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Emotional Cognition: Establishing Constructs and Neural-Behavioral Mechanisms in Older Adults With Depression (ENSURE)
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.
• Male and female participants
• Age between 21-80 years old
• DSM-5 diagnosis of major depressive disorder (MDD) based on Mini Neuropsychiatric Interview
• Inventory of Depressive Symptomatology-Clinician Rated version (IDS-C) total score > 14
• Able to read, write, and comprehend English
• Provide informed consent; willing to comply with study protocol
• History of bipolar disorder, schizophrenia, or schizoaffective disorder
• Presence of psychotic features
• Lifetime central nervous system (CNS) disease (including head injury with loss of consciousness > 5 minutes)
• History of neurodevelopmental disorder (e.g., Autism spectrum disorder)
• History of medical conditions that can affect neurocognitive function as well as be confounded with age (e.g., thyroid disease, endocrine illnesses)
• History and current use of hormonal replacement therapy
• Women who are pregnant
• Current use of medications with known impacts on neurocognitive function (e.g., acetylcholinesterase inhibitors, amphetamine, methylphenidate, vortioxetine, sedatives)
• Alcohol/substance use disorder within past 3 months
• DSM-5 diagnosis of major cognitive impairment
• Current sensory or physical impairment that interferes with testing.
• Contraindication to MRI and MEG (only for depressed participants) (e.g., any electronic / metallic implants near or within the head or body, claustrophobia)
Obesity and OSA in Pregnancy
The purposes of this project are 1) to compare the impact of maternal obesity versus excessive gestational weight gain on obstructive sleep apnea (OSA) in obese and non-obese women; 2) to investigate the mechanism(s) by which obesity and OSA increase cardiovascular risk during pregnancy; and 3) to identify biomarker(s) for obesity-related OSA in pregnant women.
• Both obese and non-obese (normal weight) early pregnant women aged ≥18 years old will be permitted to participate in this project.
• No restriction with respect to race and socioeconomic status
• Women with a prior history of complicated pregnancy (i.e., gestational hypertension, preeclampsia, HELLP syndrome, gestational diabetes, preterm birth, intrauterine growth restriction, etc.) will be allowed to participate.
• Obese women with previously diagnosed OSA will be allowed to participate if they are not currently on any recognized treatments such as Continuous Positive Airway Pressure (CPAP), oral appliances or nasal expiratory positive airway pressure.
• Those who have had surgery for OSA in the past will be excluded.
• Women taking low-dose aspirin will be allowed to participate in this project.
• Current multiple pregnancy;
• Known major fetal chromosomal or anatomical abnormalities;
• Recurrent miscarriage (three or more);
• Chronic essential hypertension (systolic BP >140 mmHg and/or diastolic BP >90 mmHg);
• Any evidence of cardiovascular and pulmonary diseases by history or by physical examination;
• Kidney disease (serum creatinine >1.5 mg/dL);
• Coagulation disorders;
• Diabetes mellitus (fasting glucose ≥126 mg/dL or 2-hour oral glucose tolerance test glucose level ≥200 mg/dL) or other systemic illness;
• Any evidence of neurological disease;
• Psychiatric disease or psychological disorders;
• History of drug or alcohol abuse within the last 2 years; and
• Given the effects of exercise training on sympathetic neural control, endurance-trained athletes will be excluded. As this project focuses on sleep apnea in pregnancy, Women with other significant sleep disorders such as restless legs syndrome by Rest Leg Syndrome Diagnostic Index and insomnia by the Insomnia Severity Index or Pittsburgh Sleep Quality Index will be excluded; In addition, women who report taking a sleeping aid >1 time per month will be excluded.
A Research Study to See How Semaglutide Helps People With Excess Weight and Type 2 Diabetes Lose Weight
This study will look at how much weight participants will lose and how much blood sugar control they achieve from the start to the end of the study. The weight loss in participants taking the investigational high dose of semaglutide will be compared to the weight loss in people taking "dummy" medicine and a lower dose of semaglutide. In addition to taking the medicine, participants will have talks with study staff about healthy food choices and how to be more physically active. Participants will either get semaglutide or "dummy" medicine. Which treatment participants get is decided by chance. Participants are more likely (4 out of 5) to get semaglutide than the "dummy" medicine. The study medicine will be injected briefly, under skin, with a thin needle, typically in the stomach, thighs, or upper arms. After receiving first dose, the dose of semaglutide will be gradually increased until reaching the target dose. The study will last for about 1.5 years.
• Male or female.
• Age above or equal to 18 years at the time of signing informed consent.
• BMI greater than or equal to 30.0 kilograms per square meter (kg/m^2).
• Diagnosed with type 2 diabetes (T2D) greater than or equal to 180 days prior to the day of screening.
• History of at least one self-reported unsuccessful dietary effort to lose body weight.
• HbA1c 7.0-10.0 percent (53-86 millimoles per mole [mmol/mol]) (both inclusive) as measured by central laboratory at screening.
• A self-reported change in body weight greater than 5 kilograms (kg) (11 pounds [lbs]) within 90 days before screening irrespective of medical records.
• Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
• Renal impairment with estimated Glomerular Filtration Rate (eGFR) less than 30 milliliters per minute per 1.73 square meter (30 mL/min/1.73 m^2) (less than 45 mL/min/1.73 m^2 in participants treated with Sodium-glucose Cotransporter-2 [SGLT2i]) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation as defined by Kidney Disease: Improving Global Outcomes (KDIGO) 2012 by the central laboratory at screening.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within 90 days before screening or in the period between screening and randomization. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.
Cognitive Outcomes of Brain Stimulation As a Later-in-Life Treatment (COBALT)
This is a pilot study being done to attempt to improve episodic memory problems in persons with mild cognitive impairment (MCI) or dementia. The pre-supplemental motor area (preSMA) and dorsal anterior cingulate cortex (dACC) have been shown to play a role in episodic memory and language retrieval. Prior studies have suggested that neurostimulation targeting this region can improve episodic memory and word recall. The purpose of this study is to examine the efficacy of high-definition transcranial direct current stimulation (HD-tDCS) to the preSMA/dACC region and its influence on word retrieval and other cognitive functions in patients with MCI or dementia. Entraining the preSMA/dACC circuit with 10 sessions of HD-tDCS will allow us to study whether neurostimulation may be an effective treatment.
Pathways Relating Amnestic MCI to a Mild Traumatic Brain Injury History (PATH)
This study will probe if the biological changes in amnestic mild cognitive impairment (aMCI) are related to a history of mild traumatic brain injury (mTBI) using high definition transcranial direct current stimulation (HD-tDCS) and blood-derived biomarker tools. Participants who Do as well as those who Do Not have a history of mTBI will be enrolled in the study.
• Active diagnosis of amnestic mild cognitive impairment
• Presence of an mTBI history for the mTBI+ group; absence of an mTBI history for a control sample
• Female and male subjects
• All races/ethnicities
• Age 55 years and older
• Fluent in English
• Mild traumatic brain injury within past year
• Lifetime history of moderate or severe brain injury
• Lifetime major neurologic syndromes (e.g., stroke, epilepsy, brain tumor)
• Lifetime major cardiovascular conditions (e.g., heart attack, heart failure)
• Current substance use disorder
• Current major psychiatric disorders (e.g., major depressive disorder, bipolar disorder)
• Current vision or hearing impairment that interferes with testing
• Any electronic and or metallic implants in the skull or brain
• Current medication use known to alter HD-tDCS reactivity
Noninvasive Brain Stimulation in Mild Cognitive Impairment and Dementia
The research objective of this study is to examine the efficacy of HD-tDCS to the preSMA/DACC region and its influence on verbal episodic memory in patients with MCI or dementia after 10 sessions of HD-tDCS. There will be three treatment arms: two active HD-tDCS (1 mA or 2 mA) and a sham group. A verbal episodic memory task will be completed at baseline, immediately following the last HD-tDCS session, and a 2-month follow-up.
• Age 50 and older
• Fluent in English
• Active diagnosis of MCI or dementia
• Substance use disorder
• Has metal fragments in head
• Taking medications that may interact with the HD-tDCS effect (i.e., amphetamines, L-dopa, carbamazepine, sulpiride, pergolide, lorazepam, dextromethorphan, D-cycloserine, flunarizine, or ropinirole)
Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL (IDEAL2)
This study is for older children, adolescents, and young adults with B-cell Acute Lymphoblastic Leukemia (B-ALL). Higher amounts of body fat is associated with resistance to chemotherapy in patients with B-ALL. Chemotherapy during the first month causes large gains in body fat in most people, even those who start chemotherapy at a healthy weight. This study is being done to find out if caloric restriction achieved by a personalized nutritional menu and exercise plan during routine chemotherapy can make the patient's ALL more sensitive to chemotherapy and also reduce the amount of body fat gained during treatment. The goals of this study are to help make chemotherapy more effective in treating the patient's leukemia as demonstrated by fewer patients with leukemia minimal residual disease (MRD) while also trying to reduce the amount of body fat that chemotherapy causes the patient to gain in the first month.
• Patients must be ≥ 10.0 and <26.0 years of age.
• Patients must have a diagnosis of de novo B-ALL
• Patients must have a M3 marrow (>25% blasts by morphology) or at least 1,000/µL circulating leukemia cells in PB confirmed by Flow Cytometry (or other convincing evidence of a B-ALL diagnosis not meeting above criteria following central review by the Study Hematopathologist and Study Chair or Vice-Chair).
• The treatment regimen must be the first treatment attempt for B-ALL-
• Must be a multi-agent induction regimen inclusive of vincristine, glucocorticoid, pegaspargase/calaspargase, and daunorubicin or doxorubicin and with a planned duration <35 days.
• Organ function must meet that required for initiation of chemotherapy
• Patients at diagnosis must meet Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age (or be expected to recover prior to Day 8) .
• If the patient is a female of childbearing potential, a negative urine or serum pregnancy test is required within two weeks prior to enrollment.
• Patient will be excluded if they are underweight at time of enrollment (BMI% <5th percentile for age for patients age 10-19 years, BMI <18.5 in patients 20-29 years).
• Patients with Down syndrome or a DNA fragility syndrome (such as Fanconi anemia, Bloom syndrome) will be excluded.
• Patient receiving a SJCRH-style "Total Therapy" regimen will be excluded.
• Patients receiving anti-CD20 monoclonal antibody therapy during induction therapy.
• Patients will be excluded if they received treatment for a previous malignancy.
• Patient will be excluded if they are pregnant.
• Patient will be excluded if they have a pre-diagnosis requirement for enteral or parenteral supplementation .
• Patient will be excluded due to inability to perform the intervention (e.g., specific nutritional needs, severe developmental delay, paraplegia)
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results
Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel Therapeutic Targets (UNIKET)
The study is investigating dysfunctions in neurocircuitry in regards to irritability with healthy controls (HC) and individuals with Major Depressive Disorder (MDD) by performing MRIs. The MDD group will also be randomized to receive ketamine or midazolam to investigate changes post-treatment in neurocircuitry with regards to irritability.
• Male or female subjects, 18-65 years of age and body weight less than or equal to 120 kg on baseline visit.
• Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.
• For Healthy Controls: Subjects must be free of any lifetime psychiatric condition based on the Mini-International Neuropsychiatric Interview (MINI). For MDD: Subjects must meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for current unipolar depression [major depressive disorder (MDD) or persistent depressive disorder (PDD) in a current major depressive episode (MDE)] based on MINI.
• A woman of childbearing potential who is sexually active with a male must agree to use an acceptable method of contraception [defined as either one highly effective (permanent sterilization, intrauterine device or hormonal implant) or two other forms of contraception (such as oral contraceptive pill and condom)] to avoid pregnancy throughout the study. Throughout the study and for 90 days (one spermatogenesis cycle) after receiving the last dose of study drug (ketamine/midazolam) man who is sexually active with a woman of childbearing potential must use an acceptable method of contraception (described above) with his female partner and must agree not to donate sperm.
• Subjects must either be free of psychotropic medications (including antidepressants, antipsychotics, benzodiazepines, mood stabilizers, sedative/hypnotics, dopamine agonists, stimulants, buspirone, and triptans) and certain anticonvulsants (topiramate and levetiracetam) or be stable on these medications for four weeks prior to the baseline visit [first magnetic resonance imaging (MRI) scan].
• Subjects with MDD should be willing to participate in neuroimaging scans before and after infusions, and be willing to undergo infusions with study drug.
• Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, pervasive developmental disorder or intellectual development disorder.
• Current diagnosis of obsessive-compulsive disorder, anorexia nervosa or bulimia. Comorbid anxiety, stress and trauma-related disorders are permitted as long as unipolar depression is the primary diagnosis.
• Diagnosis of a moderate or severe substance use disorder within the past 6 months per MINI; all subjects must have a negative urine toxicology test on the day of the MRI, prior to the scan.
• Female subjects who are pregnant, nursing, for may become pregnant. Women of childbearing potential must have a negative urine pregnancy test on the day of the fMRI, prior to scan, and on days of study drug infusion, prior to infusion.
• Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, immunologic, or hematologic disease.
• Inadequately treated obstructive sleep apnea (STOP-Bang score of 5-8 if untreated, if using positive airway pressure device then past-month apnea hypopnea index ≥ 15 per hour representing moderate or higher severity).
• Presence of a significant neurological disease such as Parkinson's disease, primary or secondary seizure disorders, intracranial tumors, or severe head trauma.
• Presence of neurocognitive or dementing disorders.
• Clinically significant abnormalities of laboratories, physical examination (including unstable hypertension - systolic blood pressure >170, diastolic blood pressure >100), or electrocardiogram at screening visit.
• Subjects judged to be at serious and imminent suicidal or homicidal risk by the PI or another study-affiliated psychiatrist.
• Any contraindications to MRI, including pacemakers or metallic objects in the body.
• Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more.
• Allergy to ketamine or midazolam in subjects with MDD.
• Must not be on any prohibited concomitant medication.
Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia
The 2020 NIMH Strategic Plan for Research calls for investigations targeting neurobiology of mental illness across the lifespan. Growing evidence suggests that lifespan neurobiology of schizophrenia (SZ) incorporates two distinct dimensions: aging and disease course. However, their clinical correlates, associated biomarker trajectories, and implications for treatment are unknown. This study will investigate differential aspects of SZ neurobiology captured by aging and disease course, in order to develop specific biomarkers which may offer actionable targets for SZ stage-dependent intervention. The study is predicated on a novel mechanistic Model of SZ Trajectories across the Adult Lifespan, positing distinct biological fingerprints within the anterior limbic system for aging and disease course in SZ: (1) alterations in the circuit's function and structure that occur earlier in the lifespan and are larger in magnitude than the alterations expected with normal aging (accelerated aging dimension); and (2) regionally-specific anterior limbic "hyperactivity" in early SZ, with a subsequent transformation into "hypoactivity" in advanced SZ (disease course dimension). In a sample of SZ and matched healthy controls (n=168, 84/group) aged 18-75 years the investigators will ascertain a broad panel of biomarkers [via multimodal brain imaging: optimized 1H-MRS, high-resolution task-based fMRI, perfusion (Vascular Space Occupancy) and structural MRI], along with comprehensive cognitive and clinical assessments. All measures will be acquired at baseline and repeated at 2-year longitudinal follow-up. Using cutting-edge computational approaches, the study will examine (i) effects of aging and SZ course on anterior limbic system biomarkers; (ii) lifespan trajectories for different biomarkers; (iii) patterns of limbic system biomarkers in age- and SZ course-based subgroups (e.g., Younger vs. Older, Early-Course vs. Advanced SZ), as well as in data-driven subgroups (e.g., those with vs. without accelerated aging profiles); and (iv) associations between biomarkers and cognitive and clinical outcomes. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan and development of precision treatments.
• 18-65 years of age (SZ); 18-75 years of age (CON)
• Women and men
• All races and ethnicities
• Psychiatric diagnoses: Patient participants (SZ): Meet DSM-5 criteria for schizophrenia or schizoaffective disorder Healthy control participants (CON): No personal history of lifetime psychiatric disorders, or a family history of psychotic disorders in 1st-or 2nd- degree relatives
• Able to read, speak, and understand English
• Able and willing to provide written informed consent; and willing to commit to the study protocol, including 2-year longitudinal follow-up
• Neurological or medical disorder that may affect brain function (history of stroke, head injury with a loss of consciousness >10 min, seizure disorder, AIDS, poorly controlled hypertension, poorly controlled diabetes, decompensated lung disease, etc.)
• Co-morbid DSM-5 diagnosis of drug/alcohol use disorder in prior 3 months
• Current treatment with benzodiazepine or non-benzodiazepine sedatives/hypnotics, and/or anticonvulsants
• Presence of ferromagnetic objects in body
• Weight or body size exceeding MRI scanner capacity [>300 lbs]
• Claustrophobia in MRI scanner
• Pregnant women
• Breastfeeding women (VASO scan will not be administered. All other imaging modalities are safe to administer.)
• Impaired kidney function: Glomerular Filtration Rate (GFR) < 30 ml/min/1.73m2 (VASO scan will not be administered due to an association between Gadolinium-based MR contrast use and Nephrogenic Systemic Fibrosis in individuals with severely impaired renal function. All other imaging modalities are safe to administer.)
• History of hypersensitivity to any MRI contrast agent (VASO scan will not be administered. All other imaging modalities are safe to administer.)
A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adolescents With Major Depressive Disorder Who Have an Inadequate Response to Selective Serotonin Reuptake Inhibitor (SSRI) and Psychotherapy
The purpose of this study is to assess the safety and tolerability of Seltorexant as adjunctive therapy to an antidepressant in adolescents with major depressive disorder (MDD) in the short-term compared with placebo.
• Has inadequate response to trial of at least 1, but no more than 2 antidepressant treatments during the current major depressive episode including their current antidepressant fluoxetine or escitalopram (SSRI). Inadequate response is determined as less than (<) 50 percentage (%) symptom reduction after adequate antidepressant treatment for at least 6 weeks at or above the minimum therapeutic dose prior to screening
• Has had access to adequate psychotherapy in the current depressive episode (based on investigator judgement/local guidance) prior to randomization
• Must have Children's Depression Rating Scale-Revised (CDRS-R) total score greater than or equal to (>=) 48 at screening and >=40 at the baseline visit
• Participants weighing between fifth and ninety-fifth percentile for age and sex. Obese participants greater than ninety-fifth percentile and underweight participants below fifth percentile may participate following medical clearance, as long as their baseline weight is >=30 kilograms (kg)
• A female participant of childbearing potential must have a negative urine pregnancy test at screening and baseline
• Has a history of liver or renal insufficiency, significant cardiac (example, congenital heart disease, cardiomyopathy, or tachyarrhythmias), vascular, pulmonary, gastrointestinal, endocrine (including uncontrolled hyperthyroidism), neurologic (including seizure disorder), hematologic, rheumatologic, psychiatric, or metabolic disturbances. Stable medical conditions are allowed
• Has current the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) diagnosis of conduct disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, somatoform disorders, or fibromyalgia. A prior history of one or more of these disorders is allowed as long as the disorder(s) are currently stable and major depressive disorder (MDD) is not secondary to the original diagnosis. Has a current or prior DSM-5 diagnosis of a psychotic disorder, or bipolar disorder
• Has a significant primary sleep disorder (example, obstructive sleep apnea, parasomnias) at screening but participants with insomnia or hypersomnia disorders are allowed
• At significant risk of committing suicide based on history or according to the investigator's experience, or based on active suicidal ideation, intent or plan, item 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) within the past 3 months or a history of suicidal behavior within the last 6 months
• Has known allergies, hypersensitivity, or intolerance to seltorexant or its excipients
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating loss of appetite in patients with cancer that has spread to other places in the body (advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and preventing weight loss.
• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the "Please rate your appetite…." question that requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
• Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the past month
• Patient should not have poorly controlled hypertension or congestive heart failure at registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
• Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Fasting glucose < 140 mg/dL
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)
Characterizing Inflammatory Profiles and Suicidal Behavior in Adolescents
Despite increasing suicide rates in adolescents, there remains a paucity of approaches to use to prevent re-attempts. Any hope for breaking the code to prevent youth suicide lies in understanding biological factors that play a role. Evidence suggests that inflammation and immune system dysfunction may be linked to suicide. The investigators will develop immune profiles for adolescents with suicidal behavior and those at risk in order to develop tools that can be implemented for prevention efforts. This study involves blood draws, answering questions, and completing questionnaires - no treatment or intervention is provided as part of this study. Participants will be screened to see if they qualify for this study using questionnaires. Participants will be teens (ages 12-18 years) with recent suicidal behavior, teens at-risk for developing depression, and healthy control teens. Participants complete all study-related tasks four times over a period of 12 months. Electronic surveys will be sent to participants to complete monthly. Both the adolescent and if applicable, their parent (or legally authorized representatives, LARs), will answer questions regarding depression, anxiety, and suicidal thoughts/behaviors.
• Be adolescents (aged 12-18 years);
• Have the ability to speak, read, and understand English. The parent(s) or legal guardians of minors must also speak, read and understand English;
• Be willing to provide consent/assent. Consent will be provided by parents/LAR/guardian for youth under age 18 or by young adult participant, aged 18. Youth, aged 8-17, must be willing to provide assent;
• Have the ability to complete clinical evaluations and self-report measures;
• Meet criteria for one of these three groups:
• Adolescent with suicidal behaviors, defined as having a recent (within 3 months) suicide attempt or suicidal ideation warranting urgent evaluation;
• Adolescents at risk for mood disorders, defined by either personal history of anxiety disorder or substance use disorder or a history of trauma, or a first degree relative with a history of a mood disorder or suicidal history;
• Healthy adolescents with no lifetime history of any psychiatric or substance use disorders or a history of trauma. Additionally, no first-degree family member with a history of a mood disorder or suicidal history.. Exclusion Criteria Study participants must not:
• Have current poorly controlled asthma, acute/chronic infection or other medical condition(s) that may affect immune marker levels;
• Have a current medication (e.g., corticosteroids) that may affect immune marker levels of reactivity;
• Have any condition for which, in the opinion of the investigator or designee, study participation would not be in their best interest (including but not limited to cognitive impairment, unstable general medical condition, intoxication, active psychosis) or that could prevent, limit, or confound the protocol-specified assessments;
• Be unable to provide a stable home address and contact information
A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression
The purpose of this study is to evaluate the efficacy of each individual dose of esketamine nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving depressive symptoms in participants with treatment resistant depression (TRD), as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).
• Participant must meet the Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for single-episode MDD or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI. Participants 65 years of age or older must have had the first onset of depression prior to 55 years of age
• Participant must have had nonresponse (<=25% improvement) to >=2 oral antidepressant treatments in the current episode of depression, assessed using the MGH-ATRQ, and confirmed by documented records (example, medical/pharmacy/prescription records or a letter from a treating physician)
• Participant must have an Inventory of Depressive Symptomatology-Clinician rated, 30-item (IDS-C30) total score of >=34
• The participant's current major depressive episode, depression symptom severity, and antidepressant treatment response in the current depressive episode, must be confirmed by the State vs. Trait, Assessibility, Face Validity, Ecological Validity, Rule of Three P's (SAFER) Interview
• Participant must be medically stable on the basis of physical examination, medical history, vital signs (including blood pressure), and 12-lead electrocardiogram (ECG) performed in the screening phase. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, the determination of their clinical significance must be determined by the investigator and recorded in the participant's source documents and initiated by the investigator
• Participant must be medically stable on the basis of clinical laboratory tests performed in the screening phase. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator: (a) Participants with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones must be on a stable dosage for 3 months prior to the start of the screening phase; (b) For any participant (regardless of thyroid history), if the thyroid-stimulating hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. If the FT4 value is abnormal and considered to be clinically significant (after discussion with the medical monitor), the participant is not eligible
• Participant must be comfortable with self-administration of nasal spray medication and be able to follow the nasal spray administration instructions provided
• The participant has used ketamine/esketamine (lifetime)
• The participant's depressive symptoms have previously demonstrated nonresponse to an adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
• Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression
• Participant has a current or history of seizures (uncomplicated childhood febrile seizures with no sequelae are not exclusionary)
• Participant has any anatomical or medical condition that, per the investigator's clinical judgment based on assessment, may impede delivery or absorption of nasal spray study drug
Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents
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.
• Be adolescents (aged 13-18 years);
• Have had a recent suicidal event (suicide attempt or significant suicidal ideation with a plan or intent warranting emergency evaluation or inpatient hospitalization within the past 90 days);
• Receiving standard of care treatment that includes clinically indicated psychosocial and/or psychopharmacological treatment;
• Have a current primary diagnosis of a depressive disorder based on the MINI-KID (other psychiatric disorders are acceptable, but must not be primary);
• Both participants and their designated caregiver must be able to complete assessments in English, as the rating scales vital to study efficacy and safety evaluations have not been validated in Spanish. (NOTE: Most potential participants ages 13 to 18 years old, as well as most of their parents, have a good working knowledge of English);
• Use effective method of contraception during and for 90 days following the end of treatment for female and male participants. Recommended methods of birth control are namely, consistent use of an approved hormonal birth control (pill/patches, rings), an intrauterine device (IUD), contraceptive injection, double barrier methods, sexual abstinence, or sterilization; Exclusion Criteria Study participants must not:
• Have a psychotic disorder, such as lifetime schizophrenia, or a pervasive or intellectual developmental disorder requiring substantial or very substantial support;
• Have current mania, hypomania, mixed episode, or obsessive-compulsive disorder;
• Have a primary diagnosis other than a depressive disorder;
• Have moderate to severe alcohol or substance use disorder within the past six months (based on MINI-KID); If there is a positive urine drug screen at screening, the urine drug screen will be repeated at each infusion visit. Positive urine drug screen will be reviewed by study physician and infusion will proceed as long as no safety risk was identified;
• If female, be pregnant, lactating, or nursing; Women of childbearing potential must have a negative urine pregnancy test prior to all infusions;
• Have unstable medical conditions (stable for less than 3 months) or with clinically significant laboratory values or an electrocardiogram (ECG) that would pose significant risk;
• Be at serious suicidal risk that cannot be managed in the outpatient setting;
• Have prior treatment for depression with or contraindications to ketamine, esketamine, or, midazolam;
• Treatment with medications that may alter pharmacokinetics of ketamine, including moderate-to-strong inhibitors or inducers of CYP3A4 and CYP2B6, is exclusionary. Regarding pharmacodynamic interactions, medications that may increase heart rate or blood pressure such as the ADHD stimulant medications will be permitted with last dose at least 24 hours prior to infusion. All concomitant medications will be evaluated by the study physician to determine if the type and dose of concomitant medication requires discontinuation and will be excluded if the concomitant medication could substantially increase the risk of study infusion. A complete list of medications that are Not Allowed is available in Appendix D of the protocol. The study team will not ask the participant to discontinue any treatment (except for not taking ADHD medications for 24 hours before study treatment) just for the sake of taking part in this study;
• Weigh >120 kilograms at baseline. If participants are enrolled but exceed 120 kilograms at any time during the treatment period, they will be removed from the treatment portion of the study.
Youth Depression and Suicide Research Network (YDSRN)
The objective of this study is to build the Texas Youth Depression and Suicide Research Network to support the development of a Network Participant Registry and characterization of systems and interventions to examine statewide population health outcomes. All 12-13 sites represented in the Texas Child Mental Health Care Consortium (https://www.utsystem.edu/pophealth/tcmhcc/) have been invited to participate in the Texas Youth Depression and Suicide Research Network as "Nodes." 12 Nodes have been selected for this project. Each Node has obtained support of senior institutional leadership including the department chair. Leadership from each Node provided input and edits in the study design process by committee, with a focus on the inclusion of the "end user" in design decisions. Nodes will work closely with the Network Hub leadership to recruit, monitor, and retain participants. This will require active engagement and sustained relationships with clinics within the academic medical center as well as clinics in the community (i.e., psychiatry, psychology, counselling).
• Be 8 to 20 years of age;
• Have a positive screen for depression (e.g., based on PHQ-2 (score ≥3) and/or PHQ-A of 10 or greater, OR positive for suicidal ideation or behavior (e.g., based on CHRT-SR or PHQ-A item 9); OR be in treatment for depression;
• Be willing to provide consent/assent (parents/LAR/guardian or young adult participant, aged 18-20, must be willing to provide consent; youth, aged 8-17, must be willing to provide assent);
• Be able to speak English or Spanish sufficiently to understand the study procedures and provide written informed consent to participate in the study;
• Be willing to dedicate appropriate time to complete scheduled study assessments and measures (both parent/LAR/guardian and youth).
• Be able to provide a reliable means of contact.
• Have an acute medical or psychological condition(s) that that would, in the judgment of the study medical clinician, make participation difficult or unsafe;
• Have an acute medical or psychological condition(s) that would result in an inability to accurately complete study requirements (e.g., neurological conditions or significant neurodevelopmental concerns);
• Have active psychotic symptoms resulting in altered mental status and inability to provide assent or requiring immediate attention and/or higher level of intervention;
• Have a parent/LAR/guardian who is deemed cognitively unable to provide consent (if youth participant, aged 8-17).
Combination of Novel Therapies for CKD Comorbid Depression (CONCORD)
The overall goal of the study is to determine if treatment of a Major Depressive Disorder (MDD) improves the outcomes of patients with chronic kidney disease (CKD). We showed that MDD is present in 25% of CKD patients and independently associated with progression to End-Stage Kidney Disease, hospitalization, and death. Depression is also associated with lower quality of life (QOL), fatigue, poor sleep, and non-adherence to diet and medications. However, evidence for efficacy and tolerability of commonly-used antidepressant medications or nonpharmacologic treatments are limited in CKD patients. Our group was the first to conduct a double-blind randomized controlled trial for MDD treatment in 201 patients with non-dialysis CKD, and showed that sertraline, a commonly used selective serotonin reuptake inhibitor (SSRI), was no more efficacious than placebo for improving depressive symptoms. It becomes imperative to test novel strategies to treat MDD in CKD. We propose to compare with a control group, the efficacy and tolerability of two novel treatment strategies - (1) Behavioral Activation Teletherapy (BAT) for 16 weeks, with the addition of bupropion, a non-SSRI antidepressant, at 8 weeks for patients whose depression has not remitted (non-remitters); and (2) bupropion for 16 weeks, with the addition of BAT at 8 weeks for non-remitters. In Aim 1, we will investigate the efficacy and tolerability of these 2 strategies vs. control for improvement in a primary endpoint of depressive symptoms in 201 patients (67 per group) with non-dialysis CKD stages 3b-5 and MDD at 2 sites, randomized 1:1:1 to either strategy or a control group of Clinical Management plus placebo. We hypothesize that either approach vs. control will result in a minimal clinically important difference of 2 points improvement in depressive symptoms, as ascertained blindly by the Quick Inventory of Depressive Symptomatology. In Aim 2 we will investigate the efficacy and tolerability of 8 weeks of (1) single-blind BAT plus placebo or (2) double-blind bupropion plus Clinical Management vs. control for improvement in depressive symptoms. In Aim 3, we will compare the efficacy of these 2 treatments strategies vs. control for improvement in CKD patient-centered outcomes including a. adherence to medications and healthcare visits; b. fatigue; c. sleep; and d. overall functioning. A clinical trial is urgently needed to address the evidence gap that exists for MDD treatment in CKD patients.
• Male or female adults aged 18 years or greater. There will be no upper age limit.
• Presence of CKD stages 3b, 4 or non-dialysis stage 5, with an estimated glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 for a period of at least 3 months, as defined by the National Kidney Foundation and determined using the four-variable Modification of Diet for Renal Diseases Study formula.
• Presence of a current Major Depressive Disorder (MDD) based on MINI DSM IV-based criteria
• Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR) score of ≥11 at enrollment and ≥11 on QIDS-Clinician Rated (QIDS-C) at randomization.
• Able to understand and sign informed consent after the nature of the study has been fully explained
• Kidney transplant patients that are at least 6 month post-transplantation (3 months post-transplant, with at least another 3 months to confirm eGFR <45)
• Unable to understand or give informed consent.
• Unwilling or unable to participate in the protocol or comply with any of its components
• Receiving chronic dialysis
• Significant hepatic dysfunction or liver enzyme abnormalities 3 times or greater than the upper limit of normal
• Terminal chronic obstructive pulmonary disease or cancer
• Presence of seizure disorder
• Current use of class I anti-arrhythmic medications (such as 1C propafenone and flecanide), pimozide, MAO inhibitors, reserpine, guanethidine, cimetidine, or methyldopa; tri-cyclic anti-depressants, neuroleptics, or anti-convulsants
• Use of serotonergic drugs or supplements such as triptans, tramadol, linezolid, tryptophan, and St. John's Wort.
• Use of medications known to cause QT prolongation on EKG
• Ongoing use of antidepressant medications for depression treatment
• Past treatment failure on bupropion
• Initiation of depression-focused psychotherapy in the 3 months prior to study entry
• Active alcohol or substance abuse or dependence that requires acute detoxification at study entry
• Present or past psychosis or Bipolar I or II disorder
• Dementia or a Mini-Mental State Examination score <23
• Active suicidal intent
• Pregnancy, lactation, or women of childbearing potential not willing to use adequate contraception
Metformin in Alzheimer's Dementia Prevention (MAP)
MAP will be a multisite phase II/III 1:1 randomized controlled trial (RCT) of long acting metformin (reduced mass Glucophage XR) vs. matching placebo in 326 men and women with early and late aMCI, without diabetes, not treated with metformin, overweight or obese, aged 55 years to 90 years. The RCT will last 18 months and have 4 visits: baseline, 6-months, 12-months, and 18-months. The RCT will be preceded by a screening phase followed by randomization and a titration period in which drug/placebo will be titrated from 500 mg a day (one tablet) to 2,000 mg a day (4 tablets), in increments of 500 mg (one tablet) every 10 days. Participants will remain in the RCT on the tolerated dose, and included in analyses on an intent to treat basis. We expect the attrition rate to be 10%/year. Neuropsychological battery, clinical interviews, physical exam, and phlebotomy will be conducted at baseline and every 6 months. Brain MRI will be conducted in approximately half of the participants (186) twice, at baseline, and after the last study visit at month 18. We will also conduct brain amyloid Positron Emission Tomography (PET) using 18F-Florbetaben, and tau PET using 18F-MK6240 in half of the participants at baseline and end of the RCT. The primary clinical outcome of the study will be changes in the Free and Cued Selective Reminding Test. The secondary clinical outcome will be changes in the Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite. Secondary subclinical outcomes will be changes in cortical thickness AD signature areas, changes in white matter hyperintensity volume, changes in brain amyloid burden, changes in brain tau burden, and changes in plasma biomarkers of amyloid, tau, and neurodegeneration. The data coordinating center and Imaging Core is located at John Hopkins University. The PET coordinating center is located at UC-Berkeley. The Clinical Coordinating and Monitoring Center and the central laboratory will be located at Columbia. The Research pharmacy function will be shared by the University of Rochester, which will dispense randomization kits, and the University of Iowa, which will receive bulk metformin and identical matching placebo from EMD Serono.
• Participants must have subjective memory concern reported by participant, study partner, or clinician.
• A mini-mental state exam between ≥ 22 for subjects with more than 8 years of education. For subjects with less than 8 years of education, a MMSE ≥ 20 will be allowed.
• Clinical Dementia Rating 0.5. The memory box score must be at least 0.5.
• General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit.
• Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised.
• For early MCI:
• 9-11 for 16 or more years of education
• 5-9 for 8-15 years of education
• 3-6 for 0-7 years of education
• For late MCI
• ≤ 8 for 16 or more years of education
• ≤ 4 for 8-15 years of education
• ≤ 2 for 0-7 years of education
• Age range: 55 years to 90 years.
• Sex distribution: all eligible men and women will be included and no one will be excluded because of gender.
• Languages: fluent in English or Spanish. We have reliable, well-validated Spanish tests for all outcome measures.
• Participants without a known history of diabetes. If diabetes is diagnosed during screening (hemoglobin A1c of 6.5 % or greater) they will also be excluded. The main justification for this exclusion is the potential for these participants to be placed on other diabetes medications that may confound our study.
• General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-V criteria.
• Vision and hearing must be sufficient for compliance with testing procedures.
• Must have an informant to come to all appointments or be available by telephone at follow-up visits. Study Partner Inclusion Criteria
• The study partner can provide an independent evaluation of functioning for a person enrolled in the MAP study as a participant
• The study partner agrees to attend study visits with the MAP participant or be available by telephone.
• Use of metformin for any indication.
• Body mass index < 20 k/m2.
• Metformin is contraindicated in persons with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min. For persons with an eGFR of 30 to 45 mL/min, a reduction of the dose or discontinuation of the medication is recommended for those on metformin; in this range, it is also recommended that persons do not initiate metformin. Thus, participants with eGFR < 45 mL/min will not be eligible to participate.
• The risk of lactic acidosis is increased in persons with liver disease and class III or IV congestive heart failure. Thus, persons with liver disease other than non-fatty liver disease (e.g., cirrhosis) or class III or IV congestive heart failure will not be eligible to participate due to the risks of side effects.
• A history of intolerance to metformin used for indications other than diabetes.
• History of cerebrovascular accident with residual neurological deficits.
• Moderate to severe depression, indicated by a score in the Geriatric Depression Scale of 9/15 or higher.
• Dementia diagnosis
• Lack of capacity to consent
• Participants with neurologic diseases associated with neurologic deficits on clinical examination.
• Participants with other current Axis I psychiatric diagnoses such as bipolar disorder or schizophrenia.
• Alcohol or substance abuse or dependence in the past 6 months.
• Use of medications rated as being the likely cause of cognitive impairment. These include benzodiazepines in dose equivalents greater than 2 mg daily of lorazepam, and regular use of prescription narcotics.
• Normal individuals without cognitive complaints.
• Participants with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg).
• Participants with active cancer or a history of cancer within the last two years, with the exception of squamous or basal cell carcinoma of the skin.
• Participants who for any reason may not complete the study as judged by the study physician.
• Participants planning to move to another city or state within the next 24 months.
• Participants with a known history of diabetes. The rationale for this exclusion is persons with diabetes may already be on metformin or on other medications that increase insulin levels and could confound the trial.
• Participants with diabetes discovered on screening based on American Diabetes Association criteria using HbA1c (HbA1c of 6.5% or greater). Although metformin could be a first treatment of diabetes for these participants, addition of treatments for diabetes by physicians could confound the study.
• Use of aducanumab (Aduhelm™) of any other amyloid modifying treatment for AD.
• Not able to undergo phlebotomy as reported by the participant or determined by the study coordinator or physician.
• Participants with known, suspected, or plan for becoming pregnant. Exclusion Criteria for MRI Contraindications for MRI include inability to lie flat, claustrophobia, or presence of indwelling metal objects or implants that are not MRI compatible. Exclusion Criteria for PET History of adverse reactions to radiocontrast agents.
Suicide Treatment Alternatives for Teens (START)
Quasi-Randomized trial to compare inpatient care versus outpatient crisis intervention clinic. This study plans to enroll up to 1,000 participants across 4 sites in a 5 years period.
• Adolescents that are 12 through 17 years old (including 17 year olds who will turn 18 years old during the course of the study).
• Are brought to the Emergency Department (ED) due to suicidal thoughts or behaviors
• Require a higher level of care (OCIC or Inpatient) indicated by clinician determination and a CHRT-SR score of 15 to 52.
• The presence of a legal guardian
• Capable of giving signed informed consent/assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Adolescents with suicidal thoughts that place themselves at a serious imminent risk of suicide based on clinical judgment.
• Adolescents who require 24 hour/day supervision but no adult can provide 24 hour/day supervision outside of the hospital
• Adolescents without the ability to read and answer survey questions
• Adolescents that are non-English speaking due to the scales and surveys that are used for this study only being available in English.
Tractography Guided Subcallosal Cingulate Deep Brain Stimulation for Treatment Resistant Depression
Treatment resistant depression remains a major problem for individuals and society. Surgical procedures may provide relief for some of these patients. The most frequently considered surgical approach is deep brain stimulation (DBS) of a part of the brain called the subcallosal cingulate region. However, the effectiveness and safety is not well established. The investigators will use a novel approach using advanced imaging technique (magnetic resonance tractography) to evaluate the feasibility and safety of this surgical approach. An innovative method for the definition of DBS target will be applied that redefines the concept of targeting as one of targeting a symptomatic network rather than a structural brain region using subject-based brain anatomy to define the target location. The correlation between imaging findings at baseline with the mood score changes at different time points of the study will be investigated.
• Men and women (non-pregnant) between ages 21 and 70;
• DSM-5 diagnosis a current major depressive episode (MDE) for 10 years of less, recurrent or single episode with first episode after adulthood and did not start during childhood or adolescence, secondary to nonpsychotic unipolar major depressive disorder;
• Current index MDE ≥24 months duration and/or recurrent illness with at least a total of 2 lifetime episodes (including current episode >12 months);
• Treatment resistance (defined by criteria on the Antidepressant Treatment History Form (ATHF)28): Failure to respond to a minimum of four adequate depression treatments from different categories;
• Symptom severity for Screening: Hamilton Depression Rating Scale-17 item (HDRS17) ≥20;
• Symptom severity for Outcome: Montgomery Asberg Rating Scale (MADRS) ≥27 to be met at assessment one week pre-op;
• Normal brain MRI within 3 months of surgery;
• Antidepressant medication regimen has been held stable for ≥ 30 days prior to the study screening MADRS;
• Remain on stable antidepressant medication throughout the study, unless there are safety concerns;
• Montreal Cognitive Assessment (MoCA) >25;
• Able and willing to give informed consent and agree to attend regular clinic visits for at least 12 months.
• DSM-5 Axis I Disorders: any lifetime history of psychotic disorder or bipolar disorder;
• Alcohol or substance use disorder within 6 months, excluding nicotine;
• History of childhood abuse (physical or sexual) 18
• Personality disorders;
• Seeking disability during the trial;
• Current substantial suicidal risk as defined by a plan or clear immediate intent for self-harm, or made any suicide attempt within the last year; (MADRS ≥ 5 including the day of surgery);
• No stable work history;
• Neurological/Medical condition that makes the patient, in the opinion of the surgeon, a poor candidate;
• Pregnant or has plans to become pregnant in the next 36 months;
• Unable/unable to practice birth control through the period of randomization and withdrawal of therapy;
• Subjects who have a history of a seizure disorder;
• Subjects who will be exposed to diathermy;
• Subjects who have any medical contraindications to undergoing DBS surgery (e.g. infection, coagulopathy, or significant cardiac or other medical risk factors for surgery);
• Subjects with another implanted device such as a cardiac pacemaker, defibrillator or neurostimulator;
• Subjects who have a history of hemorrhagic stroke;
• Subjects who are unable to undergo MRI;
• Subjects who are at increased risk of hemorrhage due to underlying medical conditions or medication.
Exploring the Effects of Corticosteroids on the Human Hippocampus
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.
• Men and women age 18-40 years with vision corrected to at least 20-40 (needed for fMRI tasks)
• Education of ≥ 12 years
• Baseline RAVLT total words recalled T-score ≥ 40 (normal range)
• BMI between 18.5-35.0 (neither underweight nor severely obese)
• Baseline QIDS-C ≤ 5 (virtual absence of depressive symptoms) for "healthy controls" and for the "depressed" group a QIDS-C between 11-20 (≥ moderate depressive symptoms but < very severe depressive symptoms)
• History of major psychiatric illness other than MDD for the depressed group, defined as bipolar disorder, posttraumatic stress disorder, schizoaffective disorder, schizophrenia, eating disorders, or MDD with psychotic features. For the control group, a past episode of MDD (per SCID) is also exclusionary
• History of drug or alcohol use disorder
• History of neurological disorders including seizures, brain surgery, multiple sclerosis, Parkinson's disease
• Taking CNS-acting medications (e.g., antidepressants, antipsychotics, lithium, anticonvulsants, sedative/hypnotic/anxiolytics). Thus, the depressed group will be medication free.
• History of allergic reaction or medical contraindication to hydrocortisone
• Metal implants, claustrophobia, or other contraindications to MRI
• Significant medical conditions (e.g., cancer, heart disease, diabetes)
• Vulnerable population including pregnant or nursing women, prisoners, and people with intellectual disability, history of special education classes, dementia, or other severe cognitive disorders
• Current suicidal ideation, a suicide attempt in the past 12 months or more than one lifetime attempt
• History of systemic CS use in the past 12 months, lifetime cumulative use of more than 12 weeks, or recent (defined as past 28 days) inhaled CS use
• Women who are using estrogen containing oral contraceptive agents (other contraceptives are acceptable, see Protection of Human Subjects section for a list of acceptable birth control methods) or who are post- or peri-menopausal or with irregular menstrual cycles (i.e., inconsistent menstruation patterns)
Resilience in Adolescent Development (RAD)
The RAD study is a longitudinal study to prospectively characterize the biological mechanisms of resilience in adolescents and young adults at risk for developing depression. The study will capture biomarkers from the domains of socio-demographic and clinical data, cognitive and psychological assessments, fluid-based biomarkers, neuroimaging and EEG. Such biomarkers will compose a human biosignature of resilience and identify risk factors for depression, contributing to effective treatment selection or may represent moderators of response or non-response to treatments in subjects with depression. A cohort of 1,500 participants, age 10-24 will be recruited over a 5 year period. Participants will be followed for 10 years following an initial baseline visit. Study visits are conducted 4 times per year.
• Adolescents and young adults aged 10-24, male and female of all races and ethnicity.
• Participants must be English-speaking (because several study assessments are only available in the English language), however the parent(s) or legal guardian may either speak English or Spanish as the consenting process can be conducted bilingually.
• Adults age 18 and older must be able to provide written informed consent; for youth younger than age 18, a parent or legal guardian must provide written informed consent, and the child or teen must provide written informed assent.
• Ability to complete clinical evaluations and neuropsychological testing.
• Individuals who are unable to provide informed consent.
• Participants who are non-English speaking.
• Individuals with any of the following psychotic features: MDD with psychotic features, schizophrenia, schizoaffective disorder, or other Axis I psychotic disorder.
• Individuals with a depression diagnosis or a history of depression diagnosis at the initial visit (participants who develop depression during the longitudinal follow-up will continue in the study).
• A PHQ-9 score of 10 or greater.
• Individuals who are unable to provide a permanent home address and contact information.
• Individuals with any condition for which, in the opinion of the investigator, study participation would not be in their best interest (e.g., compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST)
This trial aims to assess the efficacy and tolerability of Magnetic Seizure Therapy (MST) as an alternative to electroconvulsive therapy (ECT) for depression. Even with multiple medication trials, 30 - 40% of patients will experience a pharmacologically resistant form of illness. The ineffectiveness of current treatments for major depressive disorder (MDD) coupled with the economic burden associated with the disorder engenders a need for novel therapeutic interventions that can provide greater response and remission rates.
• are inpatients or outpatients;
• are voluntary and competent to consent to treatment and research procedures according to ECT/MST attending psychiatrist;
• have a MINI International Neuropsychiatric Interview diagnosis, Version 6 (MINI-6.0) diagnosis of non-psychotic MDD
• are 18 years of age or older
• have a baseline HRSD-24 score > or = 21;
• are considered to be appropriate to receive convulsive therapy as assessed by an ECT attending psychiatrist and a consultant anaesthesiologist
• are agreeable to keeping their current antidepressant treatment constant during the intervention;
• are likely able to adhere to the intervention schedule;
• meet the MST safety criteria ;
• If a woman of child-bearing potential: is willing to provide a negative pregnancy test and agrees not to become pregnant during trial participation. Exclusion Criteria Patients will be excluded if they:
• have a history of MINI diagnosis of substance dependence or abuse within the past three months;
• have a concomitant major unstable medical illness;
• are pregnant or intend to get pregnant during the study;
• have a MINI diagnosis of any primary psychotic disorder
• have a MINI diagnosis of obsessive compulsive disorder, or post-traumatic stress disorder deemed to be primary and causing more functional impairment than the depressive disorder
• have probable dementia based on study investigator assessment;
• have any significant neurological disorder or condition likely to be associated with increased intracranial pressure or a space occupying brain lesion, e.g., cerebral aneurysm;
• present with a medical condition, a medication, or a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator (e.g., hypothyroidism with low TSH, rheumatoid arthritis requiring high dose prednisone, or Cushing's disease);
• have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed;
• require a benzodiazepine with a dose > lorazepam 2 mg/day or equivalent or any anticonvulsant due to the potential of these medications to limit the efficacy of both MST and ECT;
• are unable to communicate in English fluently enough to complete the neuropsychological tests;
• have a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete the neuropsychological tests).
Dallas 2K: A Natural History Study of Depression (D2K)
The Dallas 2K is a 10-year natural history, longitudinal, prospective study of a cohort of 2,000 participants that will help uncover the socio-demographic, lifestyle, clinical, psychological and neurobiological factors that contribute to anti-depressant treatment response: remission, recurrence, relapse and individual outcomes in depressive disorders. Hence, the expected duration of this study is 20 years in length. Since this is an observational study, investigators will explore a comprehensive panel of carefully selected participant specific parameters: socio-demographic (age, ethnicity, economic); lifestyle (physical activity, substance use); clinical (medical history, anxious depression, early life trauma), biological (biomarkers in blood, saliva, urine), behavioral (cognitive, emotional), neurophysiological (EEG), and neuroimaging (structural, functional brain circuitry) with the goal to develop the most robust predictive models of treatment response and of depression outcomes. There is no medication or non-medication treatment or intervention provided by this study. Subjects will have elevated symptomatology of nonpsychotic chronic or recurrent depressive disorder and will be currently receiving or will be prescribed standard of care medication or non-medication based treatments by their providers/clinicians. The study cohort will reflect the wide range of patients seen in typical primary or psychiatric care settings, and may include unipolar or bipolar disorders and dysthymia (a more chronic form of depression). The cohort will be broadly representative of and generalizable to the US general population as a whole.
• Male and female adult or youth aged 10 and older of any race or ethnicity.
• Ability to speak, read, and understand English. However, the parent(s) or legal guardians of minors may either speak English or Spanish as the consenting process can be conducted bilingually.
• A lifetime or a current diagnosis of a mood disorder based upon a semi-structured diagnostic interview.
• Adults age 18 and older must be able to provide written informed consent; for youth younger than age 18, a parent or legal guardian must provide written informed consent, and the child or teen must provide written informed assent. Eligibility for Healthy Controls For comparison purposes, potential health control participants who do NOT have a psychiatric diagnosis will be enrolled as part of the healthy control arm of this study.
• Male and female adult or youth aged 10 and older of any race or ethnicity.
• Ability to speak, read, and understand English. However, the parent(s) or legal guardians of minors may either speak English or Spanish as the consenting process can be conducted bilingually.
• Adults age 18 and older must be able to provide written informed consent; for youth younger than age 18, a parent or legal guardian must provide written informed consent, and the child or teen must provide written informed assent. Criteria for Exclusion of Participants A potential participant will NOT be eligible for participation in this study if any of the following criteria are met:
• History of schizophrenia, schizoaffective disorders or chronic psychotic disorders based upon a semi-structured diagnostic interview.
• Diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C (human immunodeficiency virus (HIV) testing is not required for this study).
• Unable to provide a stable home address and contact information.
• Has any condition for which, in the opinion of the investigator or designee, study participation would not be in their best interest (including but not limited to cognitive impairment, unstable general medical condition, intoxication, active psychosis) or that could prevent, limit, or confound the protocol-specified assessments.
• Requires immediate hospitalization for psychiatric disorder or suicidal risk as assessed by a licensed study clinician. Eligibility for Healthy Controls A potential Healthy Control participant will NOT be eligible for participation in this study if any of the following criteria are met:
• A lifetime or a current history of a mood disorder based upon a semi-structured diagnostic interview.
• Meets any exclusion criteria as part of the main D2K study interview.
A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
HYPOTHESIS: Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD. STUDY AIMS: Primary Aim: Determine if pregnenolone is associated with greater reduction in depressive symptom severity than placebo in women with mMDD, as measured by MADRS. Secondary Aims: 1. Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD. 2. Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD. 3. Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD. 4. Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo. Mechanistic Aims: 1. Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response. 2. Determine if baseline neurosteroid levels predict pregnenolone response. 3. Determine whether depressive symptoms, anxiety, sleep or vasomotor symptoms improve first. A crossed-lagged panel model will explore serial correlations between changes in outcome measures.
• Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
• Greene Climacteric Scale total scores > 20
• Greene Climacteric Scale sub-score for vasomotor symptoms >3
• 5 or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Positive baseline urine drug screen of an illicit substance (in this study: opioids and cocaine,) with the exception of a medication used with a prescription (use of a detected substance that is used with a prescription, such as an opioid pain medication, is not necessarily exclusionary and will be based upon judgment of the PI, particularly in the cases of chronic opioid use). Participants who screen positive for marijuana will be offered a rescreen for eligibility at a later date.
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as <50% improvement based on her subjective experience).
• High risk for suicidal acts including active suicidal ideation with plan and intent or > 2 suicide attempts in lifetime or any attempt in the past 6 months
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed) within 2 weeks of the baseline visit and randomization. Antidepressants will be allowed for those participants who have been taking the antidepressant for 6 weeks with a stable dose for at least 4 weeks.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of any disallowed medications (specified in the Excluded Concomitant Medication section below).
• Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited.
• Uncontrolled hypertension (>160/95mmHg)
• Active coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
• Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
• Personal or first degree family history of known hormone sensitive tumors
• History of allergic reaction or side effects with prior pregnenolone use
• Clinically significant laboratory or physical examination findings
• Concurrent enrollment in another clinical trial Exclusion of Concomitant Medications:
• Selective estrogen-receptor modulators (SERMs)
• Hormone replacement therapy
• Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
• Natural menopause or antidepressant supplements
• Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
• Sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin.
• Soy-based medications or supplements
Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
The protocol aims to comprehensively define the phenotype of Phelan-McDermid Syndrome and to identify potential genetic factors, which may play a role in the variability of the disease's outcomes. The first aim involves a physical exam, a neurological exam, collection of medical history information, a clinical genetic evaluation, blood work and neuropsychological assessments. If clinically indicated, the protocol collects information from medical tests. These medical tests may include electrocardiography, echocardiography, renal ultrasonography, and renal ultrasound.
• Participant is 22 years of age and older at the time of enrollment
• Participant has been diagnosed with pathogenic deletions or mutations of the SHANK3 gene
• Participant is proficient in English
• Participant provided consent
Noninvasive Brain Stimulation on Memory in Individuals With Mild Cognitive Impairment and History of Brain Injury
The study will examine the efficacy of high definition transcranial direct current stimulation (HD-tDCS) and its influence on episodic memory in patients with amnestic mild cognitive impairment and a history of Traumatic brain injury. Ten sessions of HD-tDCS to the dorsal anterior cingulate region is expected to result in improvements in episodic memory measures immediately following the last session and at a 3-month follow-up.
• Age 50 and older
• Native English speakers
• 12 years of education or higher
• Active diagnosis of aMCI
• History of TBI based on VA/DOD criteria
• TBI within the past 2 years
• Lifetime history of stroke, transient ischemic attack, heart attack, or congestive heart failure
• Lifetime history of epilepsy
• Major psychiatric disorders (i.e., posttraumatic stress disorder, bipolar disorder, schizophrenia)
• Substance use disorder
• Has metal fragments in head
• Taking medications that may interact with the HD-tDCS effect (i.e., amphetamines, L-dopa, carbamazepine, sulpiride, pergolide, lorazepam, dextromethorphan, D-cycloserine, flunarizine, or ropinirole)
Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (Clozapine)
The CLOZAPINE study is designed as a multisite study across 5 sites and is a clinical trial, involving human participants who are prospectively assigned to an intervention. The study will utilize a stringent randomized, double-blinded, parallel group clinical trial design. B2 group will serve as psychosis control with risperidone as medication control. The study is designed to evaluate effect of clozapine on the B1 participants, and the effect that will be evaluated is a biomedical outcome. The study sample will be comprised of individuals with psychosis, including 1) schizophrenia, 2) schizoaffective disorder and 3) psychotic bipolar I disorder. The investigators plan to initially screen and recruit n=524 (from both the existing B-SNIP library and newly-identified psychosis cases, ~50% each) in order to enroll n=320 (B1 and B2) into the RCT.
• 18-60y/o; males and females; all races and ethnicities; able to provide written informed consent; able to read, speak, and understand English; medically stable; meeting DSM-IV (SCID-based) criteria for schizophrenia, schizoaffective disorder, or bipolar I disorder with psychotic features (we will use DSM-IV to be consistent with prior B-SNIP samples); PANSS total score of ≥70 and at least one item scored ≥5 or two items scored ≥4 on PANSS Positive Subscale; normal baseline values for absolute neutrophil count (ANC above 1500/mm3)
• premorbid intellectual ability estimate below 70 (WRAT-4, Word Reading subtest, age-corrected standardized score); comorbid DSM-IV diagnosis of alcohol or substance abuse in prior 1 month or substance dependence in prior 3 months; neurological (e.g., seizure disorder, stroke, traumatic brain injury with a loss of consciousness ≥ 30min) or severe medical condition (e.g., decompensated cardiovascular disorder, AIDS) that may affect central nervous system function; concomitant medications known to affect EEG properties (i.e., lithium, anticonvulsants, benzodiazepines) or strong CYP 1A2 inhibitors (e.g., ciprofloxacin, enoxacin) or strong CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, rifampin) which cannot be safely discontinued; vulnerable populations (e.g., pregnant, nursing, incarcerated); unwilling to use reliable means of contraception; history of neuroleptic malignant syndrome; prior treatment with clozapine, prior treatment with long-acting injectable antipsychotics that are 1-month formulations within the past 3 months and for 3-month formulations within the past 6 months; intolerable side effects to either clozapine or risperidone in lifetime, or a previously failed trial of either clozapine or risperidone at adequate doses in lifetime; history of drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS); high risk for suicide defined as more than 1 attempt in past 12 months that required medical attention, any attempt in the past 3 months or current suicidal ideation with plan and intent such that outpatient care is precluded; current homicidal ideation with plan and intent such that outpatient care is precluded.
Impact of Intensive Treatment of SBP on Brain Perfusion, Amyloid, and Tau (IPAT Study) (IPAT)
The purpose of this study is to determine if intensive lowering of systolic blood pressure (SBP), using FDA approved medications (antihypertensive), reduces Alzheimer's Disease pathology (i.e., excessive brain amyloid and tau protein deposition) in older adults at high risk for memory decline or dementia.
• Age 60-80, all races/ethnicities, and both sexes are eligible;
• a) A positive family history of dementia defined as having at least one first-degree relative with a history of AD or other type of dementia or
• b) having subjective memory complaints defined as a positive answer to BOTH of the following questions:
• "Are you worried about your memory or thinking abilities? a) Not at all, b) A little bit, c) A lot"; B and C - includes
• "Do you feel you have difficulty with your memory or thinking that is worse than in the past?" b) Yes or No; Yes - includes
• Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; based on clinical judgment, may be rescreened in ≥ 7 days;
• Individuals with SBP ≥ 130 and SBP ≤ 180; Those on antihypertensives are eligible. If an individual, not treated for HTN, has a SBP ≥ 125 mmHg, consider rescreening after 24 hours;
• Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months;
• Fluency in English or Spanish or both, adequate visual and auditory acuity to allow neuropsychological testing;
• Participants must have a regular healthcare provider.
• Clinically documented history of stroke, focal neurological signs or other major cerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidence of infection, infarction, or other brain lesions;
• Diagnosis of AD or other type of dementia, or significant neurologic diseases such as Parkinson's disease, seizure disorder, multiple sclerosis, history of severe head trauma or normal pressure hydrocephalus;
• Evidence of severe major depression (GDS ≥ 12, may be rescreened after 12 weeks or longer if evidence of reactive depression or temporary mood disturbances) or clinically significant psychopathology, (e.g., psychosis and schizophrenia); if hospitalized in past year, can be rescreened in 6 months; or presence of a major psychiatric disorder that in the investigator's opinion, could interfere with adherence to research assessments or procedures.
• Unstable heart disease based on clinical judgment (e.g., heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure), or other severe medical conditions;
• History of atrial fibrillation and evidence on ECG with any of the following: active symptoms of persistent palpitation, dizziness, history of syncope, chest pain, dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspnea within the past 6 months; resting heart rate of < 30 or > 110 bpm; taking class I or III antiarrhythmic drugs including flecainide, propafenone, dronedarone, sotalol, dofetilide, and amiodarone; or clinical concerns for safely participating in lowering blood pressure.
• Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.
• Orthostatic hypotension, defined as the third standing SBP < 100mmHg, may be rescreened after 2 weeks;
• History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis or polymyalgia rheumatica;
• Significant history of alcoholism or drug abuse within the last five years;
• Uncontrolled diabetes mellitus, defined as hemoglobin A1C > 6.5%, or requiring insulin treatment;
• Clinically diagnosed and untreated sleep apnea;
• Regularly smoking cigarettes within the past year;
• Pacemaker or other medical device of metal that precludes performing MRI;
• Women with a potential for pregnancy, lactation/childbearing (2 year post-menopausal or surgically sterile to be considered not childbearing potential);
• Participant enrolled in another investigational drug or device study, either currently or within the past 2 months;
• Severe obesity with BMI > 40 ; clinical judgment should be applied in all cases to assess patient safety and anticipated compliance;
• Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan"; allergy to amlodipine;
• Abnormal screening laboratory tests (e.g., liver ALT and AST > 3 x ULN, GFR < 30 or Hct < 28%); may be rescreened after 2 weeks or longer;
• A medical condition likely to limit survival to less than 3 years;
• Participant has any condition(s) judged by the study investigator to be medically inappropriate, risky or likely to cause poor study compliance. For example:
• Plans to move outside the clinic catchment area in the next 2 years;
• Significant concerns about participation in the study from spouse, significant other, or family members;
• Lack of support from primary health care provider;
• Residence too far from the study clinic site such that transportation is a barrier including persons who require transportation assistance provided by the study clinic funds for screening or randomization visits;
• Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria;
• Other medical, psychiatric, or behavioral factors that, in the judgment of the site PI or clinician, may interfere with study participation or the ability to follow the study Protocol.
• Couples or significant partners who live together cannot be enrolled or participate simultaneously in the study.
Study to Assess the Efficacy and Safety of Adjunctive NBI-1065845 in Adults With Major Depressive Disorder (MDD) (SAVITRI)
The purpose of this study is to evaluate the efficacy of NBI-1065845 compared with placebo used in addition to oral antidepressants in adults with MDD on improving symptoms of depression.
• The subject has completed written informed consent.
• At the time of signing the informed consent, subject must be 18 to 65 years of age, inclusive.
• The subject has a primary diagnosis of Major Depressive Disorder (MDD), without psychotic features, meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.
• Subject must have had inadequate response to antidepressant treatment.
• Subject is currently on stable pharmacological treatment for depression.
• Subject must have a total Hamilton Depression Rating Scale-17 Item (HAMD17) score ≥ 22 at screening.
• Subjects must have been taking current antidepressant medication(s) for ≥ 8 weeks.
• Subjects must be willing to comply with all study procedures and restrictions.
• Subject is pregnant or breastfeeding.
• Subject has an unstable medical condition or chronic disease.
• Subject has a history of neurological abnormalities.
• Subject is currently diagnosed with or prior diagnoses of psychiatric disorder which was the primary focus of treatment other than MDD.
• The subject's depressive symptoms have previously demonstrated nonresponse to an adequate course of treatment with electroconvulsive therapy (ECT).
• The subject has an alcohol or substance use disorder.
• In the Investigator's opinion, the subject is not capable of adhering to the protocol requirements.
A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER)
Objectives of this study are to determine whether active VNS Therapy treatment is superior to a no stimulation control in producing a reduction in baseline depressive symptom severity, based on multiple depression scale assessment tools at 12 months from randomization.