New research shows that bipolar disorder risk is higher in the US than in the Netherlands. At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researchers Manon Hillegers and Esther Mesman described a study in which they compared the offspring of mothers with bipolar disorder in the US to those in the Netherlands. The offspring ranged in age from 10–18.
In the US, the mothers had, on average, an earlier age of onset, more substance abuse comorbidity, and were more likely to have been diagnosed with bipolar II disorder. Among the US offspring, 66% had been diagnosed with a psychiatric illness compared to 44% of the Dutch offspring. This included significantly higher rates of anxiety, ADHD, and disruptive behavior disorders in the US offspring. Among the offspring who had been diagnosed with a mood disorder, 80% of those in the US had other additional psychiatric disorders, but only 34% of the Dutch did. Bipolar disorder is more rare among children under the age of 12 in the Netherlands compared to the US.
Dutch children and adolescents were typically treated with lithium and with only one drug at a time. In the US, lithium is less widely used, and simultaneous treatment with several medications (usually including atypical antipsychotics) is common.
Editor’s Note: The research by Hillegers and Mesman replicates research by this editor (Robert M. Post) and colleagues that compared bipolar disorder incidence and severity in the US, Germany, and the Netherlands. Other comparisons have been made between the US and Europe. A 2014 article by Frank Bellivier and colleagues in the World Journal of Biological Psychiatry also showed that bipolar disorder onset occurs earlier in the US than in 10 different European countries, while Bruno Etain and colleagues found that bipolar disorder onset occurs earlier in the US than in France in a 2012 article in the Journal of Clinical Psychiatry.
Together this research shows that bipolar disorder is more serious in the US than in a number of European countries. Two-thirds of adults with bipolar disorder report that their illness began in childhood or adolescence. Most of these cases are not properly diagnosed or treated. A concerted effort must be made by the medical establishment and healthcare policymakers in the US to provide better and earlier treatment of bipolar illness.
At the 2015 meeting of the Transcranial Magnetic Stimulation Society, Linda Carpenter, an American researcher who specializes in repeated transcranial magnetic stimulation (rTMS), a method of treating depression by using a magnetic coil placed near the scalp to stimulate neurons, compared notes with Jeff Daskalakis, a Canadian researcher who also studies rTMS.
Carpenter described the limited approval rTMS enjoys in the US. RTMS has been approved by the Federal Drug Administration for the treatment of unipolar depression under very limited parameters (only at a frequency of 10Hz). RTMS has limited availability in the US, and many healthcare companies do not cover it. Providers face scrutiny of study recruitment practices and recordkeeping by insurers and the Joint Commission (formerly the Joint Commission of Accreditation of Healthcare Organizations), which assesses healthcare quality.
In contrast, Daskalakis and his Canadian colleagues can and do use rTMS to treat a broader range of illnesses including bipolar disorder. In Canada rTMS is used to treat unipolar depression, schizophrenia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), and clinicians can adjust the parameters to treat adolescents and the elderly.
The situation in the US is unfair. Because rTMS has not been approved for the treatment of bipolar disorder, Carpenter and other clinicians in the US are unable to treat bipolar depression even though a wide range of experts and published studies report that rTMS is as effective (or possibly even more so) for patients with bipolar depression than for those with unipolar depression.
Few treatments are available for bipolar depression. The discrepancy is even sadder when one considers that there are already more than 20 FDA-approved antidepressants that can be used to treat unipolar depression, but only three approved medications for bipolar depression. Bipolar depression is an orphan illness, which lacks a powerful voice advocating for more treatment research about optimal therapeutic strategies. Read more
At a symposium celebrating the retirement of Willem Nolen, a researcher who spent 40 years studying unipolar and bipolar disorder, from his position at Groningen Hospital in the Netherlands, this editor (Robert Post) discussed progress in the treatment of bipolar disorder over the past 40 years. Despite the availability of lithium; many new mood stabilizers (carbamazepine, valproate, lamotrigine); and many atypical antipsychotics, all of which are anti-manic and some of which are antidepressant (quetiapine and lurasidone), there is still a very high rate of continued illness and treatment resistance, especially in the US.
In fact, research from the Bipolar Collaborative Network, a treatment research network including sites around the US (one run by this editor) and in Germany and the Netherlands, shows that almost everything about bipolar disorder is worse in the US. Americans have more genetic vulnerability because more of their parents have bipolar disorder, and they are more likely to have environmental vulnerability as a result of childhood adversity. Patients in the US also reported having had more stressors at the onset of their illness and more stressors prior to the last episode they had before entering the network at an average age of 40.
Age at illness onset is much lower in the US than in the Netherlands and Germany. About two-thirds of American patients had onset in childhood or adolescence (under 19 years), while only about one-third of the European patients in this study showed these early onsets.
The course of illness is also more difficult in the US. There is more anxiety, substance abuse, and medical comorbidity, and there are more episodes and more rapid cycling. All this resulted in more US patients than European ones who did not respond to naturalistic treatment in our treatment network despite being prescribed multiple medications.
The implication of these data is that we need a new and more concerted approach to bipolar disorder in the US, beginning with early diagnosis and treatment during childhood and adolescence, instead of the 10- to 15-year average delay that was typical about twenty years ago. The duration of the delay to first treatment with a drug to treat mania or depression was an independent predictor of a worse outcome in adulthood. Early intervention should also include therapy and education.
Family-Focused Treatment (FFT), a method pioneered by researchers David Miklowitz and Kiki Chang, has been shown to be much more effective than treatment as usual in children who are at high risk for developing bipolar disorder because they have a family history of the illness and symptoms of an anxiety or depressive disorder or bipolar not otherwise specified (BP-NOS). In this way it may even be possible to head off the full-blown illness before it starts in those children at highest risk.
Our editor Robert M. Post served as discussant at a symposium on special topics in bipolar disorder at the 2013 meeting of the American Psychiatic Association. Here are some of the findings that were presented at the symposium.
Michael Gitlin of the University of California, Los Angeles (UCLA) emphasized the importance of treating patients until remission in order to achieve functional recovery and prevent cognitive impairment.
Michael Bauer of Dresden, Germany reviewed data showing that early onset of the illness and long delays to first treatment are important predictors of poor response to treatment.
Mark Frye of the Mayo Clinic discussed the promise of pharmacogenomics to aid in the selection of the best medicine for a given individual (i.e. personalized medicine). Currently the presence of one of a few relatively rare gene variations—HLA-B 1502 (in Asian populations) and HLA-A 3101 (in European populations)—can predict that an individual may develop a severe rash when taking the anticonvulsant carbamazepine. Researcher J. Rybakowski has found that a somewhat common variant in the gene responsible for producing brain-derived neurotrophic factor (the val-66-met allele for proBDNF) is associated with a good response to lithium. This may be explained by the fact that lithium increases BDNF, and this could be crucial in those with the val-66-met allele, which functions less efficiently than the more common and better functioning allele val-66-val.
David Miklowitz, also of UCLA, reviewed data that strongly indicates psychotherapy is effective in the treatment and prevention of bipolar depression. He and Kiki Chang of Stanford University found that family focused therapy (FFT) was effective in treating early syndromes that sometimes lead to bipolar disorder (including depression, anxiety, or BP-NOS) in children at high risk for bipolar disorder because of a family history that includes bipolar disorder in a first degree relative. Yesterday we shared the 8 key ingredients to family focused therapy.
In his discussion, Post emphasized several points from each presentation. Among these was the recommendation by both Gitlin and Bauer that patients use a personal calendar to monitor symptoms and side effects. (We offer an easy download of a personal calendar.)
Post also endorsed Bauer’s emphasis on the need for early intervention, since delay to first treatment is an independent risk factor for a poor outcome in adulthood. (This finding has been replicated in three studies — Franchini et al. in 1999, Post et al. in 2010, and Drancourt et al. in 2012.
Each of these factors and family focused therapy need greater attention in the US, since Post noted that all aspects of bipolar disorder are more difficult for patients in the US compared to those in Germany, the Netherlands, and many other European countries. About two-thirds of the adults with bipolar disorder in the US had onset of the illness before age 19, while in most European countries, only about one-third of adult patients had an early onset. These data are also consistent with the low incidence of bipolar disorder in children at high risk for the disorder because of a parent with bipolar disorder in studies from the Netherlands, Switzerland, and Germany. In contrast, similar studies of children with at least on parent diagnosed with bipolar disorder in the US (by Chang et al., Nurnberger et al., Wozniak et al., and Birmaher et al.) show a higher incidence of the illness. Canadian studies by Duffy et al. and studies of an isolated Amish community in Pennsylvania by Egeland et al. show a low incidence much like the Europeans.
Given the great need for care of children with signs of bipolar disorder in the US and the shortage of child psychiatrists and pediatricians knowledgeable about bipolar disorder, Post recommended that in the absence of other alternatives, adult psychiatrists of parents with bipolar disorder who have children with the disorder should fill this gap by treating the children themselves. If the child has only early symptoms, family focused therapy as described by Miklowitz above would be recommended.
Tomorrow and Friday we’ll share tables with recommendations for the treatment of parents with bipolar disorder and their children.
In research published since 2008, our Editor-in-Chief Robert M. Post and colleagues in the Bipolar Collaborative Network have compared patients with bipolar disorder in the United States to those in Germany and the Netherlands. Compared to the European sample, patients in the US have more genetic vulnerability to bipolar disorder (by having a parent with bipolar disorder), earlier onsets of their illness, more complicated courses of illness, greater treatment resistance, and more medical comorbidities. Patients in the US also have more psychosocial stress.
The researchers are now turning their attention to these psychosocial vulnerabilities, and in a new paper that will be published in Psychiatry Research (late in 2013 or early in 2014), the authors show that patients in the US had more stressors both in childhood and just prior to the onset of their illness. Childhood stressors analyzed in the study were verbal abuse, physical abuse, and sexual abuse. Stressors in adulthood included indicators of a lack of social support, troubles with finances or employment, lack of access to health care, and medical comorbidities.
The stressors patients experienced just prior to their most recent episode of bipolar illness were related to: stressors in childhood, an earlier age of illness onset, anxiety and substance abuse comorbidity, lower income, both parents having an affective illness such as depression, and feeling more stigma.
The new research suggests that for patients with bipolar disorder in the US, adverse life events in childhood and later in life are more prevalent than they are for patients in the Netherlands or Germany. Earlier and more effective approaches to these stressors, such as the Family-Focused Therapy developed by David Miklowitz and Kiki Chang, could potentially slow the onset or progression of bipolar illness in this country.
Anxiety and Depressive Disorders Often Precede the Onset of Bipolar Disorder in Those At High Risk Due to Family History
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) meeting, Anne Duffy and Gabrielle A. Carlson sponsored a symposium on the association between anxiety and minor mood disorders and subsequent bipolar disorder in those at high risk. Researchers presenting at the symposium consistently found that there is a sequence in which young people at high risk for bipolar disorder develop increasingly severe illnesses: first anxiety, then mood disorders, then bipolar illness.
One difference: the incidence of childhood-onset bipolar disorders in those at high risk because a parent has the disorder was lower in Canada, Switzerland, and the Netherlands than it was in the US.
Duffy, a professor of psychiatry in Calgary, noted that bipolar disorder is highly heritable even though most adults with bipolar illness do not have a family history of bipolar illness among their first-degree relatives. She shared estimates that if one parent has bipolar disorder their offspring have a 5% lifetime risk of developing bipolar disorder. If both parents have bipolar disorder their offspring have a 25% risk of developing bipolar disorder and a 35% incidence of developing any affective disorder (although other data by Lapalme et al. suggest it may be as high as 60%).
Duffy found that when parents responded well to lithium, their children tended to do the same. Lithium-responsive patients tended to be those without anxiety disorder and substance abuse and who had classic bipolar episodes and clear well intervals between episodes. Read more
Epigenetics is a relatively new area of study that examines changes in DNA regulation and structure that can come about as a result of environmental events, as opposed to the genetic inheritance (DNA sequence) people receive through their parents’ genes. Epigenetic effects occur when an environmental stressor or chemical causes methyl or acetyl groups to attach to DNA or to histones (around which DNA are wound). These epigenetic changes determine how difficult it is to turn on genes coded in the DNA (see here for more information about the way the environment produces these epigenetic effects).
After the jump: Several studies presented at the 65th Annual Scientific Convention of the Society of Biological Psychiatry earlier this year suggested a link between environmental stress and both inflammation and abnormalities in DNA.
New research shows that there are more early onsets of illness and more difficult courses of bipolar illness in the US than in the Netherlands or Germany.
This editor was invited to give a plenary presentation at the 4th Biennial Conference of the International Society for Bipolar Disorders in Sao Paulo, Brazil in March. The talk, titled “A greater incidence of early onset bipolar illness and poor prognosis factors in patients in the US compared with those in The Netherlands and Germany,” was based on studies in our Bipolar Collaborative Network.
We found that patients who were studied and treated at four sites in the US (Los Angeles, Dallas, Cincinnati, and Bethesda) had more poor-prognosis factors and indices of difficult courses of bipolar illness compared with patients studied in the same fashion at three sites in Utrecht, the Netherlands and Freiberg and Munich, Germany. We presented some of these data in a preliminary report in the British Journal of Psychiatry in 2008 and further analyzed these data for an article published last year in the Journal of Clinical Psychiatry. Read more
An article by Geller et al. in Bipolar Disorders last year illustrates the crisis in the treatment of childhood-onset bipolar illness in the US. The article indicates that almost 40% of the children with a credible diagnosis of bipolar disorder in this study never received anything near the appropriate treatment for their illness.
It is unfortunate when children fail to receive appropriate treatment because of ambiguity about a diagnosis, but it is even more frustrating when one of the world’s experts makes a diagnosis, and a child still fails to receive treatment based on consensus guidelines.
Over 8 years of follow-up treatment in their communities, these very ill children not only did not receive helpful drugs such as atypical antipsychotics or mood stabilizers, but they often received treatments that can be counterproductive, such as antidepressants or psychomotor stimulants. Those children who did receive appropriate treatment with lithium fared better and recovered significantly earlier than the others. Read more
A poster by Aditya Sharma of Newcastle University and colleagues at the Pediatric Bipolar Conference assessed the incidence of childhood-onset bipolar illness based on monthly letters sent to approximately 750 consultants in child and adolescent psychiatry in the British Isles. Only five confirmed cases were reported, with the youngest child being 11 years old.
EDITOR’S NOTE: These data are of particular interest in relationship to earlier data indicating that childhood-onset bipolar disorder may be relatively rare in some European countries, including the British Isles, France, the Netherlands, and Germany, as well as in Australia, South Korea, and New Zealand.
In contrast, childhood-onset bipolar illness with an onset prior to age 13 appears to be prevalent in the US, with one-fifth to one-quarter of adult outpatients reporting onsets of either depression with dysfunction or mania prior to age 13. Another substantial group of patients report onsets in adolescence, indicating that some 50-66% of bipolar illness in the US begins in either childhood or adolescence.
Similarly higher amounts of childhood-onset bipolar illness are reported in Italy, Turkey, and Norway, indicating some heterogeneity of vulnerability factors and course of illness outcomes among different European countries.