Clinical Research Directory

Leucine in Midlife Depression

The study aims to investigate the effects of a 6-week leucine challenge on brain chemistry, connectivity, and behavior in people with midlife depression. The researchers will compare the leucine and an active comparator arm (lysine) for 6 weeks.

Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression

Background: Most drugs that treat mood disorders take a long time to work. Ketamine works within hours. A dose can last for a week or more. Certain receptors in the brain might help ketamine work. A drug that blocks these receptors might affect how it works. Objective: To see if the antidepressant response of ketamine is linked to AMPA receptors. Eligibility: Adults ages 18-70 with major depression disorder without psychotic features Design: Participants will be screened under protocol 01-M-0254. They will have blood tests and a physical exam. Participants will stay at the NIH Clinical Center for 5 weeks. Phase 1 lasts 4 weeks. For 2 weeks, participants will taper off their psychiatric medicine. Then they will have the following tests: * Blood draws * Psychological tests * MRI: Participants will lie in a machine that takes pictures of their brain. * MEG: Participants will lie down and do tasks. A cone lowered on their head will record brain activity. * Optional sleep tests: Electrodes on the scalp and body and belts around the body will monitor participants while they sleep. * Optional TMS: Participants will do tasks while a wire coil is held on their scalp. An electrical current will pass through the coil that affects brain activity. For phase 2, on day 0 participants will take the study drug or a placebo orally. While having a MEG, they will get ketamine infused into a vein in one arm while blood is drawn from a vein in the other arm. On day 1, participants will again take the study drug or a placebo orally. On days 3-7, they will repeat many of the phase 1 tests. Days 8 and 9 are optional and include an open label ketamine treatment and many of the phase 1 tests.

Study on iTBS Regulating the Reward Circuit Function to Improve Anhedonia in Depression

The goal of this clinical trial is to learn if the proposed intermittent theta burst stimulation (iTBS) protocol can effectively improve anhedonia symptoms in depressed patients. The stimulation targets in our protocol include (1) dual-target stimulation at the left dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). (2) single-target stimulation at the left DLPFC. The main questions it aims to answer are: * Whether iTBS of dual-target stimulation (left DLPFC and OFC) can improve the symptoms of anhedonia and better than single-target stimulation at the left DLPFC? * Whether iTBS of the dual targets of left DLPFC and OFC can improve the symptoms of anhedonia by correcting the abnormal functional connectivity of DLPFC-NAc and OFC-sgACC, regulating the functional abnormalities of NAc and sgACC, and indirectly repairing the overall dysfunction of the reward circuit. * Researchers will compare dual-target stimulation to single-target stimulation and sham dual-target stimulation (a dedicated sham coil is utilized which produces an identical audible click and physical sensation) to see if the proposed iTBS protocol works to treat anhedonia. Participants will: * Take 6 sessions of dual-target iTBS or single-target iTBS every day, for 5 consecutive days. * Visit our hospital at 1 week, 4 weeks, and 8weeks after the iTBS treatment completion, for clinical evaluation and brain image examination.

Individual Narratives of Stimulation (ECT and TMS)

Electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are two evidence-based treatments for major depressive disorder. Both work by stimulating the brain (a process known as neuromodulation), but they differ markedly in invasiveness. ECT requires a general anaesthetic, whereas TMS is delivered while a person is awake and alert and they can go home immediately afterwards. TMS has been proposed as an alternative to ECT for some people. However, TMS is not as effective as ECT in all cases, is generally slower acting, and remains less widely available. In Nottingham and Liverpool, we have identified a small number of individuals who have experienced both ECT and TMS across different episodes of depression. One such individual is a lived experience co-researcher on our team. Whilst previous studies have explored experiences of ECT and TMS separately, often using relatively superficial methods, none have examined the perspectives of people who have received both treatments. This study addresses that gap through an in-depth exploration of their experiences. We will use a narrative inquiry approach that encourages participants to tell the story of their experiences of ECT and TMS in their own words. Eligible participants will be adults who have previously received both treatments for depression. Participation involves four sessions: a structured discussion to map the timeline of their depression and treatments, two in-depth open-ended interview sessions (narrative inquiry), and a follow-up discussion about the researchers' reconstruction of their story. Recruitment will take place through services in Nottingham and Liverpool. This study will help us understand how patients relate to, and make sense of, ECT and TMS, which contextual factors shape their experiences, and how these treatments fit into broader recovery journeys. The findings will inform development of patient-centred services, support shared decision-making, and promote a compassionate understanding of treatment experiences among healthcare professionals.

Evaluation of an 8-week Behavior Skills-based Virtual Reality Program for Adolescents With Depression. (MDD)

Evaluation of an 8-week Behavior Skills-based Virtual Reality Program for Adolescents With Depression.

Accelerated High-Dose tDCS for Depression

In this study, investigators are testing whether a higher dose of a non-invasive brain stimulation technique, called transcranial direct current stimulation (tDCS), can be safely used in people with depression. Participants will come to the Brain Stimulation Lab and receive mild electrical stimulation through electrodes placed on their scalp. The study begins with a safety run-in, where the first few participants will receive stimulation at gradually increasing levels (2, 4, and 6 milliamps) while being closely monitored. If no serious side effects are found, later participants will receive repeated 6 milliamp sessions for 5 days total. Investigators will check skin comfort, mood, and overall tolerability after each session.

Single Day of Ultra-accelerated TMS With a Single Dose of NRX-101

In this pilot study, investigators aim to combine D-cycloserine, lurasidone, and single-day repeated intermittent Theta Burst Stimulation (iTBS) to preliminarily assess clinical improvement in an open-label cohort and monitor for adverse events over a 6-week follow-up period.

Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

The purpose of this multi-site randomized controlled trial is to evaluate the efficacy and risks of psilocybin for the treatment of depression in U.S. military Veterans with and without (±) concurrent posttraumatic stress disorder.

Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder

Many people with depression do not get better with standard treatments like medications or talk therapy. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation treatment that uses magnetic pulses to stimulate areas of the brain involved in depression. One form of TMS called intermittent theta burst stimulation (iTBS) is FDA-cleared for depression and takes only 3 minutes to deliver. However, about one-third of patients do not respond to iTBS, and another one-third do not reach full remission. Improving iTBS requires a better understanding of how it works in the brain. iTBS is thought to work by strengthening connections between brain cells, a process called synaptic plasticity. This process depends on a type of brain receptor called the NMDA receptor. Most of what researchers know about how iTBS affects these connections comes from studies of healthy people. It is not known whether iTBS works the same way in the prefrontal cortex - the brain region targeted during depression treatment - or in people who actually have depression. This study has two phases. In Phase 1, both healthy volunteers and people with depression will complete 4 research visits to test how iTBS changes brain activity in the prefrontal cortex and whether medications that increase or decrease NMDA receptor activity change those effects. Each visit involves active or sham (inactive) iTBS combined with one of three study medications: a placebo (inactive pill), d-cycloserine (a medication that increases NMDA receptor activity), or dextromethorphan (a medication that decreases NMDA receptor activity). Brain activity is measured before and after each TMS session using electroencephalography (EEG), a painless test that records electrical signals from the scalp through a cap placed on the head. All participants also complete a brain MRI before beginning study visits for targeting purposes. In Phase 2, participants with depression will be offered a standard clinical course of 30 daily iTBS sessions (Monday through Friday over 6 weeks). Each session is combined with one blinded study medication (placebo, d-cycloserine, or dextromethorphan) taken daily. Brain activity measurements and standard depression and anxiety questionnaires are collected weekly throughout this phase to track how the brain changes over the course of treatment and whether those changes relate to improvements in symptoms. Together, the two phases of this study aim to identify the brain mechanism by which iTBS works in people with depression. This knowledge could lead to more effective TMS treatments for people who have not responded to medications or other therapies.

NIMH Rhythms and Blues Study: A Prospective Natural History Study of Motor Activity, Mood States, and Bipolar Disorder

Background: Mood disorders, such as bipolar disorder, can have serious effects on a person s life. People with bipolar disorder are more likely to have heart disease and abuse substances. In this natural history study, researchers would like to learn more about the connection between exercise and mental health in people with and without mood disorders. Objective: To better understand relationships among physical activity, sleep, and mental health. Eligibility: People aged 8 to 60 years with a history of a mood disorder. Healthy spouses and relatives with no mood disorders are also needed. Design: Participants will be in the study up to 2 years. For up to 20 days in a row, at 4 times during the study, participants will: Complete an electronic diary on their smartphone. Participants will answer questions about their mood, health, sleep, and daily activities. Wear an activity monitor, like a wristwatch, that records how much they move. Wear a light sensor, as a necklace, to record the amount of light in their environment. Some participants will do additional tests. Twice during the study, for 3 days in a row, they will: Wear monitors to record their temperature, heart rate, and sleep. Provide saliva samples. Complete cognitive tasks on their smartphone. Participants will visit the NIH clinic 2 times. They will have a physical exam, with blood and urine tests. They will wear a heart monitor. They will ride a stationary bike for 30 minutes. They may have an imaging scan. Some participants will stay overnight. They will go to sleep wearing a cap to measure their brain activity.

RCT of At-Home tDCS for Depression in Pregnancy

This is a randomized, sham-controlled trial to determine whether treatment with transcranial direct current stimulation (tDCS) is superior to a sham condition at reducing the symptoms of depression in pregnant people with moderate to severe depression. The study aims to enrol 156 participants across all sites. Data collection occurs at baseline, immediately after treatment, every 4 weeks during pregnancy and 4-, 12-, 26- and 52-weeks postpartum

Effect of Aerobic Exercise on Biomarkers in Depression

This study aims to investigate changes in the levels of biomarkers (IGF-1, FGF2, and EGF) involved in neuron development in patients diagnosed with major depression through the effects of breathing exercises and aerobic exercise, as well as to examine the levels of biomarkers (TNF-α, IL-6, and IL-1) and oxidative stress (TAS, TOS, MDA, and F2-isoprostane) that are thought to play a role in the pathophysiology of depression.

EEG Microstate Parameters and Neuroinflammatory Biomarkers in Patients With Treatment-Resistant Major Depressive Disorder Receiving ECT

This study aims to investigate the neurophysiological and inflammatory changes associated with electroconvulsive therapy (ECT) in patients diagnosed with Major Depressive Disorder who are resistant to at least two antidepressant treatments, using microstate analysis derived from resting-state electroencephalography (EEG) recordings. Within this scope, EEG recordings obtained before and after ECT will be compared to determine the relationships between changes in microstate parameters and inflammatory marker levels, clinical variables, and psychometric scale scores reflecting clinical improvement. Peripheral blood samples collected from the same patient group will be analyzed for complete blood count parameters as well as levels of interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), soluble glycoprotein 130 (sgp-130), soluble interleukin-6 receptor (sIL-6R), interferon gamma-induced protein 10 kDa (IP-10), and C-reactive protein (CRP). In addition, inflammatory indices, including the Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Monocyte-to-Lymphocyte Ratio (MLR), will be calculated. The association between baseline levels of these biomarkers and treatment response will be evaluated. Moreover, changes in biomarker levels following ECT will be statistically examined in relation to clinical scale scores and EEG microstate parameters. Although microstate analysis and inflammatory biomarkers have each been extensively investigated in psychiatric disorders, studies evaluating these two biomarkers together, particularly with the inclusion of healthy control participants, remain limited. In this regard, the present study aims to evaluate the effects of ECT on patients with treatment-resistant depression using objective neurophysiological indicators, to contribute to the understanding of the pathophysiology of depression at the level of brain networks, and to provide a scientific basis for the development of personalized treatment approaches in the future.

Assessing of Behavioral Risk and Response to Electromagnetic and Psychedelic Therapies

PRE-EMPT will assemble a cohort of 150 participants from three populations (low risk, intermediate risk, and high risk for self-harm). We will obtain clinical assessments, structural and functional MRI utilizing tasks pioneered by our team to assess cognitive control (CC) and emotion regulation (ER), and peripheral circular RNA (circRNA) levels to characterize the molecular brain states associated with behavioral risk. The clinical, imaging, and transcriptomic data will be fused and jointly analyzed to increase the accuracy of our risk prediction models. PRE-EMPT in three separate Aims will then prospectively assess three promising and innovative interventions for their potential to reduce suicidal ideation and alter activity in key neural networks: 1) neurofeedback (NF) using real-time fMRI with simultaneous electroencephalography (EEG), 2) a form of transcranial magnetic stimulation (TMS) called accelerated intermittent theta burst stimulation (aiTBS) with dose optimization through electric field modeling; and 3) psilocybin assisted therapy (PSI), with flexible dosing plan to maximize the depth of psychedelic experience. These therapies were chosen based on our team's prior work in all three interventions demonstrating rapid action and large effects.

Clinical Effectiveness of Choline Alphoscerate for Older Adults With Major Depression and Subjective Memory Complaints

To evaluate the efficacy of choline alphoscerate on improving symptoms related to depression, anxiety, and subjective memory complaints compared to placebo in patients with Major Depressive Disorder(MDD) accompanied with subjective cognitive decline, who are over the age of 60.

Neuroimaging Sleep and Mood in Depression

This study will investigate how sleep and mood are related in patients with depression and in healthy controls. It will use MRI-based measures of brain function to determine how neural systems are modulated by sleep and sleep deprivation, and its links to mood in depression.

Shortened LSD Intervention for Major Depressive Disorder

The purpose of this study is to determine the safety and clinical effectiveness of a shortened lysergic acid diethylamide (LSD) experience. This will be achieved by administering the drug risperidone 45-minutes after the administration of LSD.

Effect of Psychobiotics With Standard Antiddepressants in Treatment of Major Depressive Disorder

The goal of this clinical trial is to learn whether adding psychobiotics (a combination of Lactobacillus helveticus and Bifidobacterium longum) to standard antidepressant treatment works better than antidepressants alone for adults with major depressive disorder. The study will also learn about the safety of taking these psychobiotics with antidepressants. The main questions it aims to answer are: 1. Does adding psychobiotics lower depression symptoms more than a placebo (a look-alike capsule with no active ingredients)? 2. Is it safe and well tolerated when taken with standard antidepressant treatment? Researchers will compare psychobiotic capsules with placebo capsules to see whether psychobiotics improve depression symptoms when used together with standard antidepressants. Participants will: 1. Continue taking their prescribed antidepressant medicine. Be randomly assigned to receive either a psychobiotic capsule or a placebo capsule once daily for 6 weeks. 2. Complete depression assessments at the start of the study and again at 3 and 6 weeks. 3. Attend regular follow-up visits so researchers can monitor symptoms, side effects, and overall progress

Inhaled DMT for Major Depressive Disorder

This Phase 2b, randomized, double-blind, active-controlled clinical trial will evaluate the efficacy and safety of inhaled N,N-dimethyltryptamine (DMT) in adults with Major Depressive Disorder (MDD). The study will test whether inhaled DMT can rapidly reduce depressive symptoms and suicide risk compared with a low-dose active comparator. A total of 140 participants will be randomized 1:1 to receive either 15 mg followed 1 hour later by 60 mg of inhaled DMT, or 1 mg followed 1 hour later by 4 mg of inhaled DMT. Participants who do not achieve remission at Day 7 will enter an open-label extension and receive a high-dose DMT session on Day 14 (±3 days). All participants will be followed for up to 12 months to evaluate the durability of response, safety, functioning, and quality of life.

Effect of Participating in a Study of Causes of Pregnancy Loss on Mental Health Outcomes: A Target Trial Emulation Using the COPL Cohort and Danish National Registries

Pregnancy loss is the most common severe pregnancy complication and is associated with significant mental health sequelae, including depression and anxiety. Standard care in Denmark does not include systematic follow-up or aetiological investigation after pregnancy loss. The Copenhagen Odense Pregnancy Loss (COPL) Cohort offered extensive aetiological investigations, and a dedicated clinical follow-up visit 4-10 weeks post-loss. This is a target trial emulation (TTE) designed to estimate the causal effect of COPL participation on women's mental health outcomes one year after pregnancy loss. We will emulate a target trial comparing (1) enrolment into COPL versus (2) standard pregnancy loss care. The study population comprises women aged ≥18 years with a confirmed intrauterine pregnancy loss (ICD-10: DO020, DO021, DO030-DO034) before 22 weeks' gestation treated at Danish public hospitals between November 2020 and April 2025. The primary outcome is new-onset affective disorder (ICD-10: F32\*-F39\*), neurotic/stress-related disorder (F41\*, F43\*, F48\*), or dispensing of antidepressant (N06A\*), anxiolytic (N05B\*), or sedating (N05C\*) medication within 12 months of pregnancy loss diagnosis. All data will be sourced from Danish National Registries. The difference-in-differences estimator will serve as the primary analytical approach, complemented by instrumental variable analysis (hospital of treatment as instrument) and regression discontinuity design. Inverse probability of treatment weighting will be used to control for measured confounders. Results will be reported as risk ratios and risk differences with 95% confidence intervals. Sensitivity analyses will include per-protocol estimation and exclusion of women with treatable findings identified in COPL.

Sleep TMS for Depression

The goal of this study is to establish the feasibility, tolerability, and preliminary efficacy of sleep-state transcranial magnetic stimulation (TMS) for enhancing plasticity in depression treatment.

Non-Coding RNAs Gene Expression in Psychiatric Disorders

This study aims to investigate whether specific non-coding RNAs, molecules involved in the regulation of gene expression, are altered in individuals with psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, panic disorder, and obsessive-compulsive disorder. Researchers will compare the expression levels of these molecules in patients who are drug-naïve or have been free from psychiatric treatment for at least six months with those observed in healthy volunteers. The study will also evaluate whether the expression of these non-coding RNAs changes after approximately five months of standard psychiatric treatment. Blood samples collected during routine clinical care will be used to measure the expression levels of selected non-coding RNAs using reverse transcription quantitative polymerase chain reaction (RT-qPCR), a laboratory technique used to assess gene expression. This is an observational study and does not assign specific treatments. All therapies will be prescribed according to standard clinical practice. The main objective is to determine whether alterations in non-coding RNA expression may serve as biological markers of psychiatric disorders and whether these markers may help monitor treatment-related changes over time. The findings may contribute to a better understanding of the biological mechanisms underlying major psychiatric disorders and support the future development of more accurate diagnostic and therapeutic approaches.

Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

Many people with depression do not get better with standard treatments like medication. One promising alternative is transcranial magnetic stimulation (TMS), a non-invasive procedure that uses magnetic pulses to stimulate specific brain regions. A particular pattern of TMS called continuous theta-burst stimulation (cTBS) is thought to reduce overactive brain activity in depression, but the investigators do not yet fully understand how it works at the level of brain cells and connections. This study aims to determine the biological mechanism by which cTBS changes brain activity in people with depression. Specifically, the investigators are testing two competing ideas: (1) that cTBS works by weakening the connections between brain cells through a process called long-term depression (LTD), which is driven by a chemical messenger system called glutamate; or (2) that cTBS works by increasing the brain's natural "braking" system, driven by a different chemical messenger called GABA. To test these ideas, participants with depression will receive cTBS along with one of four FDA-approved medications, or placebo, that either boost or block these chemical messenger systems. The investigators will measure changes in brain activity using electroencephalography (EEG) recorded simultaneously with TMS. Specific patterns in the EEG signal, called TMS-evoked potentials (TEPs), act as a window into how different brain cell types are responding to stimulation. Each participant will complete four study visits, each testing a different drug-TMS combination in random order. One group of participants will test drugs targeting the glutamate system (d-cycloserine and memantine). A second group will test drugs targeting the GABA system (lorazepam and baclofen). All drugs are given as a single oral dose and are commonly used in clinical practice. Understanding exactly how cTBS works at a biological level could open the door to more effective, personalized TMS treatments.

Modular Intervention for Depression Study

The goal of this psychotherapy clinical trial is to evaluate whether a algorithm-based personalized modular psychotherapy is more effective than usual individual psychotherapy in treating major depressive disorder complicated by personality dysfunction and/or complex trauma in adults aged 18 to 65 receiving care in the Chilean public mental health system. The main questions it aims to answer are: * Does algorithm-based modular psychotherapy lead to greater clinically significant reduction and remission of depressive symptoms compared to usual psychotherapy? * Does algorithm-based modular psychotherapy lead to greater improvement in emotional regulation, interpersonal functioning, and self-related functioning, including changes observed in daily life? Researchers will compare algorithm-based modular psychotherapy to usual individual psychotherapy provided in public community mental health centers to see if the modular, personalized approach results in better clinical outcomes, stronger therapeutic alliance, and higher treatment satisfaction. Participants will: * Be randomly assigned to receive either algorithm-based modular psychotherapy or usual individual psychotherapy * Attend weekly individual psychotherapy sessions * Complete structured diagnostic interviews and self-report questionnaires before, during, and after treatment * Provide brief daily reports on mood, emotions, and interpersonal experiences using a smartphone before and after treatment