Multinutrient supplement as treatment: literature review and case report of a 12-year-old boy with bipolar disorder

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 19, Number 4, 2009ª Mary Ann Liebert, Inc.
Pp. 453–460DOI: 10.1089=cap.2008.0157 Multinutrient Supplement as Treatment: Literature Review and Case Report of a 12-Year-Old Boy with Bipolar Disorder Elisabeth A. Frazier, B.S., Mary A. Fristad, Ph.D., ABPP, and L. Eugene Arnold, M.D., M.Ed.
Early-onset bipolar disorder has significant morbidity and mortality. Development of safe, effective treatments towhich patients will adhere is critical. Pharmacologic interventions for childhood bipolar spectrum disorders arelimited and are associated with significant risk for adverse events. Diet and nutrition research suggests vitamins,minerals, and other nutrients are important underpinnings of general physical and mental health; furthermore,they may even be useful in treating mood dysregulation by providing a more favorable risk–benefit ratio thancontemporary psychotropic agents. This article reviews the literature on multinutrient supplementation andmental health, and examines a case study of a 12-year-old boy with bipolar disorder and co-morbid diagnosestreated for 6 years with conventional medication and finally a multinutrient supplement. The multinutrient sup-plement in this case study is EMPowerplus (EMPþ), a 36-ingredient supplement containing 16 minerals, 14 vita-mins, 3 amino acids, and 3 antioxidants. It was used to treat a 12-year-old boy initially diagnosed with bipolardisorder not otherwise specified (BP-NOS) at age 6, and whose diagnosis evolved by age 10 to bipolar I (BP-I),mixed, with psychotic features. He also met criteria for generalized anxiety disorder by age 8 and obsessive-compulsive disorder by age 10. After 6 years of conventional treatment (ages 6–12), he received 14 months of EMPþ.
Symptom manifestation over 7 years is described in conjunction with treatment history. EMPþ resulted in outcomesuperior to conventional treatment. This report adds to accumulating preliminary evidence that further basicscience and clinical studies of multinutrient supplements are warranted.
tions, dyslipidemia, and orthostatic hypotension. Researchersfound metabolic and cardiovascular risks increased for Childhood-onset bipolar spectrum disorders (BPSD; youths taking multiple antipsychotics (McIntyre and Jerrell bipolar I [BP-I], bipolar II [BP-II], Bipolar not otherwise specified [BP-NOS], and cyclothymia) represent a significant In another study monitoring side effects of atypical neu- public health concern (McClellan et al. 2006; Brown et al.
roleptics, including clozapine, olanzapine, and risperidone, 2008). Although recent clinical trials have found efficacy in all three drugs caused drowsiness and hypoactivity. A total of using atypical antipsychotics for BP-I, treatment literature is 30–60% of children and adolescents taking clozapine experi- lacking for children with BP-II, BP-NOS, and cyclothymia, enced constipation, increased salivation, orthostatic hypo- despite the functional impairment inherent to these diagnoses tension, and nasal congestion. These side effects were seen in (Kowatch et al. 2009). Medications recommended in current patients taking olanzapine and risperidone less often, but treatment guidelines (Kowatch et al. 2005; McClellan et al.
5–15% of participants taking olanzapine or risperidone suf- 2006) appear beneficial but carry significant risk for adverse fered from rigidity, tremor, and dystonia. Participants in all three atypical neuroleptic conditions gained weight during In a recent retrospective study of medical and phar- the study, but those in the olanzapine group gained signifi- macy claims from a cohort of 4140 youths prescribed one of cantly more weight than those in the other two treatment five types of atypical or two conventional antipsychotics groups (4.6 Æ 1.9 kg; Fleischhaker et al. 2006).
compared to a random sample of 4500 youth not treated Recent clinical trials of depression and bipolar disorders in with psychotropics, the treated cohort had higher rates of youth show approximately 20–25% of participants dropped a variety of metabolic and cardiovascular side effects (Mc- out of psychotropic medication treatment (Biederman et al.
Intyre and Jerrell 2008). These adverse events included higher 2007; DelBello et al. 2007). DelBello and colleagues (2007) risk of obesity, type 2 diabetes mellitus, cardiovascular condi- conducted a single-blind, 12-week study of quetiapine in Department of Psychiatry, The Ohio State University, Columbus, Ohio.
adolescents aged 12–18 in which researchers observed a nate metabolism malfunctions, ultimately affecting brain 25% drop out rate of adolescents whose diagnoses included functioning; such innate mechanisms could involve inefficient dysthymia, BP-II, BP-NOS, major depressive disorder, or cy- use of nutrients. Second, they state mood instability may re- clothymia. Biederman and colleagues (2007) conducted an sult from deficiencies in methylation of molecules responsible 8-week, open-label trial of aripiprazole in children aged 6–17 for completing DNA transcription, switching on genes, reg- with BP in which they observed a 21% drop out rate. Ad- ulating protein generation, activating enzymes, and synthe- ditionally, a recent study of an anticonvulsant mood stabilizer sizing neurotransmitters. Third, nutrition deficiencies may in children failed to show any superiority to placebo (Wagner alter gene expression, leading to mood instability. Fourth, unstable mood may result from long-latency effects of nutri-ent deficiencies that alter brain development directly or byway of dysfunctional nutrient absorption. Although these Dietary supplementation and mental health four frameworks require considerable empirical evaluation, Previous research on diet and nutrition suggests multi- they provide possible mechanisms through which nutrient nutrient supplements may have a beneficial effect on mood supplementation may affect mood symptoms (Kaplan et al.
with limited side effects, which might provide a primary treatment with a more favorable risk–benefit ratio for some Gesch et al. (2002) examined the effects of vitamins, min- youth suffering from BPSD than currently available phar- erals, and essential fatty acids on antisocial behavior in a macologic interventions (Kaplan et al. 2001; Popper 2001; randomized, double-blind, placebo-controlled study of 231 Kaplan et al. 2002; Kaplan et al. 2004; Kaplan et al. 2007).
adult prisoners. Participants spent, on average, 142 days on Increasing evidence suggests that nutrition affects the struc- the recommended daily dose of two supplements (one cap- ture and functioning of the brain due to the high percentage of sule of Forceval, a vitamin-mineral supplement that contains human metabolic activity accounted for by this organ. In 25 vitamins and minerals, and four capsules of Efamol Mar- adulthood, the brain accounts for 20% of the human basal ine, an essential fatty acid supplement containing omega-6 metabolic rate; as a neonate, this number is as high as 44% and omega-3 essential fatty acids) or placebo (identically ap- (Benton 2008). Nutritional interventions, particularly multi- pearing oil-based gelatin capsules). The Efamol Marine dose ingredient multinutrient supplements, have several possible contains 1260 mg of linoleic acid, 160 mg of gamma linolenic mechanisms of action to explain a hypothesized association acid, 80 of eicosapentaenoic acid, and 44 mg of docosahex- with clinical improvement in mood. These are summarized below. Preliminary studies have been conducted with the Participants’ antisocial behavior was measured throughout multinutrient supplement EMPowerPlus (EMPþ) (Truehope the study period using disciplinary reports. Results revealed Nutritional Support Ltd., Raymond, Alberta, Canada). This a decrease in overall antisocial behavior for participants tak- supplement consists of 16 minerals, 14 vitamins, 3 amino ing nutritional supplements compared to placebo. Neither acids, and 3 antioxidants (a full list of ingredients can be found group reported notable side effects. Overall infringements on the manufacturer’s website at http:==www.truehope.com).
resulting in disciplinary reports decreased by 35.1% in the Relevant literature is discussed below.
active condition for participants who took the supplement forat least 2 weeks compared to placebo participants, whose disciplinary reports decreased by 6.7% ( p < 0.001). Intent- ric effects of certain frank nutritional deficiencies are well to-treat analyses showed active condition participants ex- known: e.g., thiamine=B1 (Wernicke encephalopathy), niacin= perienced a 26% decrease in overall infringements resulting B3 (pellagra), cyanocobalamin=B12 (psychosis of pernicious in disciplinary reports compared to placebo participants anemia), and iodine (myxedema madness). Milder effects of ( p < 0.03). This research suggests a combination of vitamin– more subtle deficiencies are increasingly recognized, possibly mineral supplements and essential fatty acids may decrease related either to genetic variations in which some patients antisocial behavior; the researchers speculate that physiolog- may be more vulnerable or to historical changes in diet ical changes caused by dietary intervention affect mental composition. Nutritional supplements have been related to a health and warrant further clinical investigation (Gesch et al.
wide range of human health factors from neuronal develop- ment to depression (Hibbeln 1998; Noaghiul and Hibbeln Schoenthaler and Bier (2000) examined the impact of low- 2003). Specific nutrients linked to mental health include dose vitamin–mineral tablets on rates of violent, antisocial iron, copper, zinc, vitamins B1, B6, B12, D, E, and folate behavior in 468 school children aged 6–12. Using a stratified randomized double-blind, placebo-controlled design, halfthe sample received daily vitamin–mineral supplementation at 50% of the U.S. recommended daily allowance (RDA) for to combinations of nutritional deficiencies, because there is 4 months. The other half received placebo. Eighty children plausible reasoning to support the concept that if one nutrient were disciplined at least once during the September 1 to May 1 is deficient, a grouping of nutrients are deficient, and the level study interval. The 40 who received supplementation had a of one nutrient can affect the adequacy of others (Benton 2008; 47% lower mean rating of antisocial behavior than the 40 on Kaplan et al. 2007). Kaplan and colleagues (2007) review placebo (1 vs. 1.875 disciplinary actions). Children on sup- studies of vitamins and minerals and their relationship with plementation had lower antisocial behavior ratings for every mood symptoms, then present four conceptual frameworks type of recorded infraction: Threats=fights, vandalism, dis- that are compatible, can coexist, and may aid understanding respect, disorderly conduct, assault=battery, defiance, ob- of how nutrients may improve mood (Kaplan et al. 2007).
scenities, refusal to work=serve, endangering others, and First, they suggest mood dysregulation may result from in- experienced severe temper tantrums multiple hours a day for there is clear scientific rationale for studying multinutrient 4 months in his clinical practice. After 2 days of taking EMPþ formulations. Early clinical findings suggest multinutrient at full dose, the boy’s behavior improved significantly. Within supplements may have promising therapeutic effects in pa- 5 days, all tantrums and irritability ceased. After 14 days, tients with BP (Kaplan et al. 2001; Kaplan et al. 2002; Simmons EMPþ was discontinued. Within 2 days of discontinuation, 2003). EMPþ is a commercially available product with the tantrums began again. The boy was then put on a different most extensive foundation of empirical support to date.
supplement, which, according to parent and teacher re- Background research on this product, summarized below, ports, provided 60% of the benefit noted on EMPþ. EMPþ suggests it is worthy of more rigorous scientific evaluation.
was resumed a second time, resulting in resolution of thetantrums and irritability. In a follow-up study, Popper fol- Halliwell and Kolb (2003) studied newborn lowed 22 more patients with BP in his clinical practice (2001).
rats who received frontal or posterior parietal lesions on day Participants included 10 adults, 9 adolescents, and 3 preado- 3, then subsequently were fed either normal rat chow or rat lescents. Although mild side effects were common (e.g., chow enhanced with a rodent-appropriate dose of EMPþ. At headache), a majority of participants (19=22, 86%) responded day 60, the supplemented animals exhibited reversal of be- positively. Furthermore, 11 of the 15 patients (73%) previously havioral deficits (e.g., performance on spatial learning tasks) on psychotropics remained stable without resumption of and had significant regrowth of cortical tissue compared to these medications at 6-month and 9-month follow-up as- unsupplemented rats. Behaviorally, the animals were signif- icantly calmer than unsupplemented rats.
Kaplan and associates also conducted an open-label ABAB trial with 2 boys aged 8 and 12 (Kaplan et al. 2002). Theseparticipants displayed irritability, mood lability, and explosive Initial studies were conducted with adult rage at baseline. The 8-year-old boy had diagnoses of atypical patients resistant to conventional treatments. Open-label tri- obsessive-compulsive disorder (OCD) and attention-deficit= als were first reported on adults diagnosed with BP (Kaplan hyperactivity disorder (ADHD). The 12-year-old boy was di- et al. 2001). Kaplan and colleagues studied 11 patients aged agnosed with pervasive developmental disorder (PDD). The 19–46 years for 6–21 months. The effects of EMPþ on symp- 8-year-old displayed consistent explosive rage, irritability, and toms of bipolar disorder were assessed using the Hamilton obsessions with guns (but no compulsions) during baseline Depression Rating Scale (HAM-D) (Hamilton 1960), the and each withdrawal phase. When on EMPþ these behaviors Young Mania Rating Scale (YMRS) (Young et al. 1978), and were almost completely eliminated. His obsessive thoughts the Brief Psychiatric Rating Scale (BPRS) (Overall and Gor- ceased, the frequency and duration of his temper outbursts ham 1962). Participants could continue using concurrent decreased significantly, and his mood fluctuations minimized.
psychiatric medications under the supervision of their psy- After more than 2 years of treatment, the boy remained well chiatrist. Results indicated a 55–66% reduction in symptoms and free of side effects while taking 25% of his initial dose of reported on the HAM-D, YMRS, and BPRS as well as a 50% EMPþ. The second boy, 12 years old, displayed consistent ir- decrease in the need for psychotropic medications. Partici- ritability, negative attitude, temper outbursts, and extremely pants reported one mild side effect, infrequent=transitory disruptive behavior in school at baseline. These behaviors nausea, which occurred most commonly when participants subsided markedly while on EMPþ. His mood impairment took their supplement without food (Kaplan et al. 2001). The and temper levels returned to baseline status during treatment researchers recommended further empirical investigation of withdrawal. He demonstrated marked improvement in mood stabilization and behavior when treatment was reintroduced.
Simmons (2003) described his use of EMPþ in private Stimulant medication was still required in addition to EMPþ to clinical practice. He reported that 12 out of 19 treatment- control ADHD symptoms. After almost 3 years of treatment, resistant adult patients diagnosed with BP-I (n ¼ 14) and BP-II this boy also maintained wellness without adverse side effects (n ¼ 5) who began what is now an outdated version of EMPþ on 25% of his original dose (Kaplan et al. 2002).
displayed marked improvement; 3 appeared moderately im- Kaplan and colleagues also completed a case series to further proved and 1 person showed mild improvement after a mean test the impact of EMPþ in 11 children ages 8–15 (Kaplan et al.
of 5.3 weeks on the supplement. Thirteen participants com- 2004). All had mood and=or behavioral problems. Diagnoses at pletely stopped taking their original psychiatric medications intake included: BP (n ¼ 3; 1 co-morbid with anxiety, 1 with after an average of 5.2 weeks on EMPþ (range ¼ 3–10 weeks) behavior disorders); Asperger plus an anxiety disorder (n ¼ 2); and remained stable. Side effects included mild gastrointes- ADHD þ co-morbid anxiety and=or behavior disorders (n ¼ 5); tinal problems, but a majority of patients (11 of 19, 58%) and Praeder–Willi syndrome, ODD þ anxiety (n ¼ 1). Nine of continued using this supplement instead of their previously the 11 (82%) completed the open-label trial. Intent-to-treat prescribed psychopharmacological medications (Simmons analyses indicated significantly decreased scores on the Youth 2003). While placebo-controlled trials are currently being Outcome Questionnaire (YOQ) ( p < 0.001) and YMRS ( p < conducted by Kaplan and colleagues in adults, placebo- 0.01) from baseline to final visit. For the 9 completers, im- controlled trials have not yet commenced with children provement was significant on 7=8 (88%) Child Behavior (Kaplan et al. 2001). However, several case series and open Checklist scales, YOQ and YMRS ( p < 0.05 to p < 0.001). The trial studies have been conducted, reviewed below.
authors concluded that results from this study support the needfor formal clinical trials of nutritional interventions in children with mood and behavioral dysregulation (Kaplan et al. 2004).
EMPþ in children. In a naturalistic ABACB trial, Popper It is important to note all above publications used a now- (2001) followed a 10-year-old boy diagnosed with BP who outdated version of EMPþ, one that often caused gastrointestinal side effects. In the new version, the ingredi- psychiatrist. The family continued to report John’s progress to ents are processed differently; in particular, the minerals are his therapist over the subsequent 14 months.
pulverized so the individual particle size has been signifi- John’s transition from psychotropic medication to EMPþ is cantly reduced to as low as 14–15 microns. Consequently, the chronicled in Table 2. John took 5 capsules per day, then 10 per ingredients now look like powder and pack into fewer cap- day, and then the recommended 15 capsules per day. After sules. There have also been some small reductions in quanti- 7 days on EMPþ, he began to reduce his lithium carbonate ties of several vitamins (e.g., vitamin A). This updated version and lamotrigine as recommended by the Truehope consul- is the one used in the intervention described below.
tant and his psychiatrist. After 19 days on EMPþ, John wascompletely off all psychotropic medications.
Throughout this tapering-and-titration process, John ex- perienced transient episodes of irritability, headache, dizzi- This case presentation follows the treatment of a 12-year- ness, and fatigue. However, his global functioning notably old boy (‘‘John’’) diagnosed with BP-NOS, which later de- increased. As treatment continued, John began interacting veloped into BP-I with psychotic features, generalized anxiety more appropriately with peers, remained calm and playful disorder (GAD), and OCD. Enuresis also emerged while throughout most of the day, slept throughout the night, re- taking lithium. By age 6, John experienced severe mood cy- mained focused and efficient while completing schoolwork, cling, sadness, irritability, self-harming behaviors, sleep dis- and experienced decreased compulsions. Hallucinations turbance, and severe tantrums. He also experienced elevated ceased. John continued to experience brief periods in the af- mood, poor peer relations, low frustration tolerance, flight of ternoon when he would become frustrated, irritable, or defi- ideas, aggressive behavior, hyperactivity, and impulsive ant with his parents. However, his parents reported these negative behaviors. By age 8, John developed impairing behaviors were consistently followed by a sincere apology, anxiety and worsening mood symptom intensity and cycling, which they viewed as an improvement compared to previous increased destructive behavior, transient suicidal ideation, behavior. The night terrors and previously mentioned side and increased global impairment. These symptoms continued effects ceased, his bowel movements normalized, his skin as he grew older, and between ages 10 and 11, John began appeared smooth without dry patches, and his symptoms experiencing auditory hallucinations, developed obsessions remained stable. His anxiety decreased, functioning was no and compulsions, and displayed increasingly disrespectful longer impaired at home, with schoolwork, or with peers, and and aggressive behaviors. He reported hearing intrusive, his impulsivity and fidgeting decreased substantially. All di- commanding voices when he became anxious, telling him to act on his obsessions and do things he did not want to do, andthreatening him. At one point, John reported hearing voices almost 100 times in one week telling him, ‘‘If you don’t do this After 4 months of EMPþ, John’s mother increased his dose you’ll surely die.’’ and ‘‘Don’t listen to them [referring to from 15 capsules a day to 18 capsules to manage emerging parents and other adults],’’ When he was 10 years old, John irritability, possible mood cycling, and ‘‘odd’’ behavior. She specifically noted the voices told him he would die on the day reported this increase relieved his symptoms. One month John Glenn dies. John’s symptoms became so impairing he later, the dose was returned to 15 capsules of EMPþ daily.
was removed from his private school and transferred to home John has maintained health over the subsequent 9 months. He enrolled in regular public school for the first time, where he John’s treatment team frequently altered his medications plays successfully on the school soccer and baseball teams and from the time he was 6 years old until he was 12 years old maintains friendships. His parents subjectively report that (2001–2007) in conjunction with individual=family psycho- improvements in his functioning while taking EMPþ are educational psychotherapy (Fristad et al., in press ) provided greater than those he made in the past on other medications.
by the second author (see Table 1). Medication changes were His only additional interventions are drinking a half cup of due to intolerable side effects and=or inadequate treatment whey protein mixed in milk in the morning during sports response. During this time, he took various combinations of seasons while very active and using a lightbox during the prescription and over-the-counter agents, including lithium winter. According to his mother, EMPþ helps keep him citrate, risperidone, lithium carbonate, clonidine, flax seed, ‘‘clear, slowed down, peaceful, settled and happy.’’ desmopressin, omega-3 fatty acids, magnesium, trazodone,gabapentin, valproic acid, propranolol, quetiapine, aripipra- zole, lorazepam, and lamotrigine. No medication, alone or incombination, maintained a desirable mood balance or con- Pharmacological intervention is considered to be the first- sistent improvement in global functioning over an extended line treatment for children with BP, and recent reviews of the research suggest mood stabilizers or atypical antipsychotics When John was 12 years old, his mother approached his should be the first psychotropics considered for children with therapist (the second author) asking about EMPþ. Coin- BP-I (Kowatch, et al. 2009). Unfortunately, research on other cidentally, the authors were intending to begin an open-label psychotropic medications and varying presentations of pe- trial of EMPþ at their treatment center; however, there was a diatric bipolar disorder (BP-II, BP-NOS, cyclothymia) is lim- considerable delay in commencing the study due to impedi- ited, and those agents found efficacious are associated with ments in receiving all research approvals needed. Thus, rather risk for adverse events (Kowatch et al. 2005). It may take an than wait, the family chose to work independently with the average of 9 months to 2 years until an efficacious drug Truehope staff in starting EMPþ and received directions to combination is found to stabilize mood in youths, and relapse taper psychotropic medication from his child and adolescent rates are high (Kowatch et al. 2009). The Food and Drug Administration (FDA) recently approved the use of risper- Brown RT, Antonuccio D, DuPaul GJ, Fristad MA, King CA, idone and aripiprizole in children with BP, although many Leslie LK, Pelham WE, Piacentini J, Vitiello B, Campbell M, children experience significant metabolic side effects on McCormick G: Childhood Mental Health Disorders: Evidence therapeutic doses (Slatko 2007). Lithium is another FDA- Base and Contextual Factors for Psychosocial, Psycho- approved psychotropic medication for youths as young as pharmacological, and Combined Interventions. Washington 12 years, and it also is associated with numerous adverse side (DC): American Psychological Association Press, 2008.
effects. Developing safe and effective treatments for early- DelBello MP, Adler CM, Whitsel RM, Stanford KE, Strakowski onset BP to which patients will adhere is critical.
SMA: 12-Week single-blind trial of quetiapine for the treat- An additional reason for considering nutritional supple- ment of mood symptoms in adolescents at high risk for de- mentation in cases like this, with a long history of conven- veloping bipolar I disorder. J Clin Psychiat 68:789–795, 2007.
Fleischhaker C, Heiser P, Hennighausen K, Herpertz-Dahlmann tional medication, is that many of the drugs routinely used for B, Holtkamp K, Mehler-Wex C, Rauh R, Remschmidt H, BP, especially anticonvulsant mood stabilizers, are reported Schulz E, Warnke A: Clinical drug monitoring in child and to cause deficiencies or inefficient utilization of vitamins B6, adolescent psychiatry: Side effects of atypical neuroleptics.
B12, folate, and D (Apeland et al. 2003; Mintzer et al. 2006).
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This case study provides additional support in the litera- Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder, MJ: ture for the use of multinutrient supplements as a method of Influence of supplementary vitamins, minerals, and essential treating BP in children. John’s story documents a long treat- fatty acids on the antisocial behavior of young adult prisoners.
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Dr. Arnold receives consulting and speaking honoraria and Kaplan BJ, Crawford SG, Field CJ, Simpson J, Steven A: Vita- research funding from numerous drug companies, but none mins, minerals, and mood. Psychol Bull 133:747–760, 2007.
from Truehope, which sells EMPþ. Dr. Arnold has had re- Kowatch RA, Fristad M, Birmaher B, Wagner KD, Findling RL, search funding from Autism Speaks, Curemark, National Hellander M, the workgroup members: Treatment guidelines Institute of Mental Health (NIMH), Neuropharm, Novartis, for children and adolescents with bipolar disorder: Child Noven, Shire, Sigma Tau, and Targacept; has consulted for psychiatric workgroup on bipolar disorder. J Am Acad Child Abbott, Neuropharm, Novartis, Noven, Organon, Shire, and Kowatch RA, Fristad MA, Findling RL, Post RM: A Clinical Manual Sigma Tau; and is=was on speaker’s bureau for McNeil, No- for the Management of Bipolar Disorder in Children and Adoles- vartis, and Shire. Ms. Frazier and Dr. Fristad have no conflicts cents. Arlington (Virginia): American Psychiatric Press, Inc., 2009.
of interest or financial ties to disclose.
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