The MIND Study: The MGH/MIT Investigation of NAC on Dysregulation

The investigators will enroll 120 subjects. Participants will be 80 children with emotion dysregulation, 6-12 years of age. In addition, the investigators will include 40 children without emotion dysregulation as healthy controls to provide a normative comparison group for neuroimaging analyses.

All subjects that enter the study will undergo standard screening and diagnostic procedures. Individuals who express interest in the study, either by responding to advertising or by giving a referring clinician explicit permission to be contacted for research, will be screened for eligibility by the study coordinator or a research assistant via phone. If the interested youth meet criteria for either the ED or TD group, the parent/guardian will be asked to complete the Child Behavior Checklist (CBCL) online via RedCap, a secure online data capture system.

The study coordinator will send a link to complete the CBCL electronically to the parent/guardian via email. An online consent statement will appear, prompting parents to indicate their agreement to participate in the online questionnaire portion of the study. If the parent/guardian indicates their agreement, the data capture system will proceed to the CBCL.

After completing the CBCL, eligible participants based on inclusion and exclusion criteria will either be assigned to the ED or TD group. Eligible participants will be scheduled to speak with a study clinician via phone or secure Zoom call to obtain informed consent prior to completing further screening and baseline study procedures.

Written informed consent will be obtained from subjects' parent/guardian prior to initiation of the study protocol. Subjects aged 7 and older will sign age-appropriate assent forms. The study subjects and their parent may take as much time as they feel necessary to consider their participation in the study as well as consult with their family members or physician. Subjects may remain on most current treatments while participating in this study. Participation in this study is voluntary, and subjects may withdraw from the study at any time.

Informed consent will be obtained virtually. Study staff will send the consent form and assent form (when applicable) to subjects in PDF form ready for Adobe eSignature via email with a brief statement explaining why they are receiving this form and further instructions. Study staff will schedule a time for the subject and their parent(s)/guardian to meet with a study clinician via phone or secure Zoom to complete consent. For the ED group, the study clinician will have a conversation over the phone or Zoom with the subject and their parent(s)/guardian to obtain consent in the usual fashion: review the consent form, review inclusion and exclusion criteria, review risks and benefits of the study, review alternatives to participation, and answer any questions subjects and their parent(s)/guardian may have. If the subject and their parent(s)/guardian decide to participate, they will sign the consent form and assent form (when applicable) using Adobe eSignature. The study clinician will also sign the consent form using Adobe eSignature prior to beginning any study procedures. Subjects will be sent a copy of the signed form by email for their records. For the TD group, the same procedure will be followed but will be completed by the clinical research coordinator.

STUDY PROCEDURES

This will be an 8-week, double-blind randomized controlled study of NAC in the treatment of emotional dysregulation in children and adolescents. Subjects will include youth ages 6-12 years old. The primary outcome measures will be improvement in manic symptoms as measured by the Young Mania Rating Scale (YMRS) and improvement in depressive symptoms as measured by the Child Depression Rating Scale (CDRS).

The main outcome measures will be GSH levels in participants pre- and post- treatment as well as the Young Mania Rating Scale (YMRS) and the Children's Depression Rating Scale (CDRS).

The Child Behavior Checklist (CBCL) will be collected during pre-screening procedures and at post-treatment. The CBCL is used for inclusion in the study and a measure of psychiatric symptoms across multiple domains.

Pre-Screening Parents/guardians who inquire about having their child participate in this study and who provide explicit permission to be contacted for research will be contacted by a member of study staff to be screened by phone for inclusion and exclusion criteria. If a child may be eligible, detailed contact information will be collected. If a parent/guardian gives consent and their child gives assent to participate at the following screening/baseline visit, information regarding the child's medical, health, and psychiatric history that was collected in the phone screen will be stored securely with the other data that is collected during study participation. If the child does not enroll in the study for any reason, this information will be de-identified.

Potential subjects who meet eligibility criteria during the phone screen will be asked to complete the CBCL electronically via RedCap. The study coordinator will send the parent/guardian a link to complete the CBCL electronically via encrypted email, unless the parent/guardian has explicitly requested to receive email correspondence without encryption. The links will be unique to the subject, preventing subjects and their parent/guardian from accessing any other data stored on the password-protected database. This link will direct the parent/guardian to a page with a written consent statement about this portion of the research. The parent/guardian will then be asked to indicate their agreement to continue with the CBCL by clicking the appropriate button, providing electronic consent to participate in the online questionnaire. If the parent agrees to complete the CBCL, they will be directed to the online questionnaire.

The CBCL should take approximately 20 minutes to complete. If the potential subject meets eligibility criteria based on the CBCL scores, the coordinator will contact the parent/guardian to schedule a virtual screening/baseline visit with a study clinician. If the parent/guardian gives consent and their child gives assent to participate at the following screening/baseline visit, the parent/guardian's responses to the online CBCL questionnaire completed during pre-screening will be stored securely with the other data that is collected during study participation. If the child does not enroll in the study for any reason, this information will be de-identified.

Baseline Visit

After the consent/assent form is signed, the investigators will do the following:

Have the parent/guardian complete questionnaires through REDCap prior to the visit (study coordinator will email link ahead of time) regarding:

* Current medications * Demographic details * Parent-Young Mania Rating Scale (P-YMRS) * Social Responsiveness Scale (SRS) questionnaire (ED only) * Parent-completed Children's Depression Rating Scale (CDRS) (ED only) * The Modified Overt Aggression Scale (MOAS) (ED only) * MIT MRI Metal Safety Screening Form

A study clinician will review this information and meet with parent/guardian and child during a virtual visit over Zoom. In this visit, the clinician will:

* Review current medications (ED only) * Complete the Columbia Suicide Severity Rating Scale (C-SSRS) assessing past and current suicidality and self-harmful behaviors * Record baseline severity scores of Clinical Global Impression (severity scores) for mania, depression and overall bipolar disorder (ED only) * Complete the Young Mania Rating Scale (YMRS) to assess manic symptoms

All assessments and scales will be completed via REDCap.

The study coordinator will also complete a phone call with the ED subjects and their parent(s)/guardian on the same day as the tele-visit with the study clinician in order to complete the following procedures. Parents/guardians will be asked to self-report height and weight of their child. It will be noted that these measurements were provided by a parent/guardian report rather than study staff measurement.

The investigators expect most homes will have measures for weight and height and will request this information at the first visit. However, if this is not the case, the investigators can provide measuring tools. Proper safety procedures will be reviewed with subjects and parents, including the use of 911 for emergencies and how to contact the study clinician or covering clinician 24/7. Those subjects who terminate study participation before the completion of the study will be asked to complete all tasks scheduled to take place on the final study visit at the time of study discontinuation.

Randomization Randomization to NAC or placebo will occur once a subject is scheduled for a baseline visit when the clinical trials pharmacy will be given a subject name that the pharmacy will associate with a number identifier. Randomization lists stratified by gender and age will be generated by our statistician and utilized by the MGH Clinical Trials Pharmacy. The investigators have extensive experience maintaining blinding, wherein the investigators have our central Mass General Hospital Clinical Trials Pharmacy serve as the only part of the greater trial team that is aware of the assignment to active or placebo during study participation. The trials pharmacy will receive products identified by the sponsor as active or placebo fill package these products with unique identifiers, maintain the placebo-active ratio, and maintain blinding until study completion. For the purpose of the final analysis, the official clinical database will not be unblinded until medical/scientific review has been completed, protocol violators have been identified (if appropriate), and data collection has been declared complete. In the extreme event where subject safety will be compromised by maintaining the blind, eg. an adverse event where treatment is dependent on knowing if they were on active or placebo medication, the investigators will unblind the status of the subject's study agent, following emergency protocols in place in our department and institution.

Dosing Active and placebo study treatment will be purchased from BioAdvantex. ED subjects will receive effervescent tablets of NAC. Subjects will receive 1800mg (2 900mg tablets) of NAC daily or a matched placebo. This dosing was selected based on a previous successful open-label trials of NAC in youth (Wozniak, DiSalvo et al. 2022). The child will take the study drug (or placebo) by drinking a tablet dissolved in a liquid, either twice a day or once a day according to personal preference, for the entire study.

Remote Study Medication Dispensation Study medication will be shipped by BioAdvantex to MGH Clinical Trials Pharmacy (CTP) where it will be stored and dispensed. Randomization lists stratified by gender and age will be generated by our statistician and utilized by the MGH Clinical Trials Pharmacy. Study staff will pick up the study medication that is assigned to each participant from the MGH CTP, remaining blinded to whether it is an active or placebo product, and send it via courier mail service directly to the participant's home address, only if the participants reside in the state of Massachusetts. Staff will be trained to follow all guidelines elaborated by the MGH CTP and Drug Enforcement Agency in this process. The study medication will be ordered and shipped following the baseline study visit, with sufficient supply to cover participation for all 8 weeks. An additional week of study treatment will be sent to cover any time between the end of Week 8 and when the final MRI scan is scheduled. Patients will remain on study drug until the follow up visit after the EP MRI and thus overage is being provided to get them through to that visit. A member of the study staff will contact the participant with the estimated date and time of the prescription d

• Mean Change in Child Behavior Checklist (CBCL) scores [Time frame: Baseline to Endpoint (Week 8)]
• Mean Change in Social Responsiveness Scale (SRS) Scores [Time frame: Baseline to Endpoint (Week 8)]
• Mean Change in the Parent-Young Mania Rating Scale (P-YMRS) Score [Time frame: Baseline to Endpoint (Week 8)]
• Mean Change in the Children's Depression Rating Scale-Parent (CDRS-P) Score [Time frame: Baseline to Endpoint (Week 8)]
• Mean Change in the Modified Overt Aggression Scale (MOAS)- Parent [Time frame: Baseline to Endpoint (Week 8)]