Clinical Research Directory

Study of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder

This is a multicenter, randomized, double-blind, placebo-controlled parallel-group, fixed-dose study in patients with a primary diagnosis of MDD according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) who have an inadequate response to ongoing ADT.

Precision Closed-loop Brain-Computer Interface Neuromodulation for Treatment-Resistant Depression

The goal of this clinical trial is to evaluate whether precision closed-loop neuromodulation treatments can improve depressive symptoms and daily functioning in people with treatment-resistant major depressive disorder (TRD). The study will assess the effectiveness and safety of two neuromodulation approaches: closed-loop deep brain stimulation (DBS) and transcutaneous auricular vagus nerve stimulation (taVNS). Treatment-resistant major depressive disorder refers to depression that does not improve sufficiently after adequate treatment with standard antidepressant therapies. This study focuses on people with TRD, including individuals with early-onset depression, a history of self-harm or suicidal thoughts, or depression associated with traumatic experiences. This study aims to answer whether closed-loop DBS and taVNS can reduce depressive symptoms compared with sham stimulation, whether these treatments are safe and well tolerated, and whether changes in brain activity are associated with clinical improvement. This is a multicenter, prospective clinical study conducted at Shanghai Mental Health Center, Beijing Anding Hospital, and Xuanwu Hospital. Eligible participants with TRD will receive either DBS or taVNS according to patient preference. Within each intervention group, participants will be randomly assigned to active stimulation or sham stimulation groups to assess treatment effects. During the study, participants will receive neuromodulation treatment and complete regular follow-up assessments. These assessments will include evaluation of depressive symptoms, anxiety symptoms, cognitive function, social functioning, brain electrical activity using electroencephalography (EEG), brain imaging using magnetic resonance imaging (MRI), and monitoring of adverse events. The study will compare changes in clinical symptoms, brain-related measures, and safety outcomes between active and sham stimulation groups. The findings may help determine whether precision neuromodulation approaches can provide a new treatment option for people with treatment-resistant major depressive disorder.

A Phase 3 Trial of DT120 for Major Depressive Disorder (Emerge)

A Phase 3 Double-blind, Placebo-controlled Study (Part A) with an Open-label Extension (Part B) Evaluating DT120 Compared to Placebo in Major Depressive Disorder - Emerge

5-HTP and Creatine for Depression R33 Phase

This is a three-armed clinical trial examining the effect of 5-hydroxytryptophan and creatine monohydrate as augmenting agents for the treatment of depression. Subjects will be randomized between 5-HTP 100mg BID + creatine 5g daily, 5-HTP 200mg BID + creatine 10g daily, vs double placebo, for 8 weeks. The ability of the interventions to affect biomarkers associated with depression will be assessed using brain phosphorus magnetic resonance spectroscopy, functional connectivity imaging, and plasma serotonin levels.

Study of Neuro-Cognitive Correlates of Pediatric Anxiety Disorders

Study Description: This study examines relations between neurocognitive and clinical features of pediatric anxiety disorders. The study uses neuro-cognitive tasks, functional magnetic resonance imaging (fMRI), as well as magneto- and electro-encephalography (M/EEG). Patients will be studied over one year, before and after receiving either one of two standard-of-care treatments: cognitive behavioral therapy (CBT) or fluoxetine, a serotonin reuptake inhibitor (SSRI). Healthy comparisons will be studied at comparable time points. Primary Objectives: To compare healthy youth and symptomatic, medication-free pediatric patients studied prior to receipt of treatment. The study seeks to detect relations between clinical features of anxiety disorders at baseline and a wide range of neurocognitive features associated with attention, memory, and response to motivational stimuli. Secondary Objectives: 1. To document relations between baseline neurocognitive features and response to Cognitive Behavioral Therapy (CBT) or fluoxetine, as defined by the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Improvement (CGI) Scale. 2. To document relations between post-treatment changes in neurocognitive features and anxiety symptoms on the PARS following treatment with Cognitive Behavioral Therapy (CBT) or fluoxetine. 3. To document relations among broad arrays of clinical, cognitive, and neural measures Primary Endpoints: Indices of percent-signal change in hypothesized brain regions, comprising amygdala, striatum, and prefrontal cortex (PFC) for each fMRI and MEG paradigm. Secondary Endpoints: 1. Treatment-response as defined by a continuous measure, the Pediatric Anxiety Rating Scale score (PARS), and a categorial measure, the Clinical Global Improvement (CGI) score. 2. Levels of symptoms and behaviors evoked by tasks that engage attention, memory, and elicit responses to motivational stimuli.

CBT+ for Depression

This study investigates the effects of a novel intervention approach, intentionally sequencing aerobic exercise immediately prior to therapy sessions (i.e., cognitive behavioral therapy \[CBT\]) to determine its effects on both specific and common factors underlying the antidepressant effect of CBT (i.e., mechanisms of CBT). To assess the utility of this treatment augmentation, investigators plan to conduct a randomized controlled trial involving 40 adults with Major Depressive Disorder who will watch a nature documentary while either resting quietly (termed 'CalmCBT') or exercising at a moderate intensity ('ActiveCBT') immediately prior to 8 weekly sessions of CBT. It is hypothesized that target CBT mechanisms of antidepressant action (i.e., self-reported working alliance and behavioral activation) will be more effectively engaged by ActiveCBT vs. CalmCBT.

Patient-oriented Randomized Pragmatic Feasibility Trial With rTMS in Depression and Anxiety

This trial compares intermittent theta-burst stimulation (iTBS) to low frequency repetitive transcranial magnetic stimulation (LFR) in regards to depression and anxiety outcomes in 100 patients with treatment resistant depression (TRD).

Left vs. Right Non-Inferiority Trial

The aim of this study is to test the hypothesis that low-frequency rTMS (LFR) works as well as the established intermittent thetaburst rTMS (iTBS) treatment for treatment resistant depression (TRD).

Home-Based Wearable rTMS Therapy for Moderate to Severe Depression

Background and Rationale With rapid economic development and increasing societal pressures, the incidence of neuropsychiatric disorders has risen annually, ranking as the leading cause of disability worldwide and imposing a severe societal burden. Among these, depressive disorders represent a primary contributor. However, the efficacy and accessibility of transcranial magnetic stimulation (TMS) for depression face significant challenges. Key limitations include: Low targeting accuracy with traditional localization methods. Limited clinical penetration of individualized precision paradigms . In this context, wearable repetitive TMS (wrTMS) technology offers a transformative solution. The rTMS-Tiny device, developed by the Institute of Automation, Chinese Academy of Sciences, exemplifies this innovation with the following features: Battery-powered with a pulse capacity exceeding 8,000 pulses per charge. Ultra-lightweight design: Total system weight \<3 kg, coil helmet \<2 kg (10% of conventional devices). Performance parity: Comparable efficacy to standard rTMS systems while enabling protocols like Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) . Advantages of rTMS-Tiny Portable Design and Wearable Application Ergonomically optimized helmet allows near-unrestricted daily activities during treatment . Streamlined Operational Workflow Simplified protocols significantly reduce clinician workload . Enhanced Treatment Tolerability Improved comfort increases treatment completion rates and long-term adherence, directly enhancing therapeutic outcomes . These advantages enable high-dose, intensive regimens (e.g., SAINT-like protocols) in routine clinical practice . Scientific Imperative for a Multicenter RCT A multicenter randomized controlled trial (RCT) of rTMS-Tiny is clinically and scientifically warranted to: Test two core hypotheses: Hypothesis 1: Efficacy of rTMS-Tiny in reducing depressive symptoms. Hypothesis 2: Safety of home-based rTMS-Tiny administration . Generate high-level evidence to advance neuromodulation into an era of precision, personalization, and artificial intelligence-driven therapy .

Effectiveness of an Integrated Care Pathway for Depression: Cluster Randomized Controlled Trial

This is a quasi-experimental, multi-site cluster controlled clinical trial design with two intervention arms--Treatment As Usual (TAU) and an Integrated Care Pathway (ICP). Eligible participants are between the ages of 13 and 18, who present to community mental health agencies with depressive symptoms as the primary concern. The primary clinical outcome of interest is the difference between treatment groups in the rate of change of depressive symptoms from baseline to 24-week endpoint as measured by the Mood and Feelings Questionnaire. The secondary outcomes include rate of change of functional improvement, as measured by the Childhood Anxiety and Depression Life Interference Scale, and caregiver-rated internalizing symptoms as rated by the Childhood Behaviour Checklist. This study will also be examining implementation outcomes such as feasibility, fidelity cost and acceptability.

A Study to Evaluate BMS-986511 in Adults With Major Depressive Disorder

A Study to Evaluate BMS-986511 in Adults with Major Depressive Disorder

Positive Processes and Transition to Health (PATH)

The R33 will be a randomized controlled trial to replicate changes in the targets (unproductive processing, avoidance, reward deficits) from the R61 phase in a larger sample of 135 participants who have experienced a destabilizing life event involving profound loss or threat, report persistent stressor-related symptoms of PTSD and/or depression, and are elevated on symptoms related to 2 of the 3 therapeutic targets. Additionally, this study will examine Positive Processes and Transition to Health (PATH)'s impact on stressor-related psychopathology in comparison to Progressive Muscle Relaxation (PMR). In the R33 phase, the investigators will examine changes in target mechanisms predicting improvements in PTSD and depressive symptoms, as well as feasibility and acceptability. Patients will receive 6 sessions of PATH or PMR (with 2 boosters, if partial responders). Primary targets will be assessed at pre-treatment, week 3, post-treatment, and at 1- and 3-month follow-up; secondary targets at pre-treatment, weekly during treatment, post-treatment, and at 1- and 3-month follow-ups.

Accelerated Intermittent Theta Burst in Treatment-Naive Adolescents

This is a single-site open-label clinical trial of fMRI-guided accelerated intermittent theta burst stimulation. The goal of this clinical trial is to learn if a new form of transcranial magnetic stimulation (TMS)-known generally as accelerated intermittent theta burst stimulation (aiTBS)-is effective as a first-line therapy in treating adolescents aged 13-20 years-old in their first episode of depression who have not undergone a full course of depression treatment prior to starting the trial and who remain antidepressant-free throughout the trial. The main questions this trial aims to answer are: * Does aiTBS relieve symptoms of depression as a first-line therapy in adolescents? * Is aiTBS a feasible option as a first-line treatment for adolescent depression? Researchers will measure the depression symptoms in adolescent participants before and after aiTBS. Parents of the adolescent participant will also participate in the study providing information about their experience and preference for TMS as a first-line treatment. Adolescent participants will: * Remain antidepressant-free throughout the study period of 6-7 weeks. * Receive an fMRI of their head for precision targeting * Receive 5 days of aiTBS

Enhancing Veteran-Clinical Collaboration in VA PRRCs

Over 60% of Veterans with serious mental illness have a service-connected disability that impairs their ability to work, go to school, and/or have successful personal lives. Although traditional treatments tend to focus on symptom remission, Veterans prioritize a range of treatment goals, including personal empowerment and gaining personally meaningful skills. Increasing Veteran-clinician collaboration can help effectively align care with each Veteran's goals and support an empowering therapeutic experience. This project will evaluate the effectiveness of a group-based intervention intended to increase Veterans' comfort, confidence, knowledge, and skills to collaborate with their treatment teams. Findings from this study will contribute important knowledge about this intervention's effectiveness and how to enhance its effectiveness, especially for Veterans from minoritized groups. If the decision-making intervention is effective, it would help Veterans with serious mental illness, and might also help Veterans with other chronic health conditions, like PTSD and chronic pain.

Trial of Mirtazapine for Depression in IBD

This study will test whether it is feasible to conduct a clinical trial of mirtazapine (an antidepressant tablet) in patients who have both depression and inflammatory bowel disease (IBD). The study design is a randomised controlled trial (a study in which people are allocated by chance to receive different interventions). The trial will compare mirtazapine against a placebo (dummy) tablet in 76 patients with both depression and IBD. The investigators will recruit outpatients aged 18 or over with a diagnosis of any IBD attending gastroenterology clinics. Either in person or remotely, patients will complete a brief screening questionnaire for depression. Those scoring positive for depression will be invited for a 15-minute interview for clinical depression. Those with clinical depression will be invited to take part. Participants will be randomly allocated by a computer to take either 1) mirtazapine tablet once at night for 12 weeks; or 2) placebo (dummy) tablet once at night for 12 weeks. The study is 'blinded', meaning neither patients nor the study team will know which medication they are taking. Throughout, participants will be able to access other treatments for depression, such as talking therapies. The investigators will measure how many people join the study; how many remain in the trial; how many complete treatment; how many tablets people take; and assess overall acceptability of the trial. Participants will complete brief questionnaires to measure their mental health and IBD symptoms after 4 weeks, 8 weeks, 12 weeks and 16 weeks. Participants will also provide blood samples and faecal samples to measure inflammation. If successful, this trial will support an application for a larger version of the study.

A Study of the Efficacy and Safety of SP-624 in the Treatment of Adults With Major Depressive Disorder

This is a Phase 2B clinical study evaluating the effectiveness and safety of SP-624 as compared to placebo in the treatment of adults with Major Depressive Disorder.

Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder

Background: Most medications that treat depression take weeks or months to work. Researchers want to develop fast-acting treatments. One dose of ketamine has a rapid antidepressant effect. For most people, this lasts a week or less. Repeated doses of ketamine may help maintain this effect. Objective: Main Study: To study the effects of ketamine in treating depression. Ketamine Metabolites Substudy: To study how ketamine effects brain chemistry. To study how ketamine effects the brain. This is done by looking at metabolites, which are created when a drug is broken down. Eligibility: Main Study: People ages 18-65 with major depressive disorder and healthy volunteers Ketamine Metabolites Substudy: Healthy volunteers ages 18-65 Design: Main Study: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 phases totaling 14-20 weeks. Phase I (2-7 weeks): * Gradually stop current medications * MRI: Participants lie and perform tasks in a machine that takes pictures of the body. * Mood and thinking tests * Blood and urine tests * Sleep test: Monitors on the skin record brain waves, breathing, heart rate, and movement during sleep. * Transcranial magnetic stimulation: A coil on the scalp gives an electrical current that affects brain activity. * Stress tests: Electrodes on the skin measure reactions to loud noises or electric shocks. Phase I tests are repeated in Phases II and III and in the final visit. Phase II (4-5 weeks): * 4 weekly IV infusions of ketamine or a placebo during an MRI or MEG. For the MEG, a cone over the head records brain activity. Phase III (optional): * 8 infusions of ketamine over 4 weeks Phase IV (optional): * Symptoms monitoring for 4 weeks * Participants will have a final visit. They will be offered standard treatment at NIH for up to 2 months. Ketamine Metabolites Substudy: Participants will be screened in another study, with: * Medical and psychiatric history * Psychiatric and physical exam * Blood, urine, and heart tests Participants will be inpatients at NIH for 4 days. Study Procedures: Mood and thinking tests Blood and urine tests 1 infusion of ketamine Spinal tap and spinal catheter: Used to get samples of cerebrospinal fluid (CSF). This is a fluid that moves around and within the brain and spinal cord. Studying CSF will help us learn how ketamine effects brain chemistry

Integrated Suicide & Trauma Therapy for Suicide Risk

The investigators have developed a novel suicide intervention, Integrated Suicide and Trauma Therapy (ISTT). ISTT combines Brief-Skills for Safer Living (Brief-SfSL)-a promising method to enhance coping skills and reduce suicidality-with a trauma therapy component to alleviate the specific impacts of childhood trauma on suicide risk. The aim of this pilot is to test 12-weeks of ISTT to alleviate suicide risk among individuals with a history of childhood trauma and current suicidality.

Examination of Glutamate and mGluR5 in Psychiatric Disorders

This research study is designed to look at the involvement of the glutamate system in depression. Each subject will undergo a screening appointment to determine study eligibility. Thereafter, the study will take 2 or 3 visits depending on schedule availability and will consist of one MRI scan, and PET scan. Subjects will also participate in cognitive testing. Depending on camera time, staff availability and subject schedule, total study participation may last 1-2 months.

Natural History of Depression, Bipolar Disorder and Suicide Risk

Mood disorders, such as depression and bipolar disorder, are difficult to treat. One reason is that there are no objective ways to measure how these disorders affect the body and respond to different treatments. In this study, researchers want to perform tests on people undergoing clinical care for mood disorders. The purpose is to understand the experience of receiving treatment for depression, bipolar disorder, and suicide risk. We also hope that this study will help us to predict which medications will improve thoughts of suicide. People 18 years or older who are receiving treatment for depression, bipolar disorder, or suicide risk may take part in this study. Participants must have also been enrolled in protocol 01-M-0254. This study will be conducted at the NIH Clinical Center in Bethesda, MD. The study typically lasts up to 12 weeks, but may last longer if a participant s treatment continues past that time. Participants will have weekly interviews and questionnaires while they are being treated for their mood disorder. Other tests are optional and include psychological testing, blood draws, sleep tests, and imaging scans. These will be done at the start and the end of research participation.

Impact of Transcutaneous Vagal Nerve Stimulation on Stress Response in Major Depression

This study will identify the sex-dependent impact of expiratory-gated transcutaneous vagus nerve stimulation (tVNS) on the modulation of the stress response circuitry and associated physiology in major depressive disorder (MDD). We will evaluate a sample of 80 adults with recurrent MDD randomized to receive active or sham expiratory-gated tVNS during a functional magnetic resonance imaging (fMRI) session, with simultaneous mood and physiological assessments. We hypothesize that expiratory-gated tVNS will effectively modulate, in a sex-dependent manner, specific brainstem-cortical pathways of the stress circuitry and attenuate physiological deficits in MDD.

The Effects of Psilocybin on Self-Focus and Self-Related Processing in Major Depressive Disorder

This open-label functional Magnetic Resonance Imaging (fMRI) study will assess the effects of a single dose of psilocybin on rumination and the neural correlates of rumination in individuals with major depressive disorder.

Low Amplitude Pulse Seizure Therapy Versus Standard Ultra-Brief Right Unilateral Electroconvulsive Therapy

This protocol proposes an initial randomized clinical trial that includes all patients with suicidal ideation (SI) at baseline, and with SI as the primary outcome measure to examine whether Right Unilateral Low-Amplitude Pulse - Seizure Therapy (RUL LAP-ST) treatment has more magnitude and rate of remission of SI as conventional pulse amplitude Right Unilateral Electroconvulsive Therapy (RUL ECT) (based on our prior secondary analysis). Our central hypothesis is that RUL LAP-ST has significantly less cognitive/memory side effects (no memory side effects were noted in our prior studies for 500mA and 600mA) and thus is more favorable in terms of side effects compared to RUL conventional pulse amplitude ECT, while maintaining better anti-suicidal effect.

Transcranial Electric Stimulation Therapy (TEST) for Treatment Resistant Depression (TRD)

Background: People with TRD are often helped by electroconvulsive therapy (ECT). But ECT can affect memory and thinking. Researchers want to study a treatment called TEST that uses less electricity. Objective: To study the safety and feasibility of TEST and assess its antidepressant effects. Eligibility: Adults aged 25-64 with major depression that has not been relieved by current treatments. Design: Participants will be admitted to the NIH Clinical Center for 5 18 weeks over 2 3 treatment phases. Their medications may be adjusted. Participants will be interviewed about their depression, side effects, and other treatments they are receiving. They will complete questionnaires. They will give blood and urine samples. Their brain waves and heart rhythm will be recorded. They will take tests of memory, attention, mental functioning, and thinking. Participants will have magnetic resonance imaging (MRI) scans of the head and brain. They will lie on a table that slides in and out of the scanner. Pictures of brain chemicals will also be taken. They may complete tasks during the MRI. Participants will receive TEST and/or sham treatments. They may receive optional ECT. An intravenous catheter will be placed in an arm vein to receive general anesthesia. Two electrodes will be placed on the front of their head. An electric current will be passed from the ECT machine through the electrodes. For sham treatments, they will not receive the electric current. Their breathing, heart rate, brain function, blood pressure, and body movements will be measured. Participants will have 7 follow-up visits over 6 months. Visits can be done via telehealth. Participation will last for up to 42 weeks.