Children at Risk for Bipolar Disorder May Have Adverse Reactions to Antidepressants
At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Jeffrey R. Strawn reported that among children at high risk for bipolar disorder (because of a family history of the disorder) who are prescribed antidepressants for depression and anxiety, adverse reactions are common. These reactions include irritability, aggression, impulsivity, and hyperactivity, and often lead to discontinuation of the antidepressant treatment.
Younger patients at risk for bipolar disorder were more likely to have an adverse reaction to antidepressants. Risk of an adverse reaction decreased 27% with each year of age.
Predictors of Bipolar Disorder in At-Risk Youth
A new longitudinal study of 391 youth at risk for bipolar disorder revealed some predictors of the disorder. The study by Danella M. Hafeman and colleagues was presented at the 2015 meeting of the Society of Biological Psychiatry. The participants were aged 6–18 and each had a parent with bipolar disorder. Over the course of the study, 40 developed an illness on the bipolar spectrum, including 21 who developed bipolar I or II. The participants were assessed for various descriptive characteristics and those who developed bipolar disorder were compared to those who developed major depressive disorder.
The most important predictors of bipolar disorder were parental assessment of internalizing symptoms of anxiety or depression, self-assessment of mood changeability, and self-assessment of hostility. A diagnosis of bipolar disorder not otherwise specified (BP-NOS) was the only predictor of a later diagnosis of bipolar I or II.
Editors Note: These data resemble findings from a 2015 study by David Axelson and colleagues in the American Journal of Psychiatry that used the same cohort of participants. The Axelson study indicated that a categorical diagnosis of a major psychiatric disorder occurred in 74% of the offspring of a bipolar parent compared to about 50% in a control group from the community. Depression, anxiety, attention deficit hyperactivity disorder (ADHD), and oppositional disorders were even more common than bipolar disorder in the at-risk population.
The presence of a major psychiatric diagnosis in about three-quarters of the offspring of a parent with bipolar disorder suggests the importance of early vigilance. One way to track symptoms of depression, anxiety, ADHD, oppositional behavior, and bipolar disorder is to join the Child Network, a secure online platform for rating children’s moods, medications, and side effects. These weekly ratings can be collected longitudinally and printed out to help parents and clinicians assess mood difficulties in their children.
Primates Shed Light on the Neurobiology of Anxiety Disorders in Children
Studies of primates suggest that the amygdala plays an important role in the development of anxiety disorders. Researcher Ned Kalin suggested at the 2015 meeting of the Society of Biological Psychiatry that the pathology of anxiety begins early in life. When a child with anxiety faces uncertainty, the brain increases activity in the amygdala, the insula, and the prefrontal cortex. Children with an anxious temperament, who are sensitive to new social experiences, are at almost sevenfold risk of developing a social anxiety disorder, and later experiencing depression or substance abuse.
A study by Patrick H. Roseboom and colleagues presented at the meeting was based on the finding that corticotropin-releasing hormone (CRH) plays a role in stress and is found in the central nucleus of the amygdala (as well as in the hypothalamus). The researchers used viral vectors to increase CRH in the central nucleus of the amygdala in young rhesus monkeys, hoping to determine what impact increased CRH has on a young brain. Rhesus monkeys and humans share similar genetic and neural structures that allow for complex social and emotional functioning.
Roseboom and colleagues compared the temperaments of five monkeys who received injections increasing the CRH in their amygdala region to five monkeys who received control injections. As expected, the monkeys with increased CRH showed increases in anxious temperament. Brain scans also revealed increases in metabolism not only in the central nucleus of the amygdala, but also in other parts of the brain that have been linked to anxiety, including the orbitofrontal cortex, the hippocampus, and the brainstem, in the affected monkeys. The degree of increase in amygdala metabolism was directly proportional to the increase in anxious temperament in the monkeys, further linking CRH’s effects in the amygdala to anxiety.
Adolescence is a Sensitive Period for Fear Learning
Adolescence can be a time of vulnerability to illness. Anxiety disorders increase during this period, and three-quarters of adults with anxiety disorders trace the illness back to their childhood or adolescence. The most common treatments for anxiety disorder are based on the idea of fear extinction. A certain stimulus, like a social situation or seeing a spider, provokes a fear reaction in the brain. Through gradually increasing exposure to the stimulus and extinction training, the person becomes desensitized to the stimulus. New research on rodents presented by Francis S. Lee at the 2015 meeting of the Society for Biological Psychiatry suggests that the extinction process is diminished during adolescence.
At specific stages of maturation, neural circuits related to particular abilities can become flexible. Brain and behavior become sensitive to and are increasingly shaped by experience. Studies of rodents and humans have shown that adolescence is a time when the neural circuitry for fear extinction is in flux. In mice, this period falls around their 29th day of life. Lee reported that around this time, the mice begin to exhibit resistance to extinction of fear learning.
In adolescent rodents, there is a surge of contextual fear learning and retrieval that is mediated by hyper-connectivity of the ventral hippocampus and the amygdala to the prelimbic part of the prefrontal cortex. In contrast, the pathway from the amygdala to the infralimbic cortex mediates the extinction of this type of learning. Because the prelimbic pathway for fear learning is overactive, the infralimbic pathway for extinction learning is less effective.
Adolescent mice temporarily lose their ability to retrieve memories related to cue-dependent (as opposed to context-dependent) fear learning. Remarkably, when these animals proceed into adulthood, the fear learning associated with cues returns and becomes accessible again.
This could help explain how teenagers can lose fear conditioning to cues (for example, speeding through a red light) they learned in childhood. The fear is forgotten (or becomes inaccessible) in adolescence, but then what had been learned is again “remembered” (retrieved) in adulthood. Read more
Nutritional Supplement Minimizes Stress After a Natural Disaster
Certain nutritional supplements may help people cope following natural disasters. Following a 7.1 magnitude earthquake in Christchurch, New Zealand, in 2010, researchers there who were working on a clinical trial of a broad spectrum mineral and vitamin formula for ADHD realized that they could compare participants who had been taking the nutritional supplements at the time of the earthquake with those who had either already completed the trial or had not yet begun it. Two weeks after the quake, those who had been taking the multivitamin at the time of the quake were less anxious and stressed than those who hadn’t been taking the formula.
When another large earthquake struck five months later, the researchers implemented a randomized trial comparing two doses of the same broad spectrum supplement with a B Complex vitamin formula that had previously shown efficacy for stress and anxiety. Those participants taking any supplement showed fewer symptoms of post-traumatic stress disorder (PTSD) a month after the second quake compared to controls, and those taking the higher dose of the broad spectrum formula had greater improvements in mood and anxiety than those taking the B Complex supplement.
More recently, in Alberta, Canada, flooding forced many people from their homes. Researchers there who were studying the effects of micronutrients on stress and anxiety realized they had the opportunity to replicate the research from New Zealand in a different type of environmental disaster.
Researcher Bonnie J. Kaplan and colleagues recruited adults who had been affected by the flood, and randomized the participants to receive different types of supplements: vitamin D (1 pill/day); a B complex vitamin containing B6, B12, and several other nutrients (1 pill/day); or a broad spectrum supplement containing 24 vitamins and minerals and several botanical extracts (4 pills/day). No placebo was used—it was considered unethical to deny participants access to a potentially helpful treatment.
In a 2015 article in the journal Psychiatry Research, the Alberta team reported that while all of the nutrient supplements minimized stress after the flood, patients randomized to the B complex vitamin or the broad spectrum formula had less stress and anxiety following the flood than those randomized to vitamin D.
We have previously described a broad spectrum vitamin preparation called EMPowerplus, used by psychiatrist Charles Popper and psychologist Mary A. Fristad to treat children with treatment-resistant bipolar disorder. This may be the same formula used in the Alberta study. We await larger trials of this preparation in children with bipolar disorder.
Childhood Adversity, Gene Methylation, and Internalizing Behaviors Linked
Life experiences such as adversity in childhood have been linked to epigenetic changes to DNA. These changes do not affect the sequence of DNA, but can change how tightly DNA is wound, and thus how easily it is transcribed. One epigenetic change that can occur following adversity in childhood is methylation of the gene for the glucocorticoid receptor (NR3C1). A recent study by Kathryn Ridout and colleagues examined links between early adversity, methylation of this gene, and behavioral problems in childhood. Adversity was linked to methylation of the gene at exons 1D and 1F in the promoter of NR3C1. Methylation of the gene was associated with internalizing behaviors (e.g. depression, anxiety) but not externalizing behaviors (e.g. attention deficit hyperactivity disorder (ADHD) or oppositional defiant disorder) in children of preschool age. The NR3C1 methylation was a significant mediator of the internalizing behaviors in children who had experienced adversity.
Editor’s Note: Similar associations of methylation of the glucocorticoid receptor with childhood adversity have been reported in other clinical and animal studies and provide a mechanism for the long-lasting adverse effects of stressors in childhood.
Lavender Oil Has Anti-Anxiety Effects and Possibly Antidepressant Effects
An oral preparation of lavender oil called Silexan was previously found to reduce anxiety in people with generalized anxiety disorders or subthreshold anxiety symptoms without causing sedation. It seems to work by inhibiting voltage dependent calcium channels in a manner similar to the anti-anxiety drug pregabalin. Unlike pregabalin, the lavender oil treatment also reduced depression in the people with subthreshold anxiety. Researchers are now exploring lavender oil’s effects on rats who exhibit behaviors that resemble human depression, and on rat and human cells in vitro.
Silexan had positive effects on rats with depression-like behaviors, increasing the time they would swim before giving up in a forced swim test. It also increased the growth of rat and human neurons in a lab setting. These effects are usually connected with activation of a protein called CREB that turns on some genes that affect mood. The researchers, led by Walter Mueller, were able to clarify the pathway for this activation by inhibiting specific kinases, enzymes responsible for transferring phosphates across different molecules. The kinases involved included PKA, PI3K, MAPK and CaMK IV.
Editor’s Note: Oral lavender supplements may help improve anxiety and depression without sedation.
Childhood Adversity Associated with Shorter Telomeres
Telomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are associated with aging and an increase in multiple medical and psychiatric disorders. New research draws connections between the production of mitochondrial DNA, telomere length, the experience of childhood adversity, and mental illness.
Researcher Audrey Tyrka and colleagues divided 290 healthy adults into four categories based on whether or not they had experienced adversity in childhood and whether they had been diagnosed with a mental illness in their lifetime, including depression, anxiety, and substance abuse. The researchers also analyzed the participants’ telomere lengths and the copy number of their mitochondrial DNA. Both stressful events in childhood (such as maltreatment or the loss of a parent) and a history of mental illnesses (depression and anxiety) were associated with shorter telomeres and higher mitochondrial DNA copy numbers, a measure of cellular aging. Substance abuse was associated with higher mitochondrial DNA copy numbers.
Editor’s Note: This research replicates earlier findings that adversity is associated with shortening telomeres. The finding that mitochondrial DNA could play a role in the long-term effects of early life adversity and mental illnesses is new.
Psychotherapy More Effective Than Collaborative Care in Bipolar Depression with Anxiety Disorder Comorbidity
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a long-term study of treatments for bipolar disorder, recently found that psychotherapy was more effective than their normal collaborative care model (consisting of regular illness evaluation and treatment) for patients with bipolar disorder and a current or lifetime presence of an anxiety disorder.
An anxiety disorder comorbidity is consistently associated with a poor outcome in patients with bipolar disorder. In a 2014 article by Deckersbach et al. in the American Journal of Psychiatry, the STEP-BD research group reported that the effect of psychotherapy was particularly strong in those with comorbid post-traumatic stress disorder (PTSD) or generalized anxiety disorder.
While antidepressants are typically used to treat anxiety disorders in unipolar depression, this has not been proven effective in bipolar disorder. Not only do patients with bipolar disorder tend to respond poorly to antidepressants, but in research collected by this editor Robert Post and colleagues in the Bipolar Collaborative Network, patients with bipolar disorder who had an anxiety disorder fared even more poorly on antidepressants as adjuncts to mood stabilizers than those with bipolar disorder without an accompanying anxiety disorder.
The poor response to antidepressants in bipolar depression in general, and particularly in those with a comorbid anxiety disorder, together with the finding that psychotherapy is highly effective, suggest that adjunctive psychotherapy is a more appropriate choice for patients with bipolar depression and a comorbid anxiety disorder.
The choice of the best pharmacological treatment of this comorbid anxiety disorder deserves specific comparative study. Candidates would include the mood stabilizing anticonvulsants valproate, lamotrigine, and carbamazepine; the atypical antipsychotics with efficacy in bipolar depression (quetiapine, lurasidone, and olanzapine combined with fluoxetine); and those used as an adjunct in unipolar depression (quetiapine again and aripiprazole).
Methylene Blue Treats Bipolar Depression in Adults
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
