Clinical Research Directory

Treating Immuno-metabolic Depression With Anti-inflammatory Drugs

As the role of (neuro)inflammation in depression is emerging, augmentation of antidepressant treatments with anti-inflammatory drugs such as celecoxib has shown encouraging preliminary results. However, inflammation is not present in all depressed patients. Depression is heterogeneous: patients express diverse and sometimes opposing symptoms and biological profiles. The investigators of the present trial recently introduced the concept of ImmunoMetabolic Depression (IMD), characterized by the clustering of inflammatory/metabolic dysregulations and atypical, energy-related symptoms (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis), and present in approximately 30% of cases. Converging evidence suggests that in this subgroup of depression cases, inflammation may exert a crucial pathobiological mechanism, representing therefore an actionable therapeutic target. In this trial IMD will be applied as a tool to personalize treatment, by matching depressed subjects with IMD with a targeted anti-inflammatory add-on treatment. In this study, 140 persons with IMD will be selected. In this specific group of patients, the investigators will test whether celecoxib add-on (400 mg/d) is more effective than placebo in the treatment of depression through a 12-week double-blind, randomized (1:1), placebo-controlled trial. By selecting specifically depressed patients with IMD, the proposed treatment selectively targets key inflammatory pathophysiological pathways to enhance clinical outcome for depression. This personalized approach is expected to lead to large health gains for a sizable proportion of patients. The main hypothesis is that the group of patients with IMD receiving TAU + celecoxib, as compared to the TAU + placebo, will show a better symptom course over the 12-week follow-up.

A Study of Brenipatide in Adult Participants With Major Depressive Disorder

This study evaluates the safety and efficacy of brenipatide when administered with standard of care (SoC) compared to placebo plus SoC in delaying the return of major depressive symptoms. The trial is divided into three periods as follows: a screening period that will last approximately 1 month, a treatment period that will last a minimum of 12 months, and the follow up period that will last approximately 2 months. The duration of study participation may vary and may be shortened if depression symptoms worsen or if withdrawal from the study occurs for any reason.

Dopamine Modulation of Motivation and Motor Function in Major Depression & Inflammation

A large body of evidence on depression heterogeneity point to an "immunometabolic" subtype characterized by the clustering of immunometabolic dysregulations with atypical behavioral symptoms related to energy homeostasis. Motivational and motor impairments reflected by symptoms of anhedonia and psychomotor retardation in major depression are closely related to alterations in energy homeostasis, are associated with increased inflammation, and may be a direct consequence of the impact of inflammatory cytokines on the dopamine system in the brain. In the proposed project, the investigators will examine the effect of dopamine stimulation on motivation and motor function in patients with major depression and healthy controls and the role of inflammation using a double-blind, randomized, placebo-controlled, cross-over design. If successful, this study would provide crucial evidence that pharmacologic strategies that increase dopamine may effectively treat inflammation-related symptoms of anhedonia and psychomotor retardation in major depression.

A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder

The purpose of this study is to evaluate how well JNJ-54135419 works (efficacy) in addition to comprehensive standard of care (SoC) in rapidly reducing the symptoms of major depressive disorder (MDD, a mental disorder characterized by a persistent feeling of sadness and loss of interest in activities) as compared with psychoactive placebo (does not contain JNJ-54135419) plus SoC in adolescent participants with acute suicidal ideation or behavior.

A Study to Explore the Efficacy of JNJ-89495120 in the Treatment of Major Depressive Disorder

The purpose of this study is to evaluate how well JNJ-89495120 works (anti-depressant effects) and how well it is tolerated as compared to placebo on reducing the symptoms of depression in participants with major depressive disorder (MDD).

A Study to Evaluate Sleep Electroencephalogram (EEG) Features (Brain Activity While Sleeping) in Participants With Major Depressive Disorder (MDD)

The purpose of this study is to evaluate sleep in participants with Major Depressive Disorder with moderate to severe insomnia symptoms (MDDIS) or MDD with no or mild insomnia symptoms (non-MDDIS), using an at-home sleep Electroencephalogram (EEG; a device that records brain activity during sleep). The study also aims to examine the association between objective sleep EEG features (measured using devices) and subjective sleep measures (self-reported experiences, such as how a person feels about their sleep) in participants with MDDIS or non-MDDIS.

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms

The purpose of this study is to know how well seltorexant works, and also to evaluate safety and maintenance effect of seltorexant compared with placebo as an adjunctive therapy to an antidepressant in improving depressive symptoms in participants with major depressive disorder with insomnia symptoms (MDDIS) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

A Study in Participants With Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Norepinephrine Reuptake Inhibitor (SNRI)

The purpose of this study is to assess the socio-demographic, disease-related and treatment-related characteristics, and the standard of care (SOC) treatment patterns of participants with major depressive disorder (MDD) with anhedonia with inadequate response to their current antidepressant treatments and treated according to the standard of care treatment.

Acupuncture and Escitalopram for Treating Major Depression Clinical Study

We will be able to investigate in a sample of patients free of antidepressants whether acupuncture is more effective than placebo.

Self Neuro-modulation Therapy for Major Depressive Disorder (MDD) With Anhedonia

The purpose of this research is to learn more about a new treatment for individuals with Major Depressive Disorder (MDD) with heightened symptoms of anhedonia (i.e. loss of pleasure or interest in activities). The treatment is called Prism, and it is a software device intended for a novel form of neurofeedback training to be used in a clinic setting. During this study, the subject will use different techniques to measure brain activities, including magnetic resonance imaging (MRI) and electroencephalography (EEG).

Biomarkers of Depression and Treatment Response

This study is a stratified, parallel-group, single-center study utilizing multimodal imaging techniques to identify biomarkers for Major Depressive Disorder (MDD). The study goal is to identify biomarkers for MDD and treatment response that can be implemented in clinical diagnosis and care as valid and reliable measures, through monitoring neurophysiological and electrophysiological changes across the course of transcranial magnetic stimulation (TMS) treatment.

Psychiatric Genotype/Phenotype Project Repository

The purpose of this project is to obtain DNA, brain imaging data, other biological samples (e.g., urine, serum), and a comprehensive clinical assessment on patients with schizophrenia and other psychotic disorders, bipolar disorder, major depression, and normal volunteer controls. Understanding the physical and genetic factors related to these disorders will help us make progress in fitting treatments to an individual's needs. Participants will take part in a detailed clinical assessment, two blood draws, and an MRI scan over two visits. Participants will also be asked to provide urine and saliva samples.

Dosing rTMS for Depression Post-SCI

Depression is a leading cause of disability worldwide and is more commonly seen in individual's post-spinal cord injury (SCI) than in the general population. Depression post-SCI impacts an individuals' quality of life and recovery. It has been reported that among Veterans with an SCI, those without depression live longer than those with depression. Thus, depression must be treated appropriately. Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, but dosing is based on a motor response or movement in the thumb. Over half of individuals with SCI have some degree of arm or hand impairment, so these individuals might not be eligible for rTMS, or they may receive the wrong dose. This study proposes clinical trial in individuals with depression post-SCI to assess the anti-depressant effect of a novel technique to dose rTMS that does not require a motor response in the thumb. By gaining a better understanding of the application of rTMS for depression post-SCI, the investigators aim to advance the rehabilitative care of Veterans.

Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Pharmacological Manipulation

The study will investigate whether a nociceptin receptor antagonist will normalize neural and behavioral processes of approach/avoidance decision-making in unmedicated individuals with major depressive disorder (MDD) and anxiety disorders. More specifically, the study aims to investigate dysregulation within (1) corticostriatal-midbrain circuitry and (2) nociceptin/orphanin FQ peptide and the nociceptin receptor (NOPR).

Comparing the Efficacy of fMRI-Guided vs. Standard iTBS in Treating Depression

In this triple-blind randomized controlled trial, we ask if targeting intermittent theta burst stimulation (iTBS) based on individual resting state connectivity improves treatment outcomes in major depressive disorder (MDD). For the trial, we will recruit 210 patients with major depressive disorder. Each patient will undergo a 30-40-minute MRI scan, after which they will receive a 6-week standard iTBS treatment. Participants will be randomized to receive iTBS either to the standard neuronavigated target (a technique for treatment location targeting, based on group-average connectivity) or to a personalized connectivity-guided target selected based on individual functional connectivity scans. The main outcome of this trial is response rate as determined by ≥ 50% reduction in Grid HRSD-17 scores. Secondary outcomes include remission rate, change in depression, anxiety and anhedonia symptoms, quality of life, and biological measures of heart rate variability, objective sleep measures and daily activity as a proxy of anhedonia - defined as a reduced ability to experience pleasure.

Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression

Background: Major depressive disorder (MDD) is a serious mental illness that can put people at risk of self-harm and death. Many drugs are used to treat MDD, but it can take a long time for them to be effective. Researchers want to know if a faster-acting drug, (2R,6R)-hydroxynorketamine (HNK), can better treat the symptoms of MDD. Objective: To test a study drug (HNK) in people with MDD. Eligibility: People aged 18 to 70 years with MDD. They must have had a screening assessment under protocol 01-M-0254. Design: Participants will be tapered off their current MDD drugs over 2 to 5 weeks. They will stay off of the drugs for up to 2 weeks prior to starting the study medication and procedures. They will have a physical exam with blood tests. They will have tests of their heart function, mood, and thinking. They will answer questions about their symptoms. They may choose to have imaging scans and scans of their brain activity. HNK is given through a tube attached to a needle inserted into a vein. Participants will receive infusions on this schedule: They will receive 4 infusions over 2 weeks. They will stay in the clinical center overnight after each infusion or for the duration of the study. They will receive no drugs for 2 to 3 weeks. They will have 4 more infusions over 2 weeks, with overnight stays after each or for the duration of the study. One set of 4 infusions will be the HNK. The other set of 4 infusions will be a placebo. A placebo looks just like the real drug but contains no medicine. Participants will not know when they are getting the HNK or placebo. ...

Psilocybin for Major Depressive Disorder (MDD)

Approximately 240 eligible adult participants (≥18 years old) who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) criteria for Major Depressive Disorder (MDD) will be enrolled. Participants will be randomly assigned to receive a single oral dose of Psilocybin 25 mg, Psilocybin 5 mg, or inactive placebo. The purpose of this study is to evaluate the efficacy, safety, and tolerability of Psilocybin 25 mg versus placebo in adults with MDD, as assessed by the difference between groups in change in depressive symptoms from Baseline to Day 43 post-dose, and to characterize the durability of initial treatment effect and subsequent response to optional Psilocybin 25 mg re-administration(s) during the 1-year Follow-up Period.

Treatment of Acute Mood Depressive Episode in Borderline Personality Disorder With rTMS

This study evaluates the antidepressant effects of an accelerated schedule of theta-burst stimulation, termed accelerated intermittent theta-burst stimulation (aiTBS), in individuals with borderline personality disorder (BPD) or trait and comorbid mood depressive disorder (MDD) or bipolar II disorder in a current mood depressive episode (MDE).

A Mobile Health Intervention to Improve Psychosocial Functioning in Veterans With Posttraumatic Stress Disorder and Depression Symptoms

Posttraumatic stress disorder (PTSD) and depression are the two most common mental health conditions among Veterans. When Veterans experience both, there is a negative impact on their functioning, making it difficult to function at work or at home and socially with other people. Although talk therapies can result in improvements in functioning, they are difficult to access because there are limited clinicians who can provide them. As most US adults now own a smartphone, mobile apps are a way for Veterans to access content traditionally delivered through talk therapies at their own pace. This study will test a mobile app based on a trauma-informed talk therapy that has helped Veterans with PTSD and depression make large improvements in functioning, through learning skills to navigate emotions and relationships. Additionally, through answering brief surveys and enabling passive tracking on their smartphones, Veterans will see real-time information on their functioning and mental health and on potential benefits from using these skills.

Acceptability and Feasibility of Work-Oriented Social-Cognitive Skills Training for Veterans With Serious Mental Illness

Many individuals with serious mental illness have difficulty accurately interpreting interpersonal cues and effectively engaging in social exchanges. Difficulties related to the interpersonal aspects of work can lead to isolation, poor productivity, and job loss. The goals of this study are to: 1) adapt an evidence-based social cognitive skills intervention for work settings and use with Veterans, 2) examine the acceptability of the work focused skills training intervention, 3) assess the feasibility of combining the social cognitive skills training program with supported employment, and 4) examine change on functional outcomes. The current study will use feedback from veteran and employment specialist stakeholders to adapt an evidence-based social cognitive skills training program, Social Cognition and Interaction Training (SCIT). The intervention will be modified to tailor it to work relationships and to address any unique relationship concerns among Veterans that are identified by stakeholders. SCIT-Work Edition (SCIT-WE) will add: 1) education about work-related social norms; 2) examples of work-related social interactions that require perspective taking and problem- solving; 3) individual sessions with the study therapist to enhance learning and relevance to each participant's goals; 4) structured interactions with the participant's employment specialist to practice skills outside of group; and 5) skill application sessions with the participant's employment specialist that prompt use of skills after training is completed. SCIT-WE will be developed and piloted in an open trial with 20 Veterans enrolled in the supported employment program at the Minneapolis VA who have a qualifying serious mental illness diagnosis. SCIT-WE will be offered for 2 hours weekly over 13 weeks, when most participants are in the job development and job search phases of supported employment. While participating in the group skills training, participants will have weekly, individual homework review sessions with the group facilitator to promote understanding of the skills and to discuss relevance of the skills to personal goals. Participants also will practice skills weekly with their employment specialist for 10-15 minutes to promote use of skills outside of group sessions. In the 3-months following skills training completion, participants will complete 10 15-minute skills review sessions with their employment specialist to encourage continued skill application in a work setting. Participants will complete assessments at baseline, before receiving the intervention; 3-months post-enrollment, after participating in a weekly skills training group; and 6-months post-enrollment, after receiving 10 additional individual skills review sessions with their employment specialist. Accessibility will be measured with rate of treatment uptake, rate of treatment completion, and participant attitudes toward the intervention. Feasibility of the intervention will be assessed by examining retention in supported employment and the study at 3- and 6-months post-enrollment. Impact of the intervention will be examined with measures of quality of life, social adjustment, self-efficacy, and work relationship quality. It is hypothesized that the intervention will be acceptable to Veterans. The investigators predict a 50% treatment uptake rate, a 70% intervention completion rate, and positive ratings on measures of satisfaction, interest, and value. The investigators hypothesize that it will be feasible to complete this intervention in combination with supported employment activities. The investigators predict that retention in both skills training and supported employment will be 75% at 3-months post-enrollment and 60% 6-months post enrollment. The investigators hypothesize that positive change will be seen at 3-months post-enrollment and sustained at 6-months post-enrollment on measures of quality of life and social adjustment. The investigators predicted that self-efficacy regarding return to work will be improved at 3-months post-enrollment. The investigators predict that Veterans will report being productive and having positive work relationships 6-months post-enrollment. The findings will inform the development of a novel intervention targeting the social and functional impairments associated with serious mental illness. The knowledge gained from this study will guide the development of the next generation of interventions. Given that employment is a critical part of recovery, advancement in therapeutic interventions that support Veterans in this process will be of significance.

Prediction of Antidepressant Effects of Electroconvulsive Therapy

Despite its successful use for more than 80 years, the mechanisms of action of electroconvulsive therapy (ECT) are still not fully understood. ECT has been shown to be accompanied by changes in regional brain volumes and connectivity measures, as well as biochemical alterations. However, how these changes relate to ECT response remains to be further elucidated; up to now, there are no objective markers for the targeted use of ECT in clinical practice. Methods: Study design: longitudinal mono-centre study with duration of 36 months. Subjects: 30 depressed patients (aged 18-65 years) eligible for ECT. Measurements: subjects will undergo 2 3-Tesla MRI scans (one before and one after a course of ECT), including structural MRI, resting-state functional MRI, task-based functional MRI and MR spectroscopy. Blood, CSF sampling and clinical assessments will be performed once before and once after the ECT course. ECT: Each patient will be treated in a min. of 8 bitemporal ECT sessions (\~4 weeks). Data analysis: Longitudinal changes in brain imaging parameters and laboratory measures (before/after ECT) will be assessed using repeated-measures analysis of covariance. Machine learning with random forests will be employed to identify a pattern of pretreatment imaging, biochemical (serum and CSF) and clinical parameters that are best qualified to predict response to ECT as defined by a reduction of ≥50% of baseline HAMD17. Hypotheses: 1. ECT will be accompanied by changes in brain morphology, functional connectivity, neuronal activation in response to cognitive and reward-related stimuli and neurochemical signals in the brain. 2. ECT leads to changes in blood- and CSF-based markers of neuronal plasticity, neurodegeneration and inflammation, as well as genetic/epigenetic markers. 3. Predictive markers of ECT response can be established based on the relationships between imaging, neurochemical and clinical markers and treatment response. Innovation: This study would be the first to combine multimodal MRI measures with the assessment of biomarkers in the CSF in the context of ECT. The implementation of the proposed trial represents an important step towards a better understanding of the powerful antidepressant properties of ECT. By relating treatment effects and potentially underlying biological mechanisms on numerous complementary levels, the study might help to identify biomarkers that distinguish patients who are likely to benefit from ECT from non-responders. Ultimately, results of the study might be useful in order to establish an individualized medical indication for ECT.

The Motor Activity - Subjective Energy (MASE) Project

This approach utilizes accelerometry to measure NEA and electronic diaries for real-time psychological assessments, overcoming limitations of traditional methods such as retrospective bias and low ecological validity. Brief episodes of physical activity in daily life, which are distinctly different from structured exercise sessions, are generally linked to improved affective well-being. Notably, feelings of energy are particularly associated with incidental, unstructured, and non-exercise activities. Clinically, psychomotor retardation and diminished mood are key diagnostic features of MDD, with evidence suggesting that lower motor activity differentiates MDD patients from controls and that increased activity correlates with treatment response. In this context, the MASE project aims to design personalized BA interventions that focus on increasing NEA and, in turn, enhancing subjective energy levels to reduce depressive symptoms and prevent relapse.

Comparing the Efficacy of Accelerated vs. Standard fMRI-guided iTBS in Treating Adolescents Depression

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Theta burst stimulation (TBS), a type of rTMS, is a very promising new treatment for major depression in adults and adolescents. However, very few studies have assessed the efficacy of accelerated, three times a day TBS in comparison with standard once a day TBS in adolescents. The study aims to explore further evidence in hopes to conduct a large-scale, randomized, multisite, placebo-controlled clinical trial evaluating the effects of a functional magnetic resonance imaging (fMRI)-guided accelerated rTMS protocol vs. standard once/daily rTMS for treatment-resistant depression in adolescents.

A Study on Functional Connectome and rTMS Intervention of Cognitive Flexibility Impairment in Patients With Major Depressive Disorder

Persistent cognitive impairment in major depressive disorder (MDD) affects both treatment outcomes and psychosocial functioning, emphasizing the critical need for effective treatment. However, there is still a lack of effective treatment at present. Our previous studies found that the impairment in cognitive flexibility (CF) persisted even in remitted patients with MDD. This impairment was correlated with hypo-connectivity between the left inferior parietal lobule (IPL) and the right dorsal prefrontal cortex (dPFC). Based on these findings, we hypothesize that the hypo-connectivity between the left IPL and the right dPFC is the neural basis of CF impairment, and targeted interventions of this connection may alleviate CF impairment and thus improve treatment outcomes as well as psychosocial functioning of patients with MDD. The present study proposes to employ cognitive training for MDD patients with CF impairment. By comparing changes in CF and brain functional connectivity via task-based fMRI before and after the intervention, we aim to clarify the effect of cognitive training on cognitive performance, treatment outcomes and psychosocial functioning, and identify the critical role of the hypo-connectivity between the left IPL and the right dPFC underlying CF impairment. Furthermore, we will conduct a randomized controlled trial to investigate the effect of individualized dual-target repetitive transcranial magnetic stimulation (rTMS) on CF by targeting the hypo connectivity between the left IPL and the right dPFC. The results will further validate the critical role of this connection in modulating CF performance and provide a reliable intervention target for reducing CF impairment.