Children of Bipolar Parents Are At Risk for Depression and Bipolar Disorder
The Pittsburgh Bipolar Offspring study, led by Boris Birmaher of the University of Pittsburgh, investigated risk of illness in the offspring of parents with bipolar disorder. The study included 233 parents with bipolar disorder and 143 controls. In addition to bipolar disorder, parents in the study had many other disorders, including anxiety (70%), panic (40%), a disruptive behavior disorder (35%), attention-deficit hyperactivity disorder or ADHD (25%), and substance use disorder (35%).
The offspring averaged age 12 at entry in the study. Offspring of parents with bipolar disorder had more illness than those of control parents, including bipolar spectrum disorders (10.6% versus 0.8%), depression (10.6% versus 3.6%), anxiety disorder (25.8% versus 10.8%), oppositional defiant disorder or conduct disorder (19.1% versus 8.0%), and ADHD (24.5% versus 6.7%). Of these differences, only bipolar spectrum disorders and anxiety were statistically significant after correcting for differences in the parents’ other diagnoses.
Two factors predicted bipolar spectrum disorders in the offspring: younger age of a parent at birth of child and bipolar disorder in both parents. Older children and those with diagnoses of anxiety or oppositional defiant disorder were more likely to be diagnosed with bipolar disorder.
On long-term follow-up that continued on average until the offspring reached age 20, 23% of those participants who had a parent with bipolar disorder developed any type of bipolar disorder, versus only 1.2% of the children of controls. Of these 23%, about two-thirds had a depressive episode prior to the onset of their bipolar disorder.
Of the offspring of parents with bipolar disorder who developed a bipolar spectrum illness, 12.3% developed bipolar I or II disorders, while 10.7% were diagnosed with bipolar not otherwise specified (NOS). Of those with bipolar NOS, which some consider to be sub-threshold bipolar disorder, about 45% converted to a bipolar I or II diagnosis after several years of prospective follow-up. These data, along with the finding that children with bipolar NOS are highly impaired and take more than a year on average to remit, stress the importance of vigorously treating this subtype, even if it does not meet the full threshold for bipolar I or bipolar II.
Birmaher indicated that although about 50% of the offspring of a bipolar patient had no diagnosis, the high incidence of multiple psychiatric difficulties developing over childhood and adolescence spoke to the importance of attempts at early intervention and prevention. Studies of effective treatment and prevention strategies are desperately needed. So far only family focused therapy (FFT), an intervention developed by researcher David Miklowitz, has shown significant benefits over standard treatment in children with a positive family history of bipolar disorder who already have a diagnosis of anxiety, depression, or bipolar not otherwise specified.
Low Omega-3s in Children Associated with Poor Cognitive Performance
Omega-3 fatty acids (especially the type known as DHA) are essential for brain development and functioning, but most people eating a modern western diet consume low amounts of these compared to omega-6 fatty acids. Omega-3s are anti-inflammatory while omega-6s are pro-inflammatory. A large UK study published in the journal PLOS One in 2013 reported that healthy 7- to 9-year-olds with lower levels of omega-3 long-chain polyunsaturated fatty acids in their blood (including DHA, DPA, and EPA) had lower reading ability and working memory, and also had more behavior problems.
The oils in fish are the best source of omega-3 fatty acids, and most of the children with poor reading ability in the study fell short of the UK nutritional guideline that recommends eating two portions of fish per week.
Girls in the study had more dramatic deficits in omega-3 levels than boys. In adults, women tend to metabolize long chain polyunsaturated fatty acids more easily than men, but this difference is driven by hormones, and because the girls in the study had not yet reached child-bearing age, they did not reflect this benefit.
Omega-3 deficits in children have been connected with attention deficit hyperactivity disorder (ADHD), and supplementation with extra omega-3 fatty acids in the diet has led to improvements in ADHD.
Iron Deficiency Linked to Psychiatric Disorders in Children
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.
Longitudinal Trajectory of Childhood Bipolar Disorder
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%)
Explaining Wellness
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.
Irritable, Elated, And Combined Bipolar Subtypes in Children Are Similar
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.
Treatment Research Needs More Advocacy
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.
Cognitive Behavioral Therapy Tailored For Children and Adolescents
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).
Continuation Cognitive Behavioral Therapy Prevents Relapse in Kids
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.
Malnutrition Early in Life Has Lasting Effects
Severe malnutrition in the first year of life even when corrected for the rest of a person’s life leaves a legacy of permanent cognitive deficits, marked deficits in attention, and increases in depression, conduct disorders, and medical disorders compared to carefully matched controls. Jamina Galler, a researcher at Harvard Medical School, gave a plenary talk at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry on the long-term effects of even short-term childhood malnutrition, including marasmus (calorie deficiency) and kwashiorkor (protein deficiency).
Galler’s studies followed three generations of people born in Barbados and observed the consequences of prior malnutrition, which was completely eliminated in Barbados by 1980. The consequences of malnutrition in the first year of life not only affected the first (G1) generation, but subsequently their offspring in the G2 generation who also suffered an excess of attention-deficit hyperactivity disorder, low IQ, and low annual income into adulthood. That is, the early malnutrition had transgenerational effects.
Malnutrition is a huge problem worldwide and is especially bad in sub-Saharan Africa and some parts of Asia. Globally, malnutrition accounts for 50% of the deaths of children under age five. However, even in the US hunger is a problem for one in four children, or about 16 million individuals, and the long-term consequences of hunger remain to be further studied.
Studies in animals indicate that early malnutrition has epigenetic effects that can be passed on to four future generations before they are reversed. Epigenetic effects refer to environmental factors that cannot change the sequence of DNA, but change how easily it is transcribed by adding or taking away acetyl and methyl groups on DNA and histones, the structures around which DNA is wound. Malnutrition (defined as 6–8% casein, a type of protein, in the diet instead of the normal 25%) in rodents affects cognitive abilities and blood pressure and can lead to diabetes, obesity, and other metabolic abnormalities. The next generation is also affected because a previously malnourished mother huddles too much with her offspring, and they become obese as a result of these poor parenting skills. The second generation also exhibits epigenetic changes in the prefrontal cortex (such as too few glucocorticoid receptors due to methylation of the glucocorticoid promoter) and fewer neurons in the hippocampus.
Editor’s Note: Other data indicate similar long-lasting epigenetic and transgenerational effects of other types of childhood adversity, such as verbal, physical, or sexual abuse. These findings in humans are also paralleled by findings in animals, and give strong credence to the idea that the environment can have long-lasting effects on neurobiology and behavior via epigenetic effects that can be superimposed on whatever genetic effects are inherited.
Data from this editor (Robert Post) and colleagues on verbal abuse in childhood is striking; this supposedly less severe form of abuse is still associated with a more difficult course of bipolar disorder and an increase in medical comorbidities. Thus, the experience of early abuse, even just verbal abuse, appears to have long-lasting consequences for psychiatric and medical health into adulthood.
Omega-3-Fatty Acids Promising For At-Risk Kids with Depression
Several studies in adults and children suggest that omega-3 fatty acid supplementation may have antidepressant effects. At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry in October, Melissa DelBello, a professor at the University of Cincinnati, reported on a new study of omega-3 fatty acids in depressed children who had a parent with bipolar disorder. The children taking omega-3 fatty acids were more likely to improve than those taking a placebo, but the findings were only of marginal significance.
Cold-water fish are a good source of omega-3 fatty acids, and DelBello said salmon is by far the best in this regard. People who live in countries where fish is consumed in greater quantities are less likely to suffer from depression. Other sources of omega-3 fatty acids include shellfish, plant and nut oils, English walnuts, flaxseed, algae oils, and fortified foods.
The omega-3 fatty acids from fish are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), while the omega-3 fatty acids from plants are alpha-linolenic acid (ALA), which breaks down into EPA and DHA. All of these are anti-inflammatory, though one must consume much greater quantities of ALA to match the benefits of EPA and DHA. In contrast, omega-6 fatty acids, which are much more common in the typical American diet, are pro-inflammatory.
In DelBello’s study of 56 depressed children of a parent with bipolar disorder, the participants were randomized to either 1.8 g of omega-3 fatty acids (1.2 g of EPA and 0.6 g of DHA) or placebo (olive oil). Those who received the omega-3 fatty acids had a 55.6% rate of remission versus 34.5% for those who received placebo, but while the odds ratio of 2.4 favored the omega-3 fatty acids, the difference in remission rates was not statistically significant, likely because of the small size of the study. However, improvement on the Children’s Depression Rating Scale was significantly different across the two groups, with children taking omega-3s improving more. Omega-3 fatty acids are known to have an anticoagulant effect (preventing the clotting of blood), and four children in the study did have prolonged clotting times (but no clinical problems with bleeding).
Editor’s Note: Given the existing literature on omega-3 fatty acids and the trend in this study, omega-3s are worthy of consideration for the treatment and potentially for the prevention of depression in children. This later possibility is further suggested by findings from Australia that, when compared to placebo, omega-3 fatty acids significantly reduced the rate of conversion from prodromal (preliminary) psychotic symptoms to a full-blown diagnosis of schizophrenia.
