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Fish Oil for Bipolar Disorder in Children
By James Phelps, MD
May 12, 2016
The very existence of pre-pubertal bipolar disorder remains somewhat controversial,1-3 although several US research groups consistently identify and study it (eg, at Stanford University4 and at Washington University in St. Louis5).
Another such group, at Harvard, has just published an important study of treatment in pre-pubertal and peri-pubertal children with bipolar symptoms. The combination of fish oil and inositol produced, in a small sample, results better than either alone (inositol < fish oil < combination).6
This study is notable for several reasons, independent of the results, which themselves suggest an important alternative to pharmaceutical treatments may be at hand. First, whereas child/adolescent psychiatrists are usually forced to extrapolate to their population from research done in adults, here may be a case of the reverse: these researchers may have found a treatment approach worthy of consideration in adults with bipolar disorder.
Second, this work was done in the pediatric psychopharmacology research program at Massachusetts General Hospital, in Boston, by Joseph Biederman, MD, and colleagues.6 They have been criticized for aggressive diagnosis and treatment of very young children.7 Dr Biederman was sanctioned for links to the pharmaceutical industry.8 But with this study they have addressed these criticisms, at least in part.
Indeed, their new work may take some pressure off the need to firmly diagnose bipolar disorder. If a very low-risk alternative exists, treatment can begin without having to wait for the high degree of certainty needed to justify use of medications commonly regarded as first line for bipolar disorder in children, such as risperidone and aripiprazole (per their oft-cited FDA indications: eg, the American Academy of Child and Adolescent Psychiatry?s Parents? Medication Guide for Bipolar Disorder in Children & Adolescents9[PDF]).
The bottom line
The bottom line of their small pilot study: fish oil plus inositol was significantly better than fish oil alone, which was superior to inositol alone in most primary outcomes. The sample was small, the dropout rate was nearly 50%, and the children were only moderately symptomatic, so conclusions are limited. However, the results quite strongly suggest that adding inositol to fish oil makes the omega-3s work better.
What dosages? In fish oil studies in adults, doses have been quite variable, but an important meta-analysis suggests that there is a threshold for efficacy. Few studies of fish oil for depression found it better than placebo if the dose was less than 1 gram of eicosapentaenoic acid (EPA) per day and?critically?the composition was at least 60% EPA (ie, EPA/EPA plus docosahexaenoic acid [DHA]). If anything, the EPA content relative to DHA was more important than its total dose: 2 studies that used lower doses but over 60% EPA had positive results.10
In the new study by Biederman?s group, all participants received the same dose of 975 mg of EPA per day regardless of their weight, using a version that was 59.1% EPA. Although there was no placebo arm in this study to determine whether 59% EPA at that dose was actually better than placebo, it was statistically better than inositol, which served as a so-called ?active comparator? in lieu of a placebo?an ethical decision in this study population. The dose of inositol was roughly 80 mg/kg, for doses of 1500 to 2000 mg/d.
Adverse effects? Because the sample was so small, this is hard to evaluate for certain, but there were no worrisome outcomes related to study medications. Subjects who took fish oil had more gastrointestinal (GI) complaints than those who took inositol alone (5/17 versus 1/7).
Note that the dose was not weight-adjusted and was only 25 mg less than the 1 gram of EPA thought necessary for adults; perhaps a slightly lower dose might be sufficient and cause less GI distress.
Is the addition of inositol the key to making fish oil really work as a mood stabilizer?
Children in this study were 5 to 12 years old. They had been diagnosed with ?bipolar spectrum disorder? (bipolar I or II or not otherwise specified). Diagnoses were established by ?an experienced clinician? whose interview was supplemented with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children: Epidemiologic Version.
Exclusions included a Young Mania Rating Scale (YMRS) over 40. Thus, as the authors emphasize, generalizability is limited to children with ?mild to moderate? manic symptoms.
In addition to significant reductions in YMRS, this small study also found significant reductions in depression scores and, interestingly, in anxiety scores as well. Perhaps the addition of inositol is the key to making fish oil really work as a mood stabilizer?
A larger trial of similar design (same 3 arms of inositol, omega-3, and combination, compared) is recruiting at the Massachusetts General Hospital team?s site, due for completion in January 2017 (NCT01396486). Thanks to Dr Biederman and his group for this work on a non-pharmaceutical option for children with mild to moderate symptoms?the child literature leading the way for adult research this time.
References
1. Paris J. Problems in the boundaries of bipolar disorders. Curr Psychiatry Rep. 2014;16:461.
2. Parry P, Allison S. Pre-pubertal paediatric bipolar disorder: a controversy from America. Australas Psychiatry. 2008;16:80-84.
3. Douglas J, Scott J. A systematic review of gender-specific rates of unipolar and bipolar disorders in community studies of pre-pubertal children. Bipolar Disord. 2014;16:5-15.
4. Holtzman JN, Miller S, Hooshmand F, et al. Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients. J Psychiatr Res. 2016;76:128-135.
5. Geller B, Tillman R. Prepubertal and early adolescent bipolar I disorder: review of diagnostic validation by Robins and Guze criteria. J Clin Psychiatry. 2005;66(suppl 7):21-28.
6. Wozniak J, Faraone SV, Chan J, et al. A randomized clinical trial of high eicosapentaenoic acid omega-3 fatty acids and inositol as monotherapy and in combination in the treatment of pediatric bipolar spectrum disorders: a pilot study. J Clin Psychiatry. 2015;76:1548-1555.
7. Allen S. Backlash on bipolar diagnoses in children: MGH psychiatrist?s work stirs debate. Boston Globe. June 17, 2015. Backlash on bipolar diagnoses in children - The Boston Globe. Accessed May 10, 2016.
8. The Harvard Crimson. Document: Doctor?s Apology Letter. July 2, 2011. http://www.thecrimson.com/flash-graphic/2011/7/2/medical-school-colleagues-letter/. Accessed May 10, 2016
9. American Academy of Child and Adolescent Psychiatry. Parents? Medication Guide for Bipolar Disorder in Children & Adolescents. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Professional-Topics/Child-Adolescent-Psychiatry/Bipolar-parentes-med-guide.pdf. Accessed May 10, 2016.
10. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.
By James Phelps, MD
May 12, 2016
The very existence of pre-pubertal bipolar disorder remains somewhat controversial,1-3 although several US research groups consistently identify and study it (eg, at Stanford University4 and at Washington University in St. Louis5).
Another such group, at Harvard, has just published an important study of treatment in pre-pubertal and peri-pubertal children with bipolar symptoms. The combination of fish oil and inositol produced, in a small sample, results better than either alone (inositol < fish oil < combination).6
This study is notable for several reasons, independent of the results, which themselves suggest an important alternative to pharmaceutical treatments may be at hand. First, whereas child/adolescent psychiatrists are usually forced to extrapolate to their population from research done in adults, here may be a case of the reverse: these researchers may have found a treatment approach worthy of consideration in adults with bipolar disorder.
Second, this work was done in the pediatric psychopharmacology research program at Massachusetts General Hospital, in Boston, by Joseph Biederman, MD, and colleagues.6 They have been criticized for aggressive diagnosis and treatment of very young children.7 Dr Biederman was sanctioned for links to the pharmaceutical industry.8 But with this study they have addressed these criticisms, at least in part.
Indeed, their new work may take some pressure off the need to firmly diagnose bipolar disorder. If a very low-risk alternative exists, treatment can begin without having to wait for the high degree of certainty needed to justify use of medications commonly regarded as first line for bipolar disorder in children, such as risperidone and aripiprazole (per their oft-cited FDA indications: eg, the American Academy of Child and Adolescent Psychiatry?s Parents? Medication Guide for Bipolar Disorder in Children & Adolescents9[PDF]).
The bottom line
The bottom line of their small pilot study: fish oil plus inositol was significantly better than fish oil alone, which was superior to inositol alone in most primary outcomes. The sample was small, the dropout rate was nearly 50%, and the children were only moderately symptomatic, so conclusions are limited. However, the results quite strongly suggest that adding inositol to fish oil makes the omega-3s work better.
What dosages? In fish oil studies in adults, doses have been quite variable, but an important meta-analysis suggests that there is a threshold for efficacy. Few studies of fish oil for depression found it better than placebo if the dose was less than 1 gram of eicosapentaenoic acid (EPA) per day and?critically?the composition was at least 60% EPA (ie, EPA/EPA plus docosahexaenoic acid [DHA]). If anything, the EPA content relative to DHA was more important than its total dose: 2 studies that used lower doses but over 60% EPA had positive results.10
In the new study by Biederman?s group, all participants received the same dose of 975 mg of EPA per day regardless of their weight, using a version that was 59.1% EPA. Although there was no placebo arm in this study to determine whether 59% EPA at that dose was actually better than placebo, it was statistically better than inositol, which served as a so-called ?active comparator? in lieu of a placebo?an ethical decision in this study population. The dose of inositol was roughly 80 mg/kg, for doses of 1500 to 2000 mg/d.
Adverse effects? Because the sample was so small, this is hard to evaluate for certain, but there were no worrisome outcomes related to study medications. Subjects who took fish oil had more gastrointestinal (GI) complaints than those who took inositol alone (5/17 versus 1/7).
Note that the dose was not weight-adjusted and was only 25 mg less than the 1 gram of EPA thought necessary for adults; perhaps a slightly lower dose might be sufficient and cause less GI distress.
Is the addition of inositol the key to making fish oil really work as a mood stabilizer?
Children in this study were 5 to 12 years old. They had been diagnosed with ?bipolar spectrum disorder? (bipolar I or II or not otherwise specified). Diagnoses were established by ?an experienced clinician? whose interview was supplemented with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children: Epidemiologic Version.
Exclusions included a Young Mania Rating Scale (YMRS) over 40. Thus, as the authors emphasize, generalizability is limited to children with ?mild to moderate? manic symptoms.
In addition to significant reductions in YMRS, this small study also found significant reductions in depression scores and, interestingly, in anxiety scores as well. Perhaps the addition of inositol is the key to making fish oil really work as a mood stabilizer?
A larger trial of similar design (same 3 arms of inositol, omega-3, and combination, compared) is recruiting at the Massachusetts General Hospital team?s site, due for completion in January 2017 (NCT01396486). Thanks to Dr Biederman and his group for this work on a non-pharmaceutical option for children with mild to moderate symptoms?the child literature leading the way for adult research this time.
References
1. Paris J. Problems in the boundaries of bipolar disorders. Curr Psychiatry Rep. 2014;16:461.
2. Parry P, Allison S. Pre-pubertal paediatric bipolar disorder: a controversy from America. Australas Psychiatry. 2008;16:80-84.
3. Douglas J, Scott J. A systematic review of gender-specific rates of unipolar and bipolar disorders in community studies of pre-pubertal children. Bipolar Disord. 2014;16:5-15.
4. Holtzman JN, Miller S, Hooshmand F, et al. Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients. J Psychiatr Res. 2016;76:128-135.
5. Geller B, Tillman R. Prepubertal and early adolescent bipolar I disorder: review of diagnostic validation by Robins and Guze criteria. J Clin Psychiatry. 2005;66(suppl 7):21-28.
6. Wozniak J, Faraone SV, Chan J, et al. A randomized clinical trial of high eicosapentaenoic acid omega-3 fatty acids and inositol as monotherapy and in combination in the treatment of pediatric bipolar spectrum disorders: a pilot study. J Clin Psychiatry. 2015;76:1548-1555.
7. Allen S. Backlash on bipolar diagnoses in children: MGH psychiatrist?s work stirs debate. Boston Globe. June 17, 2015. Backlash on bipolar diagnoses in children - The Boston Globe. Accessed May 10, 2016.
8. The Harvard Crimson. Document: Doctor?s Apology Letter. July 2, 2011. http://www.thecrimson.com/flash-graphic/2011/7/2/medical-school-colleagues-letter/. Accessed May 10, 2016
9. American Academy of Child and Adolescent Psychiatry. Parents? Medication Guide for Bipolar Disorder in Children & Adolescents. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Professional-Topics/Child-Adolescent-Psychiatry/Bipolar-parentes-med-guide.pdf. Accessed May 10, 2016.
10. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.
