Depression

Background:

Electroconvulsive therapy (ECT) is used to treat people with severe depression. During ECT, the brain is given electric pulses that cause a seizure. Although it is effective, it can cause side effects, including memory loss. Researchers want to study a new way to give ECT called iLAST.

Objective:

To see if iLAST is safe and feasible in treating depression.

Eligibility:

People ages 22 70 years old who have major depressive disorder and are eligible for ECT

Design:

Participants will be screened under protocol 01-M-0254. This includes:

Medical and psychiatric history and exam

Blood and urine tests

Participants will be inpatients at the Clinical Center. They study has 3 phases and will last up to 20 weeks.

Phase I will last 1 week. It includes:

MRI: Participants will lie in a scanner that takes pictures of the body

MEG: A cone over the participant s head will record brain activity.

TMS: A wire coil placed on the participant s scalp will produce an electrical current to affect brain activity.

SEP: An electrode on the participant s wrist will give a small electrical shock to test nerve function.

Phase II will last 2 and a half weeks. It includes:

Seven sessions of iLAST under general anesthesia. Participants may also get standard ECT.

EEG: A small electrode placed on the participant s scalp will record brain waves.

Interviews about mood, symptoms, and side effects. Participants facial expressions may be video recorded.

TMS

Phase III will last at least 1 week. It will include:

MRI

EEG

TMS

MEG

Standard ECT if needed. Participants will have sessions every other day, 3 times a week.

Sponsoring Institution: National Institute of Mental Health

...

Background:

Major depressive disorder (MDD) is one of the most impairing medical conditions in the world. Medication and some kinds of talk therapy are standard treatments for teens with MDD, but these do not work well for everyone. Transcranial magnetic stimulation (TMS) has been approved to treat MDD in adults. TMS might help adolescents, too.

Objective:

To test TMS combined with cognitive behavioral therapy (CBT) in teens with MDD.

Eligibility:

People aged 13 to 17 years with MDD that has not responded to treatment.

Design:

Participants will be screened. They will have a physical exam and psychiatric evaluation. They will have an MRI scan and a test of their heart function. They will enroll in 2 NIH protocols (01-M-0254 and 18-M-0037).

For 2 to 6 weeks, participants will have weekly CBT, a kind of talk therapy. They will taper off of their psychiatric medicines.

For 2 weeks, participants will come to the clinic every weekday. They will receive 3 or 4 sessions of TMS on each of those days. A wire coil will be held on their scalp. A brief electrical current in the coil creates a magnetic pulse that affects brain activity. They will receive 30 TMS pulses in 10-second bursts; these will be repeated 60 times in each 15-minute session. Participants may hear a click and feel a pulling sensation under the coil. They may feel their muscles twitch. Each day, they will have tests of concentration, thinking, and memory. Some may have a 3rd week of TMS.

Participants will remain in the study for 5 more weeks. They will begin taking their medications again.

In a sample of patients already receiving ketamine treatment as part of their clinical care, this project seeks to test whether we can enhance and/or extend ketamine's rapid effects by introducing helpful information delivered by a computer-based cognitive training protocol. This work could ultimately lead to the ability to treat depression more efficiently and with broader dissemination by rapidly priming the brain for helpful forms of learning.

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.

...

Although psychological interventions exist for the prevention of PPD, a yoga-based intervention to prevent PPD among at-risk women utilizes a similar theoretical foundation (i.e., mindfulness), may be more acceptable to women of minority status, and may confer additional physical activity benefits. The purpose of this pilot study is to determine the effectiveness of using a virtually delivered prenatal yoga intervention for the prevention of PPD among at-risk women in a diverse health care system and explore preliminary factors which influence implementation of the intervention. This study has 2 phases: Phase 1 will evaluate facilitators and barriers to intervention implementation among patient, clinician, and health system stakeholders, followed by an open trial, and Phase 2 will include conducting an 8-session pilot randomized controlled trial to assess the feasibility and acceptability of the proposed prenatal yoga intervention among women with a history of depression, as well as the onset and course of PPD and mediating factors. The specific aims are to: 1) Optimize delivery of a yoga intervention within a healthcare system to prevent PPD through examining facilitators and barriers of implementation, 2) Examine feasibility, acceptability and satisfaction of the intervention within a health care system, and 3) Evaluate preliminary effectiveness of the intervention on PPD and proposed mechanisms. For Phase 1, separate focus groups with patient stakeholders and clinician and administrative stakeholders will inform intervention implementation, and an open trial to refine and optimize the intervention. For Phase 2, women with a history of depression who are 8-28 weeks pregnant will be randomized to the intervention group (n=24) or treatment-as-usual (n=24) and will complete survey measures at baseline, post-intervention, and 1 and 3 months postpartum. It is hypothesized that the intervention will be feasible and acceptable, engage women of racial/ethnic minority status, and contribute to lower rates of PPD onset. Embodiment and mindfulness are the proposed mediators. Knowledge gained from this study can support prevention efforts for PPD and improve the adverse public health impact of this disorder.

This study is a randomized Type I hybrid effectiveness-implementation trial aimed at evaluating the effectiveness of Empower@Home, an internet-delivered cognitive-behavioral therapy (CBT) program supported by aging service providers, in comparison to enhanced usual care for homebound older adults with depressive symptoms. A total of 256 participants will be randomly assigned to either the treatment group (Empower@Home) or the control group (enhanced usual care) in a 1:1 allocation ratio, with randomization stratified by participating agencies.

The primary aim of this study is to determine the clinical effectiveness of the Empower@Home program. It is hypothesized that participants receiving Empower@Home will show greater improvements in depressive symptoms at 12, 24, and 36 weeks after entering the study compared to those receiving enhanced usual care. Additionally, treatment moderators will be explored and a cost-effectiveness analysis will be conducted to assess the economic viability of the intervention.

The second aim is to investigate the mechanisms of change facilitated by the intervention using a mixed-methods approach. Causal mediation analysis will examine whether the acquisition of CBT skills, reduction in cognitive distortions, and increased behavioral activation, as well as participant engagement and the therapeutic alliance with the coach, mediate the treatment effects. Qualitative interviews with participants will be conducted to provide deeper insights into these mechanisms and enhance the interpretation of the mediation analysis.

The third aim focuses on evaluating the implementation process using the updated Consolidated Framework for Implementation Research (CFIR). This will involve a qualitative process evaluation to identify barriers and facilitators to the implementation of Empower@Home, drawing on perspectives from multiple stakeholders.

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.

The goal of this clinical trial is to learn how hormonal changes over the menstrual cycle affect mood symptoms in reproductive-aged women with depression that worsens during the premenstrual period. The main questions it aims to answer are:

--How do fluctuations in estradiol and progesterone across the menstrual cycle affect the ability to experience pleasure and the neural sensitivity to reward in hormone-sensitive, depressed women? And consequently, how does stabilizing the luteal phase decline in estrogen and progesterone (using estradiol patches and progesterone pills) affect these changes?

Participants will:

* Receive hormones followed by placebo, or vice versa, for a total of four weeks across three menstrual cycles * Complete daily mood ratings * Collect home urine samples for hormone testing * Complete five biobehavioral testing sessions during which neural responses are recorded (via electroencephalography, or EEG) during an acute stress task and computer tasks

This project is the second phase of a two-phased project investigating the impact of a proven sleep intervention, Cognitive Behavioral Therapy for Insomnia (CBT-I) on engagement of the emotion regulation brain network as a putative mechanistic target.

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.

Despite efforts to prevent suicide, US rates are climbing, and suicide is the second leading cause of death among youth. Digital tools, especially personal smartphones, are promising avenues to address these issues and can be used to provide a unique understanding of risk factors, including psychological distress, anhedonia and behavioral withdrawal, and sleep disturbance among high-risk individuals. This project aims to enhance the effectiveness of the delivery of preventative health care to youth at risk for suicide by developing a comprehensive digital platform that allows practitioners to integrate mobile sensing data and HIPAA-compliant client communication tools into their management of these young people.

The purpose of this study is to test whether a dietary supplement (low-dose melatonin) commonly used to treat night owls, administered in conjunction with a behavioral sleep intervention, will help to shift the brain clock earlier and improve mood and sleep in bipolar disorder. Eligible participants will be randomized to receive melatonin plus a behavioral sleep intervention or placebo plus a behavioral sleep placebo.

The hypotheses for this study include:

* Melatonin plus behavioral sleep intervention (compared to placebo plus behavioral sleep placebo) will produce a greater advance of dim light melatonin onset (DLMO), between pre- and post-treatment. * Melatonin (compared to placebo) will produce a greater reduction in Patient Health Questionnaire-9 score between pre- and post-treatment.

Development and preliminary testing of a text messaging intervention that will reduce the risk of a major depressive episode and worsening depressive symptoms in perinatal individuals. The system will screen pregnant individuals, send tailored text messages with links to enhanced content, and will include a peer chat function.This accessible text platform will leverage both the ease of use inherent in text messages and the power of enhanced content drawn evidence from based behavioral interventions (Interpersonal Therapy).

This pilot study will individually randomize 105 adolescents living with HIV 1:1:1 to standard of care, adapted intervention, or enhanced intervention. The intervention is called the Friendship Bench Intervention is a counseling intervention for depression and engagement in HIV care.

This multi-site, double-blind, randomized, sham-controlled mechanistic trial aims to test the effects of Magnus Neuromodulation System (MNS) with Stanford Accelerated Intermittent Neuromodulation Therapy (SAINT®) Technology on the neural circuitry of suicidal cognitions in psychiatrically hospitalized patients with Major Depressive Disorder (MDD) and active suicidal ideation (SI). This will be accomplished by applying the MNS with SAINT to a customized target within the left dorsolateral prefrontal cortex (L-DLPFC) identified with fMRI for five consecutive days and measuring resting-state functional connectivity (RS FC) between the subgenual anterior cingulate cortex (sgACC) and the default mode network (DMN) at baseline and immediate-post visit. The relationship between changes in RS FC and changes in both Explicit and Implicit Suicidal Cognitions (ESC and ISC, respectively) will be determined. This study will also determine the relationship between changes in RS FC in neural networks underlying mediators of suicidal cognitions and changes in such mediators with active versus sham SAINT.

The proposed study draws on prior research to evaluate the feasibility, acceptability and explore preliminary effectiveness of Coffee and Family Education and Support, Version (CAFES2) using a pilot randomized type 1 hybrid effectiveness-implementation design. CAFES2 is a peer-led family and social strengthening multiple family group intervention that is designed to respond to multi-level needs of refugee families. Results of the trial will contribute to the emerging evidence base on family-based mental health interventions for refugee and newcomer communities. The trial will also generate new insights regarding implementation strategies needed to promote successful delivery of services by peer providers and the unique role of human-centered design practices for adaptation of mental health and psychosocial interventions.

The purpose of this study is to investigate the responses of the brain region known as the subgenual anterior cingulate cortex (sgACC) during transcranial magnetic stimulation (TMS) in individuals with depression. Specifically, investigators aim to determine whether the sgACC is engaged when TMS is delivered to specific targets and if the engagement of sgACC changes throughout a full TMS treatment intervention. To achieve this goal, the investigators will employ a combination of TMS and Magnetic Resonance Imaging (MRI) procedures.

Study participation will include completing various questionnaires, clinical assessments, receiving a full transcranial magnetic stimulation (TMS) treatment intervention (every weekday for 6 weeks), and undergoing MRI scans, both with and without concurrent TMS.

The goal of this study is to understand why some people act more impulsively when feeling negative emotions, which is called negative urgency. The researchers hope to understand how negative urgency relates to the way networks of brain cells communicate with one another. The researchers will measure negative urgency and brain signals in adolescents aged 13-21 years with depression and suicidal thoughts and behaviors.

The main questions it aims to answer are:

* Whether a type of brain signaling called cortical inhibition is related to negative urgency * Whether depressed adolescents with suicidal behavior have more problems with cortical inhibition than depressed adolescents with suicidal thoughts only * Whether the relationship between negative urgency and cortical inhibition changes over time

Adolescents who participate in the study will complete the following activities at the time they join the study, as well as 6 months and 12 months later:

* Interviews with researchers and questionnaires to learn about their thoughts, emotions, and symptoms * A questionnaire about impulsive behaviors and negative urgency * Computerized games that measure brain functions * An MRI scan of the brain * Transcranial magnetic stimulation with electroencephalography (TMS-EEG), a way to measure how brain cells communicate (cortical inhibition) using a magnet placed outside of the head and recording brain signals

This study seeks to understand if the medication pramipexole improves social connectedness and functioning in adults (ages 18-50) who experience anxiety or depression. The study plans to enroll 108 participants total across two sites (University of California San Diego and New York State Psychiatric Institute). Pramipexole will be given in a 6-week randomized, double-blind, placebo-controlled trial. Social reward processing will be assessed using measures of brain function (fMRI), behavior, and self-report at baseline and week 6. Knowledge gained from this study will help determine the therapeutic potential of targeting the dopamine system to remediate social disconnection as an anxiety and depression intervention.

In this study, the investigators will recruit young adults (ages 18-25 years) with elevated anxiety/depression symptoms and sleep disturbance. Participants will complete two overnights in a sleep lab. During one of the overnights, slow-wave activity will be enhanced by delivering sub-arousal auditory tones during slow-wave sleep using a headband device (Philips SmartSleep or Dreem 2). During the other overnight, tones will not be administered. Cognitive and emotional processes will be evaluated using behavioral task performance, self-report, and functional magnetic resonance imaging (fMRI). After the second overnight, participants will take the headband device home and wear it every night for approximately 2 weeks. For half of the participants, the headband will play tones every night and, for the other half, the headband will not play tones. Participants will then return for a final testing visit in which cognitive and emotional processes and anxiety/depression symptoms will be assessed using behavioral task performance and self-report.

This study will deploy a scalable secondary prevention program that leverages existing foster youth transition services to improve mental health functioning and service use before and after exiting foster care. Our short-term objective is to remotely test a group intervention called Stronger Youth Networks and Coping (SYNC) that targets cognitive schemas influencing stress responses, including mental health help-seeking and service engagement, among foster youth with behavioral health risk. SYNC aims to increase youth capacity to appraise stress and regulate emotional responses, to flexibly select adaptive coping strategies, and to promote informal and formal help-seeking as an effective coping strategy. The proposed aims will establish whether the 10-module program engages the targeted proximal mechanisms with a signal of efficacy on clinically-relevant outcomes, and whether a fully-powered randomized control trial (RCT) of SYNC is feasible in the intended service context. Our first aim is to refine our SYNC curriculum and training materials, prior to testing SYNC in a remote single-arm trial with two cohorts of 8-10 Oregon foster youth aged 16-20 (N=16). Our second aim is to conduct a remote two-arm individually-randomized group treatment trial with Oregon foster youth aged 16-20 with indicated behavioral health risk (N=80) to examine: (a) intervention group change on proximal mechanisms of coping self-efficacy and help-seeking attitudes, compared to services-as-usual at post-intervention and 6-month follow-up: and (b) association between the mechanisms and targeted outcomes, including emotional regulation, coping behaviors, mental health service use, and symptoms of depression, anxiety, and PTSD. Our third aim is to refine and standardize the intervention and research protocol for an effectiveness trial, including confirming transferability with national stakeholders.

In the United States, adolescents experience alarmingly high rates of major depression, and gold-standard treatments are only effective for approximately half of patients. Rumination may be a promising treatment target, as it is well-characterized at the neural level and contributes to depression onset, maintenance, and recurrence as well as predicts treatment non-response. Accordingly, the proposed research will investigate whether an innovative mindfulness-based real-time functional magnetic resonance imaging (fMRI) neurofeedback intervention successfully elicits change in the brain circuit underlying rumination to improve clinical outcomes among depressed adolescents.

The current best practice guidelines for treating depression call for close monitoring of patients, and periodically adjusting treatment as needed. This present study seeks to develop and investigate an innovative digital system, DepWatch, that leverages mobile health technologies and machine learning tools to provide clinicians objective, accurate, and timely assessment of depression symptoms to assist with their clinical decision making process. Specifically, DepWatch collects sensory data passively from smartphones and wristbands, without any user interaction, and uses simple user-friendly interfaces to collect ecological momentary assessments (EMA), medication adherence and safety related data from patients. The collected data will be fed to machine learning models to be developed in the project to provide weekly assessment of patient symptom levels and predict the trajectory of treatment response over time. The assessment and prediction results are then presented using a graphic interface to clinicians to help them make critical treatment decisions. The main question the present clinical trial aims to answer are as follows:

1. Feasibility of the digital tool, DepWatch, to assist clinicians in depression treatment and inform their clinical decision process 2. Effectiveness of the digital tool, DepWatch, to improve depression treatment outcomes All study participants will carry the DepWatch app on their smartphones and wear a Fitbit provided by the study team during the study period. They will also complete brief questionnaires via the app at specific time intervals throughout the study period.

Although treatments for depression are effective for many people, not everyone responds to treatment. This lack of treatment response could be due, in part, to the presence of multiple underlying causes of people's depression. This study aims to identify subtypes of depression, based on two factors: how successful people perceive themselves to be at regulating their affect in everyday life; and how much activity in the parasympathetic nervous system increases during moments when people try to regulate. The study involves ambulatory assessment of affect, regulation strategies, and physiological activity in everyday life, in a sample of young adults with remitted major depressive disorder and healthy volunteers. We will study regulation responses in the lab to further determine how subtypes differ in neural, physiological, and behavioral responses. Finally, participants will be randomly assigned to a remote, self-administered biofeedback intervention (vs. control intervention) designed to increase parasympathetic activity and physiological regulation success. While engaging in biofeedback at home for 10 days, participants will simultaneously repeat the ambulatory assessments. This design will allow us to determine the proximal impact of biofeedback on indices of regulation success in everyday life, and whether biofeedback has differential impact on regulation success for different subtypes.

This study aims to provide an evidence-based behavioral intervention to reduce violent behavior for individuals experiencing early psychosis.

The OptimizeD study aims to improve outcomes in depression in primary care in India. This study will randomize 1500 patients with moderate to severe depression to either psychotherapy based on behavioral activation called the Healthy Activity Program (HAP) or antidepressant medication (fluoxetine).

The study has two primary objectives:

1. Use patient characteristics to generate a precision treatment rule based on baseline information for predicting in advance what works best for whom (and which patients are unlikely to respond to either treatment and should be referred to specialist care). 2. Conduct a cost-effectiveness analysis by comparing relative costs and effectiveness between those who were randomly allocated to their optimal treatment with those who were randomly allocated to a non-optimal treatment based on the precision treatment rule.

The purpose of this study is to develop a technique called real time fMRI neurofeedback.

This technique uses a regular MRI scanner, except that special software allows the researchers to measure activity in participants brain, using fMRI, and then give information, in the form of a feedback signal, which indicates brain activity in real time, while in the MRI scanner. The larger goal of this study is to develop ways to help people, including those with depression, better regulate brain activity. The researchers think that this may be helpful in managing psychiatric symptoms.

This study design has three phases, however, only two phases (phase 2 and 3) are considered to be a clinical trial. Phase 2 (part 2) was registered and is NCT05934604. This is the phase 3 (part 3) for this project and is funded by the National Institutes of Health.

The overall aim of this proposal is a confirmatory efficacy trial sufficiently powered and designed to test the hypothesis that improving the relationship between biological circadian timing and waketime, a novel modifiable target, improves depression outcomes in a subgroup of adolescents with depression and a misaligned relationship between biological circadian timing and waketime utilizing a cognitive-behavioral sleep intervention.

The goal of this randomized controlled trial is to compare the impact of an integrated intervention combining poverty alleviation and depression treatment to depression treatment alone, in low income rural Bangladeshi women with depression. The main question\[s\] it aims to answer are: 1) whether adding poverty alleviation to depression treatment in an integrated intervention improves depression outcomes at 24 months, as assessed by depressive symptoms and by the presence or absence of relapse; and 2) whether adding poverty alleviation to depression treatment improves implementation outcomes including treatment uptake and retention. Participants in both arms will participate in interviews at 6,12,18 and 24 months.

Major depressive and anxiety disorders are highly prevalent in the general population and are a leading cause of disability. Black adults have a high burden of depression and anxiety. This study aims to assess a self- administered video-based intervention to reduce mental illness stigma and medical mistrust among Black adults with moderate to severe depression or anxiety.

Repetitive transcranial magnetic stimulation (rTMS) is a way of non-invasively stimulating specific brain networks and is an established treatment for Major Depressive Disorder (MDD). This proposal will reveal network mechanisms of the therapeutic effects of rTMS by investigating how stimulating each network specifically changes network connectivity and behavior. This will be done in a highly individualized manner in depressed and healthy patients, leading to more effective and more individualized treatments for depression.

This study will test a new cognitive-behavioral skills training program (CBI) delivered in the metaverse. Although initial evidence suggested CBI was feasible for individuals experiencing depression or anxiety, CBI's effectiveness compared to no intervention has yet to be determined. The intervention may be delivered through virtual reality as well as flat-screen devices, such as a computer, which may also affect CBI's effectiveness.

The study will enroll up to 306 participants with depression. One third of the participants will access CBI through virtual reality, one third of the participants will access CBI through a flat-screen device, and one third of the participants will be asked not to attend CBI sessions for the first 8 weeks of participation of the trial. For both CBI conditions, treatment will be provided over 8 weeks, with a 6-month follow-up period. Enrollment will be ongoing and groups will occur simultaneously.

Potential participants are asked to complete an initial screening and an intake evaluation to determine eligibility. They will then receive 8-weeks of treatment. Participants will complete brief weekly self-report questionnaires throughout their time in the study.

Center M is a digital health solution to Perinatal Depression (PD) which provides an alternative to Mindfulness Based Cognitive Therapy - Perinatal Depression (MBCT-PD). Center M shifts treatment to a telehealth model, reduces the number of sessions, and transitions home practice materials to a digital format. This study will include a clinical trial in which participants will be randomized to the Center M treatment with smartphone app delivery of homework compared to treatment as usual (TAU).

The goal of this study is to test the efficacy and feasibility of a clinician-guided, app-based cognitive behavioral therapy (CBT) program, SilverCloud, as a school-based mental health intervention for vulnerable youth. An open trial of SilverCloud will be conducted to determine preliminary efficacy in this sample and inform program refinements by collecting outcome self-report assessments and conducting interviews on feasibility and acceptability. After the program and its implementation strategy are refined, we will conduct an randomized controlled trial. Adolescents who screen positive for significant mental health symptoms and who are enrolled in their school-based health center (SBHC) will be randomized to receive SilverCloud or treatment as usual (TAU). Efficacy will be assessed through outcome self-reports. Feasibility and acceptability feedback will again be collected from participants, SBHC staff, and community members.

The goal of this clinical trial is to compare engagement in treatment in coordinated specialty care (CSC) to five extra care elements (CSC 2.0) in first-episode psychosis. The main question it aims to answer is:

• Does the addition of certain elements of care increase the number of visits in treatment for first-episode psychosis?

Participants will either:

* Receive care as usual (CSC) or * Receive care as usual (CSC) plus five additional care elements (CSC 2.0):

1. Individual peer support 2. Digital outreach 3. Care coordination 4. Multi-family group therapy 5. Cognitive remediation

Researchers will compare the standard of care (CSC) to CSC 2.0 to see if participants receiving CSC 2.0 have more visits to their clinic in their first year.

This project is designed to examine the role of the subgenual anterior cingulate cortex (sgACC) in anhedonia and anxiety in humans with depression, as well as the acute and sustained effects of ketamine on agACC activation and depression symptoms.

Anhedonia, the inability to seek-out and experience pleasure, is a common symptom in depression that predicts treatment-resistance and is sometimes exacerbated by first-line antidepressants. In our previous research, we found that anhedonia decreases goal-directed behavior and its related neural activity. In this study, we will investigate target engagement from five-consecutive days of stimulation for participants that are within a unipolar major depressive episode and also have high symptoms of anhedonia.

Depression is a leading cause of disability worldwide and current treatments are ineffective for many people. This trial will investigate the efficacy of a 16-week high vs low dose resistance exercise training program for the treatment of Major Depressive Disorder (MDD) in 200 adults.

The core objective of this study is to enhance the translational potential of this electroencephalogram (EEG) biomarker by using ketamine(KET)-induced gamma potentiation as a prognostic marker of 4-week treatment outcome. Previous research focused exclusively on KET-induced gamma band potentiation (GBP) in the context of a single infusion. Our study design captures the clinical variation associated with real-world treatment resistant depression (TRD) patients and allows us to analyze the relative importance of GBP to antidepressant symptom reduction across the induction phase of treatment. If successful, it provides a compelling rationale for a larger prospective investigation of gamma dynamics as a moderator of outcome to varied TRD therapies which impact the balance of cortical excitation and inhibition.

The purpose of this 10-week, double-blind, placebo-controlled study is to determine whether inflammation impacts reward and motor neural circuitry to contribute to depressive symptoms like anhedonia and psychomotor slowing in people with Human Immunodeficiency Virus (HIV) and depression. Sixty male and female patients with HIV who have depression, anhedonia and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either the anti-inflammatory drug baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study. The total length of participation is about 5 months.

This is a cross-sectional pilot study designed to establish hot and cold cognitive functions and underlying neurocircuitry in older adults with MDD. The investigators will study 60 participants aged 21-80 years old with MDD. All participants will undergo clinical and neurocognitive assessment, and Magnetoencephalography (MEG)/Magnetic resonance imaging (MRI) procedures at one time point. The investigators will also enroll 60 demographically matched comparable, never-depressed healthy participants (controls) to establish cognitive benchmarks. Healthy controls will complete clinical and neurocognitive measures at one time point. To attain a balanced sample of adults across the lifespan, the investigators will enroll participants such that each age epoch (e.g., 21-30, 31-40, etc.) has a total of ten subjects (n=10) in both the healthy control cohort and depressed cohort.

The purpose of this 8-week, double-blind, placebo-controlled, study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Seventy male and female participants with depression, between 25-55 years of age, with higher levels of inflammation and anhedonia will be randomized to receive L-DOPA or matched placebo over 8 weeks. Participants will complete lab tests, medical and psychiatric assessments, motivation and motor tasks, and MRI scans as part of the study. The total length of participation is approximately 10 to 12 weeks.

The purpose of the RISE study is to examine how the 24-hour rhythm of sleep and social activity relate to mood and suicidal ideation among older adults that recently lost a spouse or life partner.

This mechanistic study uses an anti anxiety drug and brain imaging to study the threat processing system and associated brain circuits in people with depression, anxiety disorders and comorbid depression and anxiety disorders. In a double blind, placebo controlled crossover design, up to 65 individuals will be recruited who will have a diagnosis of major depressive disorder (MDD) and at least one anxiety disorder (AD) (AD-MDD group), up to 65 participants will have a diagnosis of MDD and no diagnosis of an AD and up to 65 participants will have no diagnosis of MDD and a diagnosis of at least one AD will be enrolled to participate in an two session study to obtain 150 completers (50 per group). All participants will receive a single dose of Lorazepam and placebo (order randomized) taken orally. After the \~2.5 hr screening session, participants will complete two identical \~5 hr experimental sessions, each of which include a 30 min eyeblink startle session and a 1.5 hr functional magnetic resonance imaging (MRI) brain scan session. The total time involved in the study is approximately 10.5 hours.

The main questions the study seeks to answer are:

* are people with comorbid depression and anxiety different than those with depression alone in terms of their eyeblink startle response to threat? * are people with comorbid depression and anxiety different than those with depression alone in terms of their brain activation in response to threat? * are people with comorbid depression and anxiety different than those with depression alone in terms of their responses to anxiety drugs?

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 12 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.

The purpose of this study is to use smartphone technology to capture individual location emotional and cognitive data, to examine how real-world behaviors thoughts, emotions, and brain activity are related to one another.

In West Africa, most people with serious mental illness receive care from traditional or faith healers at prayer camps. The stepped-wedge cluster randomized trial aims to evaluate the effectiveness of a dual-pronged intervention package comprised of a mobile health program designed to train healers to deliver evidence-based psychosocial interventions combined with pharmacotherapy delivered directly to the patients at their prayer camps via a visiting nurse in Ghana.

The proposed study is designed to first test whether teaching people personalized or standardized emotion regulation skills leads to greater decreases in daily negative emotion intensity. Second, using data from an initial sample, the investigators will prospectively assign an independent sample of participants to receive their predicted optimal or non-optimal skills to determine if it is feasible and efficacious to match participants to the most appropriate training condition. Results of these studies may identify the mechanisms by which emotion regulation interventions impact emotional functioning and allow for the development of personalized, evidence-based, and scalable emotion regulation interventions.

The purpose of this randomized trial is to conduct a fully powered effectiveness trial of video-delivered PROTECT (Tele-PROTECT) compared to a video-delivered depression education (DepEd) control condition to be delivered to 140 English- and Spanish-speaking NYC elder abuse victims. Investigators hypothesize three main aims:

1. Effectiveness Aim: Tele-PROTECT participants will have significantly greater and clinically meaningful reductions in depression when compared to the DepEd control; 2. Abuse Impact Aim: Tele-PROTECT participants will demonstrate greater safety related empowerment compared to DepEd control, which can help participants take steps to reduce risk; 3. Implementation Aim: Stakeholders' views of the factors impacting the implementation of Tele-PROTECT based on characteristics of the intervention, agency setting, and population served will contribute to a national dissemination of Tele-PROTECT

Participants will

* Receive 9 weeks of tele health psychotherapy delivered by a Master's level mental health clinician from the Weill Cornell Medicine research team. Participants will be assigned to "Tele-PROTECT" or "DepEd" psychotherapy randomly. * Participate in one baseline assessment and four follow-up assessments at weeks 3, 6, 9, and 12 administered by a trained member of the research team.

The investigators hypothesized that during the 9-week course of Engage \& Connect treatment there will be an increase in brain functions of the Positive Valence System which in turn will lead to reduction in suicidality.

A randomized controlled trial will compare hippocampal neuroplasticity, antidepressant, and cognitive outcomes between individualized amplitude and fixed 800 mA amplitude ECT in older depressed subjects (n = 25 per group, n = 50 total). Relative to fixed 800 mA ECT:

H1: Individualized amplitude arm will have improved RUL antidepressant outcome (IDS-C30 response rates and reduced BT electrode placement switch at V2).

H2: Individualized amplitude arm will have improved cognitive outcomes (DKEFS-Verbal Fluency

The proposed study will assess the combined effect of perampanel and ketamine on the anti-depressant response in individuals with treatment resistant depression. The purpose of this study is to test the hypothesis that stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Propionic Acid receptors (AMPAR) is critical to the anti-depressant response of ketamine.

A randomized trial of pregnant people at risk for postpartum depression comparing the InBloom app (n = 76) to ROSE (n = 76; weekly scheduled group), and two control groups. We will assess Depression at baseline and 1, 2 and 3 months, ROI at 3 months, Satisfaction at 1 and 3 months and Perceived Access at 1 and 3 months. Subject participation will last up to 8 months (minimum 17 weeks pregnant through 3 months postpartum).

The sub-study will involve a rigorous mixed-methods design. The qualitative phase of the sub-study will consist of semi-structured interviews. During the semi-structured interviews, 10 eligible women will be recruited to identify barriers and facilitators to accessing virtual mental health services. This information will be used to adapt an evidence-based patient navigation intervention for virtual use and an engagement measure. For the intervention phase of the sub-study, 30 women with persistent postpartum depression symptoms will be recruited to participate in the adapted virtual navigator program using rapid cycle testing over a 2-month period.

Background:

Major depressive disorder (MDD) is a psychiatric condition. People with MDD have occasional bouts of depressive symptoms; these bouts are called major depressive episodes (MDEs). Researchers want to know if people having MDEs have lower levels of an enzyme called PDE4B in their brains.

Objective:

To find out (1) if PDE4B can be detected in a person s brain using a special scanning method and (2) if brain PDE4B levels are lower in people having an MDE.

Eligibility:

People aged 18-70 years with MDD. Healthy volunteers are also needed.

Design:

Participants will have up to 5 clinic visits.

Participants will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. Some participants may have a psychiatric assessment; they will answer questions about their state of mind and related topics.

Participants will have magnetic resonance imaging (MRI) of the brain. They will lie on a table that slides into a metal cylinder.

Participants will have a positron emission tomography (PET) scan. A needle will be used to guide a thin plastic tube (catheter) into a vein in one arm. An experimental substance called a radioactive tracer (\[18F\]PF-06445974) will be injected through the catheter. Participants will lie on a table that slides into a doughnut-shaped machine. The scan will last up to 4 hours with a 15-minute break.

Participants blood pressure, heart rate, and breathing will be monitored before, during, and after the PET scan. A second catheter will be inserted in the artery of the wrist so blood can be drawn during the scan.

Some participants may return for a second PET scan.

https://nimhcontent.nimh.nih.gov/start/surveys/?s=KE88DXXPLDFHHTF8

This is a clinical trial study that aims to evaluate the specificity of the relationship between reduced sensitivity to social reward and social anhedonia at both behavioral and neural levels. Individuals who recently experienced their first-episode psychosis will be recruited. Participants will be randomized 1:1 to motivational interviewing or a time- and format-matched control probe. At pre- and post-probe, participants will perform two social reward learning tasks in the scanner. With this design feature, we will examine the relationship between sensitivity to social reward and reduced subjective experience of social pleasure at both the behavioral and neural levels.

The goal of this neuroimaging pilot study is to understand developmental differences in the impact of therapeutic wavelength light (blue light) versus a non-therapeutic wavelength (red light) on emotional brain function in depression. The main questions this study aims to answer are:

* Does acute exposure to blue light (vs red light) stabilize emotional brain function in depressed individuals? * Are stabilizing effects of blue light (vs red light) stronger for blue light in adolescents than young adults?

Participants will complete:

* A magnetic resonance imaging brain scan, in which we will examine the effect of blue versus red light on emotional brain function at rest and in response to rewards and losses. * A pupillometry test of sensitivity to blue vs red light * Clinical interviews and surveys * Screening measures for drug and alcohol use, MRI safety, and current pregnancy \[if relevant\] * Home sleep tracking with sleep diary and actigraphy for one week

This study is a clinical trial that evaluates what drives patient engagement and tests the impact of two strategies-automated motivational push messaging and coach support-to improve engagement with an evidence-based mobile app intervention for depression and/or anxiety.

The goal of this study is to evaluate whether rtfMRI-nf training to increase the amygdala response to positive memories may serve as a stand-alone intervention for major depressive disorder

The purpose of this study is to perform a practice-based research project designed to assess whether cognition and motivated behavior in early psychosis can be addressed as key treatment goals within real-world settings by using a 12-week mobile intervention program. We will recruit participants who are receiving care for early psychosis from clinics across the United States. We will compare outcomes from participants who receive treatment at coordinated specialty care (CSC) early psychosis clinics to those that receive standard community care. A qualifying CSC program will provide comprehensive clinical services such as psychotherapy, medication management, psychoeducation, and work or education support. This study will be conducted remotely, and participants can participate at home with their own electronic devices.

The aim of this study is to investigate a well-defined 12-week mobile intervention program specifically designed to target cognitive functioning and motivated behavior for individuals with early psychosis. Participants will complete a screening interview which will include diagnosis and symptom ratings, neurocognitive assessment, and self-reports of symptoms, behavior, and functioning. Then participants will be randomized to receive the 12-week mobile intervention, or an active control of treatment as usual. The investigators will test for differences in the clinical trajectories after training, and at two follow up appointments at 6 and 12 months post-training.

The primary goal of this clinical trial is to evaluate the unique neural and behavioral effects of a one-session training combining emotion regulation skills training, with excitatory repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (dlPFC). The secondary aim is to identify key changes in the emotion regulation neural network following the combined intervention versus each of the components alone. The third aim is to explore personalized biomarkers for response to emotion regulation training.

Participants will undergo brain imaging while engaging in an emotional regulation task. Participants will be randomly assigned to learn one of two emotion regulation skills. Participants will be reminded of recent stressors and will undergo different types of neurostimulation, targeted using fMRI (functional MRI) results. Participants who may practice their emotion regulation skills during neurostimulation in a one-time session. Following this training, participants will undergo another fMRI and an exit interview to assess for immediate neural and behavioral changes. Measures of emotion regulation will be assessed at a one week and a one month follow up visit.

Adolescent girls and young women (AGYW) at risk of HIV in sub-Saharan Africa, frequently (20-50%) have symptoms of common mental disorders, including depression, anxiety, and stress. These symptoms are associated with suboptimal adherence to HIV pre-exposure prophylaxis (PrEP), a highly effective HIV prevention approach. In this project, the team seeks to address poor mental health and consequent impacts on PrEP adherence and among AGYW at risk of HIV by testing an evidence-based mental health intervention (the Youth Friendship Bench SA) adapted for PrEP delivery programs.

Deficits in cognitive control are core features of late-life depression (LLD), contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves Cognitive Control Network deficits in LLD.

The study examines the hypothesis that nicotine acetylcholine receptor agonists enhance Cognitive Control Network function. This effect may resultantly improve mood and cognitive performance in LLD. Small, open-label studies of transdermal nicotine (TDN) patches have supported potential clinical benefit and provided support that transdermal nicotine administration engages the Cognitive Control Network.

This blinded study will expand past open-label trials supporting potential benefit in LLD. It will examine TDN's effect on depression severity and cognitive control functions measured by neuropsychological testing. The study will evaluate 60 eligible and enrolled participants over a 3-year period.

Deficits in cognitive control are core features of late-life depression (LLD), contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves Cognitive Control Network deficits in LLD.

The study examines the hypothesis that nicotine acetylcholine receptor agonists enhance Cognitive Control Network function. This effect may resultantly improve mood and cognitive performance in LLD. Small, open-label studies of transdermal nicotine (TDN) patches have supported potential clinical benefit and provided support that transdermal nicotine administration engages the Cognitive Control Network.

This is an open-label, extension to the blinded Depressed MIND 3 (Depressed Mood Improvement through nicotine dosing) study. It will evaluate longer-term safety and efficacy of Transdermal Nicotine Patches for potential benefit in cognitive and depression outcomes in elderly depressed participants. Subjects complete blinded randomized trial of Depressed MIND-3 will be eligible for continuation in this extension. This extension study will consist of up to 12 weeks of treatment and a 3 -week safety follow-up period.

Digital mental health interventions are a cost-effective and efficient approach to expanding the accessibility and impact of psychological treatments; however, little guidance exists for selecting the most effective program for a given individual. In the proposed study, decision rules will develop for selecting the digital program that is most likely to be the optimal intervention for each user. These treatment recommendations can be implemented in the context of large healthcare delivery systems to improve the delivery of digital mental health interventions at scale.

The overarching aim of the current study is to better understand for whom and how leading digital interventions work in a large healthcare setting. The study builds on the existing literature and follows expert recommendations by using machine learning (ML) methods to develop precision treatment rules (PTRs) for three leading digital interventions for emotional disorders (e.g., anxiety, depression, and related mental health disorders). Specifically, ML methods will be used to develop PTRs to optimize clinical outcomes and associated intervention engagement. This study will leverage a unique partnership between Boston University (BU), SilverCloud Health (SC)--a leading provider of digital mental health care--and Kaiser Permanente (KP)--one of America's leading health care providers.

A clinical trial (RCT) will be conducted to evaluate the relative effectiveness of three distinct empirically supported digital mental health interventions (from SC's existing library of programs) in a sample recruited from KP primary care and other clinical settings. Data from this trial will be used to develop theoretically and empirically informed, reliable selection algorithms for managing treatment delivery decisions. Algorithms will be validated in a separate "holdout" dataset by examining whether allocation to predicted optimal treatment is associated with superior outcomes compared to allocation to a non-optimal treatment. The role of user engagement will be determined, and other mechanisms in treatment outcome.

This research will use biobehavioral approaches to generate understanding about the linkages between sleep duration and timing, stressful life events, and depressive symptoms in adolescents, with a long-term aim of developing effective preventative interventions.

The goal of this clinical trial is to test whether an established preventive intervention (group interpersonal therapy) delivered virtually shows the same benefits for preventing postpartum depression as it does when delivered in person.

This study is being conducted together by researchers at the University of Pennsylvania and Lyssn.io, Inc., ("Lyssn"), a technology start-up developing digital tools to support evidence-based psychotherapies (EBPs) for mental health disorders and addiction. This study will implement a technology to assess and enhance the quality of EBPs like Cognitive Behavioral Therapy (CBT) that includes a user interface geared to clinical, supervision, and administrative workflows and needs, and then assess this technology for effectiveness in comparison to usual care.

There is a tremendous global burden of mental illness: Over 50 million American adults have a diagnosable mental health disorder, and major depression on its own is the leading cause of disability worldwide. In the face of this burden, clinical research has documented a variety of effective EBPs (e.g. CBT), and these psychotherapies are utilized on a massive scale. Systems have invested over $2 billion in training providers in specific EBPs. Once trained, however, therapists' adherence to the EBP, also called fidelity, is both crucial for effectiveness and difficult to assess. There is no scalable method to assess the fidelity and quality of EBPs in community practice settings. This is a foundational problem for healthcare systems.

Advances in speech processing and machine learning make technology a promising solution to this problem. The use of technology - instead of humans - to evaluate EBPs means that objective, performance-based feedback can be provided quickly, efficiently, cost-effectively, and without human error. If successful, the present research will be among the first examples of a method for building, monitoring, and assessing the quality of therapy that can scale up to large, real-world healthcare settings.

In this study, the investigators will implement an existing, fully-functional prototype (LyssnCBT) that includes a user interface geared to community mental health (CMH) clinical, supervision, and administrative workflows and needs, and then assess for effectiveness of psychotherapy supported by LyssnCBT in comparison to usual care.

This study will implement LyssnCBT in 5 community mental health agencies, beginning with a single-arm pilot field trial to identify and address any specific barriers to implementing the tool in a community mental health context. The study team will then conduct a larger study in community mental health agencies comparing LyssnCBT to services as usual.

Electroconvulsive therapy (ECT) alleviates treatment-resistant depression (TRD) through repeated generalized seizures. The goal of this study is to evaluate how ECT impacts sleep-wake regulation and efficiency of information transfer in functional networks in different states of arousal.

This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have depression. Participants in this study will receive a pill of either pregnenolone or placebo, and can stay on their current antidepression medications. Brain imaging and behavioral assessments will be performed during the study.

Individuals with stroke commonly experience both depression and cognitive difficulties. The goal of this study is to evaluate the efficacy of a treatment that combines a digital therapeutic (an iPad-based cognitive training program) with learning cognitive strategies. The hypotheses are that this treatment will improve cognitive skills, depression symptoms, daily function, and brain connectivity. In the short-term, the findings will inform the efficacy of the intervention and in the long-term, may support the use of the intervention to improve co-occurring cognitive and mood difficulties after stroke.

This Hybrid 1 Study will test the effectiveness of a bundled intervention comprised of behavioral activation and medication optimization in reducing symptoms of depression and anxiety in older adults undergoing Orthopedic surgery (compared with usual care), while examining implementation outcomes.

This study will identify components for inclusion in a coping intervention package to reduce mental health problems among children exposed to high interparental conflict after parental separation/divorce. Reappraisal, distraction, and relaxation coping strategies are related to fewer mental health problems among children, making intervention components based on these strategies key candidates for inclusion in an optimized coping intervention. The primary aim is to experimentally assess the main and interactive effects of three digital intervention coping components (reappraisal, distraction, relaxation) on children's coping efficacy, emotional security, and internalizing and externalizing problems. Secondary aims are to assess indirect effects of the intervention components on children's coping efficacy, emotional security, and internalizing and externalizing problems through their cognitive, emotional, and behavioral reactions to post-separation/divorce interparental conflict events.

The investigators will be comparing brain (neural) activation of depressed adolescent patients before, during and after a course of Behavioral Activation (BA) therapy using functional magnetic resonance imaging (fMRI). In particular, the project seeks to determine whether BA targets different neural mechanisms for behavioral avoidance associated with low motivation as compared to threat avoidance. A group of healthy controls will also be scanned as a comparator group for behavioral and imaging measures.

This protocol will test the effectiveness of an intervention, iCHART (integrated Care to Help At-Risk Teens) and facilitate recruitment for other studies in the larger ETUDES Center grant, which are focused on treatment development for target risk factors for suicidal behavior, specifically, sleep, anhedonia, and stress related to cybervictimization. This study will recruit 900 adolescents which will be enrolled in a randomized controlled trial to test iCHART and will be randomized to iCHART or treatment as usual (TAU). Based on previous work, the investigators hypothesize that iCHART, compared to TAU, will decrease suicidal-related events by 50%, and the effects will be mediated by increases in referrals, treatment engagement, and safety planning. The investigators will use implementation science methods to assess contextual factors (i.e., barriers and facilitators) and implementation outcomes specifically, acceptability, feasibility, appropriateness, and cost for our predictive algorithm and iCHART to inform future implementation efforts and promote health equity.

The overall aim of this program of research is to improve the mental health of people who identify as LGBTQ+ by increasing their social support through a brief intervention. The purpose of the proposed project is to establish the effectiveness of our empirically-supported, brief acceptance-based behavioral therapy (ABBT). To achieve the specific aims, the investigators will conduct a fully-powered, randomized clinical trial (n=240) with two treatment arms: treatment-as-usual (TAU) vs. ABBT.

Approximately 200 Participants with mild-to-moderate, untreated depression and/or anxiety will be randomly assigned (by chance, like flipping a coin) to 1 of 3 study groups: Lumen Coached Problem-Solving Treatment (PST) (n=100), Human Coached PST (n=50), and optional (delayed) Lumen Coached PST as waitlist control (n=50) to improve emotional health. All participants will complete assessments at baseline and at 18 weeks post randomization.

Depending on the group assignment the PST program will be delivered by Lumen, a virtual voice-based coach on a study iPad, or by a human coach in person for the first session and then via videoconference or phone for the remaining 7 sessions. Participants assigned to the waitlist control group can receive the Lumen coached PST on a study iPad after completing their 18-week follow-up assessment.

Participants will receive 8 coaching sessions to learn problem-solving skills and work on unresolved problems in daily living that may be interfering with their emotional well-being and contributing to depression and anxiety symptoms.

The overall goal of this study is to develop an mHealth intervention (Suubi-Mhealth) for use among Ugandan youth (14-17 years) with comorbid HIV and depression, taking into account their unique contextual, cultural, and developmental needs. This digital therapy intervention delivered via a mobile application, will utilize the core tenets of cognitive-behavioral therapy (CBT) found to improve depression and ART adherence.

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.

The main purpose of this study is to investigate the effects of ketamine on decision-making and emotion processing in a sample of individuals diagnosed with Major Depressive Disorder (MDD).

This Hybrid 1 Study will test the effectiveness of a bundled intervention comprised of behavioral activation and medication optimization in reducing symptoms of depression and anxiety in older adults undergoing cardiac surgery (compared with usual care), while examining implementation outcomes.

The purpose of this study is to assess the effectiveness of a parenting intervention+usual care compared to usual care on postpartum depression and other mental health and parenting outcomes, as well as the feasibility and acceptability of the parenting intervention.

Patients, physicians, and those who fund depression research are keenly interested in depression treatments that do not involve taking medications. One promising candidate treatment is transcranial direct current stimulation (tDCS), a low-cost technique that involves placing electrodes on specific scalp locations and using a 9-volt battery to cause a small amount of electricity to pass through parts of the brain. Depending on the direction of electrical flow, tDCS can make brain cells (neurons) more likely or less likely to generate their own electrical signals. When evaluated as a treatment, tDCS is typically done in daily sessions over a period of two weeks.

One of the challenges of tDCS is to work out the best possible positioning of electrodes and direction of electricity flow to gradually cause lasting changes in brain activity in ways that might be expected to improve depression. To address this challenge, the investigators are using MRI to take pictures of the brain during tDCS. This data will help us better understand the short-term effects of tDCS in depression and help us learn how to customize future treatments to cause a lasting beneficial response.

Patients with depression between the ages of 20-55 years are eligible to take part in this research. Potential participants will undergo:

1. An assessment to confirm eligibility. This will take place over a secure videoconference call lasting no more than 3 hours. 2. Two in-person study visits lasting 30 min and 2-1/2 hours respectively. In the first visit, the investigators will use the MRI to take a picture of the brain and head structure to determine appropriate locations for placing the tDCS electrodes at the start of the second visit. Following electrode placement, an MRI scan will be performed to take pictures of the brain during tDCS. Depending on the study arm,

1. Participants may receive 'active' or 'sham' tDCS. The 'sham' condition is identical to the 'active' tDCS in every way except that it involves minimal tDCS and is designed to help rule out effects unrelated to the administered tDCS electricity. 2. Participants may also be asked to perform a mental task during MRI.

All participants will be compensated $150 + parking upon completion of all study-visits.

Depression in youth is a serious public health concern for which more personalized treatments are needed. This randomized controlled trial will test the effect of an intervention aimed at enhancing social cognitive capacities (e.g., ability to take another's perspective), thereby making treatment of depression in youth more efficient and effective. Participants in the R33 (N=82) will be youth between ages 13- through 17-years-old currently experiencing depression. Youth will be randomized to either an enhanced CBT intervention that teaches social cognitive skills, particularly social perspective taking and theory of mind (CBTSCT) as compared to CBT only. The primary target is improvement in both social cognitive skills and depressive symptoms at post-treatment and at a 6-month follow-up.

This project aims to examine the efficacy of ketamine, a rapidly acting medication shown to decrease suicidality in adults in as short as hours or days, as opposed to weeks.

The study design is a double-blind, randomized, active-control trial of adolescents (ages 13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation). All participants must be receiving standard of care treatment which may range broadly from both outpatient and inpatient programs which include clinically indicated psychosocial and/or psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during the first two weeks of the study, followed by weekly assessments through week 12.

This study is dedicated to help identify biomarkers for depression and suicide. The purpose of the study is to better understand these links to improve medical and psychiatric care in the future. This research is also to test the effects of standard treatment of depression on improvement in depressive and suicidal behavior and on biomarkers (e.g. miRNA) for these disorders.

Mood lability is an important transdiagnostic problem that is associated with poor psychosocial function and suicidal thoughts, and is a predictor of mood disorder onset, especially in youth at familial risk. Thus, particularly in youth with a family history of mood disorder, an intervention to target mood lability during a key period of development could improve outcomes. This study will allow us to test neurobehavioral mechanisms of a mindfulness-based intervention to target mood lability in early adolescents at high risk for developing mood disorders. Through this randomized controlled trial, the investigators will better understand how and for whom mindfulness interventions work, which will lead to more targeted interventions to improve emotion regulation during this key developmental period.

The purpose of this study is to expand Adhere.ly- a simple, HIPAA-compliant, web-based platform to help therapists engage clients in practicing therapeutic skills between sessions (homework) during mental health treatment by conducting a trial comparing standard therapy to therapy enhanced with Adhere.ly.

The purpose of this randomized controlled trial is to understand how a cognitive-behavioral treatment (a form of psychological treatment) for depression changes the gut microbiome (micro-organisms that regulate the health of the gut), immune system, and the brain functioning in people living with HIV.

The purpose of this study is to examine state representation in individuals aged 15-40 who have been diagnosed with a psychotic illness, as well as young adults who do not have a psychiatric diagnosis. State Representation is our ability to process information about our surroundings. The investigators will complete some observational tests as well as a cognitive training clinical trial.

This study includes a randomized experimental component where therapists will systematically deliver an experimental behavioral probe or a supportive control condition. The aim is to evaluate effects on meaningful health-relevant measures including morning activation levels, depression symptoms, rumination, and aspects brain connectivity previously linked with depression.

The goal of this project is to test whether WellPATH-PREVENT (a novel, mobile psychosocial intervention) improves a specific aspect of emotion regulation, i.e., cognitive reappraisal ability, and reduces suicide risk in middle-aged and older adults (50-90 years old) who have been discharged after a suicide-related hospitalization (i.e. for suicidal ideation or suicide attempt).

This proposal will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis symptoms as well as on brain function using simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR).

The purpose of this study is to gather information regarding the use of a new type of transcranial magnetic stimulation (TMS) called theta burst stimulation (TBS) for suicidal ideation in adolescents with Major Depressive Disorder (MDD). The investigators hope to learn if this TMS treatment improves suicidal ideation over 10 days and clinical outcomes over 1 year of follow-up.

The investigators propose to examine the effects of CSC services delivered via TH (CSC-TH) versus the standard clinic-based CSC model (CSC-SD) on engagement and outcomes in a 12-month, randomized trial.

Neuropsychiatric disorders are a leading cause of disability worldwide with depressive disorders being one of the most disabling among them. Also, millions of patients do not respond to current medications or psychotherapy, which makes it critical to find an alternative therapy. Applying electrical stimulation at various brain targets has shown promise but there is a critical need to improve efficacy.

Given inter- and intra-subject variabilities in neuropsychiatric disorders, this study aims to enable personalizing the stimulation therapy via i) tracking a patient's own symptoms based on their neural activity, and ii) a model of how their neural activity responds to stimulation therapy. The study will develop the modeling elements needed to realize a model-based personalized closed-loop system for electrical brain stimulation to achieve this aim.

The study will provide proof-of-concept demonstration in epilepsy patients who already have intracranial electroencephalography (iEEG) electrodes implanted for their standard clinical monitoring unrelated to this study, and who consent to being part of the study.

Approximately one in two individuals with bipolar disorder (BD) are non-adherent with medication, often leading to severe and negative consequences. Unfortunately, there is no widely used evidence-based approach to target poor adherence among individuals with BD. Building upon positive efficacy trial results, the proposed project will test the effectiveness of technology-facilitated Customized Adherence Enhancement (CAE) vs. enhanced treatment as usual (eTAU) using a prospective randomized controlled design in public mental health care settings and preferentially enrolling poorly adherent/high-risk individuals with BD. Deliverables include a curriculum-driven adherence enhancement approach that can be implemented in public healthcare settings and which can improve outcomes for the most vulnerable groups of people with BD.

Prevention of depressive disorders has become a key priority for the NIMH, but the investigators have no widely available public health strategy to reduce morbidity and mortality. To address this need, the investigators developed and evaluated the primary care based-technology "behavioral vaccine," Competent Adulthood Transition with Cognitive-Behavioral Humanistic and Interpersonal Therapy (CATCH-IT). The investigators will engage N=4 health systems representative of the United States health care system, and conduct a factorial design study to optimize the intervention in preparation for an implementation study and eventual dissemination.

This study looks at the role of the Nociceptin/Orphanin FQ receptor system in the brain of individuals with current or past major depressive disorder (MDD). It also examines how individuals with a history of depression make certain decisions and which brain regions are involved in such decisions. Information collected through MRI, PET, biospecimens (i.e., blood, saliva) and behavioral tasks will be used to predict depressive symptoms in the future.

This study uses a noninvasive technique called transcranial magnetic stimulation (TMS) to study how hallucinations work in schizophrenia.

TMS is a noninvasive way of stimulating the brain, using a magnetic field to change activity in the brain. The magnetic field is produced by a coil that is held next to the scalp. In this study the investigators will be stimulating the brain to learn more about how TMS might improve these symptoms of schizophrenia.

Novel invasive neurostimulation stimulation strategies through neurosurgical interventions are emerging as a promising therapeutical strategy for major depressive disorder. These have been applied mostly to the anterior cingulate cortex, but other limbic brain regions have shown promise as anatomical targets for new neurostimulation strategies. The researchers seek to study neural activity in limbic brain areas implicated in decision behavior and mood regulation to identify novel targets for treatment through electrical stimulation. To do this, the study team will record local field potentials (LFPs) from the orbitofrontal cortex, hippocampus and amygdala of epilepsy participants undergoing invasive monitoring (intracranial encephalography, iEEG) during choice behavior. Leveraging the high co-morbidity of depression and intractable epilepsy (33-50%), neural responses will be compared to reward across depression status to identify abnormal responses in depression. Finally, the researchers will use these as biomarkers to guide development of neurostimulation strategies for the treatment of depression.

Repetitive transcranial magnetic stimulation (rTMS) is a treatment for depression. The investigators are continuing to learn how to optimize outcomes from rTMS treatment. The purpose of this research project is to use brain network connectivity patterns as measured by resting state functional magnetic resonance imaging (fMRI) to confirm a way to optimize the use of rTMS to treat depression. In addition, the study aims to gain a better understanding of how rTMS influences brain networks.

Background:

More than 12,000 people have taken part in research at the Experimental Therapeutics \& Pathophysiology Branch at the National Institute of Mental Health Intramural Program. This has led to advances in the treatment of depression, bipolar disorder, and suicide risk. Researchers want to follow up with this group to see if they continue to have mental health symptoms and receive psychiatric treatments.

Objective:

To learn the long-term impact of depression, bipolar disorder, and suicide risk.

Eligibility:

Adults ages 18 and older who signed consent for Protocol 01-M-0254 over a year ago.

Design:

This study has 2 phases: an online phase and a telephone phase. It has no in-person or face-to-face contact.

In Phase 1, participants will fill out online surveys. They will access the surveys through the study website. The questions will focus on their current thoughts and feelings. The surveys will also ask about their current treatments for their mental health symptoms. At the end of the surveys, they will be asked if they would like to take part in Phase 2. If so, they will mark yes. Phase 2 includes a phone interview. They will be contacted by email to schedule the interview.

In Phase 2, participants will be asked more in-depth questions about how they are feeling. They will also be asked which psychiatric medicines and treatments they have used since they left NIH.

In both phases, participants can skip any questions they do not want to answer.

The online surveys will take 30 minutes to complete. The phone interview will last 1-4 hours.

The information that participants give in this study may be linked to their other NIH research records.

Cognitive impairment and brain abnormalities are common and persist after depression remission in those with Late Life Depression (LLD), compounding dementia risk in both individuals with acute and remitted LLD (rLLD). In this study, investigators will examine systemic neural and cognitive benefits of aerobic exercise training in older adults with remitted LLD. This will generate preliminary data regarding neural targets of aerobic exercise training that may translate to cognitive benefits in those with rLLD, a population who remains at high risk for dementia despite successful treatment of depression.

The overall aim of this study is to employ Community Health Workers (CHWs) to screen for depression in 30 Black churches and compare the effectiveness of Screening, Brief Intervention, and Referral to Treatment (SBIRT) (Intervention arm) to Referral As Usual (Control arm) on treatment engagement for depression. The investigators will assess patient-level outcomes (Mental-Health Related Quality of Life and depressive symptoms) at 3- and 6-months post-screening and conduct a mixed-methods process evaluation to assess multi-level facilitators and barriers of screening uptake.

Background:

Researchers developed \[11C\]MC1, a radioligand for cyclooxygenase-2 (COX-2). COX-2 is an enzyme induced in the brain during inflammation. Researchers want to see the levels of COX-1 (measured as distribution volume VT) are elevated in the brain of two groups of mood disorders patients undergoing MDE relative to the control group.

Objective:

To determine whether COX-1 and COX-2 are detectable in the brains of individuals with MDD experiencing a major depressive episode (MDE).

Eligibility:

People aged 18-70 years with MDD and Healthy Volunteers aged 18 70 years.

Design:

Group A: MDD participants will be studied with the same dose of \[11C\]MC1 before and after administration of 600 mg celecoxib; the study is neither randomized nor placebo-controlled. Group B: MDD participants, both medicated and unmedicated, will be studied with \[11C\]PS13 and compared to healthy volunteers..

https://nimhcontent.nimh.nih.gov/start/surveys/?s=TJW4RA4WN3LDD988

This study will test a consumer health light therapy device (Re-Timer) for women with postpartum depression to better understand how it affects mood and the body clock (also called the circadian clock).

Eligible participants will be enrolled and randomized after baseline assessments. In addition to using the Re-Timer light for 5 weeks participants will complete questionnaires at various timepoints, record sleep information, wear an actigraph watch, and provide saliva samples. Additionally, the sleep of the participants' infants will also be monitored using an ankle-worn device (actigraph) and sleep diary at certain time-points as this may influence the mother's mood/sleep, and in turn affect the results.

The hypotheses regarding the bright light versus the placebo dim light of the study are:

* morning bright light therapy will produce greater improvement from pre- to post-treatment on the Hamilton Rating Scale for Depression * morning bright light therapy will lengthen the Phase angle difference (PAD) and this will mediate change in depression symptoms. * morning bright light therapy will produce greater improvements on self-reported depression symptoms, excessive daytime sleepiness, maternal-infant bonding, social functioning, and sleep-related impairment from pre- to post-treatment.

The primary objective of this study is to assess acquisition and retention of a Cognitive Behavioral Therapy (CBT)-based "cognitive restructuring" skill, among young adolescents (12-15 years of age) with elevated depression symptoms and with population-level variability in lifetime exposure to adverse childhood experiences. This study uses a repeated-measures, longitudinal design to investigate associations between adversity exposure and learning-related cognitive control processes in the context of elevated depression (Aim 1). Adversity exposure and cognitive control will be examined as direct predictors of cognitive restructuring skill acquisition and skill retention over six-months; an indirect pathway from adversity to skill acquisition through cognitive control will also be examined (Aim 2). The study also includes exploration of key characteristics of adversity, namely the type (threat of harm versus deprivation of resources) and developmental timing of exposure, as distinct predictors of skill acquisition (exploratory Aim 3).

Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood. Here, the investigators aim to examine the immediate effect of transcranial brain stimulation (TBS) on brain activity and emotions in adults with and without BD as a first stage toward understanding the predisposing brain mechanisms of BD. The investigators hypothesize that TBS will reduce brain activity while playing a game with rewards in all adults, but the TBS will reduce brain activity more in the adults with BD compared to adults without BD. Furthermore, the investigators hypothesize that this reduced brain activity will be associated with reduced BD symptoms, such as negative emotions.

This is a rater-blinded, randomized controlled trial. All patients will receive esketamine for treatment of Major Depression with Suicidal Ideation (MDSI). Subjects will be randomized (1:1) to receive CBT (computer-assisted) or TAU alone following esketamine.

This is a research study to find out if childhood trauma and stress are associated with depression or suicidal risk. The study will assess the effects of both short-term and long-term stress on biomarker (e.g. miRNA \[MiRNA\]) levels. miRNAs are a type of RNA (genetic material that is translated into protein) that are found in throughout the body and blood. They are called microRNA because their size is much smaller than typical RNA molecules. miRNAs are highly responsive to environment. This responsiveness is reflected in their expression in individuals who are affected by environment such as stress. The investigators are gathering genetic material, including DNA and RNA, from each participant. The RNA will be taken from the small vesicles and cells in the participant's blood and analyzed. The vesicles are small objects that occur normally in the blood and that contain RNA. This information may help us to understand the cause of mental illness and to improve medical and psychiatric care in the future. There will be 450 participants enrolled in this study.

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.

In response to large numbers of senior center clients who suffer untreated depression and the dearth of geriatric mental health providers, the investigators have simplified Behavioral Activation to be delivered by lay volunteers ("Do More, Feel Better"; DMFB). The focus of Behavioral Activation is to guide clients to reengage in daily pleasant and rewarding activities, and reduce depressive symptoms. If the investigators can show that the lay delivery model has positive impact in comparison to MSW-delivered Behavioral Activation, the investigators will have identified an effective intervention that can be used by a large untapped workforce of older adult volunteers across the nation.

Our hypothesis is that targeted propofol infusion in TRD patients will induce slow wave activity during sedation and augment subsequent sleep slow wave activity. We will recruit 15 participants for this open label single arm Phase I trial. All participants will undergo two propofol infusions 2-6 days apart, with each infusion maximizing expression of EEG slow waves. To minimize bias, there will be no specific gender or ethnic background consideration for enrollment. This will be a single site investigation at Washington University Medical Center.

Using an indicated prevention approach, investigators propose to enroll 150 spousally-bereaved adults aged 60 years and older in the first 6 months after spousal death who are at high risk for major depression disorder because of subthreshold symptoms of depression. A confirmatory efficacy trial will be conducted in which participants will be randomly assigned to (a) self-monitor sleep, meals, and physical activity for 12 weeks using digital monitoring plus motivational health coaching (WELL; n=75); or (b) enhanced usual care (EUC, usual care plus study assessments, n=75). Objective actigraphic measures of the 24-hour pattern of day and nighttime activity - known as the rest-activity rhythm - will be measured to evaluate circadian rhythms as a mediator of treatment outcomes. Participants will be assessed at baseline, months 1 \& 2, post-intervention, and 3, 6,12, 18-months post-intervention. In addition, the investigators will include a subset of participants bereaved by COVID-19 (or suspected as bereaved by COVID-19). Participants in this subset will undergo the same research procedures as the main cohort. Participants in both the main cohort and subset determined to be fully eligible will be randomized into two groups with a total of: usual care (EUC;n=125) and WELL (WELL; n=125).

Depression and anxiety disorders rank in the top ten causes of years lived with disability. Less than 50% of patients experiencing long-lasting improvements to current gold-standard treatments. Two gold-standard behavioral interventions include behavioral activation, focused on enhancing approach behavior towards meaningful activities, and exposure-based therapy, focused on decreasing avoidance and challenging negative expectations. While these interventions have divergent treatment targets, there is little knowledge to inform which strategies should be used in the frequent case of comorbid anxiety and depression. Approach-avoidance decision-making paradigms focus on assessing responses when faced with potential rewards and threats, tapping into processes important for both anxiety and depression as well as behavioral activation and exposure-based therapy.

For this study, investigators will recruit individuals reporting both anxiety and depression symptoms and randomize them to one of three different interventions: (1) behavioral activation, (2) exposure-based therapy, and a non-specific therapy approach (3) supportive therapy. Participants will complete clinical, self-report, behavioral, and functional magnetic resonance imaging (fMRI) assessments before and after therapy. Investigators will use a computational approach to model factors that may influence one's behavior during approach-avoidance decision-making, including drives to avoid threat versus approach reward and confidence versus uncertainty in one's decisions.

This project will accomplish the following aims (1) Determine how changes in brain and behavior responses during approach-avoidance conflict relate to changes in mental health symptoms with the different therapy approaches, (2) Determine the degree to which baseline brain and behavior responses during approach-avoidance conflict predict response to the different therapy approaches, above and beyond the influence of demographics and baseline symptom severity. In addition, by including peripheral blood draws and measures of grace matter volume, the project will also accomplish the following aims: (1) Determine whether kynrenine metabolites measures peripherally may be beneficial as a biomarker of treatment response and (2) determine whether there is an association between change in kynurenine metabolites and changes in gray matter volume with treatment.

Results will enhance understanding of how different psychotherapy approaches (behavioral activation, exposure-based therapy) may impact brain responses and decisions when faces with potential reward versus threat and approach versus avoidance drives. In addition, results will have important implications concerning the potential for a more personalized approach to psychotherapy, enhancing knowledge of which types of therapy strategies may be most beneficial for which individuals.

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.

The purpose of this study is to better understand mental illness and will test the hypotheses that while viewing affective stimuli, patient groups will show increased blood oxygenation level dependent (BOLD) signal by fMRI after lorazepam.

This study will enroll participants between the ages of 16 and 60, who have a psychotic illness (such as psychosis which includes conditions like schizophrenia, schizoaffective disorder, and mood disorders). The study will also enroll eligible participants without any psychiatric illness, to compare their brains.

The study will require participants to have 3-4 sessions over a few weeks. The initial assessments (may be over two visits) will include a diagnostic interview and several questionnaires (qols) to assess eligibility. Subsequently, there will will be two separate functional magnetic resonance imaging (fMRI) sessions in which lorazepam or placebo will be given prior to the MRI. During the fMRI the participants will also be asked to answer questions. Additionally, the participants will have their blood drawn, women of child bearing potential will have a urine pregnancy test, vital signs taken, and asked to complete more qols.

Decision-making is an important process that is frequently shown to be impaired in patients with depression. While a number of preclinical and clinical studies have identified key regions involved in this process, it remains unclear exactly how these regions are influencing choice behavior especially when choices become more challenging. The goal of this project is to understand how these regions, such as the cingulate cortex, impact difficult choice behavior. Specifically, the researchers are interested in learning how disruptions in cognitive control might impact choice preferences during difficult decisions in depressed patients. To do this, this study will recruit participants with depression (as well as healthy controls) to perform game-like tasks in the laboratory while undergoing TMS or TI.

Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are associated with a decline in declarative memory performance (a process mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving prescription CS therapy. These findings have important implications for patients with mood disorders, as a large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to corticosteroids appears to be a consequence of MDD.

this study will examine changes in declarative memory, as well as use state-of-the-art high-resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI, in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans, provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A multidisciplinary research team with extensive experience in CS effects on the brain and hippocampal subfield neuroimaging, and a prior history of research collaboration, will conduct the project.

This study will evaluate whether a newer treatment, rumination-focused cognitive behavioral treatment, which includes mindfulness and can be used to reduce ruminative habits, change ways in which key brain regions interact with each other (e.g.., often called connectivity), and whether these changes in habits and brain connectivity can reduce the risk for recurrence of depression in the next two years.

1. To use a SMART design to evaluate which of four sequences of New Hope (NH), Elders Resilience (ER) and Case Management (CM) have the greater effects on immediate and longer-term suicidal ideation (primary outcome) and resilience (secondary outcome) among American Indian (AI) adolescents ages 10-24 identified at risk for suicide.

Hypotheses:

i. New Hope vs. CM alone will significantly reduce participant suicidal ideation.

ii. Elders Resilience vs. CM alone will significantly improve participant resilience.

iii. New Hope followed by Elders Resilience will have the strongest effects on suicidal ideation and resilience.

iv. CM alone will have the weakest effects of all combinations.

Secondary Aims: 2. To examine mediators and moderators of treatment effectiveness and sequencing in order to determine which types and sequence of interventions is best suited for which youth. 3. To assess the acceptability, feasibility and capacity for sustainability of the Hub's key intervention components (Surveillance/Case Management, New Hope and Elders' Resilience) from the perspective of multiple stakeholders as they are implemented across different tribes.

The purpose of this study is to determine the clinical efficacy of real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training to increase the amygdala's response to positive autobiographical memories in patients with depression who are considered treatment-resistant

Background:

Repetitive transcranial magnetic stimulation (rTMS) is a treatment for depression. It stimulates the brain. Researchers want to see if using magnetic resonance imaging (MRI) scans helps locate the best area for rTMS in each person. They also want to find other ways to make it more effective.

Objective:

To study the effects of combining MRI- guided transcranial magnetic stimulation (TMS) and talk therapy on the brain in people with depression.

Eligibility:

Adults ages 18-75 with a major depressive disorder and current depression. If taking an antidepressant, should have been doing so for at least 4 weeks.

Design:

Participants will be screened with medical and psychiatric history, psychiatric evaluation, physical exam, and blood and urine tests.

Phase 1 is 1-4 visits in 1 week. Participants will have:

* Brain MRI. Participants will lie on a table in a scanner. * Questions about their medical history and psychology symptoms * Tests of mood and thinking * Tests of brain activity. Participants may do tasks during these tests:

* A cone with magnetic detectors is put on the head. * A cap with electrodes is put on the scalp. * TMS. A brief electrical current passes through a wire coil on the scalp. * A metal disk will be placed on the arm. A nerve will be stimulated with a small electrical shock.

Phase 2 is about 6 to 7 weeks.

* There will be 30 daily sessions of combined therapy and repetitive TMS (rTMS) for 6 weeks. * Participants will receive rTMS and another therapy by computer. * For rTMS, repeated pulses will pass through the coil. * This is followed by up to 3 additional visits, when:

* Participants will repeat Phase 1 tests * Participants will rate their depression symptoms.

Phase 3 is 3 visits over 3 months. Participants will rate their depression symptoms and repeat some of the previous questionnaires and tests of mood and thinking.

This study originally included 140 subjects with medication-refractory depression undergoing 10 Hz transcranial magnetic stimulation (10Hz-TMS) to the left dorsal lateral prefrontal cortex (DLPFC), with the goal of having 60 completers with good quality data. Subjects were recruited from the TMS clinics at Beth Israel Deaconess Medical Center, Brigham \& Women's Hospital, and Butler Hospital. Subjects underwent an hour-long MRI scanning session, an optional DNA-sample collection, up to three 20 minute neuronavigation sessions for marking the site of TMS stimulation, questionnaires, and a behavioral testing battery before and after their TMS treatment course. The task battery included the Emotion Conflict Resolution (ECR) task, Multi-Source Interference Task (MSIT), War Game (Gambling) task, and Associative Learning with Reversal task. Subjects' scores on the Quick Inventory of Depressive Symptomatology (QIDS) and Beck Depression Inventory (BDI) were assessed before and after the TMS course. MRI data was utilized to identify brain regions whose connectivity to the stimulation site co-varies with the aforementioned measures of symptom improvement. This was the only study group until August 30, 2022, and the primary outcome was analyzed for the 10Hz-TMS group.

Due to changes in clinical standard of care from 10Hz-TMS to a newer version of TMS termed intermittent theta burst (iTBS), in September 2022 a second group was added to include patients receiving this new form of TMS. This second group included another 100 patients with medication-refractory depression undergoing iTBS to the left dorsal lateral prefrontal cortex (DLPFC), with the intent to have 80 completers. Massachusetts General Hospital was added as a data collection site in lieu of Butler Hospital. Subjects will undergo an hour-long MRI scanning session, up to three 20 minute neuronavigation sessions for marking the site of TMS stimulation, questionnaires, and a behavioral testing battery before and after their TMS treatment course. The task battery will included the Emotion Conflict Resolution (ECR) task, Multi-Source Interference Task (MSIT), Penn Emotion Recognition Test, the Suicide/Death Implicit Association Test, and Associative Learning with Reversal task. Subjects' scores on the Beck Depression Inventory (BDI) were assessed before and after the TMS course. MRI data will be utilized to identify brain regions whose connectivity to the stimulation site co-varies with the aforementioned measures of symptom improvement.

This research study seeks to find causes and treatments of depression in teenagers. The study goals are to increase our knowledge of treatments for depression and understand how the brain changes when teenagers have depression. The study will also compare teenagers with depression to those without mental health diagnoses.

This outpatient study is recruiting participants ages 11-17 who are depressed. They must have a pediatrician or other medical provider, be medically healthy, and able to perform research tasks. They may not currently be hospitalized, psychotic or actively suicidal. Teenagers with depression are eligible even if they are taking medication.

The study begins with an evaluation that includes clinical assessment, interviews, and questionnaires.

* Visits may include paper-and-pencil and computer tests of mood, memory, and thinking; specialized computer games; and structural and brain imaging. If eligible, study participants may return several times a year for up to two years. This part of the study does not involve treatment. * Participants may be eligible for outpatient treatment for up to 25 weeks. This includes evidenced-based "talk" therapy. Participants may choose either Interpersonal Psychotherapy for Adolescents (IPT-A) or Cognitive Behavioral Therapy (CBT). If indicated, participants may opt to receive standard medication treatments along with psychotherapy. Research includes computer tasks and brain imaging.

All clinical evaluations, research tasks and visits are free of cost. Participants are compensated for research activities. Parents and teenager must agree to the teenager s participation in research.

The study is conducted at the NIH in Bethesda, Maryland and enrolls participants from the Washington DC Metro region within 50 miles of NIH. Transportation expenses are reimbursed by NIMH.

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

This research study is designed to look at the involvement of the glutamate system and synaptic density in depression and bipolar disorder. Each participant 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 a combination of one magnetic resonance imaging (MRI) or functional magnetic resonance imaging (fMRI) scan, one proton magnetic resonance spectroscopy (MRS) and/or one C13 MRS scans, and up to two positron emission tomography (PET) scans. Participants will also participate in cognitive testing. Depending on camera time, staff availability and subject schedule, total study participation may last 1-2 months.

Background:

There are no good treatments for people considering suicide. Researchers want to study suicide with questions, blood tests, brain imaging, and sleep studies. They hope to better understand suicide, so they can help suicidal people.

Objective:

To understand what happens in the brain when someone has thought about or attempted suicide.

Eligibility:

Group 1: Adults ages 18 70 who have thought about or attempted suicide recently

Group 2: Adults ages 18 70 who have thought about or attempted suicide in the past

Group 3: Adults ages 18 70 who have depression or anxiety, but have never thought about suicide

Group 4: Healthy volunteers the same ages.

Design:

Participants will be screened in another protocol. Adults who have recently thought about or attempted suicide must be referred by a doctor. They may do up to 3 phases of this study. Groups 2, 3 and 4 will do only Phase 1 and will not get ketamine.

Phase 1: 1 week in hospital. Participants will have:

Physical exam.

Questions about thoughts and feelings.

Thinking and memory tests and simple tasks.

Blood and urine tests.

Two MRI scans. Participants will lie on a table that slides into a metal cylinder that takes pictures. They will have a coil over their head and earplugs and do a computer task.

Sleep test. Disks and bands will be placed on the body to monitor it during sleep.

Magnetic detectors on their head while they perform tasks.

A wrist monitor for activity and sleep.

Lumbar puncture (optional). A needle will collect fluid from the back.

Shock experiments (optional). Participants will observe pictures and sounds and feel a small shock on the hand.

Phase 2: 4 days in hospital. A thin plastic tube will be placed in each arm, one for blood draws, the other to get the drug ketamine once. Participants will repeat most of the Phase 1 tests.

Phase 3: up to 4 more ketamine doses over 2 weeks.

Participants will have follow-up calls or visits at 6 months and then maybe yearly for 5 years.

...

The purpose of this research study is to characterize the mechanisms contributing to cognitive impairment and accelerated cognitive decline in Late Life Depression (LLD).

This is a non-randomized, observational, non-treatment study that originally launched in 2015, enrolling 133 participants. From the originally enrolled participants, the continuation of the ADNI-D study will enroll 120 participants which will include following participants from the original (parent) protocol and enrollment of new participants for a period of 30 months. Data from an additional 300 non-depressed subjects will be used from ADNI studies for comparison.

Depression history, symptom severity and health information will be collected at the initial visit to determine eligibility. An magnetic resonance imaging (MRI) scan, as well as amyloid (florbetapir) and tau (flortaucipr) positron emission tomography (PET) imaging will be conducted at San Francisco VA. Collection of plasma and serum for biomarkers, clinical assessments and cognitive assessments will be conducted at two time points. Blood samples will also be collected for genetic analysis.

A single subanesthetic dose infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and robust antidepressant effects in patients with treatment-refractory major depressive disorder (TRD). A family history of an alcohol use disorder (Family History Positive, FHP) is one of the strongest identified predictors of an improved antidepressant response to ketamine. Like ketamine, alcohol is a functional NMDA receptor antagonist. FHP is associated with differential response to ketamine, e.g. blunted psychotomimetic side effects. One of the primary mechanistic hypotheses for ketamine's antidepressant action is the acute intrasynaptic release of glutamate from major output neurons, e.g. cortical pyramidal cells. Preliminary clinical studies have demonstrated this acute glutamate "surge" in response to subanesthetic dose ketamine. Based on these findings, the investigators hypothesize that ketamine's enhanced antidepressant efficacy in FHP TRD subjects is, at least in part, attributable to increased glutamate release relative to TRD subjects without a family history of alcohol use disorder (Family History Negative, FHN). To test this hypothesis, the investigators have designed a now two-site, open-label study of 18-55-year-old medically and neurologically healthy, currently moderately-to-severely depressed TRD patients. In total, the investigators plan to recruit 25 FHP and 25 FHN TRD subjects. All subjects must not have a current substance use disorder (except nicotine or caffeine). The experimental portion consists of two phases. The preliminary first phase is a medication taper (if needed) and psychotropic medication-free period. The experimental second phase comprises one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusion. The ketamine infusion will occur during 7T-magnetic resonance imaging (MRI), both resting-state functional MRI (rs-fMRI) and magnetic resonance spectroscopy (MRS) to detect glutamate in the ventromedial prefrontal cortex/ventral anterior cingulate cortex (vmPFC/vACC). The primary outcome measure is group mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from pre-ketamine infusion (baseline) to one-week post-infusion, where the investigators observed ketamine's greatest antidepressant effect in FHP TRD. Additional outcome measures are vmPFC/vACC glutamate change in response to ketamine based on family history status. In summary, this study will provide key mechanistic information on ketamine's improved antidepressant efficacy in a biologically-enriched subgroup. This will contribute to the systematic development of more efficacious, personalized treatments for major depression in an effort to reduce its enormous public health burden.

We are conducting an eight week longitudinal study to learn if blood levels of certain naturally occurring compounds and genetic markers differ between patients with depression and healthy adults who are not depressed, and if any such differences relate to memory performance, mood, and neurobiology. We are also interested in how the gut microbiome is affected by antidepressant treatment.

We will do this by comparing the unmedicated depressed patients with matched healthy controls at baseline and then following the depressed patients over the course of eight weeks of standardized antidepressant treatment to gauge which baseline abnormalities normalize over the course of treatment.

This study is intended to help develop new MRI imaging techniques for studying mood and anxiety disorders. Researchers believe that depression and anxiety disorders may cause structural and functional changes in the brain. This study will optimize the way MRI scans are collected to look at brain structure and examine how the brain behaves while subjects perform particular tasks. Healthy volunteers and individuals with major depressive disorder may be eligible for this study.

Participants undergo magnetic resonance imaging (MRI) and neuropsychological testing. : Individuals will be asked to participate in an MRI study on one of several scanners. The scanner used will measure blood flow in the brain, concentrations of certain chemicals in the brain, or magnetic properties of the brain. The scan may involve They watching a screen presenting images or doing a task in which they respond to pictures or sounds. Participants may be asked to return for additional scans.

The study also involves neuropsychological tests, which assess cognitive performance. Often, people with mood disorders have subtle changes in performance on these tests that allow researchers to pinpoint where brain abnormalities occur. Before the tests can be used in patients, they must be validated by using healthy subjects. These tests are presented either orally, in written form, or on a computer.

This study will examine how depression, anxiety, and migraine run in families. It will help in defining the risk factors for physical, mental, and health problems-as well as define ways that those problems may be prevented and treated.

A broad range of ages among family members will be included to evaluate the patterns of how these disorders are expressed throughout people's lives. Children of all ages will be included, and those ages 8 to 17 will be interviewed directly.

Assessments will be collected through criteria of the Diagnostic and Statistical Manual of Mental Disorders IV as well as the spectrum, or range, of mood disorders and co-existing conditions. A member of the study team will visit the participants at home or will do an interview by telephone. Participation will take approximately 3 to 4 hours. Children will complete questionnaires given by the research team as well as questionnaires that they will do by themselves. The questions will pertain to the children's health, including physical and mental health and medical history, social relationships, problems, skills, and ways of dealing with important or stressful issues in their lives. These questionnaires will take up to 1 hour to complete.

Health history gathered from adult participants will pertain to height, weight, exercise, and general function. Women will be asked about the use of oral contraceptives, estrogen, and progesterone. In addition, there will be questionnaires on personality and temperamental traits, that is, behavior and impulsiveness. Questions will also involve social intuition, family and other environmental factors, general functioning, and basic demographics such as ethnicity, race, socioeconomic status, marital status, education level, and employment history.

Families enrolled in this phase of the research will be invited to participate in the next phase. There would be follow-up to evaluate the development of mood disorders, subtypes, and syndromes across the lifespan.

The purpose of this study is to use brain imaging technology to examine brain changes that occur in children when they are exposed to various kinds of emotional tasks and to determine if these changes are related to the child's temperament.

Studies suggest that the risk for developing mood and anxiety disorders in preschool children may be linked to differences in temperament. The relationship between temperament and risk or resilience may reflect the influences of brain activity on behavior at different stages of childhood development. Behavioral inhibition and mood or anxiety disorders have been linked to disturbances in the circuitry of several areas in the brain. However, the involvement of this circuitry in temperament remains unclear. This study will use functional magnetic resonance imaging (fMRI) to examine the function of different parts of the brain in children who have previously undergone temperament studies and have had their temperaments classified.

Two sets of studies will be performed in the current protocol. A small set of pilot studies will be performed in infants, by staff at the University of Maryland. In terms of the studies among infants, these subjects will initially be contacted by staff at Maryland and then will be seen at the NIH for up to three visits lasting between 4- to 5- hours during the first year of life. These subjects also will undergo visits at the University of Maryland throughout the first year of life.

This study will comprise up to four clinic visits. At Visit 1, children and their parents will meet with study staff individually and together for psychiatric interviews. Children will undergo a physical examination, medical history, a urine drug test, and practice in an fMRI simulator. Saliva samples will be collected from the children and tests will be given to assess stage of puberty, temperament, intelligence, feelings, experiences, and behavior. Other visits include fMRI scans of the brain and other tasks.

This study seeks to learn more about the symptoms of severe mood dysregulation in children and adolescents ages 7-17. Children and adolescents with severe mood dysregulation (SMD) display chronic anger, sadness, or irritability, as well as hyperarousal (such as insomnia, distractibility, hyperactivity) and extreme responses to frustration (such as frequent, severe temper tantrums). Researchers will describe the moods and behaviors of children with these symptoms and use specialized testing and brain imaging to learn about the brain changes associated with this disorder.

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.

The purpose of this protocol is to allow for the careful screening of patients and healthy volunteers for participation in research protocols in the Experimental Therapeutics and Pathophysiology Lab (ETPB) at the National Institute of Mental Health (NIMH) and for the collection of natural history data. In addition the protocol will allow clinicians to gain more experience in the use of a variety of polysomnographic and high-density EEG recordings. Subjects in this protocol will undergo an evaluation which may include: a psychiatric interview; a diagnostic interview; rating scales; a medical history; a physical exam; brain magnetic resonance imaging (MRI); electroencephalography (EEG); electrocardiography (EKG), magnetoencephalography (MEG); blood, saliva and urine laboratory evaluation; and a request for medical records. Subjects may also be asked to complete questionnaires about attitudes towards research and motivation for research participation. The data collected may also be linked with data from other mood and anxiety disorder protocols (e.g., brain imaging, DNA, psychophysiology tests, treatment studies, etc) for the purposes of better understanding the diagnosis, pathophysiology, and treatment response of patients with mood disorders. Parents of minors will be interviewed. Upon conclusion of the screening process, subjects will either be offered participation in a research protocol and will sign the appropriate informed consent, or will be considered not appropriate for participation in research and will be referred back into the community. The current protocol thus serves as an entry point for individuals with mood or anxiety disorders or healthy volunteers to enter NIMH IRB approved ETPB protocols.

Determine whether postpartum depression is triggered by the abrupt withdrawal of estrogen and progesterone.

The appearance of mood and behavioral symptoms during pregnancy and the postpartum period has been extensively reported. While there has been much speculation about possible biologically based etiologies for postpartum disorders (PPD), none has ever been confirmed. Preliminary results from two related studies (protocols 90-M-0088, 92-M-0174) provide evidence that women with menstrual cycle related mood disorder, but not controls, experience mood disturbances during exogenous replacement of physiologic levels of gonadal steroids. The present protocol is designed to create a "scaled-down" hormonal milieu of pregnancy and the puerperium in order to determine whether women who have had a previous episode of postpartum major effective episode will experience differential mood and behavioral effects compared with controls and to determine whether it is the abrupt withdrawal of gonadal steroids or the prolonged exposure to gonadal steroids that is associated with mood symptoms. Supraphysiologic plasma levels of gonadal steroids will be established, maintained, and then rapidly reduced, simulating the hormonal events that occur during pregnancy and parturition. This will be accomplished by administering estradiol and progesterone to women who are pretreated with a gonadotropin releasing hormone (GnRH) agonist (Lupron). After eight weeks, administration of gonadal steroids will be stopped in one group of patients and controls, and a sudden decline in the plasma hormone levels will be precipitated. Another group will be maintained on supraphysiologic levels of estrogen and progesterone for an additional month. Outcome measures will include mood, behavioral and hormonal parameters (a separate protocol done in collaboration with NICHD).

This study looks to identify genes that may affect a person's chances of developing bipolar disorder (BP) and related conditions.

The purpose of this study is to identify and describe the symptoms of premenstrual syndrome (PMS).

Women who experience PMS symptoms will complete clinical interviews, self-rating scales, and evaluations of mood and endocrine function. A subgroup of women with severe PMS (Premenstrual Dysphoric Disorder or PMDD) will be offered additional research studies that focus on: 1) identifying the endocrine changes that may be responsible for changes in mood and behavior during the premenstrual period, 2) evaluating treatments for PMS symptoms, and/or 3) identifying genetic factors in women with and without PMS. Women with recurrent brief depression will also be recruited to serve as a comparison group.