In a symposium at the 2014 meeting of the International College of Neuropsychopharmacology, four researchers shared insights on children who are at high risk for bipolar disorder because they have a parent with the disorder.
Researcher John Nurnberger has been studying 350 children of parents with bipolar disorder in the US and 141 control children of parents with no major psychiatric disorder, following the participants into adolescence. He found a major affective disorder in 23.4% of the children with parents who have bipolar disorder and 4.4% of the controls. Of the at-risk children, 8.5% had a bipolar diagnosis versus 0% of the controls.
Nurnberger found that disruptive behavior disorders preceded the onset of mood disorders, as did anxiety disorders. These diagnoses predicted the later onset of bipolar disorder in the at-risk children, but not in the controls. A mood disorder in early adolescence predicted a substance abuse disorder later in adolescence among those at risk.
In genome-wide association studies, the genes CACNA1C and ODZ4 are consistently associated with risk of bipolar disorder, but with a very small effect size. Therefore, Nurnberger used 33 different gene variants to generate a total risk score and found that this measure was modestly effective in identifying relative risk of developing bipolar disorder. He hopes that using this improved risk calculation along with family history and clinical variables will allow better prediction of the risk of bipolar onset in the near future.
Researcher Ann Duffy reported on her Canadian studies of children who have a parent with bipolar disorder and thus are at high risk for developing the disorder. In contrast to the studies of Nurnberger et al. and many others in American patients, she found almost no childhood onset of bipolar disorder before late adolescence or early adulthood. She found that anxiety disorders emerge first, followed by depression, and then only much later bipolar disorder. Bipolar disorder occurred with comorbid substance abuse disorders in only about 10-20% of cases in 1975, but substance abuse increased to 50% of bipolar cases in 2005. The incidence of comorbid substance disorder and the year at observation correlated strongly, indicating a trend toward increased substance abuse over the 30-year period.
Duffy found that having parents who were ill as opposed to recovered was associated with a more rapid onset of mood disorder in the offspring, usually in early adulthood. Duffy emphasized the need to intervene earlier in children of parents with bipolar disorder, but this is rarely done in clinical practice. Read more
Iron deficiency is the most prevalent nutritional deficiency in industrialized countries and can cause problems with cognitive and intellectual development. New research published in the journal BMC Psychiatry shows that it has psychiatric ramifications as well. Children and adolescents with iron deficiency anemia are at greater risk for psychiatric disorders, including depression, bipolar disorder, anxiety, and autism.
Iron supplementation should be implemented in children with iron deficiency anemia in order to prevent any possible psychiatric repercussions, and similarly, psychiatrists should check iron levels in young patients with psychiatric disorders.
Iron provides myelin for white matter in the brain and plays a role in the function of neurotransmitters.
Most children recover from an episode of bipolar disorder after a considerable period of time, but the majority eventually relapse. At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Boris Birmaher of the University of Pittsburgh presented new data on the long-term prospective course of bipolar disorder in 255 children with bipolar I, 30 children with bipolar II, and 153 children with bipolar NOS (not otherwise specified), who together had an average age of onset of 9.3 +/- 3.9 years. The children participated in the study for an average of 8 years. Most of the children (81.5%) recovered from their episode, but only after an average of 2.5 years of follow up treatment. Yet 62.5% of those who recovered experience a recurrence after an average of 1.5 years.
Editor’s Note: It takes a long, long time to achieve recovery, and longer for bipolar NOS (more than 2 years on average) than for either Bipolar I or II (about 1.8 years). However, the high rate of relapse within 1 to 2 years is equally disturbing. These data are similar to those in many other prospective follow up studies of children, and suggest that it is important for parents to be aware that this illness is difficult to treat, and good results within weeks are not likely to be the norm. At the same time, 43% of the children with a bipolar diagnosis eventually achieved euthymia (wellness) in the longer term, so there is cause for some optimism.
Four Trajectories in Children with Bipolar Illness
Birmaher described four different long-term,trajectories observed over an average of 8 years of follow up with 438 children with bipolar disorder.
- Predominately euthymic (24%)
- Ill early then much improved (19%)
- Mild to moderately ill—euthymic only 47% of the time (34.6%)
- Predominantly ill—euthymic 11.5% of the time (20.3%)
The predominantly well group (1) was associated in a univariate analysis with a later onset of illness, higher socio-economic status, less conflict, fewer stressors, less sexual abuse, fewer anxiety and ADHD comorbidities, and less medication (including stimulant use). In a multivariate analysis, this group was independently associated with less severe depression/mania, less suicidal ideation, less substance use, less sexual abuse, and less family history of mania and substance abuse.
This group had the best functioning, almost to 80 on the Children’s Global Assessment Scale (C-GAS). In comparison, despite considerable time euthymic for groups 2 and 3, these children still had considerable functional impairment, in the realm of 65 on the C-GAS scale. Even in Group 1, about half of the children had low C-GAS scores.
Birmaher suggested the importance of trying to find ways to delay the onset of the illness (to graduate more children into the good prognosis group) and allowing them time to develop socially and educationally and graduate from high school. Potential preventive strategies could include omega-3 fatty acids, more time spent exercising, good sleep hygiene, family focused therapy (FFT), dialectic behavior therapy, treating subsyndromal depression, and even treating parents with mood disorders to complete remission (which has been shown to improve behavioral health in offspring).
Editor’s Note: As this editor Post, Chang, and Frye wrote in the Journal of Clinical Psychiatry in 2013, beginning to study the effectiveness of these kinds of early primary and secondary prevention strategies in children who can now be readily identified clinically as at risk for a mood disorder, should be given the highest priority.
Children who have at least one parent with a bipolar or unipolar disorder, some further environmental risk factors (such as adversity in early childhood), and early symptoms of depression, anxiety, or prodromal bipolar disorder are at very high risk for bipolar disorder, and there is an urgent need for randomized studies (even open ones) of safe potential preventive strategies for these children.
Omega-3 fatty acids in particular have a strong record of safety, compelling rationale for use in bipolar disorder, and have already been shown to have significant preventive effects in decreasing the transition from early prodromal psychosis to full-blown schizophrenia.
People with bipolar disorder often show signs of inflammation. These could eventually help clarify diagnosis, illness activity, and treatment response, and predict illness progression. Previous studies have shown increases in c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in adults with mood disorder. These high levels tend to improve with medications, are related to illness severity, and are also related to manic and mixed states.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Ben Goldstein reported on a study that examined levels of TNF alpha, IL-6, and high sensitivity CRP (hsCRP) in 123 adolescents with an average age of 20.4 years, who had been ill for an average of 12.7 years.
CRP levels in adolescents with bipolar illness were equivalent to those with rheumatoid arthritis, and much higher than healthy controls. In children with bipolar disorder, higher levels of CRP were related to more time symptomatic. High hsCRP was related to lower socio-economic status and to substance abuse disorders.
Increases in IL-6 were linked to a longer time to achieve remission and more weeks depressed. High IL-6 was related to duration of illness, positive family history of substance use, and family conflict.
High TNF alpha was related to low socioeconomic status (SES), self-injury, suicidal ideation, and positive life events.
Goldstein said studies of these markers could eventually lead to therapeutic advances, but the process would be long and would require several steps: proof of concept studies, prospective validation studies in independent samples, and demonstration of clinical gains over standard predictive markers, culminating in enhanced patient care and outcome through better, faster prediction of response.
Editor’s Note: Ideally clinicians could jump ahead by immediately attempting to determine whether adding a medication with direct anti-inflammatory effects could enhance therapeutic effects in children with elevated inflammatory markers. Treating inflammation could also theoretically help prevent cognitive deterioration and decrease the considerable risk for cardiovascular dysfunction in patients with bipolar disorder.
Research on early-onset bipolar disorder has often hinged on identifying the key characteristics of the disorder. At a symposium on the course of bipolar disorder in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Jeff Hunt of Brown University discussed findings from COBY, the Collaborative Child Bipolar Network. He described the course of illness in 446 children with bipolar disorder, including 10% who had irritability at baseline, 15% who had elated mood at baseline, and a majority (75%) who had both irritability and elation at baseline.
Most factors such as positive family history of bipolar illness and comorbidities including attention deficit hyperactivity disorder (ADHD) did not differ across the three groups. The three subtypes (irritable, elated, or mixed) did not remain stable, and most of the children eventually converted to the combined irritable and elated subtype. These data contrast with those of Ellen Liebenluft et al., who found that those with severe mood dysregulation or chronic irritability (but not other key characteristics of bipolar disorder) did not go on go on to receive a bipolar diagnosis and tended not to have a family history of bipolar disorder.
Among the hundreds of posters, workshops, clinical perspectives, and symposia presented over five days at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), there were almost no posters or presentations on new approaches to treatment (either with drugs or therapy) for children with bipolar disorder.
As we have repeatedly emphasized in the BNN and in research publications, this deficiency has adverse consequences for the many hundreds of thousands of children and adolescents in the US with unequivocal diagnoses of bipolar disorder. Suicide is now the second leading cause of death in adolescents 13 to 17 years of age in the US. Most of these young people have a mood disorder. Bipolar disorder carries with it not only a substantial risk of suicide, but also the potential for a lifetime of dysfunction, disability, and medical comorbidity if it is inadequately treated.
Please advocate for more treatment research for childhood onset bipolar disorder. A whole generation of children, their parents, and their physicians desperately need more treatment information.
At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Betsy Kennard described a course of cognitive behavioral therapy tailored to eliminating residual symptoms in children with unipolar depression who had no family history of a parent with bipolar disorder. In the same study Graham Emslie discussed, the investigators considered cognitive behavioral therapy for the treatment of childhood- and adolescent-onset depression.
The therapy was aimed at achieving health and wellbeing and focusing on positive attributes and strengths in the child, and it was designed to be a shorter than usual course (i.e. four weekly sessions, then four every other week, and one at three months). This regimen typically also included three to five family sessions. Other key components of the therapy included anticipating and dealing with stressors, setting goals, and practicing all the skills learned.
On a visual timeline, children identified and wrote down past stressors, how they felt when depressed, their automatic cognitions, ways they would know when they were feeling down again (i.e. feeling isolated, angry at parents, etc.), their strengths and skills, what obstacles to feeling better existed and how to circumvent them, and their long-term goals.
The therapy was based on the research of Martin Seligman and Giovanni A. Fava, plus Rye’s Six S’s (soothing, self-healing, social, success, spiritual, and self-acceptance). The children participated in practice and skill-building in each domain. Sleep hygiene and exercise were emphasized. The idea of “making it stick” was made concrete with phrases on sticky notes taken home and put up on a mirror. Postcards were even sent between sessions as reminders and for encouragement.
Editor’s Note: Most depressed kids don’t get completely well (only about 20% after an acute course of medication). Something must be added. This kind of specialized cognitive behavior therapy works and keeps patients from relapsing. This study included only those children with unipolar depression whose parents did not have bipolar disorder. However, Emslie noted that depressed children of a bipolar parent also had an exceedingly low rate of switching into mania (2 to 4%) in his experience, so fluoxetine followed by cognitive behavioral therapy might be considered for treating unipolar depressed children of a bipolar parent.
Once children have developed bipolar disorder, evidenced by hypomania or mania followed by depression, antidepressants are to be avoided in favor of mood stabilizers and atypical antipsychotics, since there is a higher switch rate in these youth when they are prescribed antidepressant monotherapy.
Since children with bipolar disorder are at such high risk for continued symptoms and relapses, the strategy of adding cognitive behavioral therapy to their successful drug treatment would appear appropriate for them as well as those with unipolar depression, especially since there is a large positive literature on the efficacy of cognitive behavioral therapy, psychoeducation, and Family Focused Therapy (FFT) in children and adults with bipolar depression. As noted previously, FFT is very effective for children at high risk because of a parent with bipolar disorder and who are already symptomatic with anxiety, depression or BP-NOS.
Moral of the story: getting kids with unipolar or bipolar depression well and keeping them well is a difficult endeavor that requires specialized, combined medication and therapy approaches and follow-up education and therapy. This is for sure. The hope would also be that good early and long-term intervention would yield a more benign course of recurrent unipolar or bipolar disorder than would treatment as usual (which all too often consists of medication only).
At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Graham Emslie of the University of Texas Southwestern Medical Center discussed the role of cognitive behavioral therapy in the long-term treatment of child-and adolescent-onset unipolar depression.
In Emslie’s research, the combination of the antidepressant fluoxetine and cognitive behavioral therapy reduced depressive relapses in children. Using the two treatments together did not speed onset of antidepressant response compared to fluoxetine alone, but once children responded to the medication, the addition of cognitive behavioral therapy reduced relapses over the next year compared to fluoxetine alone (even though the cognitive behavioral therapy ended after the first six months).
Emslie likened the use of cognitive behavioral therapy to the course of rehabilitation that often follows a major surgery and is meant to sustain or enhance the good effects of surgery. Getting patients to full remission (well and with no residual symptoms) was the key to staying well.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Vilma Gabbay of the Mount Sinai School of Medicine reiterated the findings from the TORDIA (Treatment of SSRI-Resistant Depression in Adolescents) study that 20% of young people with depression remained resistant to treatment, childhood-onset depression was more likely to be recurrent and more difficult than adult-onset depression in the long run, and suicide was the second leading cause of death in 12- to 17-year-olds in 2010 according to a Centers for Disease Control report in May 2013. Anhedonia (a loss of pleasure in activities once enjoyed) was the most difficult symptom to treat in adolescents.
Gabbay carefully explained some of the rationales for using ketamine in young people with depression. The presence of inflammation is a poor prognosis factor, and ketamine has anti-inflammatory effects, decreasing levels of inflammatory markers CRP, TNF-alpha, and Il-6.Given that ketamine has been widely used as an anesthetic for surgical procedures, its safety in children has already been demonstrated. Ketamine did not appear to cause behavioral sensitization (that is, increased effect upon repetition) in a report by Cho et al. in 2005 that included 295 patients.
As noted previously, Papolos et al. reported in a 2012 article in the Journal of Affective Disorders that intranasal ketamine at doses of 50 to 120 mg was well-tolerated and had positive clinical effects in 6- to 19-year-olds with the fear of harm subtype of bipolar disorder that had been highly resistant to treatment with more conventional drugs.
Gabbay reluctantly endorsed further cautious controlled trials in children and adolescents, in light of ketamine’s suggested efficacy and good safety profile, which stands in contrast to its popular reputation as a party drug or “Special K.”
Editor’s Note: The discussant of the symposium, Neal Ryan of Western Psychiatric Institute and Clinic, added an exquisitely brief discussion suggesting that ketamine should ultimately be studied in combination with behavioral and psychotherapeutic procedures to see if its therapeutic effects could be enhanced. He made this suggestion based on the data that ketamine has important synaptic effects, increasing brain-derived neurotrophic factor (BDNF), which is important for healthy cells and long-term memory, and reverting thin dendritic spines caused by stress back to their normal mushroom shape. This editor (Robert Post) could not be more in agreement.
At a symposium on ketamine for the treatment of depression in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, David Brent, a professor at the University of Pittsburg, gave the opening talk on the fact that as many as 20% of adolescents who are depressed fail to improve, develop chronic illness, and are thus in need of alternatives to traditional treatment. Predictors of non-improvement include substance use, low-level manic symptoms, poor adherence to a medication regimen, low blood levels of antidepressants, family conflict, high levels of inflammation in the body, and importantly, maternal depression. In adolescents insomnia was associated with poor response, but in younger children insomnia was associated with a better response.
Brent suggested using melatonin and sleep-focused cognitive behavioral therapy for insomnia in youth, but not using trazodone (which is commonly prescribed). Trazodone is converted to a compound called Meta-chlorophenylpiperazine or MCPP, which induces anxiety and dysphoria. MCPP is metabolized by hepatic enzymes 2D6, and fluoxetine and paroxetine inhibit 2D6, so if trazodone is combined with these antidepressants, the patient may get too much MCPP.
Surprisingly and contrary to some data in adults about the positive effects of therapy in those with abuse histories, in the study TORDIA (Treatment of SSRI-Resistant Depression in Adolescents), if youth with depression had experienced abuse in childhood, they did less well on the combination of cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) compared to SSRIs alone.