0.23 vs. 0.18 per 100,000 US adults) but increased to 0.24 in 2020. While availability of ECT consistently declined between 2014 and 2020, ketamine and TMS reportedly became available only in 2020. North Dakota, Wyoming, and Utah had the highest availability per 100,000 US adults (0.86, 0.67, and 0.65) while Nevada, Oregon and Georgia had the lowest availability (0.04, 0.06, and 0.06) regionally. ConclusionThe US had less than one mental health facility offering somatic treatment options for TRD per 100,000 US adults as of 2020. Also, the observed increase in the availability of somatic treatment options for TRD across the US between 2014 and 2020 did not reflect the increasing need for more treatment options for the treatment of TRD.

Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: a qualitative study

Psilocybin is the most researched classic psychedelic for Treatment-Resistant Depression (TRD). While optimizing set and setting are considered essential for efficacy and safety, patient perspectives on these aspects have rarely been investigated. To address this knowledge gap, the current paper explored the experiences of 11 TRD patients (8 women, 3 men) participating in a double-blind randomized clinical trial with a single session of oral (1, 10 or 25 mg) psilocybin treatment. After qualitative analysis, three major themes were identified: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Subthemes of the first theme include a general distrust in mental healthcare, trust in study therapists, limited time for preparation, and managing expectations. The second theme included the following subthemes: trusting to surrender, profound and overwhelming experiences, and music as a guide. The third theme addressed a desire for multiple psilocybin sessions, and challenges with sensemaking. Patients’ perspectives provided important insights into potential optimization of psilocybin treatment of TRD, including individualized preparation, investment in trust-building, offering additional psilocybin sessions, providing access to sustained (psycho)therapy with trusted therapists, and personalizing treatment approaches, which may also enhance real-world adaption of these treatments.

A qualitative investigation of the Montgomery-Åsberg depression rating scale: discrepancies in rater perceptions and data trends in remote assessments of rapid-acting antidepressants in treatment resistant depression.

Despite the development of many successful pharmaceutical interventions, a significant subset of patients experience treatment-resistant depression (TRD). Ketamine and its derivatives constitute a novel therapeutic approach to treat TRD; however, standard tools, such as the Montgomery-Åsberg Depression Rating Scale (MADRS) are still being used to measure symptoms and track changes. The aim of this study was to review item-level differences between rate of data change (MADRS score) and rater-weighted perception of the most useful items for assessing change in symptoms while remotely conducting the 10-item version of the MADRS in TRD in a clinical trial of rapid-acting antidepressants. Two studies of rapid-acting antidepressants in the treatment of TRD were used to identify item-scoring trends when MADRS is administered remotely and repeatedly (733 subjects across 10 visits). Scoring trends were evaluated in tandem to a rater survey completed by 75 raters. This was completed to gain insight on MADRS items' perceived level of helpfulness when assessing change of symptoms in rapid-acting antidepressant trials. MADRS items 'Reduced sleep', 'Apparent sadness', and 'Pessimistic thoughts' were found to have the greatest average data change by visit, while raters ranked 'Reported sadness', 'Lassitude' and 'Apparent sadness' as the most helpful items when assessing symptom change. The diversion between rate of data-change ranking and rater perception of helpfulness could be related to difficulty in assessing specific items, to the novel treatment itself, and/or to the sensitivity to symptom change to which raters are accustomed in traditional antidepressant treatments.

Use of intranasal esketamine in the treatment of treatment-resistant depression: A case report

Use of intranasal esketamine in the treatment of treatment-resistant depression: A case report

Use of Esketamine Nasal Spray in Patients with Treatment‐Resistant Depression in Routine Practice: A Real‐World French Study

Background. The efficacy and safety of esketamine nasal spray (ESK) were established in registration trials in patients with treatment‐resistant depression (TRD). This French real‐world study aimed to describe the treatment patterns, effectiveness, and safety of ESK in TRD patients over a 12‐month follow‐up. Materials and Methods. This study used secondary data from patient files of hospital‐based psychiatrists and started during the first French patient early access to ESK. The response and remission rates with ESK were analyzed using the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS). The time to first treatment response and work resumption were described (Kaplan–Meier method). Adverse events (AEs) were analyzed. Results. Prior to ESK initiation, the 157 analyzed patients (age ≤ 65 years, 82.8%; female, 66.2%) had depression for 10.5 years (median, IQR, 4.2–21.2) and received a median of 6 (3–8) previous treatment lines. At ESK initiation, the mean ± SD total MADRS score was 32.1 ± 7.7. At that time, ESK was combined with antidepressants (93.6% of patients; SNRI, 65.0%; SSRI, 57.3%) and/or other potentiation strategy (63.1%; atypical antipsychotics, 36.3%; lithium, 25.6%; antiepileptics, 21.7%). During the 12‐month follow‐up, 125 patients (79.6%) discontinued ESK. The median duration of ESK treatment was 19.4 weeks (IQR, 4.4–40.1). At 1 month after ESK initiation, 40.2% of still treated patients met criteria for clinical response and 19.7% for remission (median time to response, 5.7 weeks; 95% CI (4.1–8.4)). 82.6% of active patients were on sick leave at ESK initiation; the work resumption rate was 24% (13%–40%) 12 weeks later. AEs were reported in 68.6% of patients, serious AEs in 17.2%, and AEs leading to ESK discontinuation in 14.6%. Conclusion. These real‐world effectiveness and safety data were consistent with findings from previous clinical trials, describing the real‐life clinical experience of patients receiving ESK and confirming that ESK has its place in therapy for the treatment of TRD.

Effectiveness of pharmacogenomics on the response and remission of treatment-resistant depression: a meta-analysis of randomised controlled trials

BackgroundPharmacogenomics (PGx) is a promising tool to realise tailored drug therapy for depression.AimsTo investigate the treatment efficacy of PGx for treatment-resistant depression (TRD) compared with treatment as usual.MethodsA systematic search...

Oscillatory network markers of subcallosal cingulate deep brain stimulation for depression

Identifying functional biomarkers related to treatment success can aid in expediting therapy optimization, as well as contribute to a better understanding of the neural mechanisms of the treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS).Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. The first objective of the study was to identify region-specific oscillatory modulations that both (i) discriminate individuals with TRD (with SCC-DBS OFF) from healthy controls, and (ii) discriminate TRD treatment responders from non-responders (with SCC-DBS ON). The second objective of this work was to further explore the effects of stimulation intensity and frequency on oscillatory activity in the identified brain regions of interest.Oscillatory power analyses led to the identification of brain regions that differentiated responders from non-responders based on modulations of increased alpha (8–12 Hz) and decreased gamma (32–116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca's area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity.The identified functional network biomarkers implicate modulation of TRD-related activity in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or reducing frequency, which may represent potential avenues of direction in non-responders.

Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment.

Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Optimizing TMS Coil Placement Approaches for Targeting the Dorsolateral Prefrontal Cortex in Depressed Adolescents: An Electric Field Modeling Study.

High-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) shows promise as a treatment for treatment-resistant depression in adolescents. Conventional rTMS coil placement strategies include the 5 cm, the Beam F3, and the magnetic resonance imaging (MRI) neuronavigation methods. The purpose of this study was to use electric field (E-field) models to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents. Ten depressed adolescents (4 females, age: 15.9±1.1) participated in an open-label rTMS treatment study and were offered MRI-guided rTMS five times per week over 6-8 weeks. Head models were generated based on individual MRI images, and E-fields were simulated for the four targeting approaches. Results showed a significant difference in the induced E-fields at the L-DLPFC between the four targeting methods (χ2=24.7, p<0.001). Post hoc pairwise comparisons showed that there was a significant difference between any two of the targeting methods (Holm adjusted p<0.05), with the 5 cm rule producing the weakest E-field (46.0±17.4V/m), followed by the F3 method (87.4±35.4V/m), followed by MRI-guided (112.1±14.6V/m), and followed by the computational approach (130.1±18.1V/m). Variance analysis showed that there was a significant difference in sample variance between the groups (K2=8.0, p<0.05), with F3 having the largest variance. Participants who completed the full course of treatment had median E-fields correlated with depression symptom improvement (r=-0.77, p<0.05). E-field models revealed limitations of scalp-based methods compared to MRI guidance, suggesting computational optimization could enhance dose delivery to the target.

Psilocybin-assisted psychotherapy for treatment-resistant depression: Which psychotherapy?

This perspective paper explores the choice of psychotherapy for psilocybin-assisted psychotherapy for treatment-resistant depression. There is evidence to support the use of some psychotherapies in treating 'treatment-resistant' depression, and emerging evidence for the efficacy of psilocybin. The next step which is the focus of this paper is to identify psychotherapies that are both effective and congruent with the psilocybin experience. The evidence for the efficacy of the psychotherapies is drawn from a Cochrane review and the analysis of their congruence with the psilocybin experience is drawn from a qualitative meta-synthesis of the experience of psilocybin. The paper will examine whether three one-to-one psychotherapies identified as effective in the treatment of treatment-resistant depression are compatible with the psilocybin experience. Each psychotherapy will be examined in relation to its congruence with the qualitative evidence that suggests the choice of psychotherapy needs to give priority to the subjective experience, facilitate emotional processing, support connectedness with others, acceptance of the self as emotional and support change based on the person's insights into their relationships with others and the world in which they live. We conclude that interpersonal psychotherapy and intensive short-term dynamic psychotherapy align with that experience, although others are currently being trialled.

Differences in clinical presentations of patients seeking care for treatment-resistant depression across sexual orientations and gender identities.

Sexual and/or gender minority (SGM) individuals experience higher rates and greater severity of depressive disorders than non-SGM persons. SGM individuals are more likely than non-SGM individuals to seek mental health treatment and to present to treatment with unique characteristics that should be accounted for when considering treatment recommendations. Patients seeking care for treatment-resistant depression (TRD) are offered a variety of evidence-based interventions ranging in modality and invasiveness (eg, psychotherapy and neuromodulation). The current study used data from a TRD clinical research program to examine whether SGM (N = 52) and non-SGM (N = 202) patients differed in their clinical presentations and the treatment recommendations offered to them. We found that SGM patients were younger, had a more severe history of childhood trauma, and reported greater current suicidality than non-SGM patients. There were no significant differences in treatment recommendations between groups. This study adds to nascent literature investigating clinical characteristics of SGM populations seeking mental health care and provides foundational evidence for the unique treatment considerations necessary for SGM individuals seeking treatment for TRD. Research into whether treatment outcomes differ for SGM and non-SGM individuals with TRD is encouraged, given clinical differences in trauma history and suicidality.

Investigating the Effectiveness and Tolerability of Intranasal Esketamine Among Older Adults With Treatment-Resistant Depression (TRD): A Post-hoc Analysis from the REAL-ESK Study Group

IntroductionTreatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear. ObjectivesTo evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD. MethodsThis is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2). ResultsThe sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: pholm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: pholm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment. ConclusionsOur findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension.

Regulatory Clearance and Approval of Therapeutic Protocols of Transcranial Magnetic Stimulation for Psychiatric Disorders.

Non-invasive brain stimulation techniques (NIBS) have been widely used in both clinical and research contexts in neuropsychiatry. They are safe and well-tolerated, making NIBS an interesting option for application in different settings. Transcranial magnetic stimulation (TMS) is one of these strategies. It uses electromagnetic pulses for focal modulate ion of neuronal activity in brain cortical regions. When pulses are applied repeatedly (repetitive transcranial magnetic stimulation-rTMS), they are thought to induce long-lasting neuroplastic effects, proposed to be a therapeutic mechanism for rTMS, with efficacy and safety initially demonstrated for treatment-resistant depression (TRD). Since then, many rTMS treatment protocols emerged for other difficult to treat psychiatric conditions. Moreover, multiple clinical studies, including large multi-center trials and several meta-analyses, have confirmed its clinical efficacy in different neuropsychiatric disorders, resulting in evidence-based guidelines and recommendations. Currently, rTMS is cleared by multiple regulatory agencies for the treatment of TRD, depression with comorbid anxiety disorders, obsessive compulsive disorder, and substance use disorders, such as smoking cessation. Importantly, current research supports the potential future use of rTMS for other psychiatric syndromes, including the negative symptoms of schizophrenia and post-traumatic stress disorder. More precise knowledge of formal indications for rTMS therapeutic use in psychiatry is critical to enhance clinical decision making in this area.