Clinical trial NCT01396486
Conditions: Pediatric Bipolar Spectrum Disorders
Keywords: Omega-3 Fatty Acids Fish Oil Inositol Natural supplements Bipolar Spectrum Disorders Mania Depression Children
Sponsor: Massachusetts General Hospital
Start date: 2012-02-03; Completion date: 2019-04-11
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to a) evaluate the efficacy of omega-3 fatty acids versus inositol in the treatment of pediatric bipolar disorder, b) evaluate the efficacy of omega-3 fatty acid plus inositol in the treatment of pediatric bipolar disorder, and c) assess the side effect profile of omega-3 fatty acids plus inositol. This study will be a 12-week trial with children ages 5-12 years old with bipolar spectrum disorders.

Detailed description:
The investigators propose to conduct a randomized, double blind, controlled trial that will evaluate effectiveness and tolerability of omega-3 fatty acids and inositol used alone and in combination. The investigators plan to decrease the variability in the population under study by limiting the age range to 5-12 years and excluding cases with significant, untreated, comorbidity. The cognitive effects/side effects with a neuropsychological battery pre and post treatment will be measured. Subjects with a history of failing treatment with two or more conventional treatments will be excluded.

This will be a 12-week, double-blind, randomized clinical trial study to compare efficacy and tolerability of the natural treatments omega-3 fatty acids and inositol used in combination in the treatment of bipolar spectrum disorders in children and adolescents (ages 5-12). Subjects will be randomized in double blind fashion to one of three arms: omega-3 fatty acids, inositol or the combined treatment. Further, the proposed study will include measures of cognition prior to starting study medication and at endpoint. The investigators will minimize the variability of the population under study by limiting the age range to 5-12 years, minimizing untreated or clinically significant comorbidity and excluding subjects who have already failed treatment with 2 or more anti-manic agents. Subjects will include youth ages 5-12 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, Fourth Edition (American Psychiatric Association, 2000) (DSM-IV), randomized to 3 treatment arms: 1) treatment with omega-3 fatty acids (N=20); 2) treatment with inositol (N=20); 3) treatment with the combination of inositol and omega-3 fatty acids (N=20).

Arms: arm 1: Combination Omega-3 and Placebo treatment. arm 2: Combination Placebo and Inositol treatment. arm 3: Combination Omega-3 and Inositol treatment.
Interventions: intervention 1: Omega-3 intervention 2: Inositol
Intervention descriptions: intervention 1: Children with bipolar spectrum disorders ages 6-12 will receive treatment with omega-3 fatty acids. Study subjects may be randomized to receive 3000mg (6 500mg capsules) of omega-3 fatty acids for the duration of the study. Omega-3 fatty acid capsules are in the form of Nordic Naturals brand, ProOmega Junior, which contains 325mg EPA and 225mg DHA per two capsules. intervention 2: Children with bipolar spectrum disorders ages 6-12 will receive treatment with inositol, omega-3 fatty acids, or both weekly for 12 weeks. Subjects weighing 25kg or more may be randomized to receive 2000mg (4 500mg capsules) of inositol (80mg/kg for a 25kg child). Children weighing less than 25kg will be dosed at 80mg/kg rounded down to the nearest thousand mg dose. Dosage will remain constant throughout the study.

Protocol documents:
Prot_SAP_000.pdf: 
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Study Protocol: 
A Randomized Controlled Trial of Inositol and Omega-3 Fatty Acids in Pediatric 
Mania 
 
 
 
 
Janet Wozniak, MD 
Massachusetts General Hospital 
Clinical and Research Program in Pediatric Psychopharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 (Biederman, 2001). These children 
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, 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, not treating is usually not a viable option. 
 
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 which 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 (Biederman, 1998; Kowatch, 2003). Medications, such as lithium, which have been 
the mainstay of pharmacotherapy for bipolar adults, show only moderate effectiveness in 
children (Kowatch, 2000). Studies of the newer atypical antipsychotic agents such as 
risperidone, aripiprazole, olanzapine and quetiapine have been promising, but serious 
side effects limit their utility (Frazier, 2001). 
 
Nutritional and natural products including omega-3 fatty acids and inositol have 
demonstrated utility in the treatment of mood disorders. These natural agents offer the 
promise of a safe and healthful approach to controlling the symptoms of bipolar disorder 
in youth. Our pilot research (Wozniak, 2007) suggests that omega-3 fatty acids, a 
component of the human diet, may have anti-manic, mood stabilizing properties, but that 
when used alone leaves subjects with significant residual symptoms, especially of 
depression. Emerging research has demonstrated the utility of inositol in the treatment of 
depression. 
 
The overarching aim of this study will be to expand our pilot findings and to demonstrate 
the efficacy of omega-3 fatty acids and inositol, used separately and together, in the 
treatment of pediatric bipolar disorder. 
 
Common Pharmaceutical Treatments are Inadequate 
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, 2000; Sachs, 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 (Biederman, 1998; Geller, 1998; 


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Kowatch, 2000). In the naturalistic setting, mood stabilizer therapy was associated with a 
slow onset of action and substantial risk of relapse (Biederman, 1998). In the controlled 
trials, there were frequent adverse events, noncompliance and treatment dropouts 
(Kowatch, 2000; Wagner, 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 (Biederman, 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 Food and Drug Administration (FDA) for use in mania in adults (Perlis, 
2006) and, in the case of risperidone and aripiprazole, down to age 10 for children with 
mania (Biederman, 2005; Biederman, 2007; Biederman, 2005). Olanzapine has 
demonstrated efficacy in adolescents with bipolar disorder. An open label trial of 
olanzapine in bipolar youth average age of 10 demonstrated robust improvement in 
symptoms as measured by the YMRS and the Children’s Depression Rating Scale 
(CDRS) (Frazier, 2001). However, olanzapine treatment is commonly associated with 
severe weight gain, as much as 5 kg in an 8 week period. There is a very real concern 
regarding the development of diabetes in individuals treated with atypical antipsychotic 
medications (Leslie, 2004; Lindenmayer, 2001; McElroy, 2004; Meltzer, 2005; 
Regenold, 2002; Rosenbloom, 2002). 
 
In a chart review of risperidone (Frazier, 1999) for the treatment of pediatric bipolar 
disorder in 28 youth, 80% of the children improved, most in the first weeks of treatment. 
A recent re-analysis of data collected for a randomized placebo controlled clinical trial of 
risperidone in the treatment of conduct disorder in children and adolescents with low IQ 
(Snyder, 2002; Turgay, 2002) indicated that in addition to the improvement of symptoms 
of conduct disorder, risperidone was also highly effective for mood symptoms associated 
with mania and depression. However, although effective in open label trials, risperidone 
is also associated with weight gain as well as elevations of the hormone prolactin 
(Biederman, 2005), which can result in galactorrhea in youth and has unknown effects on 
pubertal development (Kim, 1999; Petty, 1999; Popli, 1998; Turgay, 2002; Wudarsky, 
1999). Thus, although extremely encouraging results have emerged with the use of 
atypical antipsychotic medications, (Frazier, 2000; Frazier, 2001; Frazier, 1999; 
DelBello, 2007; DelBello, 2006; Delbello, 2002; Biederman, 2005) these treatments have 
been associated with severe weight gain and an increased risk for the development of 
diabetes as well as tardive dyskinesia and other extrapyramidal symptoms. 
 
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 


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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 FDA 
approval, despite miserable side effects (Kowatch, 2005). 
 
Omega-3 Fatty Acids and Psychiatry 
Initial clinical evidence suggests that the omega-3 fatty acids EPA (eicosapentaenoic 
acid) and DHA (docosahexaenoic acid) may play a unique therapeutic role in the 
management of youth with mood disorders. EPA, which is metabolized to DHA, is an 
essential fatty acid, meaning the human body cannot easily metabolize this substance 
from other substrates, but rather it must be regularly ingested. EPA and DHA are a 
typical components of the human diet only if fish is consumed, a rare occurrence in 
American children. This fatty acid can be found in large quantities in the brain, 
particularly in cell membranes. If omega-3 fatty acids are not available for use, the body 
will use omega-6 fatty acids, which occur commonly in our diet, in cell membranes 
instead. It has been postulated that phospholipid abnormalities in cell membranes may be 
implicated in psychiatric disorders in general and in bipolar disorder in particular 
(Edwards, 1998; Horrobin, 1994; Horrobin, 1998; Stoll, 1999). This is the so-called 
“phospholipid theory of psychopathology.” 
 
Recent studies have proposed that dietary supplements with fish oil (a concentrated 
source of EPA and DHA) have been useful in the treatment in adults of schizophrenia 
(Peet, 1995; Peet, 2001; Puri, 2000) and depression (Peet, 2002; Nemets, 2006; Nemets, 
2002). 
 
In one of three published treatment studies of children to date Voigt et al, reported that 
omega-3 fatty acids are ineffective for ADHD, but were well tolerated (Voigt, 2001). 
Nemets et al randomized 28 children to omega-3 fatty acids or placebo and found 
improvement in depression as measured by the Childrens Depression Rating Scale 
(CDRS). The third study in children is our own preliminary study and demonstrates a 
modest improvement in supplemented youth. In this study, subjects (N=19) experienced a 
statistically significant but modest 8.9±2.9 point reduction in the YMRS scores after 8 
week open label treatment with omega-3 fatty acids (baseline YMRS=28.9±10.1; 
endpoint YMRS=19.1±2.6, p<0.001). Adverse events were few and mild, and of the 20 
subjects recruited, there were only 4 drop outs due to ineffectiveness and none dropped 
out due to adverse events. Although a decrease in the CDRS was noted, subjects 
remained in the psychopathologic range. The mean dose of omega-3 fatty acid was 
2965±991 mg / day (range 1290 – 4300, or 3-10 capsules). There was no benefit seen to 
increasing the dose beyond 2 grams per day. Laboratory analyses did not reveal any 
significant baseline-endpoint differences in chemistries, hematology, prolactin, glucose, 
or lipids. Subjects had only a 0.7±1.5 kg weight gain. 
 
Beyond our pilot study, literature regarding the use of EPA in treating bipolar disorder is 
extremely small (Stoll, 1999; Horrobin, 1999). The first study of omega-3 fatty acids for 
bipolar disorder, was a 4-month double blind placebo controlled study in which the 
authors added EPA+DHA, a total of 9.6g (6.2g and 3.4 g respectively) to ongoing 


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treatment in 30 adults with bipolar disorder (Stoll, 1999). These authors reported a 
significantly longer period of remission for those supplemented with omega-3s. 
Furthermore, these omega-3 supplemented subjects performed better on the CGI, GAS 
and HAM-D than the placebo group (there was no difference in the YMRS). On the other 
hand, a discouraging outcome was reported by authors associated with The Stanley 
Foundation Bipolar Network which conducted a 4 month double-blind randomized 
controlled study of EPA monotherapy in 116 bipolar adults. This long term monotherapy 
large scale study failed to show efficacy. Six g of EPA daily used as monotherapy was 
compared with placebo for 4 months in the treatment of either acute depression or rapid 
cycling illness (Post, 2003). The authors note that this dose may have been too large for 
demonstrating efficacy. Also, questions can be raised as to whether omega-3 fatty acids 
work better as an augmenting agent versus monotherpy. Dose ranging studies in 
depression and schizophrenia found efficacy at lower dose levels, 1-3 grams, but not for 
higher doses (Frangou, 2006; Nemets, 2002; Peet, 2002). This would suggest that omega-
3 fatty acids may be most effective in a lower dosing range and that higher doses may be 
ineffective. 
 
Although omega -3 fatty acids have produced equivocal results in studies of adults with 
bipolar disorder, using this healthful supplement in children could produce a different 
outcome. Studies supplementing infant formula with omega-3 fatty acids find positive 
effects on development and cognition (Willatts, 2002). In 1998, Willatts et al (Willatts, 
1998) published a study in Lancet describing the randomization of 44 infants to receive 
formula with and without supplementation of long chain polyunsaturated fatty acids 
(including DHA) from birth to 4 months. The supplemented infants scored better on a 
problem solving cognitive test administered at 10 months of age (6 months after the 
supplementation ended). This test correlates highly with childhood IQ scores. The 
authors note that the effect of the supplementation was evident beyond the period of 
supplementation. These studies of infants raise the possibility that intervening with fatty 
acid supplementation during critical periods can enhance brain development. Thus, an 
agent with minimal effect on the adult brain, could play a major role in a developing 
brain. 
 
Thus, while omega-3 fatty acids may hold small promise as monotherapy for some 
individuals, their use, at least, appears to do no harm and may be good for brain 
development and health. Furthermore, the question remains as to whether they could be 
more effective when used in combination with other effective agents. 
 
Inositol May Be a Useful Monotherapy or Augmenting Agent 
The natural treatment inositol has shown some promise for depression and bipolar 
depression and may offer a useful option for monotherapy or combination treatment in 
bipolar youth. Inositol is a simple sugar derivative which is a precursor for a number of 
second messengers important in intracellular activity. It is common in the human diet, 
such as in cereals. Inositol is present in numerous different foods in low amounts; it is 
present in higher amounts in beans, grains, nuts, and many fruits (Clements, 1980). In 
addition, the human body can synthesize it from glucose-6-phosphate. The average adult 
human consumes about 1 g of inositol in the daily diet (Baraban, 1989; Mischoulon, 


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2008; Belmaker, 2008). 
 
The initial rationale for recent attempts to treat depression by dietary supplementation 
with inositol came from the finding that inositol was shown to be decreased in the 
cerebrospinal fluid (CSF) of depressed patients with depression (Barkai, 1978) although 
others did not replicate this finding (Levine, 1996). An additional rationale for the use of 
inositol is its role in cell signaling and in the action of various receptors important in 
psychiatry including noradrenergic, cholinergic and serotonergic receptors. Inositol, 
located primarily within cell membranes, is ubiquitous in biologic organisms; it is a 
precursor for, as well as a product of the phosphatidylinositol (PI) cycle (Baraban, 1989; 
Mischoulon, 2008; Belmaker, 2008). The PI cycle is the second messenger system for 
numerous neurotransmitter receptors, including cholinergic muscarinic, alpha 1 
noradrenergic, serotonin (5-HT2A and 5-HT2C), and dopaminergic D1 receptors 
(Mischoulon, 2008), The activity of lithium and antiepileptic mood stabilizing 
medications in affecting inositol uptake provides an additional rationale for the use of 
inositol in psychiatric treatment and suggests that stable inositol signaling may be crucial 
in mood stability, with elevated inositol implicated in mania and depleted inositol 
implicated in depression. 
 
Silverstone et al showed that chronic treatment with either lithium or sodium valproate in 
bipolar patients may normalize PI-cycle functioning (Silverstone, 2002). Lithium may 
exert its clinical mood stabilizing effects due to its actions on the phosphoinositol second 
messenger system (PI-cycle) (Silverstone, 2002). Berridge et al (Berridge, 1989) 
suggested that lithium acts in bipolar disorder by affecting the enzyme inositol-1- 
monophosphatase and causing a relative inositol deficiency. A possible excess of inositol 
in mania suggests its possible deficit in depression. In addition, in animal models of 
depression, inositol has been shown to reduce depressive behaviors (Belmaker, 2008; 
Belmaker, 2008). Positive studies of inositol in humans have been reported in the 
treatment of depression, panic disorder, obsessive-compulsive disorder, and bulimia 
(Belmaker, 2008) (Belmaker, 2008; Mischoulon, 2008; Levine, 1997). In Europe, over-
the-counter inositol has long been used as a folk remedy for depression (Belmaker, 2008; 
Belmaker, 1996; Mischoulon, 2008). 
 
Although scientific evidence suggests that inositol and the PI-cycle are affected in 
depression and impacted by lithium treatment, the mechanism of action of inositol 
remains unclear. Indirectly from the available evidence, we presume that subjects with 
mood disorders experience a decrease in brain myo-inositol which adversely affects the 
functioning of the PI second messenger system, which in turns results in mood changes. 
Dietary supplement with inositol, therefore, improves the functioning of the PI system 
thereby treating the depressive symptoms (Moore, 1999; Moore, 1999). Lithium may 
operate conversely, and paradoxically, by lowering or blocking myo-inositol, the so 
called Inositol Depletion Hypothesis: that is, lithium produces a lowering of myo-inositol 
in the brain, via inositol monophosphatase, bringing about a mood stabilizing effect 
(Agranoff, 2001; Silverstone, 2005). 
 
Mood stabilizer medications may be better thought of, however, as producing an action 


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that stabilizes inositol and its actions. Lithium, valproate, and carbamazepine in human 
astrocyte cells decreased inositol uptake at high inositol concentrations and increased 
inositol uptake at low inositol concentrations, suggesting a much more complicated mode 
of action. (Wolfson, 2000; Wolfson, 2000; Wolfson, 2000; Evins, 2006). Kaya et al 
found that erythrocyte inositol-1-monophosphatase activity was higher in lithium treated 
euthymic patients than non-lithium treated patients. This increased inositol-1- 
monophosphatase activity with chronic lithium use suggests paradoxically, over time, an 
up-regulation of the enzyme activity (Kaya, 2004). 
 
In response to the seemingly contradictory findings, Belmaker evolved the Inositol 
Polyphosphate Signal Suppression Hypothesis and hypothesized that inositol’s effect in 
the brain was much more complex than simply being a matter of too much or too little 
(Belmaker, 1996). He writes, “Inositol has been shown to regulate the function of the PI 
cycle in a complex manner. Complex regulation of a cycle can lead to “pendulum” 
effects where a push from either direction causes an identical effect.” Belmaker notes that 
inositol supplementation with lithium reverses the effects of lithium. On the other hand, 
inositol supplementation as monotherapy had effects similar to those of lithium. This 
author writes, “This apparent paradox may hint at a solution to the mystery of how 
lithium administration benefits both mania and depression.” Further, because the PI cycle 
serves as a second messenger for several balancing and mutually interactive 
neurotransmitters, Belmaker hypothesizes that exogenous inositol could hypothetically 
alleviate inositol deficiency in one system without increasing inositol above normal 
levels in another (Belmaker, 1996). 
 
Trials with inositol in pediatric bipolar disorder are limited to measuring brain levels and 
ratios in neurochemical spectroscopic studies of treated and untreated youth; there are no 
clinical trials examining the efficacy of inositol in the treatment of pediatric bipolar 
disorder or depression. There is one clinical trial in psychiatry in youth, a negative trial of 
inositol for ADHD (Levine, 1995). Davanzo et al. (Davanzo, 2001) measured changes in 
myo-inositol levels in the anterior cingulate cortex of 11 children (mean age 11.4 years) 
diagnosed with bipolar disorder, currently manic, hypomanic, or mixed before and after 
lithium therapy (mean serum level of 0.64 mEq/L), and in 11 case-matched controls at 
baseline and day seven using proton magnetic resonance spectroscopy (1H MRS). There 
was a significant decrease in anterior cingulate myo-inositol/Cr ratio following seven 
days of lithium therapy in children and adolescents with bipolar disorder. When 
responders and non-responders were compared at week 1, myo-inositol/Cr was decreased 
versus baseline in the lithium-responder group, but not in the lithium non-responder 
group, consistent with (Moore, 1999; Moore, 1999) and contrasting with (Silverstone, 
1996) previous studies. These same authors compared myo-inositol levels in the anterior 
cingulate of 10 youth on various medications with bipolar I disorder (most recent episode 
manic or mixed), 10 youth with intermittent explosive disorder, and 13 normal 
comparison youth using 1H MRS (Davanzo, 2003). The patients with bipolar disorder had 
significantly higher mean anterior cingulate myo-inositol and myo-inositol/creatinine-
phosphocreatine measures than the patients with intermittent explosive disorder and the 
normal comparison subjects. There were no significant differences in levels between the 
youth with intermittent explosive disorder and the normal comparison subjects. There 


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was no significant difference in levels between groups in the occipital cortex. 
 
Patel et al (Patel, 2006) reported on an open-label study of 28 inpatient adolescents (12 to 
18yo, mean age 15.5 years) who met DSM-IV criteria for diagnosis of bipolar I disorder, 
currently depressed, given lithium doses adjusted to serum levels of 1.0 to 1.2 mEq/L. 
Myo-inositol concentrations in the medial as well as the left and right lateral prefrontal 
cortices were measured using 1H MRS scan at baseline, day 7, and day 42 of treatment. 
Lithium administration did not result in significant changes from baseline in myo-inositol 
concentrations in the medial as well as the left and right lateral prefrontal cortices. 
Consistent with previous studies (Moore, 1999; Moore, 1999; Friedman, 2004), these 
authors suggested, based on their findings, that the insositol-depletion hypothesis may not 
be the mechanism of action of lithium in patients with bipolar depression. 
 
Magnetic resonance spectroscopic studies have also been completed on adult subjects, 
some supplemented with inositol. Frey et al studied twenty-two unmedicated depressed 
bipolar and unipolar patients and found reduced myo-inositol concentrations in the 
frontal lobes compared with 22 healthy controls, although this finding was significant 
only when the groups were paired by age (<40yo) (Frey, 1998). Moore et al found an 
initial significant increase of myo-inositol/Cr levels in the occipital cortex gray matter 
and parietal white matter of 17 healthy subjects taking a dietary supplement of 12g/d 
myoinositol, but this level returned to baseline by day 8 (Moore, 1999; Moore, 1999). 
Moore et al also investigated lithium’s effects on in vivo brain myo-inositol levels in 12 
adults (mean age 36.6 years) diagnosed with DSM-IV diagnosis of bipolar disorder, most 
recently depressed. Patients underwent a drug washout period of at least 14 days, then 
underwent baseline MRS scan prior to initiation of treatment with lithium. Brain 
myoinositol levels were measured by 1H MRS after acute (5-7 days) and chronic (3-4 
weeks) lithium treatment. In the right frontal lobe the myo-inositol concentrations during 
both acute and chronic treatment were significantly lower than at baseline before 
correction for multiple comparisons, but not after correction. Lowering of myo-inositol 
levels per se did not appear to be associated with therapeutic efficacy. Authors 
hypothesized that the initial reduction of myo-inositol initiates a cascade of secondary 
changes in the protein kinase C signaling pathway and gene expression in the central 
nervous system, effects that may ultimately be responsible for lithium’s therapeutic 
efficacy. No significant differences were found in the temporal, occipital, and parietal 
lobes (Moore, 1999). 
 
Taken together, these neuroimaging studies suggest that inositol is implicated in the 
pathophysiology of bipolar disorder and that treatment with exogenous inositol or with 
medications which affect brain inositol levels (lithium) results in brain chemistry changes 
associated with clinical improvement. The conflicting results lend credence to 
Belmaker’s statements highlighting the complexity of the role of inositol. 
 
Three studies of inositol as an adjunctive treatment in bipolar adults have suggested a 
modest clinical effect of inositol for bipolar disorder. Twenty-two adults diagnosed with 
DSM-IV bipolar depression were given either inositol 12g/d or placebo as add-on 
treatment to current medication. There was a non-significant but encouraging difference 


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between the two groups, 50% of inositol subjects improving versus 30% of placebo 
subjects (Chengappa, 2000). The authors concluded that a controlled study with an 
adequate sample size may demonstrate efficacy for inositol in bipolar depression. In 
another study, 66 bipolar adults, currently depressed, were randomized to receive 
lamotrigine, risperidone, or inositol (target dose 10-25mg) added on to regular treatment 
for 8 weeks (Nierenberg, 2006). There were no significant between-group differences, 
however post-hoc analysis suggested that lamotrigine may be superior to inositol and 
risperidone in improving treatment-resistant bipolar depression, and inositol 
outperformed risperidone, but not reaching statistical significance. Recovery rate with 
lamotrigine was 23.8%, risperidone 4.6%, and inositol 17.4%. A similar study by Evins 
et al randomized 17 depressed bipolar adults on therapeutic levels of lithium or valproate 
to receive either inositol 5-20g/d or placebo as adjunct treatment. Although the outcome 
was not statistically significant, notably 44% on inositol versus 0% on placebo met 
response criteria for symptoms of depression. 
 
Regarding safety, like many nutriceutical agents, inositol has been found to be generally 
well tolerated in adult randomized controlled trials. Side effects reported in available 
studies include mild increases in glucose, flatus, nausea, sleepiness and insomnia, 
dizziness, headache and diarrhea. Inositol has been studied as an adjunctive agent, and no 
drug interactions have been reported to date. A study of inositol for attention deficit 
hyperactivity disorder in 11 children failed to demonstrate efficacy, but this study 
demonstrated that treatment was well-tolerated in children in doses of 200 mg per kg 
body weight (Levine, 1995). A review of controlled trials of inositol in psychiatry reports 
no changes found in hematology, kidney or liver function tests. 
 
There is no established recommended daily allowance for inositol. Studies of adults have 
used dosages ranging from 6 to 25g/d of inositol or myo-inositol given in divided doses. 
One study suggested that 12g/d of inositol has been shown to raise CSF inositol levels by 
70% (Levine, 1993). Studies for inositol are lacking, but the one study of inositol in 
psychiatry for children used a dose of 200mg per kg and offers initial evidence of the 
safety and tolerability of this dose (Levine, 1995). 
 
Why combine inositol and omega-3 fatty acids 
As pediatric bipolar disorder is most commonly characterized as mixed with co-
occurrence of manic and depressed symptoms, a treatment option combining agents with 
anti-manic and anti-depressant actions could be successful. Both omega-3 fatty acids, 
including EPA and DHA, and inositol have shown modest positive effects for depression, 
bipolar depression and, in the case of omega-3 fatty acids, mania. The mechanism of 
action of these agents are complementary, with omega-3 fatty acids increasing membrane 
fluidity and inositol working as a critical second messenger in cell processes occurring in 
the cell membrane. Thus from both clinical and purported mechanism standpoints, using 
these agents in combination makes clinical and pathophysiologic sense. Thus, we propose 
to study the efficacy and safety of the natural treatments of omega-3 fatty acids and 
inositol used singly and in combination in youth with bipolar spectrum disorders. 
 
Rationale 


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Emerging research suggests that inositol may have modest effects in the treatment of 
depression, but there have been no studies in children. Similar to the omega-3 fatty acids, 
inositol is well tolerated. Given that these nutritional supplements show promise in the 
treatment of mood disorders but to small effect, we propose to study the possible additive 
effect of combining these two alternative treatments in youth with bipolar spectrum 
disorders, an area of significant need. 
 
We propose to conduct a randomized, double blind, controlled trial that will evaluate 
effectiveness and tolerability of omega-3 fatty acids and inositol used alone and in 
combination. We plan to decrease the variability in the population under study by 
limiting the age range to 5-12 years and excluding cases with significant, untreated, 
comorbidity. We will measure cognitive effects/side effects with a neuropsychological 
battery pre and post treatment. We will exclude subjects with a history of failing 
treatment with two or more conventional treatments. 
 
2. SPECIFIC AIMS 
Specific Aim I: Assessing the efficacy of omega-3 fatty acids versus inositol in the 
treatment of pediatric bipolar spectrum disorders. Our pilot work suggests that omega-3 
fatty acids are effective in the treatment of bipolar disorder in youth, but no work has 
assessed the effectiveness of inositol for pediatric bipolar disorder. Hypothesis 1: Inositol 
will be as effective for pediatric bipolar disorder as omega-3 fatty acids. 
 
Specific Aim II: Assessing the efficacy of omega-3 fatty acids plus inositol in the 
treatment of pediatric bipolar spectrum disorders. Omega-3 fatty acids exert a modest 
effect for pediatric bipolar disorder. Studies of inositol also report modest effects for 
depression. The combined treatment will be superior to either one used as monotherapy. 
Hypothesis 2: Omega-3 fatty acids plus inositol will be superior to either used alone in 
the treatment of pediatric bipolar spectrum disorders. 
 
Specific Aim III: Assessing the side effect profile of omega-3 fatty acids plus inositol. 
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, omega-3 fatty acids and inositol have health benefits. Hypothesis 3: The 
combined use of omega-3 fatty acids plus inositol will have few side effects. 
 
3. LENGTH OF STUDY 
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 treatment phase. Subjects 
will be assessed weekly throughout the study for effects and adverse effects. 
 
4. SOURCE OF SUJECTS 
Individuals who respond to advertising will be screened for eligibility first by the 
study coordinator or a research assistant via phone and then by a study clinician. We will 
also be using Internet advertisements, including advertisements posted on Facebook, to 
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and new patients in the Pediatric Psychopharmacology Program, or via advertising in the 
local media. 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. Clinical records are not scanned in order to recruit subjects. 
 
Subjects may also be recruited from one of our screening protocols: “Screening Protocol 
for Children and Adolescents with Bipolar and Bipolar Spectrum Disorder” (Protocol # 
2001-P-001247) or “A General Screening Protocol for Child and Adolescent Research 
Studies in the Pediatric Psychopharmacology Program” (Protocol # 2014-P-001103). 
After participating in a screening protocol, subjects are assigned to 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. Other medical 
records on a subject will not be used at any point. 
 
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. 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. 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, 5-12 years of age. 
2. Subjects must have a DSM-IV diagnosis of a bipolar spectrum disorder (type 
I, II, or Not Otherwise Specified (NOS)), and currently displaying mixed, 
manic, or hypomanic symptoms (without psychotic features) according to the 
DSM-IV based on clinical assessment and confirmed with structured 
diagnostic interview (Schedule of Affective Disorders and Schizophrenia for 
School-Age Children - Epidemiological Version (K-SADS-E)) (Orvaschel, 
1994). 
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. 
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nature of the study. The subject’s authorized legal representative must sign an 
informed consent document and the subject must sign an informed assent 
document. 
6. Subjects must have an initial score on the YMRS total score of at least 20. 
7. Subject must be able to swallow pills. 
8. Subjects with ADHD and ODD will be allowed to participate in the study 
provided that the impairment associated with these disorders is of mild or 
moderate severity (not severe) and milder in severity relative to the 
impairment of the bipolar disorder, according to clinician evaluation. Subjects 
with comorbid anxiety disorders will be allowed to participate provided that 
the impairment associated with the anxiety is of minimal severity, according 
to clinician evaluation. Subjects with comorbid CD will be excluded. 
 
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. History of bleeding diathesis, including those with von Willebrand disease. 
4. Uncorrected hypothyroidism or hyperthyroidism. 
5. History of sensitivity to omega-3 fatty acids or inositol. A non-responder or 
history of intolerance to omega-3 fatty acid or inositol, after 2 months of 
treatment at adequate doses as determined by the clinician. 
6. Severe allergies or multiple adverse drug reactions. 
7. Failed 2 or more previous trials with anti-manic treatments including lithium, 
anticonvulsants and atypical antipsychotic medication. 
8. Current or past history of seizures. 
9. DSM-IV substance use, abuse or dependence (unlikely in ages 5-12). 
10. Judged clinically to be at serious suicidal risk. 
11. Current diagnosis of schizophrenia. 
12. Current diagnosis of conduct disorder 
13. Pregnancy (unlikely in ages 5-12). 
14. YMRS Item #8 (Content) score of 8 (“delusions; hallucinations”). 
15. YMRS total score above 40. 
16. Girls who have begun menstruating. 
17. C-SSRS score ≥ 4. 
18. IQ < 70. 
 
 
7. DESIGN 
This will be a 12-week, double-blind, randomized clinical trial study to compare efficacy 
and tolerability of the natural treatments omega-3 fatty acids and inositol used in 
combination in the treatment of bipolar spectrum disorders in children and adolescents 
(ages 5-12). Subjects will be randomized in double blind fashion to one of three arms: 


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omega-3 fatty acids, inositol or the combined treatment. Further, our proposed study will 
include measures of .3ion prior to starting study medication and at endpoint. We will 
minimize the variability of the population under study by limiting the age range to 5-12 
years, minimizing untreated or clinically significant comorbidity and excluding subjects 
who have already failed treatment with 2 or more anti-manic agents. Subjects will include 
youth ages 5-12 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, Fourth Edition (American Psychiatric Association, 2000) (DSM-IV), 
randomized to 3 treatment arms: 1) treatment with omega-3 fatty acids (N=30); 2) 
treatment with inositol (N=30); 3) treatment with the combination of inositol and omega-
3 fatty acids (N=30). 
 
The main 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-IV 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 > 20 and < 40. This will allow 
only children with mild or moderate symptoms to be enrolled. Only patients who are not 
responding to their current treatment regimen will be tapered from their medications. We 
will exclude subjects who have failed 2 trials or more of anti-manic agents in order to 
minimize the number of treatment resistant subjects. Concomitant medications will not be 
allowed except as indicated below. 
 
We will enroll 90 subjects to allow for randomization of 30 subjects into each treatment 
arm of the study. The subject’s first visit to the office consists of a meeting with a study 
clinician who explains the study, obtains informed consent, 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 (45-60 minutes). 
 
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 data if previously collected: 
• Diagnostic Data: If a subject has completed an evaluation with one of the study 
clinicians and/or the structured assessment within the previous 12 months prior to 
entrance into this study, they will not be asked to repeat any overlapping 
diagnostic procedures. However, the study clinician will review the interval time 
period to assess for clinically significant medical or psychiatric history, to ensure 
that the subject meets appropriate study entrance criteria. 
• Cognitive and Neuropsychological Testing: If the subset of scales assessing 
intelligence (WASI or KBIT-2 for 5 year-olds) and cognitive functioning (select 
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have been completed within 12 months prior to entrance into this study, subjects 
will not be asked to repeat these procedures at screening/baseline.  
• Screening Rating Scales: If a parent has completed the Child Behavior Checklist 
(CBCL), Social Responsiveness Scale (SRS), or the Behavior Rating Inventory of 
Executive Function – Parent Form (BRIEF) within the past six months as part of 
one of our screening protocols, we will not ask the parent/guardian to repeat these 
scales at screening/baseline. 
 
Eligible subjects will be required to come into the office for weekly visits for the 12-
week study. During this time subjects will receive treatment with inositol, omega-3 fatty 
acids, or both. Subjects will be randomized to treatment arms in a double-blind fashion. 
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 treating research clinician feels 
that subject safety will not be jeopardized by doing so, the clinician may conduct the visit 
with the subject over the phone. During the phone visit, the clinician will complete all 
study scales for that visit. This will ensure that each subject will be continuously 
monitored by the clinician throughout the course of the study despite unforeseen 
scheduling circumstances. However, neither the study evaluation visit, nor the baseline 
visit, nor the final study visit may be conducted over the phone. Additionally, phone 
visits may not occur for two consecutive visits. 
 
Vital signs (blood pressure, pulse, weight, height, temperature) will be measured at every 
visit. 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. 
 
Dosing 
 
Omega-3 Fatty Acids 
 
Study subjects may be randomized to receive 3000mg (6 500mg capsules) of omega-3 
fatty acids or placebo for the duration of the study. Omega-3 fatty acid capsules are in the 
form of Nordic Naturals brand, ProOmega Junior, which contains 325mg EPA and 
225mg DHA per two capsules. Nordic Naturals will provide the omega-3 fatty acid 
placebo in addition to the active capsules. 
 
Nordic Naturals brand is commonly used by clinic patients under our care and has been 
used in adult studies of bipolar disorder at Massachusetts General Hospital (PI: David 
Mischoulon, MD). We chose this product for its palatability (very little fishy taste or 
odor, which will facilitate the blinding process), its freedom from toxins including 
mercury, and the size of capsule which is easy for children to swallow. As omega-3 fatty 
acids are difficult to obtain and must be extracted from fish, a high quality, reliable 
product which filters toxins and mercury is critical for use in children. Omega-3 fatty 
acids can also expire and decrease in potency, arguing further for a well-regarded and 
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The rationale for the omega-3 dosing is based on the few dosing studies in adults which 
suggest that lower doses (1g) are more effective that higher doses (4g) for depression in 
adults, plus the result of our preliminary study which found no greater efficacy beyond 
2000mg. The daily dose per participant of 3000mg of omega-3 fatty acids includes 
975mg EPA, which is close to the potentially helpful 1000mg (or 1g) suggested for this 
population. 
 
Inositol 
 
Subjects weighing 25kg or more may be randomized to receive 2000mg (4 500mg 
capsules) of inositol, which is 80mg per kg for a 25kg child. Children weighing less than 
25kg will be dosed at 80mg per kg rounded down to the nearest 500 mg capsule. Inositol 
will be obtained from Jarrow Formulas, a supplier of nutritional supplements, in capsules 
containing 500mg of inositol per capsule. The Massachusetts General Hospital Research 
Pharmacy will provide the inositol placebo pill. 
 
Jarrow Formulas brand was chosen for the inositol based on clinical experience by the PI 
using various brands in clinic patients. This brand is easy to obtain and offers inositol 
powder, sold in bulk. The MGH Pharmacy will encapsulate the powder and provide a 
matched placebo. Inositol is a simple sugar substance and is easy to manufacture and 
obtain. There is little difference among the brands, although only some of the companies 
encapsulate the inositol powder. 
 
There are no dosing studies for inositol, but the only study in children (a negative study 
for ADHD) found 200mg per kg to be safe and tolerable. 2000mg is 80mg per kg for a 
25kg child. Weight corrected dosing will occur in the case of a child weighing below 
25kg. 
 
Double-blind omega-3 fatty acid and double-blind inositol treatment will commence on 
the same day. Both omega-3 fatty acid and inositol may be taken QD or BID, per 
clinician judgment. 
 
Subjects who have difficulty swallowing the inositol/placebo capsules can have his/her 
parent(s)/guardian(s) open the capsules and put the contents into soft food (such as ice 
cream or apple sauce) until the child is fully trained in swallowing pills. As inositol is a 
natural supplement found in everyday foods, this will not present an increased risk to 
subject safety, nor does it change the efficacy of the study medication. Since the inositol 
and dextrose (the contents of a placebo pill) are both similar in appearance, administering 
the medication in this fashion will not break the blind. The omega-3 fatty acid capsules 
(and matched placebo) are smaller and more easily swallowed; however, because opening 
the omega-3 fatty acid capsules will likely not allow subjects to receive the entire dose 
and risks breaking the blind, subjects who are unable to swallow the omega-3 fatty 
acid/placebo capsules will be removed from the study. 
 
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handling and packaging of medications for blinded trials utilizing encapsulation 
processes to ensure blindness by the clinicians and the subjects, who will not know which 
subjects are receiving omega-3 fatty acids, which are receiving inositol and which are 
receiving both treatments. The supplements will be stored in the research pharmacy and 
delivered the Pediatric Psychopharmacology Unit where it will be dispensed by a 
clinician. Subjects are instructed to return unused capsules. 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 the patient’s regimen remains the same throughout the study. Patients 
treated with these medications must be on a stable dose for at least two weeks 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. Our experience with 
clinical trials in this population indicates that this procedure is feasible and clinically 
indicated in cases in which subjects are not doing well on current treatment. No patient 
will be tapered from medication that is useful to him or her. If at Screening a participant 
is taking medication for a comorbid condition, the clinician will evaluate, using a CGI 
scale for the targeted condition, whether or not this condition is of moderate or greater 
severity. If the condition is found to be of moderate or greater severity, we will interpret 
this as a lack of efficacy for this Concomitant Medication, and will advise the subject to 
taper off the medication for entry into this study. In dozens of clinical trials in children 
with bipolar disorder we have used this same procedure successfully.  
 
The use of the benzodiazepine lorazepam is permitted during the study. 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 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. 
 


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Washout Period 
 
Medication washout is recommended by our clinicians to families and current providers – 
this is done according to a case-by-case assessment, considering the duration on drug, the 
dose, and the adverse effects associated with the treatment, and 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 
 
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 age 7-
12 years who, in the opinion of the Investigator, is capable of providing assent based on 
their 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 their 
parents/guardians. (For example, “Does your child have a history of any 
medical conditions such as diabetes or hypertension?”) 
• Conduct a brief demographic interview. This interview will be used to 
estimate socioeconomic status, as well as collect information about any 
educational accommodations, and past head injuries and trauma.  
• Obtain psychiatric history and administer 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-IV 
bipolar spectrum disorder (mixed, manic, or hypomanic) and has an 
YMRS score of > 20 and < 40. 
 
All exclusionary and inclusionary criteria will be reviewed. Appropriate patients will 
undergo: 
• An assessment battery (CBCL, SAICA, FES) 
• Cognitive evaluation [IQ and cognitive function (subtests of WISC-IV, 
WPPSI-III, or KBIT-2)] 


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§ 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 WISC-IV to assess IQ 
in children younger than 6 years. 
• Physical exam 
• Tanner staging exam (clinician-administered to parent or subject, clinician 
exam with subject, or the option to refuse) 
• Vital Signs (blood pressure, pulse, height, weight, temperature) 
 
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. 
 
Parents/guardians of study participants may request the results of their child’s cognitive 
testing. In this case, the subject will receive a letter providing a basic interpretation of the 
results and referring the parent/guardian to the department's supervising 
neuropsychologist for any questions or concerns.   
 
Baseline (Week 0) 
 
Subjects must continue to meet all inclusionary and exclusionary criteria at this visit 
• Study clinician will administer Baseline Scales 
• Vital signs (blood pressure, pulse, height, weight, temperature) 
• Subjects will receive study medication as indicated by a blinded 
randomization schedule 
 
Weekly Visits (Weeks 1 through 12) 
 
Weekly study visits will have a visit window of +/- 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 
• At the last visit, subjects will undergo repeat cognitive evaluation. 
Subjects who are dropping from the study will also undergo repeat 
cognitive evaluation if they have been exposed to the study medication for 
at least two weeks. 
 
Study Discontinuation 
 


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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. 
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 may be dropped from the 
study. 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 worsening of clinical course, non-compliance with treatment or inability to tolerate 
study treatment. 
 
Subjects will receive three months of optional pro bono clinical care visits (one monthly 
appointment over three months’ time) at the completion of the study (or if they are 
required to discontinue for the above reasons) in which they will be seen by study staff. 
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 treaters in their communities. 
 
Subjects who fail to return medication for two consecutive 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 treaters 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. Since our target 
subject population is children 5-12 years of age, we do not anticipate that any participant 
will be at risk for pregnancy. However, a urine pregnancy test will be completed for 
female subjects ages 11-12 at screening. A physical exam, Tanner’s staging, and parent 
report are collected at the screening as well visit to ascertain pubertal status. For 
subsequent study visits, pregnancy status is determined by verbal query of parent and/or 
subject or additional urine tests if needed. 
 
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 the visits will be 
recorded. These recordings will be used to monitor quality control and inter-rater 
reliability in this study by the PI. Each recording will be coded with patient initials and 
number to maintain confidentiality. These recordings will be stored in a password-
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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 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) 
 
1. K-SADS-E (Epidemiologic Version) 
v We will collect information for psychiatric diagnoses in children with study 
relevant modules of the KSADS-E (Epidemiologic Version) (Orvaschel, 2004). 
v This is a widely used, semistructured, diagnostic interview with established 
psychometric properties. It can be effectively administered by clinicians in 45 to 
90 minutes, although more complex cases may require additional time. 
v For all children, psychiatric data will be collected from the mother, or primary 
caretaker. All children and primary caregivers will be seen in direct clinical 
interview with the treating clinician. 
v The mania and depression modules will be administered prior to the baseline visit 
by the clinician to ensure entry criteria are met.  
 
2. Background Information 
v Prior to administering the cognitive measures at baseline, the child and a parent 
(or his/her legal guardian) will be asked a series of short questions about the 
child’s background to establish socioeconomic status. Information gathered 
includes: sex, age, race/ethnicity, intactness of parents, home environment, 
financially responsible providers (using an SES scale, see below), history of 
head injury, trauma, and academic functioning. This will be entered on both the 
standard departmental form, and the study-specific form (“Background 
Information/KSADS face page”). 
v The Four Factor Index of Social Status (SES) (Hollingshead, 1975) will be used 
as a general measure of social advantage or disadvantage. 
 
3. Child Behavior Checklist-Parent Form (CBCL) 
v The CBCL (Achenbach, 2000; Achenbach, 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. 


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v The CBCL records, in standardized format, the behavioral problems and 
competencies of children aged 4 to 18, as reported by their parents or parent- 
surrogates. 
v 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. 
v Administered at beginning of study to characterize the groups and ensure their 
similarity. 
 
4. Social Adjustment Inventory for Children and Adolescents (SAICA) 
v The SAICA (John, 1987) is a semi-structured interview of the child or parent that 
measures social functioning in children 6 to 18 years old. 
v 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. 
v We will administer this scale at beginning of study and endpoint to assess the 
impact of treatment on social functioning. 
 
5. Family Environment Scale (FES) 
v As an additional measure of the family environment, we will use the Moos Family 
Environment Scale (FES) (Moos, 1985; Moos, 1976). 
v 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. 
v Administered at beginning of study to characterize the groups and ensure their 
similarity. 
 
6. DSM-IV Global Assessment of Functioning (GAF) 
v The GAF (APA, 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. 
v 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. 
 
7. Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
(Endicott, 2006) 
v A 15-item rating scale to assess the degree of life enjoyment and satisfaction for 
children. Baseline and endpoint. 
8. Neuropsychological Tests/Cognitive Evaluation 
v 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 
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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 Kaufman Brief Intelligence Test, Second Edition (KBIT-2)(Kaufman 
 
   & Kaufman, 2004)  
 
-  Subjects ages 6-12: Vocabulary and Matrices subtests of the Wechsler 
 
   Abbreviated Scale of Intelligence (WASI)(Wechsler, 2003) 
v Cognitive Functioning Testing: At screening and endpoint, to assess 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, 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 25 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 6-12: Digit Span and Coding subtests from the  
 
   Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV)  
 
   (Wechsler, 2003) to measure working memory and processing speed 
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 Screening Visit, Baseline 
Visit, at each of the weekly visits and endpoint. 
 
1. Young Mania Rating Scale (YMRS) 
v The YMRS (Young, 1978) consists of 11 items rated on a scale from 0 (symptom 
not present) to 4 (symptom extremely severe). 
v 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. 
v 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. 


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v Collected at the Screening Visit, Baseline Visit (only subjects with a YMRS score 
of 20 or greater, but not above 40, are included), at each of the weekly visits and 
at endpoint to assess the impact of treatment on manic symptoms. 
 
2. Children’s Depression Rating Scale (CDRS) 
v The CDRS (Poznanski, 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. 
v 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. 
v This scale is generally accepted as the main outcome in studies assessing 
childhood depression and is linked directly to the core symptoms of depression. 
v Collected at the Screening Visit, Baseline Visit, at each of the weekly visits and at 
endpoint. 
 
3. Hamilton Depression Rating Scale 
v The HAM-D is a clinician rated instrument that measures the severity of 
depressive symptoms. 
v This is a clinican-rated instrument with 21 items scored on a 0 to 4 scale. 
v Collected at the Screening Visit, Baseline Visit, at each of the weekly visits and at 
endpoint. 
 
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 Impact on Family Scale at baseline and endpoint, as well as the 
Behavior Rating Inventory of Executive Function – Parent Form (BRIEF) at the baseline 
and endpoint visits.  
 
1. DSM-IV Mania Symptom Checklist 
v 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). 
v Collected at baseline visit, at each of the weekly visits and at endpoint as an 
additional measure of manic symptoms. 
 
2. Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale 


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v 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). 
v Collected at baseline visit, middle and endpoint to assess the impact of 
treatment on ADHD symptoms, which often co-occur with pediatric bipolar 
disorder. 
 
3. Brief Psychiatric Rating Scale (BPRS) 
v The Brief Psychiatric Rating Scale (BPRS) is a common scale used to assess 
overall psychopathology (Overall and Pfefferbaum, 1982).  The scale consists of 
18 items; each rated on a scale from 1 (symptom not present) to 7 (symptom 
extremely severe). 
v 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.  
 
4. Social Responsiveness Scale (SRS) 
v 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. 
v Collected at Screening and Endpoint visits as assessment of symptoms and 
capacities associated with social interaction. 
 
5. NIMH Clinical Global Improvement scale (CGI) 
v 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. 
v 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).                                                                                               
v 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. 
 
6. Impact on Family Scale 
v The Impact on Family Scale measures the effects of chronic childhood illness on 
quality of life within a family, in four dimensions: a) financial burden, b) 
disruption of social interaction, c) psychological burden on the caregiver, and d) 
coping strategies used by the family. 
v This scale will be used at screening and endpoint, completed by the parent of the 
study subject. 
  
7. Behavior Rating Inventory of Executive Function – Parent Form (BRIEF) 
v The BRIEF is an 86-item rating scale to assess level of executive function deficits 
(Roth et al., 2004). It is completed by the subject’s parent/guardian. 
v Collected at Baseline Visit, middle visit and at endpoint. 


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Safety Measures 
 
v Adverse Experiences: to record any adverse health events experienced during the 
study along with duration, severity, cause, remedy, and outcome. 
v Columbia Suicide Severity Rating Scale (C-SSRS): to assess initial and emergent 
suicidality. 
 
9. DATA ANALYSIS 
 
A. Statistical Analysis 
 
90 subjects will be randomized (1:1:1) into one of three treatment groups: inositol, 
omega-3 fatty acids, or inositol plus omega-3 fatty acids. Subjects will be block-
randomized to ensure equal age and gender distribution between groups. Because this is a 
randomized trial following subjects over a short period of time missing data are not 
expected to impact our analyses such that standard statistical analyses will be employed. 
Changes in ratings of mania within and between study groups over time will be tested 
with repeated measures analysis of covariance using the statistical software package 
STATA. All analyses will be intention to treat (ITT) with the last observation carried 
forward for subjects that do not complete the trial or are dropped from the study 
according to the exit criteria described earlier. 
 
B. Hypothesis Testing 
 
Hypothesis 1 examines the change in symptoms of mania over 12 weeks within the 
inositol and omega-3 fatty acids groups. These hypotheses will be tested with a repeated 
measures ANCOVA comparing baseline to follow-up assessments within each treatment 
group. 
 
Hypothesis 2 predicts that treatment with omega-3 fatty acids plus inositol will be 
superior to either used alone in the treatment of pediatric bipolar spectrum disorders. To 
assess this hypothesis, we will estimate two repeated measures ANCOVA models. The 
first will compare the change in bipolar symptoms over time between the inositol and 
combined inositol plus omega-3 fatty acids groups. The second will compare the change 
in bipolar symptoms over time between the omega-3 fatty acids group versus the 
combined inositol plus omega-3 fatty acids group. 
 
Hypothesis 3 examines side effects associated with the combined use of omega-3 fatty 
acids plus inositol. The prevalence of side effects reported over the course of the trial (i.e. 
the cumulative report of side effects by study endpoint) will be compared between groups 
using Pearson's chi-square test at study endpoint. Exploratory Hypothesis 1 predicts that 
combined treatment with omega-3 fatty acids plus inositol be associated with 
improvement in cognitive function at study endpoint compared to either treatment alone.  
 
C. Statistical Power 


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Power calculations were conducted with the statistical software package STATA. For 
repeated measures ANCOVA models, we assumed high correlation between follow-up 
assessments for the outcome of interest. Power was calculated for our study with 1 
prerandomization baseline assessment and 12 follow-up assessments. For Hypotheses 1, 
comparing baseline to follow-up measures within group, the power to detect differences 
in YMRS or CDRS scores of 5 points (SD=10 points) is 0.86 with alpha set at 0.05. For 
differences in YMRS or CDRS scores of 7.5 points, power increases to 99%. For 
hypothesis 2 and Exploratory Hypothesis 3, testing differences between groups, the 
power to detect differences in YMRS or CDRS scores of 5 points (SD=10 points) is 0.93 
with alpha set at 0.05 and 0.81 with alpha set at 0.01. 
 
9. 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, 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 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 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. 
 
10. 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. 
 
11. MONITORING AND QUALITY ASSURANCE 
 
The Data Safety Monitoring Committee for this study will be made up of two child 
psychiatrists. One of the child psychiatrists will be from a different institution, 
specifically the Children's Hospital Medical Center (a Harvard, but non-Partner's 
Healthcare affiliated institution). None of the members of the DSMC will be affiliated 
with the study. The DSMC will meet upon enrollment of the first subject and annually 
thereafter during the study. The DSMC will meet to discuss adherence to the protocol and 


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to monitor 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. In addition 
to the IRB, the Chairman of the DSMC 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 
within any arm of the study 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. 
 
12. 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 they are natural 
products, it appears that the omega-3 fatty acids and inositol have a low potential for 
unwanted side effects or negative effects on the child’s growth and development. It 
should also be noted that no important toxic effects have been reported in previous use in 
humans and animals. 
 
Omega-3 Fatty Acids 
 
The treatment omega-3 fatty acids has been used and studied in pediatric populations 
with few side effects. The most common side effects reported with use of omega-3 fatty 
acids are upset stomach and complaints of a fishy taste. Other side effects include nausea, 
skin rashes, decreased platelet aggregation, bleeding tendencies, and increased 
restlessness. 
 
Inositol 
 
Inositol is a safe, natural diet supplement with emerging evidence of utility in psychiatric 
populations. The most common side effects include mild increases in glucose, flatus, 
nausea, sleepiness and insomnia, dizziness, headache, and diarrhea. 
 
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 


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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 handle clinical emergencies with patients and their 
families. The PI has a beeper and is available for emergencies 24 hours per day. 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 child 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. 
 
13. 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 potentially useful 
treatments which have low risks associated with them, as the treatments are natural 
elements of the human diet. 
 
To Others 
 
The study will further our understanding of the treatment of bipolar disorder in children 


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29
by testing novel treatments, in combination. 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 
 
Despite the fact that pediatric bipolar disorder is now recognized as a significant public 
health concern, little is known about its treatment. This study furthers our knowledge 
regarding potentially useful treatments. As parents are concerned about the effect of 
pharmaceutical agents on growth and development, this study examines the efficacy of a 
safe, alternative, natural 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 omega-3 fatty acids and inositol 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 (7-12) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cognitive Tasks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Tasks: IQ Measures (WASI 
or KBIT-2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Tasks: EF Measures (WISC 
IV or WPPSI-III) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician K-SADS-E (MDD, Mania) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Background Information (SES) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBCL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FES 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAICA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, CD, 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 
PQ-LES-Q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
BRIEF Parent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BPRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
SRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Impact on Family Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tanner Staging Report 
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 
X 
       
1 99 – screening visit(s) 
2 0 – baseline visit 
 
 
 
 
 
 
 
 
 
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