Treatment Of Major Depressive Disorder Research Articles

Design, implementation and preliminary results of a type-2 hybrid cluster-randomized trial of integrating screening and treatment for major depressive disorder into specialty clinics providing opioid agonist therapies in Ukraine

IntroductionUkraine has a high prevalence of co-occurring disorders (COD), defined as having both substance use (SUD) and psychiatric disorders. Major depressive disorder (MDD) is the most prevalent psychiatric disorder among people with SUD. People with COD experience poor health outcomes, and international agencies propose integrated COD care. In Ukraine, treatment for SUD is delivered in specialized substance use clinics, without providing any other medical services for comorbidities, including MDD. Here we present the protocol, along the with the preliminary results of the MEDIUM project, including observations over the first 6 months. MethodsA cluster-randomized type-2 hybrid trial was conducted to integrate MDD treatment into specialty clinics providing opioid agonist therapies (OAT) in Ukraine. Twelve clinics in four regions underwent randomization to control (N = 1) vs experimental arms (N = 2) in each region. Clinicians at experimental sites received tele-education through modified project ECHO using a facilitated screening, evaluation, and treatment algorithm of depression, with or without financial incentives. Service-, patient- and provider-level data were collected for the analysis every 6 months for 24 months. Preliminary resultsFor service delivery outcomes, 4421 patients enrolled on OAT across all sites were assessed for MDD for screening (76.7%), evaluation with diagnosis (43.5%) and treatment (30.7%) for MDD; 13.8% continued treatment at least for 6 months. For patient-level outcomes, 1345 patients and 54 providers participated in serial surveys every six months. ConclusionThis study will be the first to explore integrated COD care in Ukraine and generate evidence on effective service integration and delivery strategies for people with COD receiving treatment at substance use clinics with broader implications for Eastern Europe and Central Asia region.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Cariprazine (Vraylar) for adjunctive treatment of depression.

The FDA has approved the second-generation antipsychotic drug cariprazine (Vraylar — Abbvie) for adjunctive treatment of major depressive disorder (MDD) in adults. Cariprazine was previously approved for treatment of schizophrenia and bipolar depression, and for acute treatment of manic or mixed episodes associated with bipolar I disorder.

The Pharmacokinetics and Bioequivalence of Desvenlafaxine Succinate in Chinese Healthy Subjects Under Fasting and Fed States.

Desvenlafaxine succinate is a selective serotonin-norepinephrine reuptake inhibitor for the treatment of major depressive disorder. The pharmacokinetic profile of desvenlafaxine succinate at the clinically recommended dose of 50mg in Chinese healthy subjects has been reported rarely. The objective of this study was to evaluate the pharmacokinetics and bioequivalence of desvenlafaxine succinate in Chinese healthy subjects. A single-dose, open-label, randomized, two-way crossover study with a 7-day washout period was conducted. A total of 88 individuals were incorporated to show bioequivalence of a generic and a reference drug, with 48 individuals in the fasting state and 40 receiving a high-fat diet. Finally, 46 and 38 individuals completed the fasting and the fed study, respectively. The 90% confidence intervals of the adjusted geometric mean ratios for maximum plasma concentration, area under the concentration-time curve from time zero to the last measurable concentration, and area under the concentration-time curve from time zero to infinity all fell in the bioequivalent interval of 80%-125% in both the fasting and fed states. A total of 33 adverse events were reported, and all were mild or moderate in severity. In summary, the generic and reference formulations were bioequivalent, with no observable safety differences in the fasting/fed state.

Effect of fluvoxamine on plasma interleukin-6 in patients with major depressive disorder: a prospective follow-up study.

Major depressive disorder (MDD) is associated with low-grade inflammation, and anti-inflammatory treatment can help improve depressive symptoms. A recent study found that fluvoxamine (FLV) can reduce Interleukin-6 (IL-6) production via sigma-1 receptor in inflammation models. However, the anti- IL-6 effect of FLV in treating patients with MDD and whether it can contribute to antidepressant effects remain unclear. A total of 65 patients with MDD and 34 healthy controls were recruited at baseline, and 50 patients completed the FLV treatment for 2 months. We assessed depression and anhedonia and collected plasma IL-6 levels at baseline, 1 month, and 2 months after baseline. This study evaluated the changes in clinical measures and IL-6 during treatment and analyzed their association. Further subgroup analyses were conducted in patients with MDD with high, medium, or low IL-6. Depression and anhedonia were significantly improved in patients with MDD, while the IL-6 did not significantly change after the FLV treatment. However, IL-6 significantly declined after the FLV treatment among patients with MDD with higher baseline IL-6. No significant associations were found between the changes in depressive symptoms and IL-6. Our study provided preliminary evidence suggesting that the anti-IL-6 effect of FLV might not play a vital role in its antidepressant treatment, at least in patients with MDD with low inflammation. However, for patients with MDD with higher IL-6, FLV can help reduce IL-6 significantly in the antidepressant treatment, which may help guide the individual treatment of MDD with higher IL-6 levels. https://clinicaltrials.gov/ct2/show/NCT04160377, identifier NCT04160377.

N°229 – Is baseline high threshold on motor evoked potential a predictor of good rTMS response for the treatment of major depressive disorder?

N°229 – Is baseline high threshold on motor evoked potential a predictor of good rTMS response for the treatment of major depressive disorder?

Balancing the beautiful and the good in pursuit of biomarkers for depression.

Balancing the beautiful and the good in pursuit of biomarkers for depression.

Implementing Digital Cognitive-Behavioral Therapy for Major Depressive Disorder in Routine Psychiatric Appointments: A Pilot Project in a Rural Population.

Psychotherapy is well-established as an effective treatment for major depressive disorder (MDD). However, many individuals with MDD in rural areas of the United States do not have access to psychotherapy. Self-management (SM) strategies are now the standard of care for chronic medical conditions and may be a viable alternative for individuals without access to psychotherapy. The current article describes the implementation of a 13-week pilot project to integrate digital cognitive-behavioral therapy (dCBT) SM programs into routine psychiatric advanced practice nurse (APN) telehealth appointments in the rural United States. Eight participants completed the project. The project did not meet the benchmark of 20 participants to improve access to treatment; however, one half (n = 4) of participants reported clinically significant improvement in MDD symptoms over 6 weeks. For clients without access to psychotherapy, dCBT SM programs can be effective in improving individual client outcomes when implemented by APNs in routine telehealth appointments. [Journal of Psychosocial Nursing and Mental Health Services, 61(10), 44-51.].

White matter microstructure changes in adults with major depressive disorder: evidence from diffusion magnetic resonance imaging

Major depressive disorder (MDD) is a serious psychiatric disorder marked by low mood and anhedonia. Understanding the neural mechanism of MDD is essential for the treatment of depression. White matter fibres, connecting different computational units in the brain, have an important effect on brain function; however, the mechanism of white matter fibre abnormality in MDD is still unclear. Our study expected to find white matter abnormalities associated with the frontal lobe and hippocampus in individuals with MDD. Using diffusion tensor imaging data and tract-based spatial statistics, we investigated the microstructural differences in white matter fibre tracts between 30 adults with MDD compared with 31 healthy controls, and calculated the association between MDD-related microstructural changes and illness duration. It was found that patients with MDD showed reduced fractional anisotropy in the genu and body of the corpus callosum, right corona radiata and part of the thalamic radiations, suggesting lower fibrous myelination levels in these regions; the decreased fractional anisotropy in these regions was associated with longer illness duration. Our results suggest that MDD may be associated with microstructural damage of key fibre tracts, which could provide insights into the understanding and treatment of MDD.

Acupuncture for Major Depressive Disorder: A Data Mining-Based Literature Study.

Acupuncture has a long history of treating major depressive disorder (MDD), yet the acupoint selection of acupuncture for MDD varies greatly. This study aimed to explore the characteristics and principles of acupuncture for MDD by analyzing clinical trials of acupuncture for MDD using data mining techniques. In this study, clinical trials of acupuncture for MDD were retrieved and relevant data were extracted, and then the data were analyzed by data mining techniques. In addition, association rule mining, network analysis and hierarchical cluster analysis were used to determine the correlation between different acupoints. The results revealed that GV20, LR3, PC6, SP6 and GV29 were used most frequently; acupoints in the Yang meridian were used more often than those in the Yin meridian, with the most applied acupoints in the Governor Vessel; the percentage of specific acupoints applied was 69.39%, with the most applied being five-shu points; the frequency of acupoints used was highest in the lower limbs, while the head, face, and neck had the most acupoints used; GV29 combined with GV20 were the most used acupoint groups; the core acupoints used for MDD were GV20, PC6 and SP36; there were 5 acupoint groups according to the cluster analysis. The most used acupuncture method was manual acupuncture; the frequency of treatment was mostly 7 times per week and the duration of treatment was mostly 42 days. We discussed the current character of acupuncture treatment on MDD, including the frequency used of acupoints, the property of used acupoints, the acupoint combination, the acupuncture method, and the frequency and duration of treatment. These findings may provide new ideas for the clinical treatment of MDD. However, further clinical/experimental studies are needed to demonstrate the significance of this concept and approach.

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series.

Transcranial magnetic stimulation (TMS) is a neuro-modulation technique for treatment-resistant major depressive disorder (MDD). Standard TMS protocols for MDD involve once-daily treatment for 6 to 9 weeks. We report a case series of an accelerated TMS protocol for outpatient MDD treatment. From July 2020 through January 2021, patients deemed appropriate candidates for TMS treatment were offered an accelerated TMS protocol consisting of intermittent theta burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex, localized by the Beam F3 method, and consisting of 5 treatments daily for 5 days. Assessment scales were obtained as part of standard clinical care. A total of 19 veterans received the accelerated protocol and 17 completed treatment. Statistically significant mean reductions from baseline to end of treatment were observed across all assessment scales. Remission and response rates, as defined by changes in Montgomery-Åsberg Depression Rating Scale scores, were 47.1% and 64.7%, respectively. Treatments were well tolerated without unexpected or serious adverse events. This case series details the safety and efficacy of an accelerated iTBS TMS protocol consisting of 25 treatments over 5 days. Improved depressive symptoms were observed, with remission and response rates similar to standard TMS protocols of daily TMS for ≥6 weeks.

Randomized trial of brief interpersonal psychotherapy and cognitive behavioral therapy for depression delivered both in-person and by telehealth

BackgroundExpert consensus guidelines recommend Cognitive Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT), interventions that were historically delivered face-to-face, as first-line treatments for Major Depressive Disorder (MDD). Despite the ubiquity of telehealth following the COVID-19 pandemic, little is known about differential outcomes with CBT versus IPT delivered in-person (IP) or via telehealth (TH) or whether working alliance is affected. MethodsAdults meeting DSM-5 criteria for MDD were randomly assigned to either 8 sessions of IPT or CBT (group). Mid-trial, COVID-19 forced a change of therapy delivery from IP to TH (study phase). We compared changes in Hamilton Rating Scale for Depression (HRSD-17) and Working Alliance Inventory (WAI) scores for individuals by group and phase: CBT-IP (n = 24), CBT-TH (n = 11), IPT-IP (n = 25) and IPT-TH (n = 17). ResultsHRSD-17 scores declined significantly from pre to post treatment (pre: M = 17.7, SD = 4.4 vs. post: M = 11.7, SD = 5.9; p < .001; d = 1.45) without significant group or phase effects. WAI scores did not differ by group or phase. Number of completed therapy sessions was greater for TH (M = 7.8, SD = 1.2) relative to IP (M = 7.2, SD = 1.6) (Mann-Whitney U = 387.50, z = −2.24, p = .025). LimitationsParticipants were not randomly assigned to IP versus TH. Sample size is small. ConclusionsThis study provides preliminary evidence supporting the efficacy of both brief IPT and CBT, delivered by either TH or IP, for depression. It showed that working alliance is preserved in TH, and delivery via TH may improve therapy adherence. Prospective, randomized controlled trials are needed to definitively test efficacy of brief IPT and CBT delivered via TH versus IP.

Effectiveness and Safety of Vortioxetine for the Treatment of Major Depressive Disorder in the Real World: A Systematic Review and Meta-Analysis.

Major depressive disorder (MDD) is a highly prevalent and burdensome condition. This study aims to evaluate the effectiveness, tolerability, and safety of vortioxetine in treating MDD based on real-world data. A systematic search of 8 electronic databases was performed from inception until October 2022 to identify real-world studies, excluding randomized controlled trials. We conducted subgroup, meta-regression, sensitivity analyses, publication bias, and quality assessments using the random-effects model. The effects were summarized by rates or standardized mean difference (SMD) with 95% confidence interval (CI). Of the 870 records identified, 11 studies (3139 participants) and 10 case reports or series were eligible for inclusion. Vortioxetine significantly relieved depression symptoms as assessed by both patients (SMD = 2.25, 95% CI = 1.60-2.89) and physicians (SMD = 3.73, 95% CI = 2.78-4.69). Cognitive function (SMD =1.86, 95% CI = 1.11-2.62) and functional disability (SMD =1.71, 95% CI = 1.14-2.29) were similarly markedly improved. Subgroup and meta-regression analyses showed that geographic location and medication regimen (whether combined with other antidepressants) were crucial factors influencing effectiveness (in terms of depression severity and cognitive function), potentially contributing to significant heterogeneity. The estimated response and remission rates were 66.4% (95% CI = 51.2%-81.5%) and 58.0% (95% CI = 48.9%-67.1%), respectively. Vortioxetine was well tolerated, with a pooled dropout rate of 3.5% (95% CI = 1.8%-5.8%), and the most common adverse event was nausea, with an estimated rate of 8.9% (95% CI = 3.8%-15.8%). The study has some limitations, including significant heterogeneity and limited evidence for some outcomes. Vortioxetine is effective, well tolerated, and safe for treating MDD in clinical practice, with significant improvements observed in depressive severity, cognitive function, and functioning. Future studies should directly compare vortioxetine with other antidepressants in real-world settings to further evaluate its clinical utility.

Systematic reviews and meta-analyses on major depressive disorder: a bibliometric perspective.

There is a vast amount of evidence-based medicine research on the major depressive disorder (MDD) available in the literature, however, no studies on the overall performance, productivity and impact of such research have been published to date. This study explored and mapped the research outputs of MDD-related systematic reviews and meta-analyses (SR/MA) from a bibliometric perspective. Relevant data were retrieved with search terms on MDD, systematic review and meta-analysis. A total of 4,870 papers with 365,402 citations published from 1983 to 2022 were included in the analysis. The publication output has grown steadily over time with the most publications originating from the USA (1,020; 20.94%), the UK (516; 10.60%) and China (448; 9.20%). The research collaborations between countries were most frequent between the USA and UK (266; 5.46%). Journal of Affective Disorders (379; 7.78%) was the most productive journal, while Cuijpers P was the most productive author (121; 2.48%), and University of Toronto (569; 11.78%) was the most productive institution. The top 10 most cited articles on MDD-related SR/MA had citations ranging from 1,806 to 3,448. The high-frequency keywords were mainly clustered into four themes, including psychiatric comorbidities, clinical trials, treatment, and brain stimulation in MDD. The rapid increase in the number of SR/MA of MDD in recent years highlights the importance of this research field. Psychiatric comorbidities, clinical interventions, and treatment of MDD have been identified as hot topics, while biological mechanisms in MDD are likely to be an emerging research priority.

The course of insomnia symptoms during the acute treatment of major depressive disorder: A CAN-BIND-1 report

Despite considerable efforts to study the relationship between insomnia and depression, there is minimal research investigating whether insomnia symptoms change over time during a course of antidepressant pharmacotherapy. This study investigated the course of insomnia symptoms during the acute treatment of major depressive disorder (MDD) using a secondary analysis of data from MDD patients (N = 180) who were treated with open-label escitalopram (10–20 mg/day) for 8-weeks. Montgomery-Asberg Depression Rating Scale without sleep item (modified-MADRS) assessed depression and Self-reported Quick Inventory Depressive Scale (QIDS-SR) measured subjective sleep-onset, mid-nocturnal, and early-morning insomnia throughout 8-weeks of treatment. Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality, duration, onset latency, and efficiency throughout 8-weeks of treatment. Remission of depression was defined as modified-MADRS ≤10 at week-8. Mixed model repeated measures (MMRMs) were conducted with remission status as an independent variable and each sleep variable as a dependent variable. MMRMs demonstrated that remitters had significantly lower QIDS-SR sleep-onset and mid-nocturnal insomnia scores as well as a significantly lower PSQI sleep quality score than non-remitters throughout 8-weeks of treatment. Monitoring subjective sleep-onset and mid-nocturnal insomnia during the course of treatment with serotonergic antidepressants may be useful for predicting acute remission of depression.

Two possible mechanisms of ganciclovir for treatment of major depressive disorder.

Two possible mechanisms of ganciclovir for treatment of major depressive disorder.

Efficacy and Safety of Vilazodone treatment for Major Depressive Disorder (MDD): A Pooled analysis of 3390 patients (P6-4.004)

Efficacy and Safety of Vilazodone treatment for Major Depressive Disorder (MDD): A Pooled analysis of 3390 patients (P6-4.004)

A critical evaluation of QIDS-SR-16 using data from a trial of psilocybin therapy versus escitalopram treatment for depression.

In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR16) did not. The present study aims to (1) rationally and psychometrically account for discrepant results between outcome measures and (2) to overcome psychometric problems particular to individual measures by re-examining between-condition differences in depressive response using all outcome measures at item-, facet-, and factor-levels of analysis. Four depression measures were compared on the basis of their validity for examining differences in depressive response between PT and ET conditions. Possible reasons for discrepant findings on the QIDS-SR16 include its higher variance, imprecision due to compound items and whole-scale and unidimensional sum-scoring, vagueness in the phrasing of scoring options for items, and its lack of focus on a core depression factor. Reanalyzing the trial data at item-, facet-, and factor-levels yielded results suggestive of PT's superior efficacy in reducing depressed mood, anhedonia, and a core depression factor, along with specific symptoms such as sexual dysfunction. Our results raise concerns about the adequacy of the QIDS-SR16 for measuring depression, as well as the practice of relying on individual scales that tend not to capture the multidimensional structure or core of depression. Using an alternative approach that captures depression more granularly and comprehensively yielded specific insight into areas where PT therapy may be particularly useful to patients and clinicians.

Pharmacokinetics of N,N-dimethyltryptamine in Humans.

N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9-21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9-12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. Registered on ClinicalTrials.gov (NCT04673383).

Association of plasma cytokines and antidepressant response following mild-intensity whole-body hyperthermia in major depressive disorder

Whole-body hyperthermia (WBH) shows promise for the treatment of major depressive disorder (MDD). Because MDD is associated with increased inflammation, and anti-inflammatory agents show some promise as antidepressants, the current study sought to identify the acute and longer-term immune effects of WBH in participants with MDD and to explore whether these effects associate with the procedure’s antidepressant properties. Thirty participants who met DSM-IV-TR criteria for MDD were randomized to receive a single session of WBH (n = 16) or sham treatment (n = 14). Hamilton Depression Rating Scale (HDRS) scores were assessed at baseline and 1, 2, 4, and 6 weeks post-treatment (WBH vs. sham), and plasma cytokine concentrations were assessed at baseline, immediately post-treatment, and 1 and 4 weeks post-treatment. As previously reported, WBH produced a rapid and sustained antidepressant effect. When compared to sham, WBH increased plasma interleukin (IL)-6 immediately post-treatment (time by treatment: χ2(3, N=108) = 47.33, p < 0.001), while having no effect on other cytokines acutely and no impact on IL-6, or any other cytokine, at 1 or 4 weeks post treatment. In the study sample as a whole, increased IL-6 post-treatment was associated with reduced HDRS depression scores over the 6 weeks of follow-up (F(1, 102.3) = 6.74, p = 0.01). These results suggest a hitherto unrecognized relationship between hyperthermia, the immune system, and depression, and may point to WBH as a novel modality for exploring behavioral effects of IL-6 when the cytokine is activated in isolation from the inflammatory mediators with which it frequently travels.