[Clinical management of treatment-resistant depression]. / Klinisches Management der therapieresistenten Depression.

Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10-4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3ß. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

Emotional Blunting in Depression in the PREDDICT Clinical Trial: Inflammation-Stratified Augmentation of Vortioxetine With Celecoxib.

BACKGROUND: Emotional symptoms are recognized as a key feature in individuals with major depressive disorder. Previously, emotional blunting has been described both as a side effect of antidepressant treatment and as a symptom of depression. Little is known about the change of emotional blunting during antidepressant treatment. METHODS: The PREDDICT trial is a randomized, placebo-controlled, 6-week trial on the augmentation of vortioxetine with the anti-inflammatory agent celecoxib or placebo. Presently we report on exploratory secondary outcomes of changes in emotional blunting in depression assessed with the Oxford Depression Questionnaire (ODQ) total score and subscores from baseline to 8-week, 3-month, and 6-month follow-up assessments. RESULTS: In the whole group, there was a significant improvement in the ODQ total score and all subscores after 8 weeks. After stratification of participants into the treatment groups, the ODQ total score as well as subscores related to emotional blunting as a symptom of depression (reduction in positive emotions, not caring) improved between baseline and all follow-up time points in both treatment groups. Changes in subscores considered as a side effect of antidepressants (general reduction in emotions, emotional detachment) were inconclusive in both treatment groups. Overall, the placebo-augmented group showed slightly better results in changes of emotional blunting scores than the celecoxib group as did those with elevated inflammation at screening, regardless of treatment group. CONCLUSIONS: This analysis suggests favorable effects of vortioxetine on emotional blunting in both short- and long-term course. The beneficial impact of vortioxetine on emotional blunting was weaker in celecoxib-augmented patients compared with placebo, possibly due to pharmacokinetic interactions. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Combination of Acute and Maintenance Esketamine Treatment With Adjunctive Long-Term Vagus Nerve Stimulation in Difficult-to-Treat Depression.

INTRODUCTION: The antidepressant effect of N-methyl-D-aspartate antagonists is often short lasting, raising the question of the best maintenance strategy, which has remained unanswered. Vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need for maintenance treatment sessions in patients receiving electroconvulsive therapy. To our knowledge, there are no published data on the combination of VNS and esketamine in the literature. MATERIALS AND METHODS: This is a naturalistic prospective and retrospective observational study in patients treated with long-term VNS owing to difficult-to-treat depression. These patients also have received esketamine maintenance sessions in addition to short-term treatment. We have investigated the need for maintenance esketamine sessions per month after VNS implantation (number of sessions/number of months between visits), the change in depression severity (mean Montgomery-Asberg Depression Rating Scale [MADRS] score), and the number of hospitalizations per month (number of hospitalizations/number of postoperative observation months). Follow-up visits have been scheduled every three months after VNS implantation (follow-up period 12-24 months, mean 17). RESULTS: All patients (n = 8, mean age 53.1 years) had severe difficult-to-treat depression (DTD) (mean MADRS at baseline 30.9). Mean number of hospitalizations per month decreased from 0.17 to 0.11 after VNS implantation (p = 0.041, T = 2.030, df = 7). Mean MADRS at 12 months was 18.3 (40.8% MADRS reduction, p = 0.008, T = 3.146, df = 7). Six of eight patients were offered maintenance esketamine treatment. Mean number of esketamine treatment sessions per month and case decreased from 2.3 at the six-month visit to 0.8 at 12 months (p = 0.076, T = 1,690, df = 5) after VNS implantation. Termination of maintenance esketamine was possible in four cases after a mean of 11.5 months. CONCLUSIONS: Combination of esketamine and VNS was effective in patients with DTD to relieve disease severity and reduce hospitalizations. The need for esketamine treatment sessions decreased after 6 months of VNS. No safety concerns arose in this study regarding the combination treatment. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03320304.

Impact of Adjunctive VNS on Drug Load, Depression Severity, and Number of Neuromodulatory Maintenance Treatments.

Vagus nerve stimulation (VNS) is a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). A total of n = 20 patients (mean age 52.6 years) were included in the multicenter, prospective, observational, naturalistic RESTORE-LIFE study and were treated with adjunctive VNS as an add-on to treatment as usual. Exploratory and secondary outcome parameters from a single center were investigated for this present analysis. The overall mean drug load slightly decreased from 4.5 at baseline to 4.4 at 12 months (Z = -0.534, p = 0.594). The drug load was lower in previous electroconvulsive therapy (ECT) responders than in non-responders. There was a reduction in the mean number of hospitalizations per month after VNS implantation (Z = 1.975, p = 0.048) and a significant decrease in the mean Montgomery Åsberg Depression Rating Scale (MADRS) score from 27.3 at baseline to 15.3 at 12 months (T = 4.230, degree of freedom (df) = 19, p = 0.001). A history of ECT response at baseline was associated with greater improvement in the MADRS score after 12 months of VNS (F = 8.171, p = 0.013). The number of neuromodulatory maintenance treatments decreased during the follow-up period. In summary, there was an alleviation in the burden of illness among DTD patients treated with VNS.

DNA methylation changes in association with trauma-focused psychotherapy efficacy in treatment-resistant depression patients: a prospective longitudinal study.

Background: Stressful events increase the risk for treatment-resistant depression (TRD), and trauma-focused psychotherapy can be useful for TRD patients exposed to early life stress (ELS). Epigenetic processes are known to be related to depression and ELS, but there is no evidence of the effects of trauma-focused psychotherapy on methylation alterations.Objective: We performed the first epigenome-wide association study to investigate methylation changes related to trauma-focused psychotherapies effects in TRD patients.Method: Thirty TRD patients assessed for ELS underwent trauma-focused psychotherapy, of those, 12 received trauma-focused cognitive behavioural therapy, and 18 Eye Movement Desensitization and Reprocessing (EMDR). DNA methylation was profiled with Illumina Infinium EPIC array at T0 (baseline), after 8 weeks (T8, end of psychotherapy) and after 12 weeks (T12 - follow-up). We examined differentially methylated CpG sites and regions, as well as pathways analysis in association with the treatment.Results: Main results obtained have shown 110 differentially methylated regions (DMRs) with a significant adjusted p-value area associated with the effects of trauma-focused psychotherapies in the entire cohort. Several annotated genes are related to inflammatory processes and psychiatric disorders, such as LTA, GFI1, ARID5B, TNFSF13, and LST1. Gene enrichment analyses revealed statistically significant processes related to tumour necrosis factor (TNF) receptor and TNF signalling pathway. Stratified analyses by type of trauma-focused psychotherapy showed statistically significant adjusted p-value area in 141 DMRs only for the group of patients receiving EMDR, with annotated genes related to inflammation and psychiatric disorders, including LTA, GFI1, and S100A8. Gene set enrichment analyses in the EMDR group indicated biological processes related to inflammatory response, particularly the TNF signalling pathway.Conclusion: We provide preliminary valuable insights into global DNA methylation changes associated with trauma-focused psychotherapies effects, in particular with EMDR treatment.

Stressful events increase treatment-resistant depression, and trauma-focused psychotherapy can be useful for these patients.Epigenome-wide data shows changes associated with trauma-focused psychotherapies, especially eye movement desensitization and reprocessing therapy, in treatment-resistant depression patients.Genes and biological pathways related to inflammatory and immune systems are among the most statistically significant results.

Childhood Trauma and Somatic and Mental Illness in Adulthood.

BACKGROUND: Childhood trauma is associated with somatic and mental illness in adulthood. The strength of the association varies as a function of age, sex, and type of trauma. Pertinent studies to date have mainly focused on individual diseases. In this study, we investigate the association between childhood trauma and a multiplicity of somatic and mental illnesses in adulthood. METHODS: Data from 156 807 NAKO Health Study participants were analyzed by means of logistic regressions, with adjustment for age, sex, years of education, and study site. The Childhood Trauma Screener differentiated between no/minor (n = 115 891) and moderate/severe childhood trauma (n = 40 916). The outcome variables were medical diagnoses of five somatic and two mental health conditions as stated in the clinical history. RESULTS: Persons with childhood trauma were more likely to bear a diagnosis of all of the studied conditions: cancer (odds ratio [OR] = 1.10; 95% confidence interval: [1.05; 1.15]), myocardial infarction (OR = 1.13 [1.03; 1.24]), diabetes (OR = 1.16, [1.10; 1.23]), stroke (OR = 1.35 [1.23; 1.48]), chronic obstructive pulmonary disease (OR = 1.45 [1.38; 1.52]), depression (OR = 2.36 [2.29; 2.43]), and anxiety disorders (OR = 2.08 [2.00; 2.17]). All of these associations were stronger in younger persons, regardless of the nature of childhood trauma. Differences between the sexes were observed only for some of these associations. CONCLUSION: Childhood trauma was associated with a higher probability of developing mental as well as somatic illness in adulthood. As childhood trauma is an element of individual history that the victim has little to no control over, and because the illnesses that can arise in adulthood in association with it are a heavy burden on the affected persons and on society, there is a need for research on these associations and for the development of preventive measures.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU): review of its possible role in schizophrenia therapy.

Most patients with schizophrenia need life-long treatment. There is therefore a continued need for effective and tolerable treatment options. A 2-monthly LAI formulation of aripiprazole, Aripiprazole 2-Month Ready-to-Use 960 mg (Ari 2MRTU 960) has recently been approved in the US. Here, the possible role in therapy for this new treatment option is discussed in a narrative review. PubMed was searched for literature on long-acting injectables with a focus on patient-reported outcomes and real-world evidence on extended injection intervals (2-3 months). Dopamine D2 partial agonists, one of which is aripiprazole, exhibit favorable tolerability and safety properties. Additionally, there are many advantages in using long-acting injectable formulations such as enhanced treatment persistence and stability of patients as well as reduced rates of relapses, hospitalizations, and death. Some of these advantages become more pronounced with longer injection intervals. Additional advantages of longer injection intervals are more room for non-medication-related communication between healthcare professionals and patients, patient and physician preferences, reduced caregiver burden, and easier transitioning from inpatient to outpatient treatment. Taken together, since aripiprazole may be a good treatment choice for many patients based on its favorable safety and tolerability profile, and given the advantages of LAI treatment over oral treatment and the advantages of reduced dosing frequency, Ari 2MRTU 960 may become an important treatment option for many clinically stable patients with schizophrenia.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

[Vagus Nerve Stimulation (VNS) in Depression]. / Vagusnervstimulation (VNS) als Behandlungsoption für Depressionen.

Major depressive disorder is a common mental health disease with a chronic and treatment-resistant course in about one-third of patients. Invasive vagus nerve stimulation (VNS) as a long-term adjunctive treatment option has increasingly been used in the last years. VNS was CE-certified in the European Union for use in chronic and treatment-resistant depression in 2001. Method In this narrative literature review we provide an overview on VNS as a treatment option in patients with depression. We particularly focus on aspects with high clinical relevance. Results Indication to conduct VNS is determined after comprehensive evaluation of the patients' symptoms and psychiatric history. After education of patients and caregivers and obtaining informed consent, a pacemaker-like pulse generator is implanted in the left chest in a short surgical procedure. In the first weeks after implantation, the stimulation is turned on stepwise in an outpatient setting. The left vagal nerve is stimulated for 30 sec. every 5 minutes. Hoarseness during stimulation is the most frequent side-effect. There is a delay in the onset of antidepressant action of about 6-12 months. In a large registry, the cumulative response rate after 5 years was significantly higher (67.6%) in patients treated with VNS plus treatment-as-usual (TAU) than TAU alone (40.9%). Long-term benefits of VNS on quality of life, cognition, morbidity and mortality have been described previously. Conclusion VNS is a long-term safe treatment option in severely affected patients with depression with positive impact on depression severity, quality of life and cognitive function. Increase of monoaminergic transmission and anti-inflammatory effects of VNS are possible mechanisms of action.

Cognitive improvement in patients with major depressive disorder after personalised multi domain training in the CERT-D study.

The CERT-D program offers a new treatment approach addressing disturbed cognitive and psychosocial functioning in major depressive disorder (MDD). The current analysis of a randomised controlled trial (RCT) comprises two objectives: Firstly, evaluating the program's efficacy of a personalised versus standard treatment and secondly, assessing the treatment's persistence longitudinally. Participants (N = 112) were randomised into a personalised or standard treatment group. Both groups received 8 weeks of cognitive training, followed by a three-month follow-up without additional training. The type of personalised training was determined by pre-treatment impairments in the domains of cognition, emotion-processing and social-cognition. Standard training addressed all three domains equivalent. Performance in these domains was assessed repeatedly during RCT and follow-up. Treatment comparisons during the RCT-period showed benefits of personalised versus standard treatment in certain aspects of social-cognition. Conversely, no benefits in the remaining domains were found, contradicting a general advantage of personalisation. Exploratory follow-up analysis on persistence of the program's effects indicated sustained intervention outcomes across the entire sample. A subsequent comparison of clinical outcomes between personalised versus standard treatment over a three-month follow-up period showed similar results. First evidence suggests that existing therapies for MDD could benefit from an adjunct administration of the CERT-D program.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Narcissistic dimensions and depressive symptoms in patients across mental disorders in cognitive behavioural therapy and in psychoanalytic interactional therapy in Germany: a prospective cohort study.

BACKGROUND: Narcissistic personality traits have been theorised to negatively affect depressive symptoms, therapeutic alliance, and treatment outcome, even in the absence of narcissistic personality disorder. We aimed to examine how the dimensional narcissistic facets of admiration and rivalry affect depressive symptoms across treatment modalities in two transdiagnostic samples. METHODS: We did a naturalistic, observational prospective cohort study in two independent adult samples in Germany: one sample pooled from an inpatient psychiatric clinic and an outpatient treatment service offering cognitive behavioural treatment (CBT), and one sample from an inpatient clinic providing psychoanalytic interactional therapy (PIT). Inpatients treated with CBT had an affective or psychotic disorder. For the other two sites, data from all service users were collected. We examined the effect of core narcissism and its facets admiration and rivalry, measured by Narcissistic Admiration and Rivalry Questionnaire-short version, on depressive symptoms, measured by Beck's Depression Inventory and Patient Health Questionnaire-Depression Scale, at baseline and after treatment in patients treated with CBT and PIT. Primary analyses were regression models, predicting baseline and post-treatment depression severity from core narcissism and its facets. Mediation analysis was done in the outpatient CBT group for the effect of the therapeutic alliance on the association between narcissism and depression severity after treatment. FINDINGS: The sample included 2371 patients (1423 [60·0%] female and 948 [40·0%] male; mean age 33·13 years [SD 13·19; range 18-81), with 517 inpatients and 1052 outpatients in the CBT group, and 802 inpatients in the PIT group. Ethnicity data were not collected. Mean treatment duration was 300 days (SD 319) for CBT and 67 days (SD 26) for PIT. Core narcissism did not predict depression severity before treatment in either group, but narcissistic rivalry was associated with higher depressive symptom load at baseline (ß 2·47 [95% CI 1·78 to 3·12] for CBT and 1·05 [0·54 to 1·55] for PIT) and narcissistic admiration showed the opposite effect (-2·02 [-2·62 to -1·41] for CBT and -0·64 [-1·11 to -0·17] for PIT). Poorer treatment response was predicted by core narcissism (ß 0·79 [0·10 to 1·47]) and narcissistic rivalry (0·89 [0·19 to 1·58]) in CBT, whereas admiration showed no effect. No effect of narcissism on treatment outcome was discernible in PIT. Therapeutic alliance mediated the effect of narcissism on post-treatment depression severity in the outpatient CBT sample. INTERPRETATION: As narcissism affects depression severity before and after treatment with CBT across psychiatric disorders, even in the absence of narcissistic personality disorder, the inclusion of dimensional assessments of narcissism should be considered in future research and clinical routines. The relevance of the therapeutic alliance and therapeutic strategy could be used to guide treatment approaches. FUNDING: IZKF Münster. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Exploratory Analysis of the Effects of Celecoxib on Cognitive Function in Vortioxetine-Treated Patients With Major Depressive Disorder in the PREDDICT Study: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Objective: Major depressive disorder (MDD) remains difficult to treat, with many patients resistant to existing treatments or experiencing relapse. Cognitive dysfunction is associated with more severe clinical outcomes. Vortioxetine has shown efficacy in remediating depression-associated cognitive impairment. Anti-inflammatory augmentation of antidepressants is a new strategy in treating depression and has not previously been assessed for effects on cognition in depression.Methods: Exploratory analyses were performed on secondary outcome cognitive data from the PREDDICT parallel-group, randomized, double-blind, placebo-controlled trial at the University of Adelaide (Australia). Participants (N = 119) with MDD (validated with Mini-International Neuropsychiatric Interview for DSM-IV) were treated with vortioxetine and celecoxib or vortioxetine and placebo for 6 weeks between December 2017 and April 2020. Measures included objective cognition composite scores (Choice Reaction Time, N-Back, Digit Symbol Substitution Test, Trail Making Task Part B), subjective cognition scores (Perceived Deficits Questionnaire), and global cognition composite scores (combined objective and subjective scores) derived from the THINC integrated tool (THINC-it). High-sensitivity C-reactive protein (hsCRP) measured at baseline and week 6 was tested for a predictive relationship with cognitive outcomes.Results: Cognition composite scores demonstrated improvement by week 6 in both treatment groups. However, there was no significant interaction between change over time and treatment group. HsCRP did not have a significant relationship with any tested cognition measures.Conclusions: Both treatment groups showed a reduction in depression-associated cognitive impairment. No superior clinical effect was reported for the add-on celecoxib group. HsCRP was modulated by neither vortioxetine nor add-on celecoxib.Trial Registration: ANZCTR identifier: ACTRN12617000527369.

Longitudinal early epigenomic signatures inform molecular paths of therapy response and remission in depressed patients.

Introduction: The etiology of major depressive disorder (MDD) involves the interaction between genes and environment, including treatment. Early molecular signatures for treatment response and remission are relevant in a context of personalized medicine and stratification and reduce the time-to-decision. Therefore, we focused the analyses on patients that responded or remitted following a cognitive intervention of 8 weeks. Methods: We used data from a randomized controlled trial (RCT) with MDD patients (N = 112) receiving a cognitive intervention. At baseline and 8 weeks, blood for DNA methylation (Illumina Infinium MethylationEPIC 850k BeadChip) was collected, as well as MADRS. First, responders (N = 24; MADRS-reduction of at least 50%) were compared with non-responders (N = 60). Then, we performed longitudinal within-individual analyses, for response (N = 21) and for remission (N = 18; MADRS smaller or equal to 9 and higher than 9 at baseline), respectively, as well as patients with no change in MADRS over time. At 8 weeks the sample comprised 84 individuals; 73 patients had DNA methylation for both time-points. The RnBeads package (R) was used for data cleaning, quality control, and differential DNA-methylation (limma). The within-individual paired longitudinal analysis was performed using Welch's t-test. Subsequently gene-ontology (GO) pathway analyses were performed. Results: No CpG was genome-wide significant CpG (p < 5 × 10-8). The most significant CpG in the differential methylation analysis comparing response versus non-response was in the IQSEC1 gene (cg01601845; p = 1.53 × 10-6), linked to neurotransmission. The most significant GO-terms were linked to telomeres. The longitudinal response analysis returned 67 GO pathways with a p < 0.05. Two of the three most significant pathways were linked to sodium transport. The analysis for remission returned 46 GO terms with a p-value smaller than 0.05 with pathways linked to phosphatase regulation and synaptic functioning. The analysis with stable patients returned mainly GO-terms linked to basic cellular processes. Discussion: Our result suggest that DNA methylation can be suitable to capture early signs of treatment response and remission following a cognitive intervention in depression. Despite not being genome-wide significant, the CpG locations and GO-terms returned by our analysis comparing patients with and without cognitive impairment, are in line with prior knowledge on pathways and genes relevant for depression treatment and cognition. Our analysis provides new hypotheses for the understanding of how treatment for depression can act through DNA methylation and induce response and remission.

Long-term effects of electroconvulsive therapy on brain structure in major depression.

BACKGROUND: Magnetic resonance imaging (MRI) studies on major depressive disorder (MDD) have predominantly found short-term electroconvulsive therapy (ECT)-related gray matter volume (GMV) increases, but research on the long-term stability of such changes is missing. Our aim was to investigate long-term GMV changes over a 2-year period after ECT administration and their associations with clinical outcome. METHODS: In this nonrandomized longitudinal study, patients with MDD undergoing ECT (n = 17) are assessed three times by structural MRI: Before ECT (t0), after ECT (t1) and 2 years later (t2). A healthy (n = 21) and MDD non-ECT (n = 33) control group are also measured three times within an equivalent time interval. A 3(group) × 3(time) ANOVA on whole-brain level and correlation analyses with clinical outcome variables is performed. RESULTS: Analyses yield a significant group × time interaction (pFWE < 0.001) resulting from significant volume increases from t0 to t1 and decreases from t1 to t2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t0 to t1 correlate with immediate and delayed symptom increase, while volume decreases from t1 to t2 correlate with long-term depressive outcome (all p ⩽ 0.049). CONCLUSIONS: Volume increases induced by ECT appear to be a transient phenomenon as volume strongly decreased 2 years after ECT. Short-term volume increases are associated with less symptom improvement suggesting that the antidepressant effect of ECT is not due to volume changes. Larger volume decreases are associated with poorer long-term outcome highlighting the interplay between disease progression and structural changes.

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.