Overcoming treatment-resistant depression with machine-learning based tools: a study protocol combining EEG and clinical data to personalize glutamatergic and brain stimulation interventions (SelecTool Project).

Treatment-Resistant Depression (TRD) poses a substantial health and economic challenge, persisting as a major concern despite decades of extensive research into novel treatment modalities. The considerable heterogeneity in TRD's clinical manifestations and neurobiological bases has complicated efforts toward effective interventions. Recognizing the need for precise biomarkers to guide treatment choices in TRD, herein we introduce the SelecTool Project. This initiative focuses on developing (WorkPlane 1/WP1) and conducting preliminary validation (WorkPlane 2/WP2) of a computational tool (SelecTool) that integrates clinical data, neurophysiological (EEG) and peripheral (blood sample) biomarkers through a machine-learning framework designed to optimize TRD treatment protocols. The SelecTool project aims to enhance clinical decision-making by enabling the selection of personalized interventions. It leverages multi-modal data analysis to navigate treatment choices towards two validated therapeutic options for TRD: esketamine nasal spray (ESK-NS) and accelerated repetitive Transcranial Magnetic Stimulation (arTMS). In WP1, 100 subjects with TRD will be randomized to receive either ESK-NS or arTMS, with comprehensive evaluations encompassing neurophysiological (EEG), clinical (psychometric scales), and peripheral (blood samples) assessments both at baseline (T0) and one month post-treatment initiation (T1). WP2 will utilize the data collected in WP1 to train the SelecTool algorithm, followed by its application in a second, out-of-sample cohort of 20 TRD subjects, assigning treatments based on the tool's recommendations. Ultimately, this research seeks to revolutionize the treatment of TRD by employing advanced machine learning strategies and thorough data analysis, aimed at unraveling the complex neurobiological landscape of depression. This effort is expected to provide pivotal insights that will promote the development of more effective and individually tailored treatment strategies, thus addressing a significant void in current TRD management and potentially reducing its profound societal and economic burdens.

Combination of Transcranial Magnetic Stimulation and Ketamine in Treatment-Resistant Depression: A Systematic Review.

Treatment-resistant depression (TRD) is a significant challenge in psychiatric practice, affecting a substantial proportion of patients with major depressive disorder (MDD). Traditional treatment modalities often fall short, necessitating the exploration of alternative therapies. This literature review examines the combined use of Transcranial Magnetic Stimulation (TMS) and ketamine in treating TRD. The objective of this study is to evaluate the efficacy, safety, and potential synergies of combining TMS and ketamine in the treatment of TRD. A comprehensive literature search was conducted using PubMed and Google Scholar databases from 2014 to 2024. The search terms included combinations of "Transcranial Magnetic Stimulation," "Ketamine," "Depression," "Major Depressive Disorder," "Treatment-Resistant Depression," and "Combination." After screening for relevance and applying inclusion and exclusion criteria, six studies were selected for review, including three case reports, a retrospective study, a pilot study, and a review study. The selected studies demonstrated that the combination of TMS and ketamine resulted in substantial and sustained improvement in depressive symptoms for patients with TRD. Case reports and retrospective studies highlighted significant reductions in depression severity and improvements in psychosocial functioning. The combination therapy showed a higher efficacy compared to monotherapies of either TMS or ketamine alone. Notably, adverse effects were generally mild and transient, with no severe adverse events reported in most studies. In conclusion, the combination of TMS and ketamine presents a promising treatment modality for patients with TRD, offering significant improvements in depressive symptoms and better outcomes compared to traditional monotherapies. However, the heterogeneity in study designs and small sample sizes underline the need for larger, randomized controlled trials to establish standardized protocols and further validate these findings.

Adjunctive Intranasal Esketamine for Comorbid Treatment-Resistant Depression with Suicidal Ideation in Patients Receiving Palliative Care at a Comprehensive Cancer Center: A Case Series.

Background: The psychiatric needs of those with cancer and other advanced illnesses are becoming increasingly recognized. Ketamine is emerging as a promising treatment option for depressive disorders in psychiatric and palliative care. In the palliative care setting, its study has been hindered by lack of consistent administration routes and dosing. Intranasal (IN) esketamine (Spravato®) has recently received U.S. Food and Drug Administration (FDA) approval as an adjunctive agent for treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal ideation (SI). Objective: We sought to offer IN esketamine to patients suffering from TRD and SI at a comprehensive cancer center. Methods: We designed and implemented a protocol to administer IN esketamine and describe three cases in which it was provided to patients with TRD and SI at a palliative care clinic in the United States. Results: Following treatment, all three patients had substantial reduction in depression severity and no further suicidalideation. These improvements were maintained for up to a year. No serious adverse events occurred. Conclusions: These cases illustrate the potential utility of IN esketamine in the palliative care setting.

Neural correlates of treatment response to ketamine for treatment-resistant depression: A systematic review of MRI-based studies.

Treatment-resistant depression (TRD) is defined as patients diagnosed with depression having a history of failure with different antidepressants with an adequate dosage and treatment duration. The NMDA receptor antagonist ketamine rapidly reduces depressive symptoms in TRD. We examined neural correlates of treatment response to ketamine in TRD through a systematic review of brain magnetic resonance imaging (MRI) studies. A comprehensive search in PubMed was performed using "ketamine AND depression AND magnetic resonance." The time span for the database queries was "Start date: 2018/01/01; End date: 2024/05/31." Total 41 original articles comprising 1,396 TRD and 587 healthy controls (HC) were included. Diagnosis of depression was made using the Structured Clinical Interview for DSM Disorders (SCID), the Mini-International Neuropsychiatric Interview (MINI), and/or the clinical assessment by psychiatrists. Patients with affective psychotic disorders were excluded. Most studies applied ketamine [0.5mg/kg racemic ketamine and/or 0.25mg/kg S-ketamine] diluted in 60cc of normal saline via intravenous infusion over 40 min one time, four times, or six times spaced 2-3 days apart over 2 weeks. Clinical outcome was defined as either remission, response, and/or percentage changes of depressive symptoms. Brain MRI of the T2*-weighted imaging (resting-state or task performance), arterial spin labeling, diffusion weighted imaging, and T1-weighted imaging were acquired at baseline and mainly 1-3days after the ketamine administration. Only the study results replicated by ≥ 2 studies and were included in the default-mode, salience, fronto-parietal, subcortical, and limbic networks were regarded as meaningful. Putative brain-based markers of treatment response to ketamine in TRD were found in the structural/functional features of limbic (subgenual ACC, hippocampus, cingulum bundle-hippocampal portion; anhedonia/suicidal ideation), salience (dorsal ACC, insula, cingulum bundle-cingulate gyrus portion; thought rumination/suicidal ideation), fronto-parietal (dorsolateral prefrontal cortex, superior longitudinal fasciculus; anhedonia/suicidal ideation), default-mode (posterior cingulate cortex; thought rumination), and subcortical (striatum; anhedonia/thought rumination) networks. Brain features of limbic, salience, and fronto-parietal networks could be useful in predicting the TRD with better response to ketamine in relief of anhedonia, thought rumination, and suicidal ideation.

Efficacy of pentoxifylline for the treatment of bipolar I/II patients with treatment-resistant depression: A proof-of-concept, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Immune dysregulation can play a role in depression pathophysiology, and immunological antagonists can improve depressive symptoms in treatment-resistant bipolar depression (TRD) patients according to studies. OBJECTIVE: To evaluate the anti-depressant effects of the anti-inflammatory drug, pentoxifylline (PTX) in TRD bipolar I/II adult subjects. METHODS: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at Hawler Psychiatric Hospital and Private Clinic in Erbil, Iraq. Participants were confirmed as being qualified for bipolar I/II depression based on DSM-5 criteria. Data were analyzed using modified intent-to-treat analysis. RESULTS: There were no significant differences between the two groups in Hamilton Rating Scale for Depression-17 (HAM-D-17) scores (χ2=1.9, P =.48) or a significant time × treatment interaction (χ2=7.1, P=.54). Nevertheless, a significant effect of time was observed with both groups' reduction in HAM-D-17 scores from the start to the endpoint (χ2= 2.11, P=.002). Besides, a significant time × treatment × CRP interaction was found (χ2=3.1, P=0.016), where there was more reduction in HAM-D-17 score in PTX-treated subjects with CRP> 7.1 mg/L. The response rate difference between PTX and the placebo group did not reach a significance level (χ2=0.84, p=0.43). Furthermore, serum concentrations of TNF-α, CRP, and IL-6 significantly reduced at week 12 in the PTX group (P=.007,.04, and <.001, respectively). CONCLUSION: The current proof of concept study found that in terms of overall anti-depressant effectiveness in bipolar patients with TRD, PTX is not superior to placebo. However, it may improve depressive mood in a subpopulation of subjects with a higher pretreatment inflammatory profile.

Compassionate use of esketamine intranasal in patients with severe major depressive disorder resistant to the treatment.

BACKGROUND: Treatment-resistant depression (TRD) is defined as the failure of at least two antidepressants in adequate doses and timing during a major depressive episode. Esketamine intranasal (ESK-IN) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of TRD in combination with other antidepressants. AIMS: To assess the effectiveness and tolerability of a sample of TRD patients who received treatment with ESK-IN as part of the compassionate use program. METHODS: A retrospective, observational study was carried out on patients with a diagnosis of TRD enrolled in the early access program of ESK-IN in nine centers. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS) at four time points: baseline, 28, 90, and 180 days of treatment. RESULTS: The sample included 71 patients (70% women) with a mean baseline MADRS score of 38.27 ± 5.9 and total or partial work disability rates of 85%. ESK-IN treatment was associated with a statistically and clinically significant reduction in the severity of depressive symptoms at all time points assessed. The presence of side effects was common but the majority were mild in severity and resolved after the observation period. Those patients who received psychotherapy in combination with ESK-IN showed a significantly lower MADRS score at 90 and 180 days than those patients who did not undergo psychotherapy. CONCLUSION: ESK-IN has proven to be effective and safe in a clinical sample of patients with severe TRD. To optimize clinical outcomes, the pharmacological treatment for TRD should always be integrated into a comprehensive therapeutic plan that encompasses strategies such as psychotherapy, social support, and family interventions.

The role of psilocybin in depressive disorders.

Depression is a serious psychiatric disorder with a high incidence of morbidity and mortality and psilocybin with psychotherapy has emerged as a promising potential in the treatment of depressive disorders. A review of psilocybin use in patients with depressive disorders is presented.A search was conducted investigating the use of psilocybin in patients with depressive disorders and treatment resistant depression via PubMed/MEDLINE, EMBASE, and Google Scholar in October 2023; all publication types were permitted and limited for English-language. Keyword search terms included: "psilocybin" or "psychedelics" and "depression", or "major depressive disorder", or "treatment-resistant depression". Controlled and uncontrolled clinical trials utilizing psilocybin with psychological support for major depressive disorder and treatment-resistant depression, as well as in patients with depression and cancer related anxiety have demonstrated immediate and sustained antidepressant and anxiolytic effects. Psilocybin has a favorable safety profile and was well-tolerated in clinical trials. Psilocybin's abuse potential is low and clinical research suggests the potential of psilocybin to produce rapid and lasting antidepressant effects up to 12 months post-treatment. Psilocybin may offer a valuable contribution as an option to the currently available pharmacological and psychotherapeutic agents for patients with major depressive disorders, treatment-resistant depression as well as for patients with depression and comorbid terminal cancer. Future studies are needed to demonstrate these findings and any synergistic interaction between psilocybin and the psychological support offered to patients during sessions.

Case report: two cases of rhabdomyolysis following esketamine treatment.

Major depressive disorder is a mental disorder affecting millions of people worldwide. A considerable proportion of patients demonstrate a lack of response to conventional treatment. With the recent introduction of esketamine, a new treatment option has been approved for treatment-resistant depression. Although the medication is efficacious in a substantial portion of cases, rare, but possibly serious, adverse effects may occur. This case series shows two cases of rhabdomyolysis, a destruction of muscle tissue with elevated creatine kinase levels, after administration of esketamine. The first case presented is about a 33 year old male patient who suffered from a severe episode of a depressive disorder. He got nasal esketamine as an emergency treatment. While there was an initial improvement regarding the depressive symptoms, the patient developed muscle pain and fatigue after the administration of the fourth dose, with creatine kinase (CK) levels above 22,000 U/L, indicating rhabdomyolysis. Following the discontinuation of esketamine and the implementation of supportive care, the CK levels returned to normal and the depressive symptoms abated. The second case is about a 22-year-old male patient who also suffered from a severe depressive episode and got eketamine as an emergency treatment. Following the tenth dose, the patient exhibited muscle weakness and elevated CK levels (8,032 U/L), which persisted even after dose reduction. Esketamine administration was stopped, and the following monitoring demonstrated a slow return to normal levels of CK and liver enzymes. In both cases, there was no known medical history and both patients developed rhabdomyolysis after administration of esketamine. The temporal connection suggests a possible causal relationship. We found no literature on esketamine-induced rhabdomyolysis following the administration of nasal esketamine. However, these two cases emphasize the need of monitoring for laboratory changes like elevated CK-levels in patients receiving esketamine, especially considering its growing use in treatment-resistant depression.

Cognitive Profiles in Treatment-Resistant Late-Life Depression and their Impact on Treatment Outcomes.

BACKGROUND: Late-life depression (LLD) is associated with cognitive impairment, yet substantial heterogeneity exists among patients. Data on the extent of cognitive impairments is inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant vs. nonresistant LLD and aimed to identify distinct cognitive subgroups. Additionally, we examined whether cognitive subgroups differentially responded to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS). METHODS: 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared to healthy controls (HC) on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups. RESULTS: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than HC. A three-cluster solution was found, including "Cognitively Intact" (n = 89), "Cognitively Diminished" (n = 29), and "Impaired Memory" (n = 47) subgroups. Both the "Cognitively Diminished" and "Impaired Memory" subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the "Cognitively Intact" group, though the latter did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment. CONCLUSIONS: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three identified cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationship among cognitive subgroups, cognitive decline, and neurodegeneration.

A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression.

BACKGROUND: For depression, ketamine is more conveniently administered by oral than by intravenous (iv) routes. The relative antidepressant efficacy of oral vs iv ketamine is unknown. OBJECTIVES: To assess the acute efficacy and the persistence of improvement with open-label oral versus iv ketamine in outpatients with treatment-resistant depression (TRD). METHODS: Adults with TRD were randomized to oral (N=30) or IV (N=31) ketamine. Oral ketamine was dosed at 150 mg in 50 mL of water, sipped across 15 min. IV ketamine was dosed at 0.5 mg/kg, infused across 40 min. Ketamine sessions (total, 7) were administered on alternate days for 2 weeks. Ongoing antidepressant drugs were continued unchanged. Patients were assessed at baseline, day 14, and day 30. The primary outcome was the endpoint Hamilton Rating Scale for Depression score on day 14. Secondary outcomes were endpoint scores on the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, and Clinical Global Impression-Severity of Illness and Improvement. RESULTS: Overall dropout was lower with oral than with iv ketamine (26.7 % vs 54.8 %; P=0.03). The 2 groups did not differ in depression ratings and in response and remission rates on all instruments on both days 14 and 30. Adverse events such as headache (56.7 % vs 74.2 %) and drowsiness (0.0 % vs 22.6 %) were less common with oral ketamine. CONCLUSION: In TRD outpatients treated in general hospitals, oral ketamine maybe better accepted and tolerated than iv ketamine. Conclusions about relative efficacy cannot be drawn because of the high dropout rate with iv ketamine.

Utilization and outcomes of transcranial magnetic stimulation and usual care for MDD in a large group psychiatric practice.

BACKGROUND: General psychiatrists' practice standards vary regarding when to implement transcranial magnetic stimulation (TMS) for care of patients with major depressive disorder (MDD). Furthermore, few studies have examined real-world utilization and clinical outcomes of TMS. This study analyzed data from a large, multi-site psychiatric practice to evaluate utilization and outcomes of TMS as well as usual care (UC) for patients with MDD. METHODS: Depression outcomes for TMS and UC among adult patients at a multi-site psychiatric group practice were examined in this retrospective cohort analysis. Patients with a primary diagnosis of MDD, PHQ-9 ≥ 10, and a visit in November 2020 with 6-month follow-up were included and categorized into the TMS or UC cohorts. RESULTS: Of 1,011 patients with qualifying PHQ-9 at the baseline visit, 9% (89) received a full course of TMS, and 583 patients receiving UC met study inclusion criteria (339 patients were excluded due to lacking a 6-month follow-up visit or receiving esketamine during the study period). The TMS cohort had higher baseline PHQ-9 than UC (17.9 vs. 15.5, p < .001) and had failed more medication trials (≥ 4 vs. 3.1, p < .001). Mean PHQ-9 decreased by 5.7 points (SD = 6.7, p < .001) in the TMS cohort and by 4.2 points (SD = 6.4, p < .001) in the UC cohort over the study period. Among patients who had failed four or more antidepressant medications, PHQ-9 decreased by 5.8 points in the TMS cohort (SD = 6.7, p < .001) and by 3.2 points in the UC cohort (SD = 6.3, p < .001). CONCLUSIONS: TMS utilization was low, despite TMS showing significant real-world clinical benefits. Future research should examine and address barriers to wider adoption of TMS into routine patient care for patients with treatment-resistant MDD. Wider adoption including routine use of TMS in less treatment-resistant patients will allow statistical comparisons of outcomes between TMS and UC populations that are difficult to do when TMS is underutilized.

Major challenges in youth psychopathology: treatment-resistant depression. A narrative review.

Major depressive disorder (MDD) represents a major health issue in adolescents and young adults, leading to high levels of disability and profoundly impacting overall functioning. The clinical presentation of MDD in this vulnerable age group may slightly differ from what can be observed in adult populations, and psychopharmacological strategies do not always lead to optimal response. Resistance to antidepressant treatment has a prevalence estimated around 40% in youths suffering from MDD and is associated with higher comorbidity rates and suicidality. Several factors, encompassing biological, environmental, and clinical features, may contribute to the emergence of treatment-resistant depression (TRD) in adolescents and young adults. Furthermore, TRD may underpin the presence of an unrecognized bipolar diathesis, increasing the overall complexity of the clinical picture and posing major differential diagnosis challenges in the clinical practice. After summarizing current evidence on epidemiological and clinical correlates of TRD in adolescents and young adults, the present review also provides an overview of possible treatment strategies, including novel fast-acting antidepressants. Despite these pharmacological agents are promising in this population, their usage is expected to rely on risk-benefit ratio and to be considered in the context of integrated models of care.

Cognitive changes in patients with unipolar TRD treated with IV ketamine: A systematic review.

BACKGROUND: Unipolar treatment-resistant depression (MDD-TRD) is associated with neurocognitive impairment. Ketamine, an emerging treatment for MDD-TRD, may have neurocognitive benefits, but evidence remains limited. METHODS: We conducted a systematic search on EMBASE, Google Scholar, PsycINFO, and PubMed and included studies exploring the cognitive effects of intravenous (IV) ketamine treatment in the management of MDD-TRD following the PRISMA guidelines. We analyzed cognitive scale score changes pre- and post-IV ketamine treatment and the quality of the evidence using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). RESULTS: Out of 1171 identified studies, fourteen studies were included in this study. Most studies reported positive cognitive outcomes post-ketamine treatment, including improvements in processing speed, working memory, verbal and visual memory, executive function, attention, emotional processing, and auditory verbal episodic memory. Variability existed, with one study reporting negative effects on verbal memory. Overall, studies exhibited a low risk of bias. LIMITATIONS: Several limitations impacted the results observed, including confining our scope to articles in English, heterogeneity of the included studies, small sample sizes, and the predominance of a female, Western, and Caucasian population, constraining the generalizability of the findings. CONCLUSIONS: IV ketamine treatment shows promise in improving neurocognitive function in MDD-TRD patients. However, further research is warranted to elucidate long-term effects, control for confounders such as concomitant medications, and explore neurocognitive subgroups within the TRD population. These findings underscore the need for comprehensive assessment and management of cognitive symptoms in TRD, informing future clinical practice.

Baseline monocyte count predicts symptom improvement during intravenous ketamine therapy in treatment-resistant depression: a single-arm open-label observational study.

Background: Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients. Methods: 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments. Results: 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all. Conclusions: Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

Understanding profiles of patients with treatment-resistant depression by stringency of health plan prior authorization criteria for approval of esketamine nasal spray.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study.

BACKGROUND: Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array. RESULTS: Longitudinal T0-T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10-5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2. CONCLUSION: Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

A Systematic Review on Ketamine and Esketamine for Treatment-Resistant Depression and Suicidality in Adolescents: A New Hope?

Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents' quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.

Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression.

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE­TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan­Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD.

Genetic Correlates of Treatment-Resistant Depression: Insights from Polygenic Scores Across Cognitive, Temperamental, and Sleep Traits in the All of US cohort.

Background: Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable economic and social burdens. The etiological factors contributing to TRD are complex and not fully understood. Objective: To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits, and to explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us Research Program (AoU). Methods: Data from 292,663 participants in the AoU were analyzed using a case-cohort design. Treatment resistant depression (TRD), treatment responsive Major Depressive Disorder (trMDD), and all others who have no formal diagnosis of Major Depressive Disorder (non-MDD) were identified through diagnostic codes and prescription patterns. Polygenic scores (PGS) for 61 unique traits from seven domains were used and logistic regressions were conducted to assess associations between PGS and TRD. Finally, Cox proportional hazard models were used to explore the predictive value of PGS for progression rate from the diagnostic event of Major Depressive Disorder (MDD) to TRD. Results: In the discovery set (104128 non-MDD, 16640 trMDD, and 4177 TRD), 44 of 61 selected PGS were found to be significantly associated with MDD, regardless of treatment responsiveness. Eleven of them were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia and specific neuroticism traits were associated with increased TRD risk (OR range from 1.05 to 1.15), while higher education and intelligence scores were protective (ORs 0.88 and 0.91, respectively). These associations are consistent across two other independent sets within AoU (n = 104,388 and 63,330). Among 28,964 individuals tracked over time, 3,854 developed TRD within an average of 944 days (95% CI: 883 ~ 992 days) after MDD diagnosis. All eleven previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD. Thus, those having higher education PGS would experiencing slower conversion rates than those who have lower education PGS with hazard ratios in 0.79 (80th versus 20th percentile, 95% CI: 0.74 ~ 0.85). Those who had higher insomnia PGS experience faster conversion rates than those who had lower insomnia PGS, with hazard ratios in 1.21 (80th versus 20th percentile, 95% CI: 1.13 ~ 1.30). Conclusions: Our results indicate that genetic predisposition related to neuroticism, cognitive function, and sleep patterns play a significant role in the development of TRD. These findings underscore the importance of considering genetic and psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance our understanding of pathways leading to treatment resistance.