The anesthetic ketamine given intranasally may help children with a certain type of bipolar disorder. In an article published in the Journal of Affective Disorders in 2013, Demetri Papolos et al. reported seeing marked improvement in a subgroup of 12 children aged 6 to 19 years of age who were nonresponsive to the usual treatment regimens of lithium, mood stabilizers, and antipsychotics. Papolos has described these children as having the “fear of harm (FOH) subtype.” In addition to having typical mood swings, these children also have a fear of aggression, separation anxiety, sleep and circadian rhythm disorders, nightmares, thermoregulatory problems, and carbohydrate craving.
Ketamine was given as an intranasal spray using an inhaler in 10mg doses. Doses were increased until the targeted symptoms remitted. Average doses ranged from 30mg to 120mg, given every 3 to 7 days. All symptom areas including depression and mania improved markedly, usually within a few hours, and this improvement lasted 3 to 4 days. Four types of aggression (measured on the Overt Aggression Scale) decreased significantly.
There were some dissociative side effects that were usually mild to moderate, but occasionally severe. They resolved spontaneously, usually within the first hour after treatment, and there appeared to be tolerance to them following repeated administration.
The authors urged caution until findings from these cases are confirmed by more controlled studies, but they concluded that the magnitude and rapidity of effects in these children with treatment resistant bipolar disorder suggested effectiveness and safety.
As childhood obesity has increased over the past several decades, the metabolic syndrome has also become more prevalent among children and adolescents. The metabolic syndrome consists of five measures related to obesity: elevations in fasting glucose levels or insulin resistance, a high proportion of LDL (“bad” cholesterol) to HDL (“good” cholesterol), elevated triglycerides, hypertension, and abdominal obesity or high waist circumference. A patient with three of these abnormalities would be diagnosed with the metabolic syndrome.
In adults, the metabolic syndrome has been associated with neurocognitive impairments. Researchers decided to look at adolescents with the metabolic syndrome to determine whether these brain effects are a result of long-term metabolic impairment or whether they can take place after short-term periods of poor metabolism as well. In a study published by Yau et al. in the journal Pediatrics last year, 49 adolescents with the metabolic syndrome were compared to 62 adolescents without the syndrome who had been matched for similar age, socioeconomic status, school grade, gender, and ethnicity.
The adolescents with the metabolic syndrome had lower scores on tests of math, spelling, attention, and mental flexibility, as well as a trend for lower overall intelligence. In brain measures such as hippocampal volume, amount of brain cerebrospinal fluid, and microstructural integrity in white matter tracts, the seriousness of the metabolic syndrome correlated with the level of abnormality on these measures.
Editor’s Note: It seems as though even short-term problems with metabolism can lead to brain impairments like lower cognitive performance and decreased integrity of brain structures. These effects are even seen before vascular disease and type 2 diabetes are manifest.
It is doubly important, in terms of both cardiovascular and neurobiological risks, to look out for one’s medical and psychiatric health. Reducing the abnormal components of the metabolic syndrome should produce benefits for both the cardiovascular system and the central nervous system.
Almost 40% of patients with bipolar illness in the US have the metabolic syndrome, so considerable effort will be required to improve this public health crisis.
A decades-long study in New Zealand suggests that people who use marijuana persistently during adolescence lose 8 IQ points by adulthood compared to their peers who never use marijuana. Quitting or reducing cannabis use after adolescence did not restore the intellectual abilities in those who used it persistently in their youth. This is the first study of its kind that controlled for differences in functioning that existed before adolescence.
Participants took part in neuropsychological testing at the age of 13, prior to any cannabis use, and then were periodically interviewed about their use of the drug (at the ages of 18, 21, 26, 32, and 38). At age 38 they underwent IQ testing again.
Although persistent cannabis users tended to have fewer years of education, the lack of education was not responsible for the difference in adult IQ.
Those participants who only began using cannabis persistently in adulthood did not see a decline in IQ, suggesting that the adolescent brain is particularly susceptible to damage from cannabis use.
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.
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.
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.
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Carrie E. Bearden presented data from a study that predicted conversion to psychosis in at-risk youth (those who have prodromal symptoms or a particular genetic mutation that leads to psychosis) by observing white matter abnormalities.
Bearden found that the degree of white matter abnormality seen during magnetic resonance imaging (MRI) was proportional to the degree of cognitive deficit in patients who subsequently developed a first episode of psychosis. The white matter abnormalities were seen particularly in the superior longitudinal fasciculus (SLF) and were associated with increased severity of symptomatology. The overall degree of white matter alteration was also significantly related to clinical outcome 15 months later.
Editor’s Note: The SLF is a major neuronal conduit between prefrontal cortical systems, which are responsible for cognition and planning, and the parietal cortex, which is responsible for spatial abilities. Disruption of this fiber track has been related to difficulties in social cognition and “theory of mind” concepts, like inferring what others might be thinking.
While the 4 major childhood-onset psychiatric illnesses we discussed this week (bipolar, unipolar, ADHD, and anxiety disorders) show long term difficulties into adulthood in the majority of instances, it appears that the most severely impacted are those with bipolar disorder. These data are also consistent with retrospective data from multiple cohorts of adults with bipolar disorder, which indicate that those whose illness began in childhood fared more poorly in adulthood than those with adult-onset illness. Thus, while there has been a modicum of treatment research in childhood depression and anxiety disorder and a plethora of treatment studies in ADHD, the dearth of treatment studies in children with bipolar disorder is all the more disconcerting.
Bipolar disorder is common, occurring in some 2 to 3% of children and adolescents, and carries a relatively grave prognosis into adulthood in the majority of instances, especially when it is inadequately treated. Virtually all of the investigators in the area of childhood-onset bipolar who presented at the AACAP meeting have pleaded for increased treatment research for bipolar disorder in children, and one can only hope that their message is soon heard.