Researcher Charles Popper gave a talk at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry on the benefits of nutritional supplements designed to provide multiple vitamins and minerals to children with bipolar disorder and other dyscontrol syndromes, such as attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder. Popper reviewed the literature on the substantial incidence of vitamin and mineral deficiencies among these children.
A modicum of data support the effectiveness of supplements for children with these disorders. One of these supplements is called EMPowerPlus and is sold online. It is moderately expensive and must be given under the supervision of a knowledgeable treating physician. While it is relatively safe in medication-free children, Popper says it can exacerbate withdrawal reactions from some psychotropic medications.
In addition, EMPowerPlus greatly increases lithium-related side effects, in patients taking lithium, the dose must be reduced to about one-tenth of a normal dose for those who are adding EMPowerPlus.
Popper and another researcher, Mary Fristad, have both seen excellent responses to this type of supplementation in children with bipolar disorder who have been unresponsive to more traditional drugs.
In another study by Rita Aouad et al., 72.3% of 980 children with a variety of psychiatric diagnoses had insufficient vitamin D levels (values < 30 nanograms/ml) and 26.7% had vitamin D deficiency (values < 20 nanograms/ml). These data support the rationale for vitamin D supplementation, especially in those who have low levels to start with.
Three articles in the September 2014 issue of the journal Psychiatric Annals (Volume 44 Issue 9) discussed differentiating pediatric bipolar disorder from attention deficit hyperactivity disorder (ADHD). The first article, by Regina Sala et al., said that reasons to suspect bipolar disorder in a child with ADHD include:
- The ADHD symptoms appear for the first time after age 12.
- The ADHD symptoms appear abruptly in an otherwise healthy child.
- The ADHD symptoms initially responded to stimulnts and then did not.
- The ADHD symptoms come and go and occur with mood changes.
- A child with ADHD begins to have periods of exaggerated elation, grandiosity, depression, decreased need for sleep, or inappropriate sexual behaviors.
- A child with ADHD has recurring severe mood swings, temper outbursts, or rages.
- A child with ADHD has hallucinations or delusions.
- A child with ADHD has a strong family history of bipolar disorder in his or her family, particularly if the child does not respond to appropriate ADHD treatments.
The second article, by this editor Robert Post, Robert Findling, and David Luckenbaugh, emphasized the greater severity and number of symptoms in childhood onset bipolar disorder versus ADHD. Children who would later develop bipolar disorder had brief and extended periods of mood elevation and decreased sleep in the early years of their lives. These, along with pressured speech, racing thoughts, bizarre behavior, and grandiose or delusional symptoms emerged differentially from age three onward. In contrast, the typical symptoms of ADHD such as hyperactivity, impulsivity, and decreased attention were equal in both diagnoses.
In the third article, Mai Uchida et al. emphasized the utility of a family history of bipolar disorder as a risk factor. Moreover, a child with depression plus ADHD is at increased risk for a switch into mania on antidepressants if there is a family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania symptoms, or psychosis.
The differential diagnosis of ADHD versus bipolar disorder (with or without comorbid ADHD) is critical, as drug treatment of these disorders is completely different.
Bipolar disorder is treated with atypical antipyschotics; anticonvulsant mood stabilizers, such as valproate, carbamazepine, or lamotrigine; and lithium. Only once mood is stabilized should small doses of stimulants be added to treat residual ADHD symptoms.
ADHD, conversely, is treated with short- or long-acting stimulants such as amphetamine or methylphenidate from the onset, and these may be augmented by the noradrenergic alpha-2 agonists guanfacine or clonidine. The selective noradrenergic re-uptake inhibitor atomoxetine is also approved by the Federal Drug Administration (FDA) for the treatment of ADHD. The dopamine-active drug bupropion and the anti-narcolepsy drugs modafinil and armodafinil have mild anti-ADHD effects but have not been FDA-approved for that purpose.
At the 2014 meeting of the International Society for Bipolar Disorders, researcher B.N. Kim discussed symptoms that could distinguish between bipolar disorder and attention deficit hyperactivity disorder (ADHD) in childhood. Both disorders are characterized by decreased attention, concentration, and frustration tolerance, and increased activity, impulsiveness, and irritability.
Kim shared several differential symptoms that are more indicative of a bipolar diagnosis and that are inconsistent with a simple ADHD diagnosis (and this editor Robert Post has added several more). Signs and symptoms that suggest bipolar disorder and not ADHD include: decreased need for sleep, brief and extended periods of euphoria, hypersexuality, delusions, hallucinations, suicidal or homicidal impulses and/or actions, extreme aggression, and multiple areas of extreme behavioral dyscontrol. ADHD, on the other hand, is characterized by more difficulty focusing attention, and by less extreme symptoms in general.
EMPowerPlus is a nutritional supplement marketed by the company Truehope as a way of correcting nutritional deficiencies that contribute to depression, anxiety, bipolar disorder, and attention-deficit hyperactivity disorder (ADHD). In 2014 Rucklidge et al. published the first controlled study of EMPowerPlus in the British Journal of Psychiatry showing that the supplement was more effective than placebo in adults with untreated ADHD.
EMPowerplus contains 36 ingredients, including 14 vitamins, 16 minerals, 3 amino acids, and 3 antioxidants. Patients were randomized to receive either 15 EMPowerPlus pills per day or 15 placebos per day for 8 weeks, and those patients receiving the supplement were rated as more improved by the end of the study. Effect sizes were moderately robust and side effects did not differ.
Editor’s Note: Multiple uncontrolled studies have suggested the efficacy of EMPowerPlus in childhood mania and related conditions, but this is the first formal placebo-controlled study of the supplement in adults with ADHD. A study in children with ADHD is planned, but it would also be important to study this micronutrient formulation in childhood bipolar disorder, where there is some anecdotal evidence (from Charles Popper at McLean Hospital in Boston and Mary Fristad at the Ohio State University) of excellent responses in children with highly treatment-resistant bipolar illness.
Many children with bipolar disorder also present with other comorbid Axis I psychiatric illnesses. Now it seems that the worsening of these comorbidities, such as attention-deficit hyperactivity disorder (ADHD) or an anxiety disorder, can signal a more difficult course of bipolar illness itself. At a symposium on the course of bipolar disorder in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Shirley Yen from Brown University discussed findings on comorbidities of childhood onset bipolar disorder from COBY, the Collaborative Child Bipolar Network. Upon study entry, 60% of children with bipolar disorder also had ADHD, 40% had oppositional defiant disorder (ODD), 39% had an anxiety disorder, 12.5% had both oppositional defiant disorder and a conduct disorder, and 9% had a substance abuse disorder.
The prevalence of most of these comorbid illnesses increased over time (e.g. anxiety disorder rates increased from 39% to 62%). The illnesses were also related to the time it took participants to achieve recovery (eight consecutive weeks well), and the time until a recurrence of a depressive or manic episode.
Increases in anxiety were linked to longer time to achieve recovery and a shorter time to a recurrence. Increases in ADHD were linked to a more rapid onset of a depressive recurrence. Increases in oppositional defiant disorder and conduct disorder had no relationship with either remission or recurrence. Increases in substance abuse disorders were linked to a longer time to recover from a manic episode. Thus, worsening of the comorbid conditions had definite consequences for both recovery and recurrence.
Synthetic marijuana, otherwise known as spice, skank, or K2, is not only vastly more potent than the tetrahydrocannabinol (THC) in marijuana plants, but it also lacks cannabidiol (CBD), the calming, antipsychotic substance also present in the plants. This makes spice much more likely to induce major psychiatric effects.
New evidence links use of spice during pregnancy to a tragic birth defect, anencephaly, or absence of the cerebral cortex. It can also lead to the later development of attention-deficit hyperactivity disorder, learning disabilities, memory impairment, depression, and aggression.
Effects of THC on gestation may occur as early as two weeks after conception, meaning by the time a woman realizes she is pregnant, the fetus may have been harmed by exposure to the drug.
Other new finding associate use of spice with acute coronary syndrome and the kind of acute kidney injury that can lead to the organ shutting down.
Editor’s Note: It has now been found that synthetic marijuana, or spice, can lead to psychosis, delirium, acute coronary syndrome (heart attack) in young people, and now kidney dysfunction, in addition to causing birth defects if used by pregnant women. Not only is spice made up of more potent THC without the calming effects of CBD, but it is often laced with unknown contaminants, which are likely the cause of the heart and kidney damage.
Smoking regular marijuana is bad enough—it doubles the risk of psychosis and may precipitate the onset of schizophrenia. It may also cause long-lasting effects on cognitive function. Since many states are legalizing marijuana, it is important to know the risks. In any case the risks are much more serious with the synthetic product, and synthetic marijuana should be avoided at all costs.
Memantine (Namenda) is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist that is FDA-approved for the treatment of Alzheimer’s dementia. Its use in other illnesses such as bipolar disorder and autism is currently being explored.
As we have written in previous issues of the BNN, A. Anand et al. reported in 2012 that in bipolar depression, memantine has an initial antidepressant augmentation effect when added to lamotrigine, an inhibitor of glutamate release. Koukopoulos et al. also reported in 2012 that in an open study, memantine had a large and sustained effect in previously treatment-resistant patients with bipolar disorder, producing an impressive 60-70% rate of excellent response at 6 months and again at 12 months of follow-up.
There is some evidence that memantine can be useful in obsessive-compulsive disorder (OCD). In a randomized double-blind placebo-controlled study of memantine combined with fluoxetine published by Ghaleiha et al. in 2012, patients with moderate to severe OCD taking memantine and fluoxetine were more likely to achieve remission after 8 weeks than patients taking placebo and fluoxetine.
Attention-deficit/hyperactivity disorder (ADHD) is another condition that memantine may be able to treat. Disturbances in NMDA receptor activity are thought to play a role in ADHD. Small, preliminary studies of memantine in ADHD have been promising.
New research has begun to explore memantine’s effects in autism. In one recent randomized, double-blind, placebo-controlled study published by Ghaleiha et al. in the International Journal of Neuropsychopharmacology, memantine produced improvement in children with autistic disorder when the drug was added to a treatment regimen that included risperidone, which blocks dopamine D2 receptors and is FDA-approved for the treatment of schizophrenia and mania, as well as autism.
However, at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, Robert Findling presented a poster on extended release memantine (Namenda) in children with autism, a study with negative results. This was a monotherapy study, unlike the above studies in which memantine was added to treatment with another drug. Findling found that extended release memantine (at doses of 3mg to 15mg per day) was well tolerated in children with autism, but the drug on its own was not significantly more effective than placebo in these preliminary studies.
Editor’s Note: Taken together, these data suggest an emerging role for memantine and possibly other drugs that work through NMDA receptor blockade in several disorders associated with repetitive behavior, like OCD and autism. The role of memantine augmentation in each of these syndromes deserves further exploration.
A symposium at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) examined long-term outcomes of childhood onset disorders, including bipolar disorder, unipolar depression, ADHD, and anxiety disorder.
Course of Childhood Onset ADHD
Lily Hechtman reported on the long-term difficulties of adolescents who had childhood onset of attention deficit hyperactivity disorder (ADHD). They often experienced: continued typical symptoms including restlessness and over-activity, decreased academic performance, deficits in social interactions, and decreased self-esteem.
Twenty-five percent developed an antisocial personality disorder with 19-50% of these having difficulties with the legal system. There were again three distinct groups that showed different patterns of outcome. Thirty percent of the sample showed essential normality into adolescence and young adulthood. Sixty percent had continuous ADHD symptomatology, and 10% had serious psychiatric illness resulting in jail or hospitalization.
Other follow-up studies that extend as far as 40 years suggest that ADHD persists in older adults at a rate of 36%, while antisocial personality persists in 10%, and substance abuse in 17%. Adolescent controls went on to experience these disorders in adulthood at respective rates of 13%, 0%, and 7%. Hechtman provided systematic data that treatment of ADHD was not a risk factor for the subsequent adoption of substance abuse.
In another study, a latent class analysis showed that about 52% of those with ADHD became well and stayed well. The predictors of this good outcome were: lack of maternal drug exposure in the prenatal period, a stable family, not being on welfare, not having a comorbid psychiatric diagnosis, not having a severe form of ADHD, and not having lower social functioning at baseline.
There is some evidence that treatment of ADHD in young adults can lead to psychosocial benefits. In one study performed in 1984, a group of college-age participants treated with stimulants for 3 to 5 years showed improvement in social skills and self-esteem, but surprisingly, no increase in academic performance.
Course of Childhood Onset Anxiety Disorders
Danny Pine presented a study of 191 adolescents with an anxiety disorder, among whom 36% showed no anxiety disorder in adulthood, while 62% continued to have an anxiety disorder. Among a control population, 390 adolescents without an anxiety disorder remained so in adulthood, while 36 developed new onset of an anxiety disorder in adulthood. Sixty-two of the 98 participants who had anxiety disorders in adulthood had had the disorder continuously from its onset in adolescence. Thus, it appears that approximately two-thirds of adults with an anxiety disorder show a persistence of their childhood onset anxiety disorder, while approximately 1/3 had a new anxiety disorder diagnosis.
A symposium on bipolar disorder and its comorbidities in children and adolescents was held at the annual meeting of the American Academy of Child and Adolescent Psychiatry in 2011. The following findings were reported there.
Researcher Janet Wozniak discussed the relationship of bipolar illness and attention deficit hyperactivity disorder (ADHD). Based on interviews of family members of children with bipolar illness alone, bipolar illness plus ADHD, ADHD alone, and controls, she concluded that bipolar illness occurred more often in families of children with bipolar illness with or without ADHD. Similarly, she showed that there was more ADHD in relatives of children with either ADHD alone or ADHD comorbid with bipolar illness. She concluded that the comorbidity of bipolar illness and ADHD is a unique subtype of bipolar disorder and requires further study.
Emotional Dysregulation and Substance Abuse
In another presentation, Tim Wilens indicated that those with bipolar disorder and emotional dysregulation had an 8- to 20-fold increased risk of having a substance abuse comorbidity with their bipolar disorder.
Substance Abuse Comorbidity
In a third presentation, Ben Goldstein reported that the onset of bipolar illness predates the onset of substance abuse in 60 to 83% of instances of comorbid illness. He emphasized the dramatic negative impact of comorbid substance use in children with bipolar disorder in terms of increasing legal entanglements, pregnancy, academic failure, suicide, and decreased compliance with medications. He reported that in the multi-site, National Institute of Mental Health (NIMH)-funded Course and Outcome of Bipolar Illness in Youth (COBY) study, the largest longitudinal study to date of youth with bipolar disorder, the risk of new onset substance abuse over the course of 4 years of follow-up was 32%. These data taken with the 15% of children who already had substance abuse at intake indicates that in this study approximately half of the children with bipolar illness had or acquired a substance abuse problem near the beginning of their illness. Two-thirds of the children in the study had abused both alcohol and cannabis. Read more
An article by Bloch & Qawasmi published in the Journal of the American Academy of Child and Adolescent Psychiatry last year suggested that omega-3 fatty acids could improve ADHD in children. The effects were milder than the standard pharmacological treatments for ADHD, but given that omega-3s have few side effects, there would be little risk to using them to supplement traditional treatments or in cases where traditional treatments cannot be used.
Editors note: It would also be worth seeing if omega-3s helped mood symptoms too. A meta-analysis we wrote about here suggests that the omega-3 fatty acid EPA or the combination of EPA plus DHA has positive effects on depression in adults.