At-Risk Children in the US Deserve Careful Assessment

May 23, 2016
Robert M. Post, MD
Volume 33, Issue 5

In an international network of patients with bipolar illness, more offspring of US patients than of those from Europe had received a mental illness diagnosis. This suggests greater epigenetic vulnerability in Americans.

A study by Axelson and colleagues1 showed that 3 of 4 children of a parent with bipolar disorder had a diagnosis of a major psychiatric illness at 7 years’ follow-up. About 20% had a bipolar spectrum disorder, but even higher percentages had depression, anxiety disorder, disruptive behavioral disorder, or ADHD-for a total of 74.2%. Perhaps an equally striking finding is that 48% of community controls had a psychiatric illness, which suggests that a great many children in the US are at high risk. These findings mirror those in the meta-analysis by Rasic and associates,2 as well as those of Weissman and colleagues3 who, in their 20-year follow-up study of offspring of a parent with depression, found that 80% had received a psychiatric diagnosis.

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More childhood illness in the US than in Europe

In an international network of patients with bipolar illness, more offspring of US patients than of those from Europe (the Netherlands and Germany) had received a mental illness diagnosis.4 The higher number of offspring with illness was related to the presence of more adverse clinical characteristics of bipolar disorder in US patients. Compared with Europeans, US patients’ spouses, parents, and grandparents also had more illness (depression, bipolar disorder, alcohol and substance abuse, and “other”), each of which related to the degree of illness in the offspring.4,5 In addition, US patients with bipolar illness had experienced more psychosocial adversity in the form of verbal, physical, or sexual abuse during their childhood than the Europeans. These results suggest the presence of greater genetic and environmental (epigenetic) vulnerability in the US.6

Compared with Europeans, US patients with bipolar disorder also had earlier illness onset.7 Similar to findings in patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) network, our research showed that two-thirds of cases of bipolar disorder in adults with well-diagnosed illness had begun in childhood or adolescence.8 Early-onset illness is associated with long delays to first treatment, and both early onset and treatment delay are poor prognostic factors for the severity and complexity of illness in adulthood.8

In Canada and some European countries, offspring of a parent with bipolar disorder tend to show an age-related sequence of illness manifestations starting with anxiety disorders, then depression, followed by the emergence of bipolar disorder in late adolescence or early adulthood.6,9 In the offspring studies from the US, the illnesses are more varied. In addition to anxiety and depression, US children have considerable rates of ADHD, disruptive behavioral disorder, and substance abuse disorders, as well as more early-onset bipolar disorder.

Lifestyle changes, psychotherapy, and pharmacotherapy

The presence of these common and diverse illnesses in children of a parent with a mood disorder-and even in the controls in the US population-indicates a great need for more careful clinical assessment and early intervention. Perhaps in the face of depression, anxiety, or subthreshold bipolar disorder in a child at high risk, one could start with family-focused therapy or a related psychotherapeutic intervention that involves families, psychoeducation, and/or cognitive-behavioral therapy.10,11

The appropriate medications and supplements are not well studied, although for the youngest children, one should follow the rubric of safety and tolerability trumping all other considerations. Omega-3 fatty acids may be beneficial for depression, for ADHD, and in decreasing the onset of psychosis in those at highest risk. N-acetylcysteine (NAC) demonstrated safety and efficacy on irritability in 3 studies in youngsters with autism. Positive placebo-controlled effects were seen for marijuana abuse in adolescents.12

Omega-3 fatty acids and NAC have anti-inflammatory effects, and increases in inflammatory markers, such as interleukin-6, tumor necrosis factor–alpha, and C-reactive protein, have been demonstrated in children with bipolar disorder.13 Vitamin D3 levels are low in a high percentage of children with major psychiatric illness. Consider vitamin D3 supplementation in those with low or borderline values, although as with omega-3 fatty acids and NAC, efficacy in children has not been definitively established.

Lifestyle and other wellness programs should also be considered for children at high risk. Development of healthy habits, such as good diet, exercise, and sleep hygiene, should be strongly encouraged, especially since children with bipolar disorder are at increased risk for obesity, diabetes, and other elements of the metabolic syndrome. Hudziak and colleagues14 recommend universal school programs involving music, mindfulness, and exercise to enhance brain development in children and suggest more supervised and intensive application of these programs for those who are at high risk or already symptomatic.

Axelson and colleagues1 reported that depression, disruptive behavioral disorders, and bipolar disorder not otherwise specified (BP NOS) were risk factors for progression to full-blown bipolar disorder. Thus, early and effective treatment of these conditions may have the dual benefit of improving symptoms and possibly preventing the conversion to full-blown bipolar disorder.

BP NOS is highly impairing and difficult to treat even with conventional psychotropics. In one study, mood stabilization for patients with bipolar I disorder or bipolar II disorder took an average of 9 months; it took more than 2 years for those with BP NOS.15 Lithium, mood-stabilizing anticonvulsants, and atypical antipsychotics are the recommended agents for children with bipolar I mania, but therapeutics for BP NOS have not been well described.

Geller and colleagues16 showed that risperidone was superior to both lithium and valproate in children with bipolar I disorder and BP NOS. Most children required combination therapy with 2 of these agents as well as psychomotor stimulants for comorbid ADHD. The combinations that included risperidone outperformed those that included lithium and valproate. Whether other, better-tolerated atypical antipsychotics would show the same superior clinical profile compared with the mood stabilizers deserves urgent study.

Monitoring children’s symptoms

Children with psychiatric disorders are increasingly being seen by pediatricians and general practitioners.17 Many of these physicians are not comfortable with or expert in the diagnosis and management of psychiatric illness. One approach to this problem is to have parents play a larger role in assessing and monitoring their child’s symptoms. A vehicle for doing this is available at (click on Child Network). The Child Network provides a brief rating of a child’s symptom severity for depression, anxiety, ADHD, oppositional behavior, and mania on a once-a-week basis on a secure website. These weekly ratings of children aged 2 to 12 years can be printed out graphically for ease of visualization of symptom fluctuations, need for treatment, and assessment of the effectiveness of any treatment given. Parents also fill out a one-time demographics form and a more detailed symptom checklist.

With these evaluations, the Network will be able to see how very young children with a variety of syndromes are actually being treated, how well treatment is working, and how well it is tolerated. This information can then be fed back to the field, to provide preliminary uncontrolled effectiveness data and to help identify critical treatment gaps in need of further study. Hopefully, clinicians will inform parents about the Child Network and encourage them to join in this project, which should help with earlier recognition and treatment of the all too common psychiatric disorders of childhood.

Early intervention can change the course of bipolar illness

When young people in Denmark with a first hospitalization for mania were randomized to either specialty clinic treatment or treatment as usual (TAU), those who received specialty treatment involving psychotherapy, pharmacotherapy, illness education, and mood monitoring had fewer relapses than patients who received TAU.18 Over the next 4 years, all participants were given TAU-those who previously had specialty treatment continued to do well, while those who had the initial TAU continued to relapse. The differences between the 2 groups were further magnified over the 6 years of follow-up.

While some academic institutions in the US can provide the equivalent of this type of specialty clinic approach, accessing this kind of multimodal treatment in the general community can be difficult. However, if parents provide critical longitudinal data on their child’s symptom course, it may help move the evaluation and treatment process in the right direction and achieve better results.


Dr Post is Professor of Psychiatry at the George Washington University School of Medicine, in Washington, DC; Head of the Bipolar Collaborative Network; and former Chief of the biological psychiatry branch of NIMH, in Bethesda, MD. He reports no conflicts of interest concerning the subject matter of this article.


1. Axelson D, Goldstein B, Goldstein T, et al. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study. Am J Psychiatry. 2015;172:638-646.

2. Rasic D, Hajek T, Alda M, Uher R. Risk of mental illness in offspring of parents with schizophrenia, bipolar disorder, and major depressive disorder: a meta-analysis of family high-risk studies. Schizophr Bull. 2014;40:28-38.

3. Weissman MM, Wickramaratne P, Nomura Y, et al. Offspring of depressed parents: 20 years later. Am J Psychiatry. 2006;163:1001-1008.

4. Post RM, Altshuler L, Kupka R, et al. More illness in offspring of patients with bipolar illness from the US compared with the Netherlands and Germany. J Affect Disorder. 2016;191:180-186.

5. Post RM, Leverich GS, Kupka R, et al. Increases in multiple psychiatric disorders in parents and grandparents of patients with bipolar disorder from the USA compared with the Netherlands and Germany. Psychiatr Genet. 2015;25:194-200.

6. Post RM, Altshuler L, Kupka R, et al. More pernicious course of bipolar disorder in the United States than in many European countries: implications for policy and treatment. J Affect Disord. 2014;160:27-33.

7. Post RM, Altshuler L, Kupka R, et al. Age of onset of bipolar disorder related to parental and grandparental illness burden. J Clin Psychiatry. 2016; In press.

8. Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71:864-872.

9. Duffy A, Alda M, Crawford L, et al. The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents. Bipolar Disord. 2007;9:828-838.

10. Miklowitz DJ, Schneck CD, Singh MK, et al. Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. J Am Acad Child Adolesc Psychiatry. 2013;52:121-131.

11. Fristad MA, Verducci JS, Walters K, Young ME. Impact of multifamily psychoeducational psychotherapy in treating children aged 8 to 12 years with mood disorders. Arch Gen Psychiatry. 2009;66:1013-1021.

12. Gray KM, Carpenter MJ, Baker NL, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012;169:805-812.

13. Goldstein BI, Young LT. Toward clinically applicable biomarkers in bipolar disorder: focus on BDNF, inflammatory markers, and endothelial function. Curr Psychiatry Rep. 2013;15:425.

14. Hudziak JJ, Albaugh MD, Ducharme S, et al. Cortical thickness maturation and duration of music training: health-promoting activities shape brain development. J Am Acad Child Adolesc Psychiatry. 2014;53:1153-1161.

15. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry. 2009;166:795-804.

16. Geller B, Luby JL, Joshi P, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry. 2012;69:515-528.

17. Anderson LE, Chen ML, Perrin JM, Van Cleave J. Outpatient visits and medication prescribing for US children with mental health conditions. Pediatrics. 2015;136:e1178-e1185.

18. Kessing LV, Hansen HV, Hvenegaard A, et al. Treatment in a specialised out-patient mood disorder clinic v. standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial. Br J Psychiatry. 2013;202:212-219.