Intranasal Ketamine Helps Some Kids with Bipolar Disorder
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.
Harsh Physical Punishment is Associated with Mood and Other Disorders
Physical punishment of children has long been a controversial subject. A 2012 article by Afifi et al. in the journal Pediatrics suggests that having experienced harsh physical punishment during childhood is associated with mood disorders, anxiety disorders, substance abuse and dependence, and personality disorders in adulthood.
In this study harsh physical punishment included pushing, grabbing, shoving, slapping, or hitting. Participants who had experienced more severe maltreatment in childhood (including physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect, and exposure to violence between intimate partners) were excluded from the study, and the results were adjusted for sociodemographic variables and family history of dysfunction, suggesting that physical punishment was the mediator of these effects.
Choline Treatment For Pregnant Mothers And Newborns Improves Babies’ Cognition and Normalizes a Risk Factor for Schizophrenia
Deficiencies in GABA inhibition have been linked to the risk of schizophrenia (and perhaps bipolar disorder). GABA receptors are initially excitatory but switch to being inhibitory early in life. Choline derived from phosphatidylcholine or from eggs and meat in the diet is important in increasing GABA receptor development and maturity.
Ross et al. reported this year in the American Journal of Psychiatry that in a placebo-controlled study in which mothers took phosphatidylcholine in the last 2 trimesters of pregnancy (at doses of 3,600mg in the morning plus 2,700mg in the evening) and infants took 100mg/day for 12 weeks, the infants who received choline showed better neuronal inhibition than infants who did not receive choline on a P50 test of auditory evoked potential, in which the brain’s response to a series of beeps is recorded. An overactive P50 response is a sign of deficiencies in GABA inhibition.
In infants with a common gene variant in the alpha 7 nicotinic receptor that makes it function less well (which also may be a risk factor for the development of schizophrenia), the choline regimen normalized the P50 test, while placebo had no effect. However, in a recent study by Cabranes et al. published in Psychiatry Research, there was no association of the alpha 7 gene variant and schizophrenia or bipolar disorder, although patients with bipolar disorder and patients with schizophrenia did perform differently on the P50 evoked potential test than controls did.
Editor’s Note: In an editorial by Judy Rapoport that accompanied the Ross et al. study, the difficulty of using the findings in clinical practice are discussed. Meck et al. showed in 1999 that choline supplementation enhanced spatial memory, and in several cases nutritional supplements can have beneficial effects on the brain. Rapoport notes the success of perinatal folate in preventing neural tube defects and the likelihood that Vitamin D supplementation can prevent some cases of schizophrenia.
However, extrapolating the choline findings of Ross et al. to clinical practice, especially given the lack of association of the alpha 7 gene variation to psychiatric illness in the study by Cabranes et al., might be premature. Instead, Rapoport recommends a good diet and prevention of infection as first steps for treatment. Choline supplementation would be roughly equivalent to three eggs a day.
Vitamin D3 Is Low In Children And Adolescents With Mania, But Supplements Help
Vitamin D supplements
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.
Irritability and Unipolar Depression in Kids
At the 2012 Pediatric Bipolar conference sponsored by the Ryan Licht Sang Foundation, Graham J. Emslie gave a talk on irritable mood and unipolar depression in youth.
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.
White Matter Abnormalities in the Brain Predict Onset of Psychosis
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.
Brain Imaging Finds Abnormalities that Appear Over the Course of Childhood-Onset Bipolar Illness
There is considerable evidence that children with bipolar disorder have smaller amygdalas, and the amygdala also appears to be hyper-reactive when these children perform facial emotion recognition tasks. A symposium on longitudinal imaging studies in pediatric bipolar disorder was held at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry to shed light on other brain abnormalities in these children.
Researcher Nancy Aldeman reported that there is some evidence children with bipolar disorder have decreased gray matter volume in parts of the brain including the subgenual cingulate gyrus, the orbital frontal cortex, and the superior temporal gyrus, as well as the left dorsolateral prefrontal cortex and amygdala. At the same time there is evidence of increased size of the basal ganglia. These abnormalities do not appear to precede the onset of the illness.
Some changes occur over the course of the illness. The basal ganglia seem to increase in volume in patients with bipolar disorder, but decrease in volume in those with severe mood dysregulation and comorbid ADHD. Moreover, parietal cortex and precuneus cortex volumes appeared to increase in children with bipolar disorder while decreasing or staying the same in normal volunteer controls.
A meta-analysis of brain imaging studies indicated that in general, the size of the amygdala appears to increase from childhood to adulthood in bipolar patients, starting out smaller than that of similarly-aged normal volunteers, but becoming larger than that of adult normal volunteers as the patients age into adulthood.
Lithium treatment increases gray matter volume in a variety of cortical areas and in the hippocampus in multiple studies. In contrast, treatment with valproate for 6 weeks appears to decrease hippocampal volume.
Long-term Course of Bipolar Illness is Most Difficult
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.
Long-term Outcomes for Childhood-Onset Disorders: Anxiety Disorders
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 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.
Editor’s Note: While all 4 of these major childhood onset psychiatric illnesses (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.
Long-term Outcomes for Childhood-Onset Disorders: ADHD
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.
