1. women and men ages 18-80, 2. with MDD, of at least 12 weeks duration, according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria confirmed by the Mini International Neuropsychiatric Interview (MINI; Sheehan et al, 1998), 3. have a Montgomery-Asberg Depression Rating Scale (MADRS
•Montgomery and Asberg, 1979) score of at least 20 at screen and baseline as assessed by site clinicians, 4. meet criteria for TRD during the current major depressive episode documented in the MGH Antidepressant Treatment History Questionnaire (ATRQ) (Chandler et al., 2010), which will be defined as being non-responders (less than 50% of symptom improvement) to two or more depression treatment trials of adequate dose and duration as defined by the MGH ATRQ, 5. are currently on an antidepressant of adequate dose (as defined by the MGH ATRQ) and duration (at least 8 weeks), with the antidepressant dose being stable over the past four weeks, and with documented (in the MGH ATRQ) non-response (less than 50% improvement) to the current antidepressant. 6. Patients who have passed the MGH CTNI remote assessment, with documentation provided to sites by MGH CTNI. 1. pregnant or breastfeeding women, women of childbearing potential who are not using an accepted means of birth control, or women with a positive urine pregnancy test, 2. patients who have received treatment with rTMS, aripiprazole, electroconvulsive therapy (ECT), or venlafaxine during the current episode, 3. patients who express an objection to receiving treatment with at least one of the three treatment arms of our study, 4. patients with any history of bipolar disorder or psychosis (diagnosed by MINI), 5. patients with active alcohol or substance abuse disorders within the past 6 months (diagnosed by MINI), 6. patients with suicidal ideation of the degree that, in the opinion of the evaluating clinician, participation in the study would place them at significantly increased risk of suicide, 7. patients with unstable medical issues of such degree that, in the opinion of the evaluating clinician, participation in the study would place them at significant risk of a serious adverse event, or patients with a screening hemoglobin A1c level greater than 7.5%, or patients with epilepsy, dementia, Parkinson's disease, or Huntington's Disease, 8. patients who have received treatment with vagus nerve stimulation (VNS), 9. patients who have not responded to more than five FDA-approved antidepressant treatment trials of adequate dose and duration during the current episode, or who did not respond to ECT in previous episodes 10. patients on excluded medications, 11. patients with a positive urine screen drug test for a substance for which they do not have a valid prescription for a valid medical reason, 12. patients with currently abnormal thyroid function tests, 13. patients who have received at least one dose of a monoamine oxidase inhibitor (MAOI) four weeks or less prior, and 14. for patients on concomitant psychotropic agents (anticonvulsants, benzodiazepines, hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone, melatonin, omega-3 fatty acids, folate, l-methylfolate, s-adenosyl methionine, lithium) not on the same dose for at least four weeks prior to study entry or who do not agree to continue at the same dose during the acute phase of the study. 15. Patients who do not meet safety criteria for TMS: history of seizures, cardiac pacemaker, DBS or VNS, brain aneurism clips or other metallic implants in the intracranial space. 16. Also excluded is an individual who has received any administration of ketamine in the current episode for the treatment of depression.

• Current primary diagnosis of nonpsychotic major depressive disorder.
• Stable antidepressant dose of no more than one antidepressant medication for 4 weeks and no anticipated changes during the study period.
• Stable doses of all concomitant medications for over 6 weeks.
• No more than two failed antidepressant trials of adequate dose and duration, as defined by ATRQ, in the current episode.
• Psychiatric co-morbidity posing safety risk.
• Pregnant or breastfeeding or plan to become pregnant over the ensuing 2 months following study entry or are sexually active and not using adequate contraception
• Exclusionary psychiatric conditions (such as substance dependence in the last 6 months, substance abuse in the last 2 months, or lifetime history of psychotic disorders.
• Unstable or terminal general medical condition (GMC).
• Concomitant medications that interact with L-leucine (e.g. sildenafil).
• Vagus nerve stimulation, ECT, or rTMS, or other somatic antidepressant treatment during current episode
• Inadequately controlled hypothyroidism.
• Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of Depression.
• Hypersensitivity to L-leucine
• Have Maple Syrup Urine Disease.

INCLUSION CRITERIA:
• Age ≥ 6 years and ≤ 18 years 10 months at the time of study entry (so that participants will be < 19 at the 6 week evaluation, which is the upper age limit for which the included instruments are valid).
• Diagnosis of a primary brain tumor treated with at least one of the following: 1. neurosurgical resection of the brain tumor; 2. cranial irradiation; or 3. any chemotherapy to treat the brain tumor.
• Off-treatment and progression-free for at least 12 months and ≤ 14 years. Treatment cessation is defined as the final dose of chemotherapy, the last dose (fraction) of radiation or date of surgery, whichever occurred last.
• Parent/Legal Guardian and child able to read English or Spanish.
• Vision and hearing (eyeglasses and/or hearing aid permissible) sufficient for valid test administration and cooperation with examinations.
• Availability of a reliable parent or legal guardian who is willing and able to complete all of the outcome measures and fulfill the requirements of the study, including administration of medications and accompanying the participant to all study visits.
• Females of childbearing potential must have a negative pregnancy test result and must agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug.
• Childbearing potential is defined as girls who are >Tanner stage 2, except for those who have documented pan pituitary insufficiency or other hormonal state incompatible with pregnancy.
• Urine pregnancy tests are acceptable. EXCLUSION CRITERIA:
• Off treatment > 14 years
• Inability to perform the testing procedure (for example, because of aphasia, motor deficits affecting the dominant hand, or IQ < 70)
• Known cardiac disorders including arrhythmias, hypertension requiring treatment or structural heart disease
• Diagnosis of narcolepsy, sick sinus syndrome, arrhythmia or prolonged QTc
• History of stroke or head injury associated with loss of consciousness within 12 months of registration
• History of grade 2 depression or anxiety or treatment with antidepressants, antipsychotics or MAO inhibitors within 30 days of registration
• Concurrent treatment with any medications or substances that are potent inhibitors or inducers of CYP3A4, hepatic enzyme inducing antiepileptic drugs (EIAEDs),or other drugs known to affect the metabolism of modafinil. Examples include but are not limited to itraconazole, ketoconazole, doxycycline, rifampin, St. John's wort, phenytoin, phenobarbital, diazepam, tricyclic antidepressants.
• If patients were previously taking, EIAEDs, they must be off for > 2 weeks prior to study enrollment.
• Treatment with other stimulant medications within 14 days of registration; however, a diagnosis of ADHD does NOT exclude a child from participation
• Participants with known hypersensitivity to modafinil, armodafinil or any of its components

• Youth admitted to the inpatient unit at either site for a recent suicide attempt or significant suicidal ideation with a plan or intent.
• The youth and parent are able to complete assessments in English, and the youth is able to complete therapy.
• The youth currently exhibits psychosis.
• The youth currently exhibits mania.
• The youth is currently <85% of their ideal body weight.
• The youth is intellectually incapable of completing the study, e.g. has an intelligence quotient (IQ) < 70.

• Has a Mini-Mental State Examination (MMSE) score at screening of 25 to 30
• Has a global Clinical Dementia Rating (CDR) scale score at screening of 0
• Has a Logical Memory II score at screening of 6 to 18
• Has a florbetapir positron emission tomography (PET) scan that shows evidence of brain amyloid pathology at screening
• Has a study partner that is willing to participate as a source of information and has at least weekly contact with the participant (contact can be in-person, via telephone or electronic communication)
• Is receiving a prescription acetylcholinesterase inhibitor (AChEI) and/or memantine at screening or baseline
• Lacks good venous access, such that intravenous drug delivery or multiple blood draws would be precluded
• Has current serious or unstable illness including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease or other conditions that, in the investigator's opinion, could interfere with the analyses of safety and efficacy in this study
• Has had a history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis) or head trauma resulting in protracted loss of consciousness
• Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of any in situ cancer that was appropriately treated and is being appropriately monitored, such as resected cutaneous squamous cell carcinoma in situ or in situ prostate cancer with normal prostate-specific antigen post-treatment
• Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis)
• Is clinically judged by the investigator to be at serious risk for suicide
• Has a history within the past 2 years of major depression or bipolar disorder as defined by the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM)
• Has a history within the past 5 years of chronic alcohol or drug abuse/dependence as defined by the most current version of the DSM Open-Label
• All participants who complete the placebo-controlled period will be allowed to continue into the open-label period

• Women and men ages 18-65
• Current diagnosis of Major Depressive Disorder
• Able to read, speak, and understand English
• Antidepressant use within the last 8 weeks
• Active infection or uncontrolled autoimmune disease
• Currently on oral corticosteroids or active immune suppressive therapy (methotrexate, cyclosporine, anti-cytokines medications, etc).
• Current diagnosis of uncontrolled HIV, hepatitis C or significant immunodeficiency
• Alcohol or substance use disorder
• Positive urine drug test for illicit substances or substances used out of the context of prescription
• Cognitively unable to give informed consent
• Pregnant or breastfeeding women, women of childbearing potential who are not using an accepted means of birth control, or women with a positive urine pregnancy test
• History of seizure disorder
• Previous significant adverse reaction to escitalopram or bupropion
• History of non-response to adequate doses of escitalopram or bupropion XL
• Current use of concomitant psychotropic agents (anticonvulsants, benzodiazepines, hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone, melatonin, folate, l-methylfolate, s-adenosyl methionine, lithium) not on the same dose for at least four weeks prior to study entry or who do not agree to continue at the same dose during the acute phase of the study.
• Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder or other psychotic disorder
• Current anorexia nervosa or bulimia nervosa
• Suicidal ideation of the degree that, in the opinion of the evaluating clinician, participation in the study would place them at significantly increased risk of suicide
• Unstable medical issues of such degree that, in the opinion of the evaluating clinician, participation in the study would place them at significant risk of a serious adverse event

• Participants must have a body mass index (BMI) between 18 and 36 kilogram per meter square (kg/m^2)
• Participants must have a primary diagnostic and statistical manual of mental disorders, 5th edition (DSM-5) diagnosis of major depressive disorder (MDD) with anxious distress, as assessed by the mini international neuropsychiatric inventory 7.0. Plus (MINI). Participants with a diagnosis of comorbid generalized anxiety disorder (GAD), post-traumatic stress disorder, persistent depressive disorder, attention deficit hyperactivity disorder (ADHD), social anxiety disorder or nicotine/caffeine dependence may be included, if MDD is primary diagnosis
• Participants must have an inventory of depressive symptomatology, clinician rating-30 (IDS-C30) total score greater than or equal to (>=) 35 (moderate to severe depression)
• Participant must not have received more than 3 failed antidepressant treatments (of adequate dose and duration), including their current treatment, in the current episode of depression, as documented by the massachusetts general hospital antidepressant treatment history questionnaire (MGH-ATRQ)
• Participant must be currently receiving 1 of the following antidepressants for at least 6 weeks duration at screening, at an adequate therapeutic dose, as determined by the MGH-ATRQ and should remain on a stable dose throughout the study: bupropion, citalopram, escitalopram, sertraline, paroxetine, venlafaxine, desvenlafaxine, duloxetine, fluoxetine, vilazodone, vortioxetine, mirtazapine, agomelatine, nortriptyline, imipramine, amitriptyline and levomilnacipran
• Participants must have a suboptimal response (improvement <50%) to the antidepressant used as their current treatment, as measured by the MGH-ATRQ
• A woman of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose
• Participant has any other psychiatric condition including but not limited to: MDD with current psychotic features, bipolar disorder (including lifetime diagnosis), obsessive-compulsive disorder, borderline personality disorder, eating disorder (example: bulimia, anorexia nervosa), or schizophrenia (lifetime)
• Age of onset of depression is after 55 years of age
• Participant has a history of alcohol or substance use disorder (abuse/dependence) within 6 months prior to screening (nicotine and caffeine dependence are not exclusionary)
• Participant has a current or recent (within the past year) history of clinically significant suicidal ideation (corresponding to a score of >= 3 for ideation) or any suicidal behavior within the past year, as validated on the Colombia suicide severity rating scale (C-SSRS) at screening or baseline
• Length of current major depressive episode >60 months
• Participant has organic brain disease or dementia or has known or suspected intellectual development disorder
• Participant has been treated with at least one of the following treatments: (a) electroconvulsive therapy in the current episode; (b) deep brain stimulation (lifetime); (c) repetitive transcranial magnetic stimulation within 4 weeks prior to baseline visit
• Participant has any clinically relevant medical condition that could potentially alter the absorption, metabolism, or excretion of the study intervention, such as liver disease or renal disease
• Participant has a relevant history of any significant and/or unstable cardiovascular, respiratory, neurological (including seizures
•uncomplicated childhood febrile seizures with no sequelae are not exclusionary) or significant cerebrovascular, renal, hepatic, dermatologic, hematologic, gastrointestinal or endocrine diseases. Hospitalization for cardiovascular event (myocardial infarction, unstable angina, stroke, transient ischemic attack) within 3 months prior to the first administration of study drug is exclusionary. Diabetes mellitus be allowed when the participant is stable (HbA1c less than 7.5% or 58 mmol/mol)
• Participant has a clinically significant abnormal physical examination, vital signs or 12-lead electrocardiogram (ECG) at screening or baseline Minor deviations in ECG, which are not considered to be of clinical significance to the investigator, are acceptable.If at screening visit QTcB or QTcF interval >=450 ms for males or >=470 ms for females, or >480 ms if bundle branch block and prolongation of the QTc interval are present;participant is excluded
• Participant has a history of known demyelinating diseases such as multiple sclerosis or optic neuritis

• Participants must meet diagnostic and statistical manual of mental disorders (5th edition) {DSM-5} diagnostic criteria for major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the mini international neuropsychiatric interview for children and adolescents (MINI KID)
• Participant must have a children's depression rating scale-revised (CDRS-R) total score of equal or more than (>=) 58 predose on Day 1
• As part of standard of care treatment, participant must agree to be hospitalized voluntarily for a recommended period of 5 days after randomization (may be shorter or longer if clinically warranted in the investigator's opinion)
• As part of the newly initiated or optimized standard of care treatment, participant must agree to take one of the prescribed non-investigational antidepressant medications (fluoxetine, escitalopram, sertraline; and 9-11 years old participants at US-sites only: fluoxetin [preferred], sertraline) at least during the double-blind treatment phase (Day 25)
• As part of standard of care treatment, participant must agree to participate in a specific psychological intervention (individual cognitive behavioral therapy [CBT], interpersonal therapy, family therapy or psychodynamic psychotherapy) at least through the initial 8-week post-treatment follow-up period (Day 81)
• Participants has a current DSM-5 diagnosis of bipolar (or related disorders), intellectual disability, autism spectrum disorder, conduct disorder, anorexia nervosa, oppositional defiant disorder, or obsessive compulsive disorder
• Participants currently meets DSM-5 criteria for borderline personality disorder. Participants not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded
• Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis
• Participant meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder (except for nicotine or caffeine) within the 6 months before screening. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary
• Participant has a history of seizure disorder

• Women, ages 18-65 years, with current MDD (mild or moderate severity per DSM-5) based on SCID-CV.
• No psychotropic medications, other than PRN (as needed) hypnotics, within 28 days of randomization (medication free).
• PRN hypnotics allowed up to 3 days prior to study drug administrations but not while receiving study drug.
• Severe MDD based on DSM-5 severity criteria and/or a baseline HRSD score > 27 (consistent with severe depressive symptom severity).
• High risk for suicide (active SI with plan/intent or > 2 lifetime attempts in lifetime or any in the past 6 months).
• Treatment resistant depression (fail two adequate antidepressant trials or ECT during current episode).
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated).
• Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder, or any severe, life threatening or unstable, medical condition.
• History of allergic reaction or side effects with prior pregnenolone use.
• Current substance use disorder defined as meeting criteria for a use disorder based on the SCID interview and self-reported use within the past 3 months, or a positive baseline urine drug screen.
• Current psychotic features (hallucinations, delusions, disorganized thought processes) or eating disorders.
• Anxiety disorders of sufficient severity to be the primary focus of clinical attention (e.g. severe obsessive compulsive or post-traumatic stress disorders).
• Hormone-sensitive conditions (i.e. breast cancer; uterine/ovarian cancer, endometriosis, uterine fibroids).
• Clinically significant laboratory, physical examination, or electrocardiogram (ECG) findings.
• Currently using oral contraceptives containing progestin (barrier methods allowed).

• Eligible patients will have locally advanced cervical cancer suitable for primary treatment with chemoradiation with curative intent, in addition to:
• Federation of Gynecology and Obstetrics (FIGO) 2008 stage IB1 & node positive, IB2, IIA, IIB, IIIB, or IVA disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix
• White blood cells (WBC) >= 3.0 x 10^9/L
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelet count >= 100 x 10^9/L
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN (if both tests are done, both results need to be =< 2.5 x ULN)
• Creatinine =< ULN (Common Toxicity Criteria [CTC] grade 0) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 60 mL/min OR >= 50 mL/min by ethylenediaminetetraacetic acid (EDTA) creatinine clearance
• Written informed consent
• Any previous pelvic radiotherapy
• Para-aortic nodal involvement above the level of the common iliac nodes or L3/L4 (if biopsy proven, PET positive, or >= 15 mm short-axis diameter on computed tomography [CT])
• FIGO 2008 stage IIIA disease
• Patients assessed at presentation as requiring interstitial brachytherapy treatment
• Patients with bilateral hydronephrosis unless at least one side has been stented and renal function fulfills the required inclusion criteria
• Previous chemotherapy for this tumor
• Evidence of distant metastases
• Prior diagnosis of Crohn's disease or ulcerative colitis
• Peripheral neuropathy >= grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v]4)
• Patients who have undergone a previous hysterectomy or will have a hysterectomy as part of their initial cervical cancer therapy; this includes patients with a prior history of supracervical hysterectomy
• Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and in situ melanoma, who had (or have) any evidence of the other cancer present within the last 5 years
• Patients who are pregnant or lactating
• Any contraindication to the use of cisplatin, carboplatin, or paclitaxel chemotherapy
• Serious illness or medical condition that precludes the safe administration of the trial treatment including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who are known to be human immunodeficiency virus (HIV) positive

Inclusion Criteria Patients will be included if they: 1. are inpatients or outpatients; 2. are voluntary and competent to consent to treatment and research procedures according to ECT/MST attending psychiatrist; 3. have a MINI International Neuropsychiatric Interview diagnosis, Version 6 (MINI-6.0) diagnosis of non-psychotic MDD 4. are 18 years of age or older 5. have a baseline HRSD-24 score > or = 21; 6. are considered to be appropriate to receive convulsive therapy as assessed by an ECT attending psychiatrist and a consultant anaesthesiologist 7. are agreeable to keeping their current antidepressant treatment constant during the intervention; 8. are likely able to adhere to the intervention schedule; 9. meet the MST safety criteria [75]; 10. 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: 1. have a history of MINI diagnosis of substance dependence or abuse within the past three months; 2. have a concomitant major unstable medical illness; 3. are pregnant or intend to get pregnant during the study; 4. have a MINI diagnosis of any primary psychotic disorder 5. 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 6. have probable dementia based on study investigator assessment; 7. 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; 8. 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); 9. 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; 10. 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; 11. are unable to communicate in English fluently enough to complete the neuropsychological tests; 12. have a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete the neuropsychological tests).

The participants must meet the following criteria:
• 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 The participants must not meet any of the following criteria:
• 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.
• Phytoestrogens
• Soy-based medications or supplements

• 18-50y/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 or risperidone within the past 1 month, prior treatment with long-acting injectable antipsychotics 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.

Criteria for Inclusion of participants: A potential participant will be eligible for participation in this study if the following criteria are met: 1. Male and female adult or youth aged 10 and older of any race or ethnicity. 2. 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. 3. A lifetime or a current diagnosis of a mood disorder based upon a semi-structured diagnostic interview. 4. 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. 1. Male and female adult or youth aged 10 and older of any race or ethnicity. 2. 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. 3. 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: 1. History of schizophrenia, schizoaffective disorders or chronic psychotic disorders based upon a semi-structured diagnostic interview. 2. Diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C (human immunodeficiency virus (HIV) testing is not required for this study). 3. Unable to provide a stable home address and contact information. 4. 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. 5. 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: 1. A lifetime or a current history of a mood disorder based upon a semi-structured diagnostic interview. 2. Meets any exclusion criteria as part of the main D2K study interview.

• Capacity for written informed consent
• Currently (or within the last 3 weeks) admitted to inpatient hospital for symptoms of mania.
• Primary Axis I diagnosis (DSM-5) at time of admission of bipolar I (single manic episode, most recent episode manic, or most recent episode mixed) OR schizoaffective disorder, bipolar type (manic or mixed state).
• Proficient in the English language.
• Available to attend follow-up visits.
• Substance- or medically-induced symptoms of mania at time of assessment.
• HIV infection or other immunodeficiency condition (such as receiving cancer chemotherapy).
• A serious medical condition that affects brain or cognitive functioning (e.g., epilepsy, serious head injury, concussion involving loss of consciousness, brain tumor, or other neurological disorder). Note that Hepatitis-C is not an exclusion criterion unless the participant has an acute infection.
• Diagnosis of Intellectual Disability or history of severe learning disorder.
• Diagnosis of alcohol or substance use disorder (moderate/severe) according to DSM-5 criteria within the last 3 months, or has a positive drug toxicity screen proximate to the time of recruitment.
• History of IV drug use.
• Participated in any investigational drug trial in the past 30 days.
• Pregnant, breastfeeding, or planning to become pregnant during the study period.
• Documented celiac disease (as such persons should be on a gluten-free diet as this is the standard care). Of note, we are not limiting the study to individuals with elevated levels of gliadin or casein antibodies as we intend to look at these levels as a predictor of response.

• Adolescents (12 to 18 years old) who were brought to the ED due to suicidal thoughts or behaviors and require a higher level of care (OCIC or inpatient)
• The presence of a legal guardian
• Adolescents with suicidal thoughts that place themselves at a serious imminent risk of suicide based on clinical judgment and/or responses on the Concise Health Risk Tracking Self-Report (CHRT-SR) (a score of 23 or higher on the 14 item CHRT-SR) 70-72
• Adolescents who require 24 hour/day supervision but no adult can provide 24 hour/day supervision outside of the hospital
• Adolescents with suicidal thoughts who had prior OCIC treatment in the past 12 months will be excluded
• Adolescents without the ability to answer survey questions will be excluded

• Subject is > 18 years
• Subject is a trauma patient experiencing traumatic injuries requiring a full trauma team response OR Subject is a patient undergoing liver transplant surgery.
• Subject, or subject's legally authorized representative (LAR), is willing to provide informed consent, either prospectively or by deferred consent, OR Institutional Review Board (IRB)/Ethics Committee (EC) has waived the requirement to obtain informed consent.
• Subject is younger than 18 years of age
• Subject is pregnant.
• Subject is incarcerated at the time of the study.
• Subject is currently enrolled in a distinct study that might confound the result of the proposed study
• Subject is affected by a condition that, in the opinion of the surgical team, may pose additional risks.

• 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)

• Younger than 2 years (chronological age)
• Scheduled for anaesthesia that is expected to last at least 2 hours (and/or total operating room time is scheduled to be at least 2.5 hours)
• Has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf.
• Known neurologic, chromosomal or congenital anomaly which is likely to be associated with poor neurobehavioural outcome
• Existing diagnosis of behavioural or neurodevelopmental disability
• Prematurity (defined as < 36 weeks gestational age at birth)
• Birth weight less than 2 kg.
• Congenital cardiac disease requiring surgery
• Intracranial neurosurgery and intracranial craniofacial surgery (isolated cleft lip is not an exclusion)
• Previous cumulative exposure to general anaesthesia exceeding 2 hours
• Planned future cumulative exposure to anaesthesia exceeding 2 hours before the age of 3 years.
• Any specific contra-indication to any aspect of the protocol
• Previous adverse reaction to any anaesthetic
• Circumstances likely to make long term follow-up impossible
• Living in a household where the primary language spoken at home is not a language in which we can administer the Wechsler Preschool and Primary School Intelligence Scale
• Planned postoperative sedation with any agent except opioids (e.g. benzodiazepines, dexmedetomidine, ketamine, barbiturates, propofol, clonidine, chloral hydrate, and other non-opioid sedatives). For example if such sedation is planned for post-operative ventilation

• Participants must have at least one parent who meets the criteria for diagnosis of Bipolar I disorder (BD-I) or Bipolar II disorder (BD-II), as confirmed by the Mini International Neuropsychiatric Interview (MINI) administered to the parent. MINI will be administered to parent if the history of BD is endorsed by Family Index of Risk for Mood (FIRM) or other medical information (psychiatrist, medical records). The MINI can be administered to the parent remotely through the telephone or video call if an in-person interview is not feasible due to logistical reasons. A diagnosis Bipolar Disorder Not Otherwise Specified in the parent would not qualify for eligibility
• Participants must be either drug-naive, or on stable treatment for at least 4 weeks.
• Participants (and/or their parents as applicable) must sign an Informed Consent Form (ICF) allowing data collection and source data verification in accordance with local requirements and/or sponsor policy. Adolescents (minors) who in the judgment of the investigator are capable of understanding the nature of the study can be enrolled only after obtaining consent of a legally acceptable representative. Assent must be obtained from any participating adolescents (minors), if applicable
• Participants must be willing and able to complete self-reported assessments via mobile electronic device, and to wear a wrist actigraphy device for the duration of the study
• Diagnostic and Statistical Manual of Mental Disorders (DSM) -IV Diagnosis of bipolar I or bipolar II disorder
• DSM-IV Diagnosis of schizophrenia, schizophreniform or schizoaffective disorder
• DSM-IV Diagnosis of neurodevelopmental disorders
• An intelligence quotient (IQ) score less than (<) 80 as determined by Kaufman Brief Intelligence Test (K-BIT)
• Uncorrected hypothyroidism or hyperthyroidism

• Outpatient men and women age 18-65 years old with bipolar I, II, Not Otherwise Specified (NOS) disorder, or Schizoaffective Bipolar Type
• If diagnosed with Bipolar I, Bipolar NOS w/history of mania or Schizoaffective Disorder Bipolar Type, current mood stabilizer therapy (lithium, valproic acid, lamotrigine, gabapentin) with stable dose for > 28 days prior to randomization.
• Baseline Barrett Impulsiveness Scale-11 Score of > 62 (above average impulsivity)
• Systolic BP > 100 and < 165 and Diastolic BP > 60 and < 105 with no evidence of orthostatic hypotension
• Current Diagnosis of Alcohol Use Disorder with at least moderate severity
• Alcohol use of an average of 15 drinks per 7 days in the past 28 days prior to intake for men, and an average of 8 drinks per 7 day period in the past 28 days prior to intake for women
• Current mood stabilizer therapy with stable dose for > 28 days
• Fluent in English or Spanish
• Baseline Hamilton Rating Scale for Depression (HRSD) or Young Mania Rating Scale (YMRS) scores > 35
• Mood disorders other than bipolar I, II, NOS or schizoaffective disorder bipolar type (e.g. cyclothymic disorders, schizophrenia, schizoaffective disorder depressive type, or unipolar depression based on the SCID), other disorders, e.g. anxiety disorders, will be allowed.
• Current diagnosis of amphetamine or cocaine use disorder or a cocaine or amphetamine positive baseline urine sample.
• Evidence of clinically significant alcohol withdrawal symptoms
• Current treatment with an atypical antipsychotic
• Current treatment with naltrexone, acamprosate, disulfiram, or topiramate in the last 28 days
• Prior treatment with Aripiprazole within the last year or lifetime history of intolerable side effects to Aripiprazole
• Vulnerable populations (e.g. pregnant, nursing, cognitively impaired, incarcerated.)
• Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar score of ≥ 10.
• High risk for suicide
• Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) > 3 times upper limit of normal
• Current use of Cytochrome P450 3A4 inducing medication (e.g. carbamazepine, rifabutin, rifampin, ritonavir).
• Use of other substances (besides cocaine/amphetamine) is allowed if the use disorder is no greater than moderate severity and alcohol is the self-identified substance of choice.
• History of neuroleptic malignant syndrome or tardive dyskinesia. More specific inclusion and exclusion criteria will be discussed with participant at baseline assessment.

• 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

• Non-obese (body mass index less than 30 kg/m2) *alternatively, individuals will be permitted to participate if they have a body mass index value below 35 kg/m2 but a waist circumference below 88 cm for females and 102 cm for males
• Systolic blood pressure <140 mmHg
• Diastolic blood pressure <90 mmHg
• Participants who have cardiac, respiratory, neurological, and/or metabolic illnesses
• Current or previous use of anti-hypertensive medications
• Any known history of renal or hepatic insufficiency/disease
• Pregnancy or breast feeding
• Current smokers, as well as individuals who regularly smoked within the past 3 years
• Individuals with a history of drug abuse
• Individuals who have an unexplained positive urine drug screen (e.g., some agents cause false-positive results, but when the agent is abstained for hours/days/weeks, the repeated drug screen is negative. One example could be an over-the-counter supplement)

• Female ASA physical status 1-3 scheduled for open abdominal hysterectomy
• Age 18-80 years old
• Able to participate personally or by legal representative in informed consent in English or Spanish
• History of relevant drug allergy
• Age less than 18 or greater than 80 years
• Chronic opioid use or drug abuse
• Active use of anticoagulant medication
• Significant psychiatric disturbance
• Inability to understand the study protocol
• Refusal to provide written consent

Inclusion Criteria Study participants must: 1. Be adolescents (aged 12-18 years); 2. Have the ability to speak, read, and understand English. The parent(s) or legal guardians of minors must also speak, read and understand English; 3. 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; 4. Have the ability to complete clinical evaluations and self-report measures; 5. Meet criteria for one of these three groups: 1. Adolescent with suicidal behaviors, defined as having a recent (within 3 months) suicide attempt or suicidal ideation warranting urgent evaluation; 2. 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; 3. 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: 1. Have current poorly controlled asthma, acute/chronic infection or other medical condition(s) that may affect immune marker levels; 2. Have a current medication (e.g., corticosteroids) that may affect immune marker levels of reactivity; 3. 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; 4. Be unable to provide a stable home address and contact information

• Caregiver: Male or female, ages 18 to 70, primary asthma caregiver of the child, currently meeting criteria for Major Depressive Disorder (MDD) (based on depression symptoms for at least 2 weeks and causing clinically significant distress or impairment in social, occupational, or other important areas of functioning) based on a Structured Clinical Interview for DSM-4 (SCID) interview.
• Child: Male or female, ages 7-17 years who have a diagnosis of persistent asthma as classified by either of the following criteria:
• A. requirement for treatment with daily controller medication; or
• B. symptoms of persistent asthma in children not on a daily controller medication:
• 1. Daytime symptoms two or more days per week; or
• 2. Rescue bronchodilator use two or more times per week; or
• 3. Nocturnal symptoms two or more nights per month; or
• 4. Two or more oral steroid bursts in the last year.
• Caregiver: Severe cognitive impairment that could impair their ability to provide informed consent; member of a vulnerable population (incarcerated, pregnant or breastfeeding women); women of childbearing age who will not use acceptable methods of birth control or abstinence during the study; severe psychiatric disorder in addition to MDD that should be a primary focus of treatment (e.g. severe and disabling eating or anxiety disorders); treatment refractory depression defined as failing ≥ 3 adequate trials of antidepressants (≥ 4 weeks at a therapeutic dose); electroconvulsive therapy or repeated transcranial magnetic stimulation during the current episode; depression as part of bipolar disorder or schizophrenia or schizoaffective disorder, or current depression secondary to substances or general medical condition, or with psychotic features or accompanied by severe obsessive compulsive disorder (OCD), or high risk for suicide defined by multiple recent suicide attempts (> 2 in the past year) or any attempt in the past month, or current suicidal ideation with a well-formed plan or intent.
• Child: Severe cognitive impairment that could impair their ability to provide informed consent; high risk for suicide defined by multiple recent suicide attempts (> 2 in the past year) or any attempt in the past month, or current suicidal ideation with a well-formed plan or intent; severe or life-threatening medical illness, such as other serious cardiopulmonary conditions (e.g. congenital heart disease, cystic fibrosis, alpha-1-antitrypsin disease) or cancer, which would confound the assessment of asthma, anxiety, depression or quality of life; severe psychiatric illness, such as autism, bipolar disorder, schizophrenia or current drug/alcohol abuse/dependence. If an eligible caregiver presents with more than one child meeting inclusion criteria for the study, only one child, randomly selected, will be enrolled.

RESTORE subjects
• Age ≤8 years and PCPC=1 at RESTORE PICU admission
• PCPC ≤3 at RESTORE hospital discharge Sibling control subjects Inclusion criteria:
• Age 4 to 17 years at time of testing
• PCPC=1
• Same biological parents as primary subject
• Lives with the primary subject RESTORE subjects
• Hospital readmission that includes MV and sedation
• History of cardiac arrest, traumatic brain injury (TBI) with loss of consciousness, genetic disorder, premature birth <32 weeks gestational age, or birth weight <2500 g Sibling control subjects
• Adopted or step siblings
• History of MV and sedation, receipt of general anesthesia, cardiac arrest, TBI with loss of consciousness, genetic disorder, premature birth <32 weeks gestational age, or birth weight <2500 gm.

1. Male or females age 14-18 inclusive 2. Diagnosed with concussion due to sports-related injury. Concussion is defined as: 1. Direct blow to the head, face, neck or a blow elsewhere on the body with an "impulsive" force transmitted to the head. 2. Rapid onset of short-lived impairment of neurologic function in one or more of the following clinical domains that resolves spontaneously: i. Symptoms: somatic (eg, headache), cognitive (eg, feeling like in a fog and/or emotional symptoms (eg, lability). ii. Physical signs (eg, loss of consciousness, amnesia). iii. Behavioral changes (eg, irritability). iv. Cognitive impairment (eg, slowed reaction times). v. Sleep disturbance (eg, drowsiness). c) No abnormality on standard structural neuroimaging studies, if such neuroimaging studies are completed for a clinically-indicated reason. Note: neuroimaging is not a part of this study protocol. Study participants will not undergo neuroimaging as part of this study. 3. Concussion within 4 days of enrollment 4. Presenting for treatment to the Sports Medicine Center at Children's Medical Center 1. Subjects not actively participating in an organized sport at time of enrollment 2. Subjects who received a concussion from an event other than playing a sport (motor vehicle accident, fall, etc.) 3. Subjects who participate in or received a concussion during participation in motorized sports (i.e., motorcross, dirt biking, jet skiing, etc.) 4. Subjects with radiographic evidence of traumatic brain injury (i.e., skull fracture, intracranial hemorrhage, cerebral contusion, etc). 5. Subjects with a prior diagnosed concussion in the previous 6 months. 6. Pregnant women. 7. Subjects sensitive to aspirin 8. Subjects diagnosed with high blood pressure and currently being treated with blood pressure medications 9. Subjects allergic to soy bean oil or corn oil. 10. Subjects currently taking fish oil or DHA supplements.

• 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.

•Male or female, age greater than or equal to 45 years at the time of signing informed consent
•Body mass index (BMI) greater than or equal to 27 kg/m^2
•Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Exclusion Criteria:
•Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
•HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening
•History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)