Vitamin D3 is low in children and adolescents with mania, but taking a supplement could help. Vitamin D3, which we absorb via food and sunlight, is converted by the liver to a form called 25-OH-D. In a small study, Elif Sikoglu et al. found that children and teens with mania had lower levels of 25-OH-D in their blood compared to typically developing youth of similar ages. This deficit was associated with lower brain GABA levels measured with magnetic resonance spectroscopy. GABA dysfunction has been implicated in the manic phase of bipolar disorder. An 8-week trial of Vitamin D3 supplements significantly reduced manic symptoms and tended to increase GABA levels.
Editor’s Note: Other data have suggested that children with psychosis have low Vitamin D3, and in a recent clinical trial in adults, Vitamin D3 supplementation improved antidepressant response more than placebo. Many children in the US are Vitamin D deficient. Test them and, if necessary, treat them, especially if they have bipolar disorder.
A recent study of patients taking fluoxetine (Prozac) for major depression found that adding 1500 IU of vitamin D3 to their treatment regimen improved their response significantly. The article was published in the Australian and New Zealand Journal of Psychiatry.
According to the Mayo Clinic:
The term “vitamin D” refers to several different forms of this vitamin. Two forms are important in humans: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D2 is synthesized by plants. Vitamin D3 is synthesized by humans in the skin when it is exposed to ultraviolet B (UVB) rays from sunlight. Foods may be fortified with vitamin D2 or D3.
Editors Note: Here is another augmenting agent that could be considered for the treatment of those with residual depression. While vitamin D has not been studied directly in bipolar depression, we could ask, “Why not try it?” Other nutritional supplements in this category might be folate and N-acetylcysteine.
Vitamin D supplements are definitely indicated for the large percentage of those in the US who are vitamin D deficient. Given the data from this randomized trial, vitamin D3 could be considered in those with normal levels of vitamin D as well.
Relaxing facial frown muscles with Botox may produce antidepressant effects. The muscles on the forehead between the eyebrows tend to tense and constrict during episodes of depression, anxiety, and grief. A placebo-controlled clinical trial by Eric Finzi and Norm Rosenthal has shown that paralyzing these frown muscles can produce antidepressant results.
Study participants with treatment-resistant depression received either paralyzing injections of botulinum toxin, better know by its trade name Botox, or placebo injections. The antidepressant response rate was 51% among patients who received Botox and 14% among those who received placebo. The remission rate was 27.3% with Botox versus 7.3% with placebo injections. These data are particularly striking because these patients had, on average, been ill for more than two years, during which time they had been through multiple unsuccessful antidepressant trials.
In 1872, Charles Darwin emphasized the importance of facial muscles in social communication and affect, and in 1890 William James suggested that sensory feedback from musculature changed people’s affect, rather than the opposite and conventional view that affective and emotional states cause muscles to tense and contract. The new data from Finzi and Rosenthal’s study are consistent with James’ view.
The investigators concluded that the data from this study suggest frowning itself may cause depression. More controlled trials using other injection sites would be helpful to further document the efficacy and selectivity of these Botox injections for the treatment of depression.
As young mice transition into adolescence, they experience a “sensitive” period in which their context-based fear memories are temporarily suppressed. In a recent study, young animals learned to avoid an environment associated with a mild shock. Later, when they entered adolescence, this learning was temporarily forgotten or suppressed. However, when the same mice aged into adulthood, they reacquired this learned fear memory and began to again avoid the environment associated with the earlier shock. This temporary loss of fear memory differs in mice depending on their genes.
At the 2012 meeting of the Society of Biological Psychiatry, researcher Francis S. Lee reported that mice with a certain genetic variation display an impairment of this fear memory process. There are several common variants of the gene responsible for the production of brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory. Mice with the poorer functioning variant known as Val66Met (as opposed to the better functioning Val66Val) fail to recall the earlier fear-related events not only in adolescence, but also in adulthood when the fear memory is usually retrievable again.
Editor’s Note: In mice and humans, Val66Val is the most frequently occurring allele in the population, but Val66Met is also a fairly common variation of the BDNF gene. It is this Val66Met allele that is associated with not retaining earlier learned experience about a “dangerous” environment that should be avoided.
These data suggest an intriguing explanation for some of the “wild” behavior and poor judgment to which even the smartest adolescents are prone. This kind of behavior may be based in part on the temporary forgetting in adolescence of earlier learning about which situations or environments are safe versus which ones are dangerous. Read more
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.
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Melissa P. DelBello presented a poster on the design of a maintenance study in bipolar youth to determine characteristics of patients who stabilized on adjunctive lamotrigine. The study included children aged 10 to 17 who had been diagnosed with bipolar disorder. Of a total 244 potential subjects, 160 individuals or 66% stabilized on lamotrigine during the open (not blind) portion of the study. Of these, 143 were randomized to either lamotrigine continuation or placebo.
Seventeen participants did not enter the randomized phase of the study, primarily because of withdrawal of consent, presumably because they were reluctant to be placed in the placebo group. The authors concluded that a study design involving randomization to medication continuation versus withdrawal with placebo substitution could underestimate the true level of treatment response.
However, the high stabilization rate of 66% using adjunctive lamotrigine in the open phase of the study suggests that the drug is effective. Clearly confirmation of this in the double-blind randomized phase is needed to confirm this prediction.
Adults with bipolar disorder have higher rates of cardiovascular disease and premature death from cardiovascular illness than the general population. At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, Benjamin Goldstein presented a poster in which he showed that youth with bipolar disorder may also have abnormal cardiovascular function.
When a tourniquet is applied, blood vessels normally expand to make up for the period of oxygen deprivation. This does not happen as readily in patients with mood disorders. This lack of flexibility and compensatory response could be one of the reasons for increased cardiovascular difficulties in those with mood disorders.
In Goldstein’s study, noninvasive ultrasound imaging was used to measure the thickness of the walls of the carotid artery and flow mediated dilation of the artery in adolescents with bipolar disorder and those without the illness. The data was collected by a certified ultrasound technologist who remained blind to the patients’ diagnostic and symptom status.
Goldstein found highly abnormal results in 14 adolescents aged 14 to 19 with bipolar disorder compared to controls. He concluded that reducing cardiovascular risk in bipolar disorder is a pressing clinical and public health challenge and that treating these patients while they are adolescents may offer considerable advantages both for prevention and for understanding the progression of cardiovascular problems in patients with bipolar disorder.
A study of 85,000 children in Norway that was recently published in the Journal of the American Medical Association showed that women who took folic acid during pregnancy were 40% less likely to have a child who developed autism.
A summary of the research by National Public Radio explained:
Folic acid is the synthetic version of a B vitamin called folate. It’s found naturally in foods such as spinach, black-eyed peas and rice. Public health officials recommend that women who may become pregnant take at least 400 micrograms of folic acid every day to reduce the chance of having a child with spina bifida.
The folic acid’s effect reduced the most severe cases of autism but did not seem to have an effect on the incidence of more mild forms, such as Asperger syndrome. The benefits were seen in those women who had been taking folic acid for 4 weeks before conception and continued to take the supplement during the first 8 weeks of pregnancy.
Irritability is common in unipolar depression. Emslie suggested that if a child’s irritability is severe and the child destroys objects and denies being irritable, bipolar disorder might be likely. Irritable unipolar depressed children will generally acknowledge being irritable.
Emslie reported that 96% of youth in his randomized placebo-controlled studies of selective serotonin reuptake inhibitor antidepressants (SSRIs) recovered from their unipolar depression, but 46.6% relapsed. Those children with residual depressive symptoms were at double the risk for relapse into a depression compared to those who remitted completely. In those without residual depressive symptoms, there were no relapses if the children stayed on their medications.
Children were excluded from Emslie’s study if they had a positive family history of bipolar disorder, and perhaps because of this, very few participants switched into mania with antidepressants.
MORAL: Treat to remission and stay on the antidepressants associated with the remission. This has previously been found to be important for adults as well. (Emslie added that he would advise that a child stay on an antidepressant for at least a year after a remission was achieved, and longer if the child had difficulties in academic performance or relationships at school.)
Children with unipolar major depression who had a few manic symptoms at a subsyndromal level had poorer outcomes in Emslie’s study. The presence of subsyndromal manic symptoms in bipolar depressed adults is a risk factor for increased switching into mania when antidepressants are added to a mood stabilizer.
Comorbid substance abuse is another risk factor for poor outcome in childhood depression.
In two posters presented at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, a research group led by Kiki Chang reported that increased severity of manic symptoms is associated with increased size of the amygdala (especially the right amygdala) in adolescents who are at high risk for developing bipolar disorder.
The amygdala is a crucial area for emotion regulation. The increasing size, either with more manic symptoms or as patients with bipolar disorder age into adulthood compared to normal volunteer controls (as we describe in the article on brain imaging at far left) could reflect increased use of the amygdala in bipolar disorder.
The increased amygdala size could be linked to increased emotion dysregulation, or it could be a compensatory mechanism in which the amygdala works harder to exert better emotion control.
Experience-dependent neuroplasticity describes a phenomenon in which the volume of a brain area increases as it gets more use (like a muscle that grows when it gets more exercise). One interesting example in which this may occur is London taxi drivers, who have larger hippocampi than the general public. (The hippocampus is responsible for some of the brain’s spatial recognition abilities.) This could be explained in two different ways. The discrepancy in size between the hippocampi of taxi drivers and of the general population may exist because the taxi drivers’ brains change over the course of their careers via experience-dependent neuroplasticity, or it may exist because those with excellent spatial recognition abilities and bigger hippocampi choose to become taxi drivers.