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Bipolar Disorder and Genetics: Beyond Question

By Manuel Mota-Castillo, MD, and Erica Auvil, MSW
Published by Psychiatric Times on Jun 2004

Many well-known researchers and academics have presented a vast array of evidence on the family of pattern of mood disorders. Janice Egeland, PhD, professor of psychiatry and behavioral sciences a University of Miami School of Medicine, has been studying this issue for almost three decades. His research has focused on an Amish community in Pennsylvania, where the closed society clearly displays the genetic trail of mood disorders (Egeland et al., 2003).
Last year, Daniel Christensen, MD, PhD, and his team at Myriad Genetics, Inc., announced the identification of a gene named DEP1 associated with an increased risk for developing depression. Another respected and well-known researcher who writes regularly about the nuances of genetics John Medina, PhD, whose Psychiatric Times column is obligatory reading for many of us.
While outstanding professionals have written books like Genetics and Mental Disorders (Faraone, S.; 1999) to dissect and explain the many aspects of inheritability, the tendency for the comment "like father, like son" to be used in casual conversations about childhood behavior possibly reflects an intuitive understanding in all of us of the genetic roots of character traits.
Most professionals seem to agree on the genetic transmission of bipolar disorder ( BD) (Tkachev, 2003; University of Maryland Medical System, 2002 ), but a search of all published papers on this matter failed to find any report of a cluster of siblings with this diagnosis.
This article cites the cases of six siblings (two sisters and four brothers sharing the same parents) have all been diagnosed with bipolar II disorder, most recent episode mixed, 296.60 in the DSM-I classification--which we are obligated to use for billing purpose despite our preference for the bipolar spectrum disorder, which could be a more accurate label (Cassano et at. , 1999).
We believe that a 100% prevalence of a mood disorder in six full siblings defies the current statist the hereditability of BD. It is generally accepted that if one parent has BD, a child has a 14% risk developing BD; if both parents have BD, the chance of developing the condition increases to 30%.
The children's ages in this report range from 4 to 13. The psychiatric evaluations were conducted for the authors of this report in Florida at the children’s clinic of a nonprofit corporation providing mental health services to a Medicaid population. With the exception of the 4-year-old boy, all the children in this family had their diagnoses corroborated by a high score on the Bipolar Spectrum Diagnostic (BSDS) (Ghaemi et al. , in press). This scale was developed by S. Nassir Ghaemi, MD, and Ronald Pies, MD, and adapted by us for use with children between the ages of 6 and 12. We started the validation protocol in August 2003 and so far, we have applied this instrument to 200 children, including 74 adolescents evaluated with a modified version, but the goal is to apply the two facets of the scale for 300 children and adolescents. This is a self- supported study, as we have not received a grant from pharmaceutical company.

The First Three Children
The index case was a 13-year-old boy who was brought to treatment by his mother, "Leticia," who is also a patient at the adult division of the same corporation caring for her children. She requested services because her son's severe disruptive behavior in school and his aggressive behavior at home concerned her. The children's case manager described Leticia's home as "a battlefield where you can hear the fights from the driveway." Leticia is a polite, psychologically minded person (stable on a combination of lithium (Eskalith, Lithobid) and ziprasidone (Geodon) who wants to contribute to a better understanding of BD by opening her family to any ongoing study on the illness's genetic component. She has also contacted the Juvenile Bipolar Research Foundation to volunteer for a study currently being conducted at the Albert Einstein College of Medicine. Given Leticia's enthusiasm to research into BD, it will be nice to see if a change in a particular chromosomal region can be identical in these children.
Initially, the 13-year-old boy, "Brad," had been diagnosed with attention-deficit/hyperactivity disorder. However, Leticia questioned the diagnosis, asking the doctor, "How come he has ADHD if I am bipolar and half of my family also?"  In response, the psychiatrist suggested a book on ADHD for her to read. In fact, our records reflect that on the maternal side, a sister, grandmother, great-grandmother a great-granduncle were admitted to psychiatric hospitals with "manic-depressive" illness. Two cousins while not corroborated by an independent assessment have been diagnosed with BD. However, it was not the possible relevance of the family history that was propelling Leticia's concerns. Her motivation was a very personal one: She was only 6 years old when a pediatrician diagnosed her with ADHD, anxiety and prescribed methylphenidate (Ritalin) and thioridazine (Mellaril). On the other hand, Leticia has reported that her children's father has severe anger problems and that most of his relatives are also "very angry people." The father has never been diagnosed with any psychiatric disorder, but the pattern of repeated domestic violence, which ended in a bitter divorce, raises the suspicion of a mixed disorder.
When Brad first came to our clinic, the chief complaints were aggressive-defiant behavior and poor performance in school. His mother said, "There is not even one teacher that can stand him." Mental status examination revealed racing thoughts. He said his "brain was going fast, really fast" and he explained that when he took his ADHD medication (a long-acting form of methylphenidate), his mind would go even faster. Falling asleep was difficult, and he was staying up after midnight and giving his mother a hard time when she tried to wake him in the morning for school.
We started him on 25 mg of lamotrigine (Lamictal) every morning and 2.5 mg of olanzapine (Zyprexa) at bedtime. His mother had discontinued methylphenidate 10 days before his evaluation, a decision she made based on her intuition about her son's true diagnosis. (In our clinic, lamotrigine is the mood stabilizer of choice because we have found that it does not cause sedation in school, and blood a serious issue with some children--is not required.)
The following week she brought Brad's 6-year-old brother, "Bobby," and his 11-year-old sister, "Kathy," for evaluation. The mother decided these two should be evaluated next because of the severity of their symptoms: Bobby was pulling out his baby teeth "for fun" and Kathy was showing random aggression at home toward her siblings. Although she was performing very well in school, her aggression was so bad that the children's case manager could not transport more than two of the siblings at a time if Kathy was included.
Bobby ended up removing seven teeth (prematurely) before we controlled his symptoms. On one occasion, he pulled a tooth while the family was at a local supermarket; he told the shocked customer at the store that he wanted money from the tooth fairy. He actually removed additional teeth even though his mother refused to give him any money after the third tooth was pulled out. We suspect that such practice could have psychotic connotations because he showed no pain when removing the teeth with his hands. On another occasion, he was laughing while blood dripped from his mouth.
Bobby's medications were adjusted to include lamotrigine in combination with olanzapine, and he is now been on that regimen for four months. At the time of this report, he is asymptomatic and doing very well in school. In fact, his mother said of her children now active in treatment, "All five of them are on the honor roll."

'A Chicken Without the Head'
Two months after the first child was evaluated, we had only seen three of the six children (appointments were delayed due to family emergencies). The reality of the situation was that the she had received for the other three children. They were each taking one pill per day. She disclosed this information months later when she was expressing her gratitude for having the quietest Chris since she became a mother. We wanted to criticize her decision, but one story kept us quiet: When she took the younger boy (he was 3 years old at that time) to his pediatrician for a regular physic examination, he ran in circles for more than half an hour. "He was like a chicken without the head" Leticia explained. The physician was so impressed by the boy's erratic behavior that he diagnosed with ADHD and wrote a prescription for Focalin, a short-acting form of methylphenidate. That medication, as should be expected, aggravated the boy's hyperactivity and his mother discontinue after a week.
Several symptoms were common to the six children: rapid mood swings with a predominance of irritability, impulsivity, aggression, poor frustration tolerance, insomnia, racing thoughts and disruptive behavior. (We share the belief expressed by many psychiatric researchers that depression in child frequently manifest as angry mood.) Other symptoms were particular to some but not all of the children. For example, anxiety was significant in the 9-year-old boy (a nail-biter) and the 6-year-old girl. The bully of the group was Kathy, the 11-year-old girl. Her mother said that she would hit her siblings for no reason. She also took the longest to calm down after a temper tantrum or an angry outburst. She responded well to medications and, six months into her treatment, her aggressiveness had stopped completely. Leticia said, "My home used to be so loud and crazy that now, with all the well-behaved kids, I have to walk around counting my children to make sure they are in the house." That peaceful dwelling emerged as the six children were put on medications to stabilize their mood along with individual and family therapy. Their medication regimens are listed in the Table 1.



At the end of January, no significant side effects had been reported, and the children spoke about good feelings and happiness with their new found way of interaction--a non-aggressive one. As of March 16, the 9-year-old boy had gained seven pounds. We decided to taper off his risperidone and start quetiapine and to also increase the lamotrigine because he was showing signs of hypomania. We plan to deal with his weight gain by advising better eating habits; if that is not enough, we are considering a trial with ziprasidone.
The children are not completely symptom-free, but their remaining problems are manageable. For example, the 9-year-old boy still bites his fingernails, but he was performing very well in school until his last episode of hypomania.The 7-year-old girl was also found to be in a hypomanic state during her last visit, and the dosages of her two medications were raised to the levels stated earlier to compensate. Her school functioning remains good.
We hope the publication of this peculiar diagnostic cluster will motivate other clinicians who have encountered similar cases to contact the investigators who are working to unveil the genetic basis of the bipolar spectrum disorders. Equally important, the publication of studies of families with simile characteristics to the one discussed here can help solidify the place of BD as one of the illnesses that exhibit a high degree of inheritability.

Dr. Mota-Castillo is a staff psychiatrist for the ACT Corporation in Daytona Beach and Deland, Fla. His practice consists of outpatient treatment of children and adolescents. He also maintains a pediatric Hispanic clinic at Lakeside Alternatives in Orlando.
Ms. Auvil is a clinician for the ACT Corporation in Daytona Beach and Deland, Fla.

References
  1. Cassano GB, Deii'Osso L, FrankE et al. (1999), The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assesmethodology. J Affect Disord 54(3):319-328.
  2. Egeland JA, Shaw JA, Endicott J et al. (2003), Prospective study of prodromal features for bipolarity in well Amish children. J Am A Child Adolesc Psychiatry 42(7):786-796 [see comment].
  3. Faraone SV, Tsuang D, Tsuang MT (1999), Genetics and Mental Disorders: A Guide for Students, Clinicians, and Researchers. NewGuilford.
  4. Ghaemi SN, Miller 0, Berv DA et al. (in press), Sensitivity and specificity of a new bipolar spectrum diagnostic scale. J Affect Disorders
  5. Tkachev D, Mimmack ML, Ryan MM et al. (2003), Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362 (9386):798-805.
  6. University of Maryland Medical System (2002), What causes bipolar disorder? Available at: www.umm.edu/patiented/articles/what_causes_ bipolar_ disorder_000066_3.htm. Accessed April 13, 2004.

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