Clinical trial NCT02357290
Conditions: Bipolar Disorder
Keywords: mania temper tantrum irritability mood bipolar
Sponsor: Massachusetts General Hospital
Start date: 2014-01-01; Completion date: 2018-09-24
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Children between the ages of 5-17 years old who have or display symptoms of emotional dysregulation (explosiveness, mood swings, irritability, and/or violent behavior) are invited to participate in a 12-week research study to determine the effectiveness and safety of the natural treatment N-acetylcysteine (NAC) for children with emotional and behavioral problems. After undergoing a comprehensive evaluation by medical doctors with a specialty in this area, children who are found eligible to participate in this research study will be treated with NAC. Following the evaluation period, this research study requires 12 weekly visits, either in our office or over the phone, in an effort to closely monitor each child's response to the medication. Eligible participants will receive study-related evaluations and weekly study visits with our study doctors at no cost.

Detailed description:
This will be a 12-week, open-label study of NAC in the treatment of bipolar disorder in children and adolescents. Subjects will include youth ages 5-17 years with a bipolar spectrum disorder (type I, II, or NOS), mixed, manic, or hypomanic state, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM-5 (American Psychiatric Association, 2013). 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).

Bipolar diagnoses will be made according to the DSM-5 in a clinical evaluation by a Child Psychiatrist and confirmed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Epidemiological Version (K-SADS-E)(Orvaschel, 1994). All subjects must have a YMRS score of at least 15. Only patients who are not responding to their current treatment regimen will be tapered from their medications; youth on concomitant psychiatric medications will be permitted to continue those medications as listed in the concomitant medication section.

Arms: arm 1: 12-week, open-label treatment with NAC. Subjects will be treated with the following dose:

Subjects ages 5-12:

Week 1: 900mg po daily Weeks 2+: 900mg po QAM, 900mg po QPM

Subjects ages 13-17:

Week 1: 900mg po daily Weeks 2-3: 900mg po QAM, 900mg po QPM Weeks 4+: 1800mg po QAM, 900mg po QPM

In Weeks 3-12 for subjects ages 13-17, we will encourage twice per day dosing, but we will permit daily dosing if needed for adherence.
Interventions: intervention 1: Open-label Treatment with N-Acetylcysteine
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
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Study Protocol: 
Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 with Bipolar 
I, Bipolar II, and Bipolar Spectrum Disorder 
 
NCT02357290 
 
 
 
 
Janet Wozniak, MD 
Massachusetts General Hospital 
Clinical and Research Program in Pediatric Psychopharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
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1. BACKGROUND AND SIGNIFICANCE 
 
As highlighted in NIMH Research Roundtables, pediatric bipolar disorder is now recognized as a 
significant public health concern (J Biederman et al., 2001). Children with bipolar disorder make 
up the most difficult psychopathologic group with poor functioning and high levels of 
psychiatric comorbidity, hospitalization and special education services. Aggressive behavior, 
suicidality and reckless impulsivity are common problems for bipolar youth and some are 
diverted to the youth criminal justice system (Wozniak & Biederman, 1997). Pediatric bipolar 
disorder is commonly characterized by high levels of irritability as well as mixed states, that is, 
concurrent features of both mania and depression. The clinical picture of concurrent depression 
and mania significantly complicates the diagnosis, course and treatment of pediatric bipolar 
disorder. The severity of illness associated with pediatric bipolar disorder is so extreme that not 
treating is usually not a viable option. 
 
Common Pharmaceutical Treatments are Inadequate 
Part of the controversy surrounding the diagnosis of bipolar disorder in youth is the concern that 
children given the diagnosis may be subjected to treatments that are fraught with potentially 
serious side effects. Children with bipolar disorder are frequently treated with a multitude of 
medications despite unclear efficacy and inadequate safety data (J. Biederman et al., 1998; 
Kowatch & DelBello, 2003). Medications such as lithium, which have been the mainstay of 
pharmacotherapy for bipolar adults, show only moderate effectiveness in children (Kowatch et 
al., 2000), and side effects of newer atypical antipsychotic agents (e.g. risperidone, aripiprazole, 
olanzapine and quetiapine) have been found to limit these drugs’ utility (Liu et al., 2011). 
 
For several decades, mood stabilizers, including lithium, valproate, and carbamazepine, have 
been the cornerstone of acute and maintenance therapy for mania in bipolar adults (Sachs, Printz, 
Kahn, Carpenter, & Docherty, 2000; Sachs & Thase, 2000). Despite various advantages of these 
compounds including putative neuroprotective effect, there is a gap between drug efficacy in 
controlled trials and the effectiveness of mood stabilizers in the clinical setting. For example, in 
controlled and naturalistic trials in children mood stabilizers were demonstrated to be only 
moderately effective for the treatment of mania (J. Biederman et al., 1998; Geller et al., 1998; 
Kowatch et al., 2000). In the naturalistic setting, mood stabilizer therapy was associated with a 
slow onset of action and substantial risk of relapse (J. Biederman et al., 1998). In the controlled 
trials, there were frequent adverse events, noncompliance, and treatment dropouts (Kowatch et 
al., 2000; Wagner et al., 2002). In a chart review of our naturalistic experience in the treatment of 
pediatric bipolar disorder, we documented that the traditional mood stabilizers lithium, valproic 
acid and carbamazepine, were minimally effective in treating children and adolescents with 
bipolar disorder (J. Biederman et al., 1998). 
 
In comparison to conventional mood stabilizers, which are limited in their efficacy and carry 
adverse side effect profiles, more encouraging results have emerged with the use of atypical 
antipsychotic medications. For years, lithium had been the only agent with FDA approval for 
bipolar disorder in youth. The atypical antipsychotic medications have been approved by the 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
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Food and Drug Administration (FDA) for use in mania in adults (Perlis, Welge, Vornik, 
Hirschfeld, & Keck, 2006), and in the case of risperidone and aripiprazole, down to age 10 for 
children with mania (J. Biederman, McDonnell, et al., 2005; J. Biederman et al., 2007; J. 
Biederman, Mick, et al., 2005). There is a very real concern, however, regarding the 
development of weight gain and diabetes in individuals treated with atypical antipsychotic 
medications (Leslie & Rosenheck, 2004; Lindenmayer, Nathan, & Smith, 2001; McElroy et al., 
2004; Meltzer, 2005; Regenold, Thapar, Marano, Gavirneni, & Kondapavuluru, 2002; 
Rosenbloom, 2002), and tardive dyskinesia remains a risk associated with these treatments 
(Aggarwal & Burnett, 2013; Gardos & Cole, 1995; J. Kim, Macmaster, & Schwartz, 2014). 
 
In addition to weight gain, risperidone is associated with elevations of the hormone prolactin (J. 
Biederman, Mick, et al., 2005), which can result in galactorrhea in youth and has unknown 
effects on pubertal development (Y. K. Kim, Kim, & Lee, 1999; Petty, 1999; Popli, Gupta, & 
Rangwani, 1998; Turgay, Binder, Snyder, & Fisman, 2002; Wudarsky et al., 1999). 
 
Furthermore, adverse effects and noncompliance may be a more significant problem in children 
than in adults. Side effects such as weight gain, acne, cognitive impairment, or gastrointestinal 
distress can make youth self-conscious and non-compliant. Also, adverse effects due to drug-
drug interactions or routine blood collection for serum level monitoring increases the risk of 
refusing medications with the attendant consequences on clinical course and adaptive life. 
Clinicians and parents would happily turn to alternative treatments were more information 
available regarding their efficacy and confirming their presumed safety. In the absence of this 
data, the tenets of evidence based medicine dictate the use of pharmaceutical agents with 
established efficacy, especially those with approval, despite miserable side effects (Kowatch et 
al., 2005). 
 
N-acetylcysteine and Psychiatry 
Alternative products, including N-acetylcysteine (NAC), may offer a healthy option for treating 
developing youth with psychiatric disturbance. As bipolar disorder is severely impairing, 
intervention of some sort is usually necessary. Alternative treatments may be acceptable to a 
subset of individuals throughout the lifecycle who refuse treatment with conventional agents.   
 
Nutritional products including NAC have demonstrated utility in the treatment of mood 
disorders. These agents offer the promise of a safe and healthful approach to controlling the 
symptoms of bipolar disorder in youth. NAC is an acetylated amino acid and a precursor of 
glutathione. When ingested, NAC increases cysteine levels, leading to the synthesis of more 
glutathione in the brain; glutathione then acts as an anti-oxidant to reduce oxidative stress, which 
has been implicated in bipolar disorder and major depression (Magalhaes et al., 2011; Smaga et 
al., 2012). Ingesting glutathione itself is not helpful, as it never reaches the brain due to poor 
absorption and rapid metabolism. NAC, however, crosses the blood-brain barrier with ease 
(Dean, Giorlando, & Berk, 2011; Witschi, Reddy, Stofer, & Lauterburg, 1992). 
 
NAC has an additional role in regulating glutamate levels. The cysteine portion of NAC is a key 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
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Last Modified: 08/22/2018 
 
 
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player in the transport of glutamate out of the cell. Excessive glutamate levels have been 
implicated as a possible mechanism of psychopathology in psychiatric conditions. Through a 
feedback mechanism with astrocytes, this can result in diminished release of glutamate into the 
extracellular space. Thus, this additional role in regulating glutamate levels may also be 
therapeutic, as malfunctions in the glutamate system result in consequent excito-toxic damage 
from activation of the N-methyl-D-Aspartate (NMDA) glutamate receptor. 
 
Coupled with the purported mechanism of action, clinical trials have also provided compelling 
interest in NAC as an evidence-based treatment for pediatric bipolar disorder. Research has 
demonstrated the utility of NAC in the treatment of bipolar disorder in adults: both open-label 
and double-blind, randomized, placebo-controlled trials of NAC have found decreases in 
depression rating scale scores and improvements in global functioning (Berk, Copolov, Dean, 
Lu, Jeavons, Schapkaitz, Anderson-Hunt, & Bush, 2008; Berk et al., 2011). NAC has also 
proven to be safe in pediatric studies: children with autistic disorder have responded well to 
treatment with NAC without any serious adverse events or side effects (Ghanizadeh & Moghimi-
Sarani, 2013; Hardan et al., 2012). NAC has been shown to be helpful in treating a multitude of 
disorders (OCD; marijuana, nicotine, and cocaine addictions; gambling; skin picking; nail biting; 
trichotillomania; schizophrenia; autism; and bipolar disorder), suggesting it may address the end 
of the line pathway targets common to multiple disturbances (Wozniak, in press). 
 
Rationale 
Emerging research suggests that NAC may be an effective treatment for bipolar disorder, but 
there are no published data to date in the pediatric bipolar population. Additional research is 
needed on NAC’s optimal dosing, side effects, and efficacy in treating pediatric bipolar disorder.  
 
2. SPECIFIC AIMS 
 
Specific Aim I: Assessing the efficacy of NAC in the treatment of pediatric bipolar spectrum 
disorders. Other research suggests that NAC is effective in the treatment of bipolar disorder in 
adults (Berk, Copolov, Dean, Lu, Jeavons, Schapkaitz, Anderson-Hunt, & Bush, 2008; Berk et 
al., 2011), but no work has assessed the effectiveness of NAC for pediatric bipolar disorder and 
associated symptoms. Hypothesis 1: NAC will yield a reduction in the symptoms of pediatric 
bipolar spectrum disorders, as measured by scores on the YMRS and the Mania Symptoms 
Checklist. 
 
Specific Aim II: Assessing the side effect profile of NAC. Medications used to treat bipolar 
disorder in youth are fraught with side effects including sedation, extra-pyramidal symptoms, 
cognitive clouding, weight gain and diabetes. In contrast, NAC has health benefits. Hypothesis 2: 
The use of NAC will have few side effects in youth, as measured by the number of adverse 
events. 
 
3. LENGTH OF STUDY 
 


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with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
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The study will last up to 15 weeks from the initial phone screen (it could take up to three weeks 
to schedule and complete the initial screening process). Once subjects have completed the 
screening process, they will begin the 12-week open-label phase. Subjects will be assessed 
weekly throughout the study for efficacy and tolerability. 
 
4. SOURCE OF SUJECTS 
 
We will recruit subjects from the pool of existing subjects, patients, and new referrals to the 
Pediatric Psychopharmacology Program at MGH, as well as through advertising in the local 
media and online. If a potential subject's clinician ascertains that the patient has an interest in 
study participation, the clinician will only offer contact information for the study to their 
patients. The patient can then contact the study coordinator for more information on the actual 
study. All subjects that enter the study will undergo standard screening and diagnostic 
procedures.  
 
The majority of subjects referred to our program first participate in our general screening 
protocol entitled, “Screening Protocol for Children and Adolescents with Bipolar and Bipolar 
Spectrum Disorder” (Protocol # 2001-P-001247). After participating in this screening protocol, 
subjects are invited to participate in specific studies based upon eligibility requirements (i.e. age, 
prior medication efficacy or tolerability). 
 
Subjects who have completed a previous medication trial in our program may be eligible to 
participate in this study, as described in the Study Design section. 
 
5. SUBJECT ENROLLMENT 
 
All subjects that enter the study will undergo standard screening and diagnostic 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. Subjects 
ages 14-17 will document their assent on a designated line of the general study consent form. 
Subjects who turn 18 years old during the trial must re-sign on a designated line in the 
parent/guardian consent when they reach age of maturity. 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. Only patients who are not responding to their 
current treatment regimen will be tapered from their medications to enter this study. 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. 
 
6. SUBJECT SELECTION CRITERIA 
 
A. Inclusion Criteria 
 
1. Male or female subjects, 5-17 years of age. 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
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2. Subjects must have a DSM-5 diagnosis of a bipolar spectrum disorder (type I, II, or 
Not Otherwise Specified (NOS)), and currently displaying mixed, manic, or 
hypomanic symptoms according to clinical assessment based on the DSM-5 and 
confirmed with structured diagnostic interview (Schedule of Affective Disorders and 
Schizophrenia for School-Age Children - Epidemiological Version (K-SADS-E)). 
3. Subjects and their legal representative must have a level of understanding sufficient to 
communicate intelligently with the investigator and study coordinator, and to 
cooperate with all tests and examinations required by the protocol. 
4. Subjects and their legal representative must be considered reliable. 
5. Each subject and his/her authorized legal representative must understand the nature of 
the study. The subject’s authorized legal representative must provide written consent 
and the subject must provide written assent. 
6. Subjects must have an initial total score on the YMRS of at least 15. 
 
B. Exclusion Criteria 
 
1. Investigator and his/her immediate family (defined as the investigator’s spouse, 
parent, child, grandparent, or grandchild). 
2. Serious or unstable illness including hepatic, renal, gastroenterological, respiratory, 
cardiovascular (including ischemic heart disease), endocrinologic, neurologic, 
immunologic, or hematologic disease. 
3. Uncorrected hypothyroidism or hyperthyroidism. 
4. History of sensitivity to N-acetylcysteine, a history of intolerance to N-acetylcysteine 
or a non-responder after 2 months of treatment at adequate doses as determined by the 
clinician. 
5. Severe allergies or multiple adverse drug reactions. 
6. Current or past history of seizures. 
7. Active substance abusers, per clinician judgment. 
8. Judged clinically to be at serious suicidal risk. 
9. Currently displaying psychotic features. 
10. Any concomitant medication with primary central nervous system activity other than 
specified in the Concomitant Medication portion of the protocol. 
11. Current diagnosis of schizophrenia. 
12. Pregnancy. 
13. C-SSRS score ≥ 4. 
14. IQ < 70. 
 
7. DESIGN 
 
This will be a 12-week, open-label study of NAC in the treatment of bipolar disorder in children 
and adolescents. Subjects will include youth ages 5-17 years with a bipolar spectrum disorder 
(type I, II, or NOS), mixed, manic, or hypomanic state, according to the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition DSM-5 (American Psychiatric Association, 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
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2013). 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). 
 
Bipolar diagnoses will be made according to the DSM-5 in a clinical evaluation by a Child 
Psychiatrist and confirmed using the Schedule for Affective Disorders and Schizophrenia for 
School-Age Children - Epidemiological Version (K-SADS-E)(Orvaschel, 1994). All subjects 
must have a YMRS score of at least 15. Only patients who are not responding to their current 
treatment regimen will be tapered from their medications; youth on concomitant psychiatric 
medications will be permitted to continue those medications as listed in the concomitant 
medication section. 
 
We will consent and screen 40 subjects to ascertain 20 subjects who complete 12 weeks of open-
label treatment. The subject’s first visit to the office consists of a meeting with a study clinician 
who explains the study, obtains informed consent and assent, and administers an abbreviated 
form of the structured diagnostic assessment (45-90 minutes). After the evaluation with the study 
clinician, the subjects will undergo a neuropsychological assessment (35-45minutes). 
 
We anticipate that subjects may enter this trial following completion of/withdrawal from other 
Bipolar Disorder protocols in our office, and that there may be procedural overlap. So as to not 
burden subjects/parents/guardians with redundant time commitments, we will use the following 
diagnostic data previously collected: 
 
• If a subject has completed an evaluation with one of the study clinicians and/or the 
structured assessment within the 12 months prior to entrance into this study, they will not 
be asked to repeat any overlapping diagnostic procedures. We will use the previously 
collected data. However, the study clinician will review the interval time period to assess 
for clinically significant medically or psychiatric history to ensure that the subject meets 
appropriate study entrance criteria, including a DSM-5 diagnosis of a bipolar spectrum 
disorder. 
 
• If the subset of scales assessing intelligence (WASI-II/KBIT-2) and cognitive functioning 
(select WISC/WPPSI-III tasks) in the neuropsychological battery have been completed 
within 12 months prior to entrance into this study, subjects will not be asked to repeat 
these procedures. We will use the previously collected data. Study participants (or their 
parent/guardian) may request the results of their cognitive testing. In this case, the subject 
will receive a letter providing a basic interpretation of the results and referring the subject 
(or their parent/guardian) to the department's supervising neuropsychologist for any 
questions or concerns. 
 
Eligible subjects will be required to come into the office for the following visits: Screening, 
Baseline (Week 0), Weeks 1-4, Week 8, and the Week 12 final visit. Visits for Weeks 5-7 and 9-
11 will be completed by the clinician over the phone; however, if the parent and subject prefer to 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
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come into the office for these visits instead, they may do so. During this time subjects will 
receive prescriptions from the study doctor for their NAC treatment. 
 
Although every effort will be made to encourage subjects to keep regularly scheduled 
appointments, in the event that a subject is unable to come into the office within a reasonable 
timeframe of a scheduled study visit, and the study doctor feels that subject safety will not be 
jeopardized by doing so, the clinician may conduct the visit with the subject and parent/guardian 
over the phone; this will ensure that each subject will be continuously monitored by the clinician 
throughout the course of the study despite unforeseen scheduling circumstances. However, if a 
subject completes a phone visit instead of a scheduled office visit, the office visit must be made 
up within two weeks. Neither the Screening visit, nor the Baseline visit, nor the final study visit 
may be conducted over the phone.  
 
Vital signs (blood pressure, pulse, temperature), height, and weight will be measured at every 
office visit. A urine drug screen will be performed for all subjects aged 12 and over at the 
screening visit. For female subjects who have begun menstruating, a urine pregnancy test will be 
performed at the screening visit, followed by a serum pregnancy test if the urine test is positive. 
If a participant has a positive serum pregnancy test, the study doctor will inform the subject, and 
she will not be able to take part in the study. The decision whether to inform the parent of these 
results will be made by the physician based on the participant’s age and maturity level and the 
requirements of the law, unless the participant agrees to parental notification. 
 
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; however, if the subject refused to complete any portions of the cognitive 
assessment at baseline, or if the subject was not yet exposed to the study treatments, it is possible 
that we will not ask him/her to complete these tasks at endpoint, per clinician judgment. 
Medication compliance for the study will be assessed at each study visit after Baseline. 
 
Dosing 
 
We plan to treat subjects with the following dose: 
 
Subjects ages 5-12 
Week 1: 900mg po daily 
Weeks 2+: 900mg po QAM, 900mg po QPM 
 
Subjects ages 13-17 
Week 1: 900mg po daily 
Week 2: 900mg po QAM, 900mg po QPM 
Weeks 3+: 1800mg po QAM, 900mg po QPM 
 
In Weeks 3-12 for subjects ages 13-17, we will encourage twice per day dosing, but we will 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
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permit daily dosing if needed for adherence. 
 
The rationale for the NAC dosing is based on two pilot clinical trials and one case report 
indicating that oral dose of NAC in the range of 800-2700mg is well-tolerated in children 
(Ghanizadeh & Derakhshan, 2012; Ghanizadeh & Moghimi-Sarani, 2013; Hardan et al., 2012). 
Hardan and colleagues’ (2012) use of increasing doses of NAC in the range of 900-2700mg 
appears to have been more efficacious than Ghanizadeh’s and Moghimi-Sarani’s (2013) dosing 
of 1200mg per day. Therefore, we decided upon an age-appropriate forced titration dosing within 
the 900-2700mg range, which has been shown to be safe for children. 
 
PharmaNAC brand was chosen to supply the NAC tablets due to its palatability and ease of 
administration. Younger subjects have difficulty swallowing pills, but PharmaNAC tablets offer 
the advantage that they dissolve in water and do not require that subjects swallow pills. This 
brand of NAC has been used in previous studies (Hardan et al., 2012; Miller & Angulo, 2014) 
and has excellent reliability of content. The Principal Investigator has successfully used this 
brand of NAC in clinical practice. 
 
The supplements will be stored in our research pharmacy and delivered to the Pediatric 
Psychopharmacology Unit, where a clinician will dispense them. Subjects are instructed to return 
unused tablets. Pill counts will be reviewed each visit to ensure compliance. 
 
Concomitant Medications 
 
A detailed past and present treatment history will be taken as part of initial evaluation. Patients 
who are partially responding to current psychotropic medication yet continue to have symptoms 
of mania and depression will be permitted to continue on their current regimen, provided that the 
patient’s regimen remains the same throughout the study. Patients treated with these medications 
must be on a stable dose for at least one month prior to study entry. No new medications (except 
for the use of the benzodiazepine lorazepam listed below) or alterations to the current regimen 
may be initiated throughout the duration of study participation.  
 
Only patients with a poor response to their current medication treatment will be advised to 
consider a taper off their medications for entry into the study. No patient will be tapered from 
medication that is useful to him or her.  
 
The use of the benzodiazepine lorazepam is permitted during the study for exacerbation of 
symptoms of agitation. Patients may not exceed a dosage of 2mg lorazepam per day and 
lorazepam is permitted for a maximum of 3 days during the study. Any greater need for 
lorazepam will be considered evidence of poor treatment response and grounds for drop from the 
study. 
 
Additionally, participants who are on a stable dose of ADHD medications may continue on that 
dose throughout the study. However, no new medications for ADHD or alterations to the current 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
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ADHD regimen may be started throughout the duration of participation in the study, per clinician 
judgment. 
 
Non-pharmacological treatments such as individual, family or group therapy will be allowed if 
they were in place before the patient joined the study. The patient’s therapy regimen must remain 
the same throughout the study. No new non-pharmacological treatments may be initiated after 
study participation has begun. 
 
Washout Period 
 
Medication washout may be recommended by our clinicians on a case-by-case assessment, 
considering the duration on drug, the dose, the adverse effects associated with the treatment, and 
potential effects of stopping that medication/treatment. Only subjects not responding to current 
treatment will be tapered from medication. No subject on a useful treatment will be tapered from 
medication for entry into this study. The referring or study clinician will monitor medication 
tapers in agreement with the research subject and his/her legal guardians. Our office does not 
take over care for the patient, but remains available during this time period. The washout 
schedule will be discussed with the subject’s family as well as the current provider.  
 
Typically a 7-day washout period is recommended for antidepressant medications and 
atomoxetine (with the exception of Prozac requiring 14 days). Mood stabilizers/atypical 
antipsychotics are generally washed out over the course of 7 days, while stimulants are 
discontinued in 2 or 3 days. 
 
Screening Visit (Week 99) 
 
Before any participant can start the study, the study clinician will discuss the details of the study 
with the participant and his/her parent/guardian. Before starting the screening process, the study 
clinician will obtain informed consent from the parent or guardian and assent from the child 
subject. Assent will be obtained, in writing, from each child aged 7 or older who, in the opinion 
of the Investigator, is capable of providing assent based on his/her age, maturity, and 
psychological state. When assent is not obtained, the Investigator will document his/her rationale 
in the research records. 
 
After the consent/assent form is signed, we will do the following: 
• Review medical and health questions with the participant and his/her 
parents/guardians. (For example, “Does your child have a history of any medical 
conditions such as diabetes or hypertension?”) 
• Obtain psychiatric history and administer the YMRS, the CDRS, the HAM-D, the 
C-SSRS, and the K-SADS-E mania and depression modules to determine that 
subject meets the diagnostic criteria of a current DSM-5 bipolar spectrum disorder 
(mixed, manic, or hypomanic) and has an YMRS score ≥ 15. 
 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
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All exclusionary and inclusionary criteria will be reviewed. Appropriate patients will undergo: 
• Assessment battery (CBCL, SAICA, FES) 
• Cognitive evaluation (IQ and cognitive function [subtests of the WASI-II or 
KBIT-2, the WISC-IV or WPPSI-III]) 
▪ Select WPPSI-III subtests will be used in the place of the WISC-IV 
processing speed subtest for children younger than 6 years. 
▪ The KBIT-2 will be used in the place of the WASI-II to assess IQ in 
children younger than 6 years. 
• Physical exam 
• Vital Signs (blood pressure, pulse, temperature), height, and weight 
• Urine pregnancy test (for females who have begun their period) 
• Urine drug screen (for subjects age 12 years and older) 
 
The above may take place over two visits over the course of three weeks, if necessary. All are to 
be completed prior to the Baseline Visit. Any subjects requiring medication washout must be 
tapered off this medication prior to Baseline Visit as indicated in the washout section. Patients 
who do not meet all the criteria for enrollment after these assessments will be discontinued. 
 
Baseline Visit (Week 0) 
 
Subjects must continue to meet all inclusionary and exclusionary criteria at this visit 
• The study clinician will ask the parents/guardians questions about their child’s 
symptoms of bipolar disorder 
• Study clinician will administer additional scales: the ADHD Rating Scale and 
BPRS 
• The parent and subject will complete  
• Vital signs (blood pressure, pulse, temperature), height, and weight 
• Subjects will receive study treatment 
 
Weekly Visits (Weeks 1 through 12) 
 
Weekly study visits will have a visit window of 7 +/- 2 days to facilitate scheduling. 
 
During these visits: 
• The study clinician will ask the parents/guardians questions about their child’s 
symptoms of bipolar disorder 
• The study clinician will also ask if the participant is having any side effects and if 
they have taken any other medications since the last visit 
• Blood pressure, pulse, height, weight, and temperature will be obtained (unless it 
is a phone visit week) 
• At the last visit (or at time of drop from study) al subjects will undergo repeat 
cognitive evaluation. 


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Study Discontinuation 
 
Subjects may drop at any time due to patient preference, physician decision, need for psychiatric 
hospitalization, or a poor response to treatment. Poor response to treatment will be measured by 
a CGI-bipolar score that is 2 points higher (more severe) than baseline for 2 weeks in a row or a 
YMRS score that is 30% higher than baseline for 2 weeks in a row, which may lead to drop from 
the study as determined by the clinician. Initial and emergent suicidality will be assessed weekly 
through administration of the Columbia Suicide Severity Rating Scale (C-SSRS). Subjects 
scoring 4 or higher will be dropped from the study. In addition, drop from study will occur at 
clinician discretion for lack of efficacy, non-compliance with treatment or inability to tolerate 
study treatment. 
 
Subjects will receive three months of optional pro bono clinical care visits (one appointment per 
month) with a study doctor at the completion of the study, or if they are required to discontinue 
for the above reasons. These appointments must take place within three months of the subject’s 
final study visit. No research data will be collected at these follow-up visits. The three months of 
follow-up care are a courtesy that is offered to help find long-term care. Subjects will receive 
referrals to clinicians in their communities. 
 
Subjects who fail to return medication for two consecutive office visits, fail to keep study 
appointments, or are non-compliant (less than 70% compliance for two weeks or longer) may be 
dropped from the study. These study subjects will be given a referral to clinicians in their area. 
 
If a subject becomes pregnant or is found to be abusing substances during the study, he or she 
will be discontinued from the study and given a referral, as well. 
 
If a subject would like us to forward their clinical history to his/her primary care physician, or a 
new clinician, we will forward any pertinent information. If a subject who has come from the 
clinic of the investigator happens to drop out of the study, he or she will return to his or her 
treating physician. 
 
Audio Recordings 
 
For quality control purposes, the rating scales completed during office visits may be recorded. 
The PI will use these recordings to monitor quality control and inter-rater reliability in this study. 
Each recording will be coded with patient initials and number to maintain confidentiality. These 
recordings will be stored in a password-protected database. 
 
Data Collection 
 
Data will be collected using StudyTRAX. StudyTRAX is an electronic data capture system that 
streamlines data collection and management and ensures data integrity. StudyTRAX software 
allows researchers to design and implement study surveys for collected, story, retrieving, and 


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manipulating data electronically. 
 
Participants and/or research staff will enter survey responses into electronic assessment forms, 
using computer terminals at the research site. The responses will then be transmitted securely via 
an encrypted connection and stored in a secured database. Electronic data capture obviates the 
need for subsequent data entry by staff, thus minimizing human error. However, it is still 
possible that rating scales will be collected in paper form in the case that StudyTRAX is not 
working or unavailable. 
 
 
8. ASSESSMENTS (see Table 1) 
 
A. K-SADS-E (Epidemiologic Version) 
❖ We will collect information for psychiatric diagnoses in children with study relevant 
modules of the KSADS-E (Epidemiologic Version)(Orvaschel, 1994). 
❖ This is a widely used, semistructured, diagnostic interview with established psychometric 
properties. Study staff can effectively administer it in 45 to 90 minutes, although more 
complex cases may require additional time. This assessment will be administered by a 
study clinician. 
❖ For all children, psychiatric data will be collected from the primary caretaker. All 
children and primary caregivers will be seen in direct clinical interview with a trained 
member of study staff. 
❖ The mania and depression modules will be administered prior to the baseline visit to 
ensure entry criteria are met.  
❖ The subject’s parent/guardian will also be asked a series of background information 
questions regarding the subject’s age, sex, education history (tutoring, placement in 
special classes, repeated grade), intactness of family of origin, and psychological and 
psychiatric treatment history, including past and current therapy and medication for 
emotional, behavioral, and attentional problems. In addition, questions about occupation 
and level of education of the subject’s parents will be asked to determine socioeconomic 
status; this information will be entered on the study-specific form (“Background 
Information/KSADS face page”). 
 
B. Child Behavior Checklist-Parent Form (CBCL) 
❖ The CBCL (T.M. Achenbach, 2000; T. M. Achenbach & Dumenci, 2001) is a 
standardized assessment of child behavior problems and social competence. Due to its 
extensive use and available norms, it provides us with an effective method of comparing 
our sample with others in the literature. 
❖ The CBCL records, in standardized format, the behavioral problems and competencies of 
children aged 4 to 18, as reported by their parents/guardians. 
❖ The CBCL is scored on the recently revised social competence and behavior problem 
scales of the Child Behavior Profile. A T-score above 70 is considered to be a clinically 
meaningful indicator of childhood psychopathology. 


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❖ Administered at beginning of study to characterize the groups and ensure their similarity. 
 
C. Social Adjustment Inventory for Children and Adolescents (SAICA) 
❖ The SAICA (John, Gammon, Prusoff, & Warner, 1987) is a semi-structured interview of 
the child or parent that measures social functioning in children 6 to 18 years old. 
❖ Content areas assessed include activities, peer relations, family relations, and academic 
performance. A total score is then calculated as the arithmetic mean of all global rating 
scores. 
❖ We will administer this scale to parents/guardians at beginning of study and endpoint to 
assess the impact of treatment on social functioning. We will administer this scale for all 
subjects, including 5 year olds. 
 
D. Family Environment Scale (FES) 
❖ As an additional measure of the family environment, we will use the Moos Family 
Environment Scale (FES) (Moos, 1985) 
❖ The FES assesses the quality of interpersonal relationships among family members. This 
scale consists of 90 true-false items to be completed by the parents. This measure permits 
an assessment of the degree of stress in the family environment and of parental discord. 
❖ Administered at beginning of study to characterize the groups and ensure their similarity. 
 
E. Global Assessment of Functioning (GAF) 
❖ The GAF (American Psychiatric Association, 1994) will assess global functioning using 
a scale from 1 (worst) to 100 (best). Guidelines and examples of how to use this scale are 
provided with the scale. 
❖ This clinician rated scale will be used at baseline visit to characterize the sample, at each 
of the 12 weekly visits to assess change, and at endpoint, to assess the impact of 
treatment on global functioning. 
 
F. Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
❖ A 15-item rating scale to assess the degree of life enjoyment and satisfaction for children 
(Endicott, Nee, Yang, & Wohlberg, 2006). 
❖ We will administer this scale to parents/guardians at baseline and endpoint. 
 
G. Neuropsychological Tests/Cognitive Evaluation 
❖ IQ Testing: At study beginning, subjects will complete a brief cognitive screen. The 
scales we will use meet the demand for quick reliable measures of intelligence in clinical, 
educational and research settings. These tests will provide estimates of verbal and 
nonverbal ability respectively, as well as the direct measure of Full Scale IQ. This portion 
of the cognitive evaluation will take approximately 30 minutes to complete. In the 
unlikely event that a subject’s estimated IQ is below 70, the subject will not be eligible to 
participate in the study. Depending upon the subject’s age, the cognitive screen will 
consist of: 
 
-  Subjects age 5: Verbal Knowledge, Riddles, and Matrices subtests of the 


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   Kaufman Brief Intelligence Test, Second Edition (KBIT-2)(Kaufman & 
 
   Kaufman, 2004) 
 
 
-  Subjects ages 6-17: Vocabulary and Matrices subtests of the Wechsler 
 
   Abbreviated Scale of Intelligence (WASI-II)(Wechsler, 2011) 
❖ Cognitive Functioning Testing: At screening and endpoint, to evaluate the impact of 
treatment on cognition, we will assess basic intellectual and cognitive functions purported 
to be deficient in patients with bipolar disorder. Cognitive deficits that have been 
observed in bipolar disorder may reflect dysfunction in the frontal subcortical circuits that 
support aspects of attention, executive functions processing speed, memory, and learning 
(Bearden, Hoffman, & Cannon, 2001). The neuropsychological battery we have 
developed to assess these functions includes both published clinical measures with large, 
normative samples and experimental measures with strong empirical evidence of validity. 
This neuropsychological battery, which has been used widely in clinical trials and family 
studies in our office, has been well-tolerated. The testing will take approximately 15 
minutes to complete. The age-appropriate testing will include: 
 
-  Subjects age 5: Symbol Search and Coding subtests of the Wechsler  
 
   Preschool and Primary Scale of Intelligence (WPPSI-III) (Wechsler &  
 
   Sattler, 2002) to measure processing speed  
 
-  Subjects ages 6-16: Digit Span and Symbol Coding subtests from the  
 
   Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV)  
 
   (Wechsler, 2003) to measure working memory and processing speed 
 
-  Subjects age 17: Digit Span and Symbol Coding subtests from the Wechsler  
 
   Adult Intelligence Scale (WAIS-IV)(Wechsler, 2008) 
The working memory scale will be omitted for subjects who are 5 years of age, as we do 
not have an age-appropriate scale available.  
 
Efficacy Measures 
 
The primary efficacy measures are the mean change from baseline to endpoint in the 
Young Mania Rating Scale (YMRS) total score and the Children’s Depression Rating 
Scale (CDRS). These will be administered by the clinician at all visits. 
 
A. Young Mania Rating Scale (YMRS) 
❖ The YMRS (Young, Biggs, Ziegler, & Meyer, 1978) consists of 11 items rated on a scale 
from 0 (symptom not present) to 4 (symptom extremely severe). 
❖ Items 5, 6, 8, and 9 are rated on a scale from 0 (symptom not present) to 8 (symptom 
extremely severe). These items assess irritability, speech, content and 
disruptive/aggressive behavior) and are given extra weight in the overall score. 
❖ The YMRS score ranges from 0-60. Questions are asked about the last week. This scale 
is generally accepted as the main outcome measure in studies of pediatric bipolar disorder 
and is linked directly to the core symptoms of mania. 
❖ Collected at the Screening Visit, Baseline Visit (only subjects with a YMRS score of 15 
or greater, but not above 40, are included), at each of the weekly visits and at endpoint to 


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assess the impact of treatment on manic symptoms. 
 
B. Children’s Depression Rating Scale (CDRS) 
❖ The CDRS (Poznanski, Freeman, & Mokros, 1985) is modeled after the Hamilton 
Depression Rating Scale for adults, but includes questions relevant to youth, such as 
questions about school, family and peer functioning. 
❖ This is a clinician-rated instrument with 17 items scored on a 1 to 5 or 1 to 7 scale. A 
rating of 1 indicates normal, thus the minimum score is 17. The maximum score is 113. 
Scores of 20-30 suggest borderline depression. Scores of 40-60 indicate moderate 
depression. 
❖ This scale is generally accepted as the main outcome in studies assessing childhood 
depression and is linked directly to the core symptoms of depression. 
❖ Collected at all visits. 
 
C. Hamilton Depression Rating Scale (HAM-D) 
❖ The HAM-D is a clinician rated instrument that measures the severity of depressive 
symptoms. 
❖ This is a clinician-rated instrument with 21 items scored on a 0 to 4 scale. 
❖ Collected at all visits. 
 
As secondary measures to assess severity and improvement relative to baseline for mania, 
depression and common comorbid conditions, we will use other measures including: a DSM-IV 
Mania Symptom Checklist; the Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale; 
the Brief Psychiatric Rating Scale (BPRS); and the NIMH Clinical Global Impression scale 
(CGI) (Severity, Improvement and Efficacy Index) for mania, depression, Bipolar Disorder 
overall, ADHD, Oppositional Defiant Disorder and Anxiety. Most of these scales will be 
administered at baseline visit, at each of the weekly visits and at endpoint by the clinician to 
assess the impact of treatment on ADHD, anxiety, and to have other measures related to the 
impact of treatment on bipolar disorder. We will also have the subject’s parent/guardian 
complete the Social Responsiveness Scale (SRS) and the Behavior Rating Inventory of 
Executive Function – Parent Form (BRIEF) at the Baseline Visit and Week 12 visit. 
 
A. DSM-IV Mania Symptom Checklist 
❖ This Checklist is adapted from the DSM-IV mania diagnostic criteria with items for 
each symptom of mania. Each item is scored 0 to 3 ranging (0=never or rarely; 
1=sometimes; 2=often; 3=very often). 
❖ Collected at baseline visit, at each of the weekly visits and at endpoint as an 
additional measure of manic symptoms. 
 
B. Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale 
❖ The ADHD Rating Scale is an 18-item scale with 1 item for each of the 18 DSM-IV 
ADHD symptoms. Each item is scored 0 to 3 (0=never or rarely; 1=sometimes; 
2=often; 3=very often). 


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❖ Collected at baseline visit, middle and endpoint to assess the impact of treatment on 
ADHD symptoms, which often co-occur with pediatric bipolar disorder. 
 
C. Brief Psychiatric Rating Scale (BPRS) 
❖ The Brief Psychiatric Rating Scale (BPRS) is a common scale used to assess overall 
psychopathology (Overall & Pfefferbaum, 1982).  The scale consists of 18 items; each 
rated on a scale from 1 (symptom not present) to 7 (symptom extremely severe). 
❖ Collected at Baseline Visit and at endpoint to assess the impact of treatment on 
depression, anxiety hallucinations and unusual behavior, which often co-occur with 
pediatric bipolar disorder.  
 
D. Social Responsiveness Scale (SRS) 
❖ The SRS is a 65 item rating scale completed by the parent or guardian. This scale 
measures the severity of autism spectrum symptoms as they occur in natural social 
settings. 
❖ Collected at Screening and Endpoint visits as assessment of symptoms and capacities 
associated with social interaction. 
 
E. NIMH Clinical Global Improvement scale (CGI) 
❖ The CGI is a measure of illness severity adapted for specific disorders. It allows rating of 
mania, depression and overall bipolar disorder illness, as well as other conditions 
frequently comorbid with bipolar disorder. 
❖ The severity score ranges from 1 (normal, not at all ill) to 7 (among the most extremely 
ill patients). The improvement score ranges from 1 (very much improved) to 7 (very 
much worse).                                                                                               
❖ Collected at Baseline Visit, at each of the weekly visits and at endpoint as an accepted 
measure of clinician rated improvement to assess the impact of treatment on bipolar 
disorder and other comorbid conditions. 
 
F. Behavior Rating Inventory of Executive Function – Parent Form (BRIEF) 
❖ The BRIEF is an 86-item rating scale to assess level of executive function deficits (Roth, 
Isquith, & Gioia, 2004). It is completed by the subject’s parent/guardian. 
❖ Collected at Baseline Visit and at the Week 12 visit for subjects who complete the study. 
 
G. MGH Autism Spectrum Disorder Rating Scale (MGH-ASD-RS-I) 
❖ This is a 37-item scale that asks informants to rate subjects on their social competence 
and abilities on a Likert scale from 0 to 6. 
❖ Collected at Baseline and Endpoint visits. 
 
Safety Measures 
 
❖ Adverse Experiences: to record any adverse health events experienced during the study along 
with duration, severity, cause, remedy, and outcome. 


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❖ Columbia Suicide Severity Rating Scale (C-SSRS): to assess initial and emergent suicidality. 
 
9. DATA ANALYSIS 
 
A. Statistical Analysis 
 
Considering our open-label single group design, we will rely on comparisons of the participants’ 
performances at baseline (week 0) prior to the initiation of treatment relative to their scores at the 
last assessment (week 12).  Thus, statistics for paired samples will be utilized.  This design 
largely protects against the bias introduced by confounding factors.  That is, since the same 
participants are tested on two occasions, all static confounding factors are perfectly balanced, 
and can have no impact on the findings.  Bias can still result from time-varying factors that are 
not associated with the outcomes, but we are confident that any such factors will have a minimal 
impact on this study, considering the duration of the trial. Specifically, we will employ Wilcoxon 
signed rank tests for continuous or discrete outcome measures, and McNemar’s test for binary 
outcomes.  These tests are free from assumptions regarding the distribution of the outcome 
variables, which is appropriate since the scales we are proposing to utilize are not considered to 
have Gaussian distributions, and will not be amenable to parametric methods. 
 
B. Power 
 
As this is a single-arm, open-label study designed to demonstrate effectiveness and safety of 
NAC, formal power analyses are not warranted.  For the purposes of an approximate power 
calculation, we used the two-sample t-tests as a proxy for the power of a Wilcoxon signed rank 
test.  We used the responses we have observed in previous trials of other atypical neuroleptics to 
estimate effect sizes for the primary outcome measure (the Young Mania Rating Scale).  Small 
and large effect sizes are estimated as mean reductions of 5 and 15 points, respectively.  With 20 
subjects and alpha set at 0.05, we estimate power to be 0.99 to detect small effects in YMRS 
scores (with a SD of 5) over the 12-week trial. 
 
10. SAFETY 
 
Consistent with good clinical practice, safety will be monitored by each subject’s study clinician 
at each study visit. This clinician will be available 24 hours a day by page. The Principal 
Investigator will supervise all study activities including ratings, reported adverse events, 
laboratory tests, and vital signs. Subjects will be monitored for adverse events at each visit and 
adverse events will be recorded on an Adverse Events Form. Treatment-emergent adverse events 
will be monitored through changes in vital signs. All adverse events will be reported according to 
PHRC guidelines. Blood pressure, pulse, height, weight, and temperature will be recorded at 
each office visit. 
 
Poor response to treatment will be measured by a CGI-bipolar score that is 2 points higher (more 
severe) than baseline for 2 weeks in a row or a YMRS score that is 30% higher than baseline for 


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2 weeks in a row, which may lead to drop from the study as determined by the clinician. Subjects 
with individual YMRS item scores of 8 on Item #8 (Content), or scores greater than 6 on 
Disruptive-Aggressive Behavior for 2 weeks in a row will be dropped from the study. In 
addition, drop from study will occur at clinician discretion for worsening of clinical course, non-
compliance with treatment or inability to tolerate study treatment. Finally, the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be administered weekly to assess initial and emergent 
suicidality in subjects. Subjects with scores of 4 or higher on the C-SSRS will be dropped from 
the study. 
 
Having treated hundreds of bipolar patients, we are aware that this is a group of very highly 
disturbed children at risk for psychosis, suicide and disruption in the family. Although it is 
unlikely that these risks will be exacerbated by the protocol, we will be vigilant regarding the 
potential for patient decompensation or dangerousness to self or others. In the execution of 
research protocols, our primary concern is always the safety of the research participant. Dr. 
Wozniak has extensive experience in working with youth with severe psychopathology in 
clinical trials and in designing and implementing safety plans in these trials. Also, Dr. Wozniak 
is expert in the diagnosis and treatment of pediatric bipolar disorder and high-risk pediatric 
psychiatry patients in clinical settings. Given the especially unstable nature of bipolar spectrum 
subjects, we are available to handle clinical emergencies with subjects and their families at any 
time: at the time of visit, whether in person or over the phone, as well as between visits. 
 
 If needed, emergency evaluation and referral is available through coverage by the clinician-
investigators on this study and through the Acute Psychiatry Service (APS) at the MGH. All 
subjects will have access to a 24 hour a day, 7-day week coverage provided by Dr. Wozniak or 
her designated substitute by pager for psychiatric emergencies. As part of the Massachusetts 
General Hospital, all research subjects can access the Acute Psychiatry Service (APS) in the 
emergency room at any time of the day or night. The APS is a well-staffed 24 hour/7 day per 
week emergency service for psychiatric emergencies. 
 
11. CONFIDENTIALITY 
 
All research-related records, initiated as a result of a subject’s participation in this study that 
reveal the subject’s identity, will remain confidential except as may be required by law. Subjects 
will only be contacted regarding future studies if they indicate that they are interested in being 
contacted by initialing in the specific section of the consent form. 
 
If subjects agree on the Consent Form, we may share subjects’ information with others within 
our research group for future research on emotional dysregulation or other related conditions. We 
will label all subjects’ study materials with a code instead of their names. The study doctor will 
not share the key to code names with researchers outside of this institution. 
 
12. MONITORING AND QUALITY ASSURANCE 
 


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The Principal Investigator is responsible for monitoring the safety and data of this trial. The PI 
will monitor adherence to the protocol, subject participation (e.g. tolerance to medication, drop-
out rates, etc.), the risk-benefit ratio, and all Adverse Events throughout the course of the study. 
The IRB will be informed of any serious adverse events occurring during the trial. If at any time 
during the study more than 10% of the patients have had a serious adverse event, the study will 
be stopped. The primary concern of the investigators of this study is the safety of the subjects. 
 
13. RISKS AND DISCOMFORTS 
 
Potential side effects are few and will be monitored for throughout the research study. Consent 
forms will clearly list potential medication side effects. Since NAC is a derivative of a naturally 
occurring amino acid, it appears to have a low potential for unwanted side effects or negative 
effects on the child’s growth and development. Although NAC is generally well tolerated, 
animal (but not human) subjects have developed pulmonary hypertension with high doses. 
Seizure with NAC has been reported in an accidental overdose of 39,207mg NAC in a 30-month-
old girl, more than 10 times the dose she should have received.  Seizure has not been reported 
with recommended dosing (Bailey, Blais, & Letarte, 2004). 
 
The most common side effects reported with use of NAC are gastrointestinal. Other less 
common side effects that have been reported include fatigue, nervousness, vivid dreams, 
heartburn, pruritus (without rash), and headaches (Berk, Copolov, Dean, Lu, Jeavons, 
Schapkaitz, Anderson-Hunt, Judd, et al., 2008; Ghanizadeh & Moghimi-Sarani, 2013; Gray et 
al., 2012; Hardan et al., 2012; Mardikian, LaRowe, Hedden, Kalivas, & Malcolm, 2007). Serious 
side effects are uncommon. 
 
Other Adverse Events 
 
Problems and side effects not listed above and not known at this time could occur. Subjects will 
be told of any changes in the way the study will be done and any newly discovered risks to 
which they may be exposed. 
 
Answering detailed questionnaires may create a mild degree of inconvenience or emotional upset 
for the subjects. Interviewers will be trained to support the subjects who raise such concerns, and 
the PI will be available to respond to any concerns or to answer other questions about the study 
(available by pager 24 hours per day). All of the information about participants will be treated 
confidentially. Subjects may refuse to answer any of these questions. 
 
Having treated hundreds of bipolar patients, we are aware that this is a group of very highly 
disturbed children at risk for psychosis, suicide and disruption in the family. Although it is 
unlikely that these risks will be exacerbated by the protocol, we will be vigilant regarding the 
potential for patient decompensation or dangerousness to self or others. In the execution of 
research protocols, our primary concern is always the safety of the research participant. Given 
the especially unstable nature of bipolar patients, we will be available to the study staff and to 


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patients and their families to handle clinical emergencies. The Massachusetts General Hospital 
has an active and well-staffed psychiatric emergency service that will be available to subjects if 
needed. This study has clearly defined exit criteria to ensure the safety of participants. 
 
Protection Against Risk 
 
Subjects’ confidentiality will be protected throughout the study. Information about subjects and 
their families will be stored in research files identified only by a code. The code key connecting 
the participant’s names to identifying information will be kept in a separate, secure location. 
Data in databases is similarly identified only by coded ID number and is password-protected. 
Data will not leave our institution in any form that would identify individual subjects or families. 
The information collected in our assessments and treatment outcome rating scales will not 
become part of the individual’s hospital medical record. In the case that serious psychopathology 
(suicidality, homocidality, psychosis) is uncovered in the course of the research study, the 
Principal Investigator or appointed proxy will be immediately contacted by the clinician. All 
efforts will be made to alert parents of the subject and, if necessary, treating clinicians, of the 
circumstances to enable the subject to secure appropriate treatment. If needed, emergency 
evaluation and referral will be available through coverage by the clinician-investigators on this 
study and through the Acute Psychiatry Service (APS) at the MGH. The APS is a well staffed 24 
hour/7 day per week emergency service for psychiatric emergencies. Subjects who do not 
respond to the study treatments will be dropped from the study using clear drop criteria 
(“patients may drop at any time due to patient preference, physician decision, need for 
psychiatric hospitalization or a poor response to treatment. Poor response to treatment leading to 
drop from the study will be measured by a CGI-mania score that is 2 points lower (more severe) 
than baseline for more than 2 weeks in a row, a YMRS score that is 30% higher than baseline for 
more than 2 weeks in a row”), or a C-SSRS score of 4 or higher. 
 
14. POTENTIAL BENEFITS 
 
To the Subject 
 
The study will offer rapid access to treatment and provide subjects with a free detailed 
psychiatric and cognitive evaluation. Subjects will be provided with a potentially useful 
treatment, which has low risks associated with it. 
 
To Others 
 
The study will further our understanding of the treatment of bipolar disorder in children by 
testing a novel treatment, N-acetylcysteine. This study will also be useful in the testing of 
specific hypotheses about the efficacy of alternative treatments. 
 
Importance of the Knowledge to be Gained 
 


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Little is known about the treatment of pediatric bipolar disorder, despite the fact that it is 
recognized as a significant public health concern. This study will further our knowledge 
regarding potentially useful treatments. As parents are often concerned about the effect of 
pharmaceutical agents on growth and development, this study examines the efficacy of a safe, 
alternative treatment that will be appealing to parents and children, due to its safety profile and 
benign side effect profile. From a scientific perspective, this study also furthers our 
understanding of the role of NAC in psychiatric disorders. 
 
 
Table 1 
Schedule of Events 
 
Visit 
991 
02 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Consenting  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental Consent & Child Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs, Height, Weight 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
Cognitive Tasks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Tasks: IQ Measures (WASI-II or 
KBIT-2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Tasks: EF Measures (WISC-IV or 
WPPSI-III) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinician Assessments/Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician K-SADS-E (MDD, Mania) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
YMRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mania Symptom Checklist 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIs (Mania, Depression, Anxiety, ADHD, 
ODD, BPD) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADHD Rating Scale 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
BPRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
GAF 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Parent Assessments/Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K-SADS Face Page 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBCL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FES 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAICA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PQ-LES-Q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
BRIEF Parent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
SRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MGH-ASD-RS-I 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
       
1 99 – Screening visit(s) 


Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
23
2 0 – Baseline visit 
 
 
 
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with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
24
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with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
25
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Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
26
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Study Protocol: Open-Label Study of N-Acetylcysteine in Children and Adolescents ages 5-17 
with Bipolar I, Bipolar II, and Bipolar Spectrum Disorder 
Version: CR 4 RtR 
Last Modified: 08/22/2018 
 
 
27
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