Clinical Research Directory

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.

EEG-Guided Transcranial Magnetic Stimulation for Adults With Depression

The purpose of this research is to see if an experimental treatment for depression called intermittent theta burst stimulation (iTBS), a form of transcranial magnetic stimulation (TMS) can be improved for better results using electroencephalography (EEG) recordings (brain waves) for individuals with Major Depressive Disorder (MDD). This is a feasibility study to test a "closed-loop" procedure which guides the timing of this FDA-cleared form of TMS. Each participant will receive an active experimental treatment, and the timing of the TMS pulses will be at one of three phases in the brain wave of interest.

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.

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.

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.

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.

Psilocybin for Depression in Veterans

More efficacious treatments for Major Depressive Disorder (MDD) in Veterans are urgently needed. Psilocybin is a promising novel treatment that is likely to be the first FDA-approved psychedelic, but its safety and efficacy remain unclear. To address this gap, the investigators propose a randomized controlled trial of a single dose of psilocybin paired with a brief course of a VA-endorsed evidence-based psychotherapy (Acceptance and Commitment Therapy) in Veterans with MDD. Our trial addresses key limitations of previous studies including the challenge of management of expectancy effects, a focus on Veterans with input from Veterans, and a study population that reflects the demographics and medical and psychiatric complexity of the VHA patient population. Our study also explores psilocybin's antidepressant mechanisms focusing on changes in psychological flexibility and synaptic plasticity. In sum, this study will provide critical and timely data to determine if psilocybin treatment is a safe and efficacious treatment for MDD in Veterans.

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.

Neural Mechanisms of Real-world Emotions and Internalizing

This study utilizes mobile health methods, including smartphone technology, subjective self-reports measures of emotion, behavioral tasks, functional Magnetic Resonance Imaging (fMRI), physiological measures of attention and arousal, and measures of health and social support to identify neural mechanisms associated with individual differences in the temporal course of emotional responses. The aim of this project is to utilize real-world and personally relevant events as stimuli to better understand how the temporal course of emotional responses relate to risk for developing mental disorders.

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.

iTBS Versus Standard 10 Hz rTMS for Treatment-Resistant Depression (TRD)

This randomised, parallel-group, non-inferiority trial compared intermittent theta burst stimulation (iTBS, 3-minute sessions) with standard 10 Hz repetitive transcranial magnetic stimulation (rTMS, 37-minute sessions) applied to the left dorsolateral prefrontal cortex (DLPFC) in adults with treatment-resistant depression (TRD). Participants received 20 sessions over 4 weeks. The primary aim was to determine whether iTBS is non-inferior to standard rTMS in reducing depressive symptoms (HDRS-17) at Week 4, and to compare patient-reported treatment experience and acceptability between protocols.

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, there are a small number of individuals who have experienced both ECT and TMS across different episodes of depression. 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. The investigators 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 to 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 the development of patient-centred services, support shared decision-making, and help healthcare professionals deepen compassionate understanding of treatment experiences.

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

Effectiveness of mHealth Post-discharge Intervention for Patients With Severe Mental Illness

The overall aim of this program of research is to improve the continuity of care for patients with serious mental illness (SMI) by supporting a safer and more efficient bridge from hospital to outpatient care using a mobile device-delivered app called Transition-FOCUS (tFOCUS), which has previously been tested in community samples. The purpose of the proposed project is to establish the effectiveness of our empirically-supported, multi-component mHealth intervention.

Relationship of Peripheral Inflammatory and Neuroprotective Biomarkers With Response to Intermittent Theta Burst Stimulation in Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a major clinical challenge affecting a substantial proportion of patients with major depressive disorder who do not adequately respond to conventional antidepressant treatments. Intermittent theta burst stimulation (iTBS), a non-invasive neuromodulation technique targeting the left dorsolateral prefrontal cortex, has emerged as an effective treatment option for these patients. However, the biological mechanisms underlying treatment response remain poorly understood. This single-center, prospective, investigator-initiated clinical study aims to investigate the effects of iTBS on clinical symptoms, executive functions, and peripheral inflammatory and neuroprotective biomarkers in patients with treatment-resistant depression. Fifty patients with treatment-resistant depression and fifty healthy control participants will be enrolled. Patients will receive active iTBS treatment for four weeks (20 sessions), while healthy controls will undergo baseline clinical, cognitive, and biological assessments without receiving any intervention. Clinical outcomes will be evaluated using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Patient Health Questionnaire-9 (PHQ-9), Clinical Global Impression (CGI), and Insomnia Severity Index (ISI). Executive functions will be assessed using the Wisconsin Card Sorting Test, Trail Making Test A and B, and verbal fluency tests. Peripheral blood samples will be collected before and after treatment to measure inflammatory, neuroplasticity, and neuroprotective biomarkers, including IL-1β, IL-6, IL-10, TNF-α, high-sensitivity C-reactive protein (hs-CRP), brain-derived neurotrophic factor (BDNF), apolipoprotein D (APOD), serum amyloid A1 (SAA1), and serum amyloid A2 (SAA2). Gene expression analyses will also be performed using quantitative polymerase chain reaction (qPCR). The study aims to identify biological mechanisms associated with iTBS treatment response and to explore potential biomarkers that may predict clinical improvement in patients with treatment-resistant depression. The findings may contribute to the development of personalized neuromodulation strategies and biomarker-guided treatment approaches for depression.

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.

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.

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.

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

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.

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.

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.