The following table analyzes the information currently available about various treatment options (including treatments NOT yet FDA approved for the treatment of children):
At another symposium at the annual meeting of the American Academy of Child and Adolescent Psychiatry, Bob Kowatch of Ohio State University discussed a controlled trial of valproate, risperidone, and placebo in children 3 to 7 years of age (average age 5.5) with a diagnosis of bipolar I disorder and a Young Mania Rating Scale score (YMRS) greater than 20 at baseline. All of the children were severely ill with an average Clinical Global Assessment of Severity (CGAS) score of 44. Seventy-six percent had comorbid attention deficit hyperactivity disorder (ADHD) and 15% had an anxiety disorder. Valproate doses started at 10mg/kg and were increased after 4 days to achieve blood levels of 80 to 100µg/ml. The average dose of valproate was 300mg/day and the average blood level was 88 µg/ml. Risperidone was started at 0.25mg and increased as needed. The average dose of risperidone was 0.5mg per day.
On the main outcome measure of decrease in the YMRS score risperidone was substantially more effective than placebo, while valproate showed only marginal nonsignificant effects. However on the Clinical Global Impressions (CGI) scale for improvement in illness, risperidone showed 87% response, valproate 75% response, and placebo no response. In terms of 50% reduction in the YMRS score, this endpoint was achieved in 88% on risperidone, 50% valproate, and 15% on placebo.
Weight gain was mild on valproate and substantially more on risperidone. Risperidone was also associated with increases in insulin and prolactin.
The effect size (the size of the change the drug brought about in this study, which is calculated by dividing the mean difference between the experimental group and the control group by the standard deviation) for risperidone was extraordinarily large (3.58); very large for valproate (1.66), and moderate for placebo (0.56). The odds of getting well were 5 times greater than placebo for risperidone and 1.9 times greater than placebo for valproate.
Editors note: These data in very young children (aged 3 to 7) resemble other controlled data in the literature about the treatment of older children and adolescents, indicating a superiority of atypical antipsychotics over placebo and a greater magnitude of effect achieved with atypicals than with valproate. Based on these new data and the Federal Drug Administration (FDA) approval of several atypical antipsychotics for children with bipolar illness from ages 10 to 17, Dr. Kowatch recommended a new treatment algorithm for childhood onset bipolar disorder. Read more
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
At the annual meeting of the American Academy of Child and Adolescent Psychiatry in Toronto in October 2011, a symposium on the impact of obesity on the course of childhood onset bipolar illness was held.
Typical Treatment of Bipolar Disorder in Youth
David Axelson described the typical outcome of bipolar illness and the medications used during naturalistic treatment. The data came from the large collaborative Course and Outcome of Bipolar Illness among Youth (COBY) study, in which he and his colleagues followed 255 patients with bipolar I disorder (BP I), 30 patients with bipolar II (BP II), and 153 patients with bipolar not otherwise specified (BP NOS) for a mean of 5 years. He discussed only BP I children at the symposium.
The study initially followed 270 BP I children for a mean of 582 weeks. They ranged in age from 7 to 17 years (average 14.4 years). Ninety-three percent of the children were treated with one or more antimanic (AM) agents. These included atypical antipsychotics (AA) in 77%, valproate or carbamazepine in 44%, and lithium in 47%. Antidepressants (ADs) were used in 46% of the children, stimulants in 43%, and benzodiazepines in 21%. Sixty percent had been on two classes of antimanic medications concurrently at some point.
A univariate analysis showed that older children received smaller amounts of antipsychotics and more anticonvulsants and lithium. Variables associated with better response, that is, a rating of either much or very much improved on the Clinical Global Impressions scale for bipolar disorder (CGI-BP), included older age and treatment with atypical antipsychotics. Those who had comorbid attention deficit hyperactivity disorder (ADHD) or psychosis at baseline did more poorly. Mean symptom scores were better when the children received any anti-manic treatment including an atypical or lithium, but worse when they received valproate or carbamazepine.
These data are similar to those from other prospective treatment outcome studies in childhood-onset bipolar I illness. Taken together they all suggest that the illness is difficult to treat and stabilize even when multiple medicines are used in combination.
Obesity and Mood Disorders in Youth
Another speaker, Ben Goldstein, indicated that in the scientific literature, obesity has been associated with a higher number of depressive episodes and longer length of depression, more recurrences of depression, more anxiety disorders, increased numbers of hospitalization, more suicide attempts, and worse functional outcomes. In the same group of patients discussed by Axelson above, 42% were overweight or obese, compared to a 34% incidence in the general population of children in this age range.
Factors associated with overweight included substance abuse, a history of physical abuse, prior hospitalization, and being on 2 or more medications. Those who were overweight or obese spent more time ill in a manic or depressive episode. Read more
A symposium at the Annual Meeting of the American Association of Child and Adolescent Psychiatry discussed the Treatment of Early Age Mania (TEAM) study, which comprised 5 different sites in Pittsburgh, Washington DC, Baltimore, St. Louis, and Cleveland. This randomized partially blinded study compared risperidone, valproate, and lithium for the treatment of children with bipolar I mania.
Participants were all severely ill with a Clinical Global Assessment of Severity score (C-GAS) of less than 60 (the mean was 39, indicating that the children were substantially impaired). More than three quarters had psychosis (i.e. hallucinations or delusions) and 99% had dramatic mood shifts within a day (ultradian cycling). All the children had the cardinal symptom of elevated mood.
Among the 290 participants, there was a high incidence of Axis I comorbidities, with 98% of patients having a disruptive behavioral disorder, 77.3% an anxiety disorder, 31% some form of sleep disturbance, and 17% an elimination disorder, of which 15% had enuresis (bedwetting). Nightmares were present in 25.9% of the sample, sleepwalking in 7.2%, and night terrors in 4.8%.
For the purposes of the study, response was considered to have been achieved when a child received a rating of 1 (not ill) or 2 (minimally ill) on the Clinical Global Impressions scale modified for bipolar illness (CGI-BP).
The children (age 6 to 15 with a mean age of 11) were randomized to treatment for 8 weeks with lithium, valproate, or risperidone. Lithium treatment reached blood levels of 1.1 to 1.3mEq/L, valproate reached levels of 111 – 225µg/ML, and risperidone doses were up to 3mg per day. Children who were taking psychomotor stimulants for treatment of ADHD remained on the stimulants after randomization to one of the three drugs. While the treating physicians and clinicians were not blind, blind ratings were performed at week 8.
With a response rate of 68.5%, risperidone was superior to lithium (35.6%) and valproate (24%) based on CGI-BP scores. The mean dose of risperidone was 2.6mg +/- 1.2 per day. The mean blood level at week 8 for lithium was 1.1mEq/L and for valproate was 114µg/ML.
The number of children who improved sufficiently for their C-GAS scores to rise above 60 was also greater for risperidone at 48.3% compared to lithium at 26.7% and valproate at 17.0%. Read more
At the American Academy of Child and Adolescent Psychiatry (AACAP) annual meeting in Toronto in October 2011, there was a symposium on risk and resilience factors in the onset of bipolar disorder in children who have a parent with the disorder.
Family Focused Therapy Highly Encouraged
Amy Garrett reported that family focused therapy (FFT) in those at risk for bipolar disorder was effective in ameliorating symptomatology compared to treatment as usual. Family focused therapy, pioneered by Dave Miklowitz, PhD of UCLA involves three components. The first component is education about the illness and methods of self-management. The second is enhancement of communication in the family with practice and rehearsal of new modes of conversation. The third component is assistance with problem solving.
In Garrett’s study, 50 children aged 7 to 17 were randomized to family focused treatment or treatment as usual. These children were not only at high risk for bipolar disorder, they were already prodromal, meaning they were already diagnosable with bipolar not otherwise specified (BP-NOS), cyclothymia, or major depressive disorder, and had also shown concurrent depressive and/or manic symptoms in the two weeks prior to the study. At baseline, compared to controls, these children at high risk for full-blown bipolar disorder by virtue of a parental history of the illness showed increased activation of the amygdala and decreased activation of the prefrontal cortex. Most interestingly, after improvement with the family focused therapy (FFT), amygdala reactivity to emotional faces became less prominent and dorsolateral prefrontal cortical activity increased in proportion to the degree of the patient’s improvement.
The discussant for the symposium was Kiki Chang of Stanford University, who indicated that the results of this study of family focused therapy were already sufficient to convince him that FFT was a useful therapeutic procedure in children at high risk for bipolar disorder by virtue of having a parent with a history of bipolar illness. Chang is now employing the therapy routinely in all of his high-risk patients.
Editors Note: This is an extremely important recommendation as it gives families a specific therapeutic process in which to engage children and others in the family when affective behavior begins to become abnormal, even if it does not meet full criteria for a bipolar I or bipolar II disorder.
FFT also meets all the important criteria needed for putting it into widespread clinical practice. Family focused therapy has repeatedly been shown to be effective in adults and adolescents with bipolar illness and now also in these children who are prodromal. The psychoeducational part of FFT is common sense, and dealing with communication difficulties and assisting with problem solving also have merit in terms of stress reduction. Finally, this treatment intervention appears to be not only safe but also highly effective in a variety of different prodromal presentations of affect disorders even if children do not meet full criteria for bipolar disorder. While the few studies of early intervention with psychopharmacological agents have not yet identified efficacious medications for the prodromes of bipolar disorder and in particular medications with a high degree of safety, such family focused therapy appears to be an ideal early intervention.
I would concur with Dr. Chang’s assessment. Family focused therapy (FFT) should be offered to all children with this high-risk status who have begun to be symptomatic. Early onset of unipolar depressive disorder or of bipolar disorder carries a more adverse prognosis than the adult onset variety and thus should not be ignored. If more serious illness is headed off early, it even raises the possibility that the full-blown illness will not develop at all.
Gray Matter Volume Abnormalities
Tomas Hajek of Dalhousie University in Halifax presented data indicating that in children at high risk for bipolar disorder, gray matter volume in the right inferior frontal gyrus is increased. Read more
There is increasing evidence of a link between inflammation, brain function, and treatment resistance in the mood disorders. Obesity is also linked to inflammatory processes and thus may contribute to the development of treatment resistance in both unipolar and bipolar mood disorders.
Causes of Inflammation
Obesity is one factor that can lead to increases in inflammation. When people gain weight, the size of fat cells can increase to the point that the cells are deprived of oxygen and disintegrate. Then macrophages and other cells come in to sweep up the remaining particles of the fat cells. These scavenger cells then become activated and produce more regulatory chemicals called cytokines. The cytokines produced in the periphery (in the body outside the brain) can then enter the brain and affect brain function in a process that may ultimately be linked to fatigue, depression, and other adverse mood and behavior states that contribute to treatment resistance. There is a two-way street: the brain can influence the body and what goes on in the body can influence the brain.
Other factors that can lead to increases in inflammation and eventually to treatment resistance in the unipolar and bipolar mood disorders include early life stress, medical illness, and anxiety and personality disorders.
Given the close links between inflammation and depression (discussed in BNN Volume 15, Issue 1 from 2011), Andrew H. Miller of Emory University decided to test a specific anti-inflammatory agent called infliximab (a TNF monoclonal antibody that inhibits TNF alpha actions) as an antidepressant. One sign of inflammation is a C-reactive protein (CRP) level of 2mg/L or greater. The effect of infliximab on the population of treatment refractory depressed patients who participated in Miller’s study was not significant on the whole, but the drug did have significantly greater antidepressant effects than placebo in those patients with the highest levels of CRP. The investigators believe this demonstrates the principle that a drug that inhibits TNF alpha may be useful in patients with the greatest degree of inflammation.
Other approaches to anti-inflammatory mechanisms are also being pursued, including use of aspirin, COX-2 inhibitors, and the antibiotic minocycline. Minocycline has anti-inflammatory and neuroprotective effects and has been reported to have positive effects in cognition and negative symptoms of schizophrenia.
At a recent conference Robin Murray, a researcher based in London, gave a talk about the potential adverse effects of tetrahydrocanabinol (THC). Considerable data indicate that chronic long-term smoking of marijuana is associated with the doubling of the risk of psychosis. Moreover, if a marijuana user has a common genetic variant in the catechol-o-methyltransferase enzyme (COMT), they are at substantially increased risk for the development of psychosis. New data also indicate that frequent use of marijuana can also be associated with an earlier onset of schizophrenic psychosis than would ordinarily occur without the substance use. Data also suggest that the psychosis associated with THC use is more difficult to treat than that without such use.
Murray also reported on a new risk that is associated with more potent new products. Older, natural forms of marijuana contained a compound called cannabidiol, which is associated with calming effects and possible antipsychotic effects. In a new synthetic preparation of THC called skank or spice, there is a higher amount of THC, but none of the positive diol compound. Thus there are some important caveats to the prevailing view that marijuana is relatively harmless.
Editor’s Note: Marijuana use brings a clear-cut increased risk for psychosis, which appears to interact with a common gene polymorphism and which is increased with use of a new synthetic preparation called skank or spice. If a marijuana user has a concurrent mood disorder, the risks appear to be even greater. The one sure pharmacological effect of marijuana is an amotivational syndrome, and motivational deficits are one of the core components of depression.
Given the difficulty of treating the mood and schizophrenic disorders, a patient should not risk worsening their illness with marijuana. N-acetylcysteine is one treatment option that may bring about decreased craving for and avoidance of marijuana and a number of other abused substances, as well as being helpful for mood and negative symptoms in schizophrenia.
At a recent scientific meeting, Carlos Zarate of the National Institute of Mental Health (NIMH) discussed a variety of rapid-onset antidepressant manipulations. The talk focused on intravenous (IV) administration of the NMDA receptor antagonist ketamine and the anticholinergic drug scopolamine.
Intravenous ketamine has been administered to approximately 1000 patients at research centers at Mount Sinai Hospital in New York, Yale University, and at the NIMH in Bethesda. The results have been consistent; more than half of the patients experienced a rapid onset of antidepressant effect, usually within the first 2 hours. However, the effects of intravenous ketamine tend to disappear after 3 to 5 days.
In both unipolar and bipolar depressed patients whose illness has been highly resistant to multiple treatments, ketamine also brings about a rapid-onset decrease in suicidal ideation and intent. In some cases these positive effects have lasted a week or more. Thus intravenous ketamine could potentially be used at hospitals to treat suicidal emergencies.
New data indicate that intravenous scopolamine, a selective blocker of muscarinic cholinergic receptors that is used to help ward off seasickness, brings about onset of antidepressant effects in up to one day and sometimes in a matter of hours. As with ketamine, these effects occur in both unipolar and bipolar depressed patients.
Mechanisms of Action of Ketamine
Editor’s Note: New data from animal studies may be able to explain some of the mechanisms behind the rapid onset of antidepressant effects that occurs with ketamine. Ketamine causes increases in brain-derived neurotrophic factor (BDNF), which is important for the development and health of neurons. In rodents, new synaptic proteins are created following intravenous administration of ketamine.
If animals are subjected to chronic unpredictable stress, dendritic spines (on which synapses are formed) appear to shrink. However, when ketamine is administered intravenously to these animals, not only is their behavior rapidly ameliorated, but the thin dendritic spines shift back to their more mature, mushroomed-shaped form within a few hours. (A slightly slower, less dramatic change in spines occurs with scopolamine.) A loss of dendritic volume has also been demonstrated in depressed people.
The data in animals are not only valuable for their potential application in clinical treatment and emergency situations involving suicidal ideation, but they also demonstrate a mechanism by which a single administration of intravenous ketamine or scopolamine is capable not only of reversing depressive behaviors in animals, but changing dendritic spine morphology. Given this development, it may be possible to identify other treatments that induce rapid-onset antidepressant effects using other parts of the same neurological pathways.
Other Rapid-Onset Approaches: TRH and Sleep Deprivation
Intravenous thyrotropin releasing hormone (TRH) also has rapid-onset antidepressant effects within 24 hours in depressed patients, but tolerance develops after repeated use.
Surprisingly, one night of complete sleep deprivation can also bring about dramatic onset of antidepressant effects the following day in approximately 50% of severely depressed patients.
In animal studies by Ron Duman and colleagues at Yale University, administration of brain-derived neurotrophic factor (BDNF) either into a rodent’s blood or its brain has induced rapid-onset antidepressant-like effects.
Taken together, these data indicate that there are ways to bring about rapid improvement in depression, even if conventional antidepressants usually require 2 to 4 weeks to exert their maximum antidepressant effects. Read more
Memories are created in a series of phases in which different neurobiological mechanisms are required. In order for short-term memories to be placed in long-term storage, new protein synthesis is required. If protein synthesis is inhibited during a window about 2-4 hours after the short-term memory was encoded, consolidation into long-term memory does not occur.
In addition to the initial phase of memory consolidation, a second phase of memory reconsolidation is now recognized. During this phase, memory is again alterable.
The alterability of memories has implications for some types of post-traumatic stress disorder (PTSD), in which emotional memories repeatedly intrude into consciousness. Pharmacological intervention during the period of memory reconsolidation may be able to reduce the impact of traumatic memories.
One example of an attempt to alter memory consolidation or reconsolidation after trauma has been reported by researcher Ariel Shalev and colleagues. These researchers found that administration of a high dose of intravenous cortisone (100 to 240mg) immediately following an extreme trauma was able to decrease the incidence of PTSD. One month after a traumatic event, the incidence of PTSD was 60% in those who received placebo, compared to only 16% in those who received the intravenous cortisone.