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.

• Positive depression screen (PHQ-9) or current antidepressant treatment
• Report <150 minutes of weekly moderate-to-vigorous physical activity (MVPA) on the GPAQ
• Physically able to engage in physical activity
• Written and verbal fluency in English
• Medical condition contraindicating physical activity participation
• Recurrence of breast cancer
• Ductal carcinoma in situ (DCIS) diagnosis
• Cognitively unable to give informed consent
• Non-English speaking

1. Male and female adults. 2. Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011) 3. Folstein MMSE 5-26 out of 30 4. Neuropsychiatric Inventory (NPI) agitation/aggression subscale score > 4. On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms. 5. Female patients need to be post-menopausal 6. Availability of informant; patients without an informant will not be recruited. Patients who lack capacity must have a surrogate. 1. Medical contraindication to lithium treatment or prior history of intolerability to lithium treatment. Contraindications to lithium in this study include: resting tremor causing functional impairment, history of falls in the last month, untreated thyroid disease or any abnormal thyroid function test (T3, T4, or TSH), creatinine level greater than 1.5 mg/100ml or a glomerular filtration rate less than 44ml/min/ 1.73m2; blood pressure > 150/90 mm Hg; heart rate < 50 bpm; unstable cardiac disease based on history, physical examination, and ECG. 2. Medications, in combination with lithium, known to have adverse renal effects, including therapeutic or higher doses of diuretics, i.e. hydrochlorothiazide greater than 25mg daily or furosemide greater than 10mg daily. Whenever feasible, patients receiving concomitant antidepressants or antipsychotics will be washed off these medications for at least 24 hours before starting lithium. Patients who do not wish to discontinue antipsychotics or antidepressants, typically because of family member/caregiver objection, will be allowed to enter the trial provided there is no contraindication to concomitant lithium use with that specific psychotropic medication. During the trial, patients will be permitted to receive lorazepam as needed up to 1 mg/day for anxiety/insomnia, and non-benzodiazepine hypnotics, e.g., zolpidem. 3. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria). 4. Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria). 5. Current major depression or suicidality as assessed by the study psychiatrist. 6. Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others. 7. Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder. 8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (smallinfarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion. 9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion. 10. QTc interval > 460 ms at the time of baseline EKG is an exclusion criterion for treatment. 11. Hypernatremia as determined by serum sodium level > 150 meq/L.

• Based on the prior study the participant is entering 54135419TRD3008 from: a) From ESKETINTRD3001 (NCT02417064) or ESKETINTRD3002 (NCT02418585) study: Participant has completed the induction phase and the 2-weeks follow up phase visit; or Participants completed the induction phase and was a responder and study ESKETINTRD3003 is terminated.; b) From ESKETINTRD3003 (NCT02493868) study: (1) Participant relapsed during the maintenance phase; or (2) Participant was in the induction phase of the ESKETINTRD3003 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization or maintenance phases at the time the study was terminated; or (4) or (5) Participants was in the induction phase and after completion of induction phase was determined to not meet response criteria (1) Participant completed ESKETINTRD3004 study (optimization/maintenance phase); or (2) Participant was in the induction phase of the ESKETINTRD3004 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization/maintenance phase at the time the study was terminated; (4) Participant was in the induction phase and did not meet criteria for response may be eligible for to be rolled over into 54135419TRD3008. d) From ESKETINTRD3005 (NCT02422186) study: Participant was in the induction phase of the ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study was closed and, after completion of the induction phase, was determined to be a responder or did not meet the criteria for response. e) From ESKETINTRD3006 study (US Study sites only) (1) Participant completed the induction phase and was a responder.
• Participant must be medically stable on the basis of physical examination, vital signs, pulse oximetry, and 12-lead Electrocardiogram (ECG) performed predose on the day of the first intranasal treatment session. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant's source documents and initialed by the investigator
• Participant must be medically stable according to the investigator's judgment and knowledge of the subject's medical stability in the parent study. This determination must be documented.
• A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) predose on the day of the first intranasal treatment session
• During the study (that is, from the first intranasal treatment session) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of intranasal study medication, a man who is sexually active with a woman of childbearing potential must be practicing a highly effective method of contraception with his female partner c) must agree not to donate sperm.
• The evaluation of the benefit versus risk of continued intranasal esketamine treatment is not favorable for the participant in the opinion of the investigator
• Since the last study visit in the participant's prior study, participant has suicidal ideation with intent to act per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS) [corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) in the suicidal ideation module of the C-SSRS] or suicidal behavior per the investigator's clinical judgment or based on the C-SSRS (corresponding to any score higher than 0 in the suicidal behavior module of the C-SSRS)
• Participant has positive test result(s) for drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of the first intranasal treatment session
• Participant has any anatomical or medical condition that, per the investigator's clinical judgment based on assessment, may impede delivery or absorption of intranasal study drug
• Participant has taken any prohibited therapies that would not permit administration of the first intranasal treatment session

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).

• Have a Major Depressive Disorder (MDD) primary diagnosis
• Have a body mass index (BMI) of 18.0 to • Be willing and able to follow the study procedures and visits as outlined in the protocol (including agreeing not to enroll in any other clinical trials)
• Have inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE)
• Additional criteria may apply
• Has any finding that would compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements
• Has any other significant medical condition (eg, neurological, psychiatric, or metabolic) or clinical symptom that could unduly risk the subject or affect the interpretation of study data
• Has any current primary diagnosis other than MDD, where primary diagnosis is defined as the primary source of current distress and functional impairment
• Has experienced hallucinations, delusions, or any psychotic symptoms in the current MDE
• Has been hospitalized for MDD within 3 months before screening
• Has used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days prior to screening
• Has received electroconvulsive therapy treatment within the last 2 years or within the current MDE or failed a course of electroconvulsive treatment at any time
• Has a significant risk for suicide
• Has a positive breath alcohol test at screening
• Has a positive test for drugs of abuse at screening or visit 2
• Is pregnant, planning to become pregnant, or is breastfeeding during the study
• Additional criteria may apply

• Current episode of Major Depressive Disorder
• Inadequate response to at least one antidepressant medication in the current episode (Treatment Resistant Depression)
• Investigator able to identify IAF using EEG
• Willingness and ability to adhere to treatment schedule (5 treatments per week for six weeks)
• Unable to unwilling to give informed consent
• Diagnosed with excluded conditions or treatment histories
• Currently hospitalized due to severity of depression symptoms
• Use of prohibited medications (as defined by protocol) within specified time frame of randomization
• Use of certain cardiac devices
• Use of certain intracranial devices
• Currently pregnant or unwilling to practice acceptable means of birth control, and women who are breastfeeding

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 with the exception of a medication used with a prescription such as an opioid pain medication
• 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
• Women who have used psychoactive or centrally acting medications within 2 weeks prior to study screening
• 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 zolpiderm, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed), and antidepressants within 2 weeks of the baseline visit and randomization.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), natural menopause supplements, episodic sleep medications (chronic, regular, stable-dose benzodiazepines allowed), antidepressants, phytoestrogens, soy-based medications, steroids within 4 weeks of 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, physical examination
• 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)
• Antidepressants used at indicated, therapeutic, FDA-approved doses (Note: 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

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.

• Are able to provide written informed consent. If the Institutional Review Board (IRB) requires consent by a legally acceptable representative in addition to the subject, all required consents must be obtained prior to the initiation of any protocol-required procedure.
• Are 18 to 60 years of age, inclusive, at the time of informed consent
• Has a current diagnosis of schizophrenia, as defined by DSM-V criteria and a history of the illness for at least 6 months prior to screening from a reliable source (e.g., health care provider, family member, or medical records).
• Have been prescribed a single oral antipsychotic medication for at least 3 months prior to screening.
• Are able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, intramuscular (IM) once monthly injection, and discontinuation of prohibited concomitant medications, read and understand the written word in order to complete subject-reported outcomes measures, and be reliably rated on assessment scales.
• Are male and female subjects who are surgically sterile (i.e., have undergone orchiectomy or hysterectomy, respectively; female subjects who have been postmenopausal for at least 12 consecutive months; or male and female subjects who agree to remain abstinent or to practice double barrier forms of birth control from study screening through 30 days (for females) and 90 days (for males) from the last dose of study drug for SOC oral antipsychotics and 150 days for females and 180 days for males for aripiprazole once monthly. If employing birth control, two of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth control once monthly injections, condom, or sponge with spermicide.
• Has a current DSM-V diagnosis other than schizophrenia, including schizophreniform disorder, schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders. Also excluded are subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
• Has had a psychiatric hospitalization within the 30 days prior to screening.
• Has received a depot antipsychotic within the 6 months prior to screening.
• Is considered resistant or refractory to antipsychotic treatment by history (failed two prior antipsychotic medication studies) or response only to clozapine.
• Is taking two or more antipsychotics.
• Has a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator's discretion.
• Has a history of seizures or any other medical condition that would expose the subject to undue risk or interfere with study assessments.
• Is involuntarily incarcerated or has been incarcerated in the past 6 months for any reason.
• Has undergone electroconvulsive therapy in the 2 years prior to enrollment in the study.
• Has used an investigational agent or has participated in a clinical study with aripiprazole once monthly or any other antipsychotic once monthly preparation within 30 days of screening.
• Has any medical condition that might preclude safe completion of the study (e.g., agranulocytosis, severe and unstable heart disease, AIDS, end-stage renal disease).
• Is taking a CYP3A4 inducer (e.g., carbamazepine).

• The patient must be currently be enrolled or plan to be enrolled on a COG therapeutic study that aims to examine neuropsychological, social, emotional, and/or behavioral functioning
• The patient must have receptive and expressive language skills in English, French, or Spanish; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
• Patients with a history of moderate to profound intellectual disability (i.e. intelligence quotient [IQ] =< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g. dyslexia) are eligible for this study

• Participants ages 10
•89 years who speak English or Spanish (consent and HIPAA authorization forms will be translated in Spanish for mono-lingual Spanish-speaking only participants).
• Provide informed consent (parent or LAR for participants aged 10 to 17).
• Participants who do not speak English or Spanish.
• Participants who are less than 10 or greater than 89 years old.

• Child participants will be adolescents (aged 12-17.11 years) admitted to an inpatient unit for a recent suicide attempt or significant suicidal ideation with a plan or intent. We define a suicide attempt, as per the Columbia Clinical Algorithm for Suicide Assessment (C-CASA), as "self-destructive behavior with inferred or stated intent to die."
• Participants must be English-speaking.
• Participants can have unipolar or bipolar disorder, conduct or oppositional disorder, eating disorder, or alcohol or substance use or abuse or dependence.
• Child participants to be excluded will be those with current psychosis, mania, <90% of ideal body weight, or IQ<70 (based on the age-appropriate Wechsler Intelligence Scale if concerns about intellectual capabilities are evident at assessment), as these conditions may require more intensive interventions or limit comprehension of the intervention components.

• a) Substudy A and Main Study:
• Primary diagnosis of Major depressive disorder (MDD), made or confirmed by the investigator according to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria
• Demonstrated an adequate clinical response within the past 24 months, and is currently maintaining this response, to a stable oral antidepressant treatment regimen of no more than 2 of the following: selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants, in any formulation (fluvoxamine, citalopram, duloxetine, escitalopram, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine), or bupropion antidepressants, without any dosing changes for the most recent 6 weeks. The dose and duration of treatment will be documented by the investigator using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and verified against the available medical and pharmacy records or medication bottles/package labels
• Required to have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of less than or equal (<=)17 at screening and baseline (Test Day 1) visits as well as less than or equal (<=)19 during subsequent testing days (main study). Participants are also required to have a Clinical Global Impression
•Severity (CGI-S) total score of <=3 during testing days (main study)
• Must have adequate visual and hearing acuity to perform all aspects of the cognitive and functional assessments as determined during physical examination
• b) Substudy B (Healthy Participants):
• Must be healthy on the basis of physical examination, vital signs examination, and medical history performed at screening. This determination must be recorded in the participant's source documents and initialed by the investigator
• Body mass index (weight [kilogram (kg)]/height^2 [meter (m)]^2) between 18 and 30 kg/m2 (inclusive)
• Blood pressure (after the participant is sitting for 5 minutes) between 90 and 140 millimeter of mercury (mmHg) inclusive, systolic, and no higher than 90 mmHg diastolic
• Must sign an Informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
• a) Substudy A and Main Study:
• Has any of the following acute or chronic psychiatric conditions, according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria: Major depressive disorder (MDD) with psychotic features (lifetime), bipolar disorder (including lifetime diagnosis), obsessive-compulsive disorder, post-traumatic stress disorder, borderline personality disorder, anorexia nervosa, schizophrenia, schizoaffective disorder, or minor and major neurocognitive disorders (including dementia)
• History of any acute or chronic neurological condition (for example (eg), stroke, epilepsy, Parkinson's disease)
• b) Substudy B (Healthy Participants):
• History of drug or alcohol abuse, with a severity of at least moderate or severe, according to DSM-5 criteria, within 6 months before screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) at screening or admission on Day 1
• Participant has clinically significant liver or renal insufficiency; cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances. A significant primary sleep disorder is exclusionary, including primary insomnia and hypersomnia, narcolepsy, breathing-related sleep disorders, circadian-rhythm sleep disorders, and dyssomnias not otherwise specified
• Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (for example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

• 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.

• Undergoing heart surgery
• Willing to provide consent
• Enrolled in a concurrent drug or device trial that precludes concurrent enrollment

• 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.

• 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.

Eligibility Criteria: 1. Histologic Documentation: All patients must have histologically or cytologically documented, non-small cell carcinoma of the lung (adenocarcinoma, large cell, squamous, or mixtures of these types). 2. Extent of Disease: Stage IIIB/IV cancer by the international staging system or any Stage I-IIIA otherwise eligible patient with recurrent or progressive NSCLC after surgery or radiotherapy.
• Patients with Stage IIIB because of a malignant pleural effusion, supraclavicular node involvement, or contralateral hilar nodes are eligible (IIIB patients eligible for CALGB protocols of combined chemotherapy and chest irradiation are not eligible.
• Patients with known CNS metastases are not eligible. 3. Measurable or Non-Measurable Disease
• Measurable Disease: Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.
• Non-measurable Disease: Only those non-measurable disease patients with ill-defined masses associated with post-obstructive changes and diffuse parenchymal malignant disease are eligible. All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions, are not eligible. Lesions that are considered non-measurable include the following:
• Bone lesions
• Leptomeningeal disease
• Ascites
• Pleural/pericardial effusion
• Abdominal masses that are not confirmed and followed by imaging techniques
• Cystic lesions 4. Prior Treatment:
• No prior chemotherapy.
• ≥ 2 weeks since radiation therapy.
• No antidepressant treatment (eg, selective serotonin reuptake inhibitors, tricyclics, novel antidepressants, St. John's Wort or monoamine oxidase inhibitors) currently or within the last month. 5. If the patient requires pain medication, pain must be managed with non-codeine preparations, including but not limited to: acetaminophen, any morphine based preparation (short or long acting), hydromorphone, fentanyl, levorphanol or methadone. 6. CTC Performance Status 0-1. 7. Non-pregnant and non-nursing because of significant risk to the fetus/infant. 8. Required Initial Laboratory Data:
• Granulocytes ≥ 1,500/µl
• Platelet count ≥ 100,000/µl
• Serum creatinine ≤ 1.5 mg/dl or Calculated CrCl ≥ 60 ml/min
• Bilirubin ≤ 2.0 x Upper Limit of Normal (ULN)
• Serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.0 x ULN

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.

• Adult (Age > 18) patients undergoing scheduled, elective cardiac surgery with cardiopulmonary bypass
• Those who do not meet the inclusion criteria, pregnant women, prisoners, those with skin or systemic infections, those who are paraplegic or quadriplegic and those with allergies to the polyurethane material comprising the FitBit strap.

• Outpatient men and women age 18-70 years old with bipolar I, II, or NOS disorders, schizoaffective disorder (bipolar type), cyclothymic disorder, or major depressive disorder with mixed features
• Current diagnosis of alcohol use disorder (DSM V terminology) with onset ≤ age 25
• Alcohol use (by self-report) of at least 15 drinks in the 7 days prior to intake
• IF diagnosis of Bipolar I, II, or NOS Disorder: Current mood stabilizer therapy (lithium, anticonvulsant, atypical antipsychotic) with stable dose for at least 14 days prior to randomization
• IF diagnosis of Schizoaffective disorder (bipolar type): Current atypical antipsychotic therapy with stable dose for at least 14 days prior to randomization
• IF diagnosis of Major Depressive Disorder with mixed features: Current antidepressant therapy with stable dose for at least 14 days prior to randomization
• Baseline YMRS or HAMD scores ≥ 35 to exclude those with very severe mood symptoms
• Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar score of ≥ 10
• Therapy in past 14 days with naltrexone, acamprosate, disulfiram, or topiramate
• Vulnerable populations (e.g. pregnant, breastfeeding, incarcerated, cognitively impaired (e.g. dementia, mentally challenged))
• High risk of suicide defined as > 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
• Intensive outpatient treatment (defined as ≥ 3 visits each week) for substance abuse (AA, NA meetings, or less intensive counseling at baseline will be allowed)
• Severe or life-threatening medical condition (e.g., hepatic cirrhosis) or laboratory or physical examination findings consistent with serious medical illness (e.g., dangerously abnormal electrolytes)
• AST or ALT > 3 times the upper limit of normal
• History of severe side effects or allergic reaction with prior ondansetron therapy (e.g. for vomiting) or use of medications with significant drug-drug interactions with ondansetron (phenytoin, carbamazepine, and rifampicin, apomorphine, tramadol)

• Must provide consent to participate after being fully informed about the study procedures and the information to be collected
• Males and females
• Ages 18-60 years old
• All races and ethnicities
• Probands: Must meet DSM-IV criteria for bipolar I disorder with or without lifetime history of psychosis; Healthy Controls: Must have no personal history of any psychotic or mood disorder, or a family history of psychotic or recurrent mood disorder among their first-degree relatives
• Must be judged to be capable of completing the study procedures by study investigators
• Must be able to read, speak, and understand English
• An estimated IQ<70
• Major neurological or cognitive disorder (e.g., seizure disorder, traumatic brain injury, cerebrovascular disease, pervasive developmental disorder)
• Serious medical, neuro-ophthalmological, or neurological illness that could affect CNS functioning (e.g., decompensated cardiovascular disease, decompensated chronic obstructive pulmonary disease, late stages of diabetes, AIDS)
• DSM-IV diagnosis of alcohol or illicit substance abuse within 1 month, or alcohol or substance dependence within 3 months, or extensive history of past substance use
• Women who are pregnant (due to unknown risks related to MRI exposure)
• Presence of medical (e.g., artificial joints, brain aneurism clips, surgical pins, rods, wires, implants) or non-medical (e.g., metal piercing) irremovable metallic objects on/inside body (due to MRI-relevant risks)

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.

• Inpatient/Emergency Admission for traumatic injury
• Non-English speaking
• Self-inflicted injury
• Actively psychotic
• Incarcerated or in custody

• 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)