Bipolar disorder is one of the most difficult illnesses to recognize and diagnose in children because it does not fit precisely the symptom criteria established for adults, and because its symptoms can resemble or co-occur with those of other common childhood-onset psychiatric disorders. Since the bipolar symptoms of inattention, impulsivity, and even hyperactivity overlap with attention deficit hyperactivity disorder (ADHD), there is concern that ADHD is being overdiagnosed and bipolar disorder is being underdiagnosed in children. Experts estimate that one-third of all the children in this country who are being diagnosed with ADHD are actually suffering from early symptoms of bipolar disorder.

Bipolar disorder (also known as manic-depression) is an illness of the brain marked by extreme changes in mood, energy, and behavior (see "Symptoms of Bipolar Disorder"). Until recently, a diagnosis of the disorder was rarely made in children because the illness looks different in children than adults. Children usually have an ongoing, continuous mood disturbance that is a mix of mania and de-pression. This rapid and severe cycling between moods produces chronic irritability and few clear periods of wellness be-tween episodes.

An estimated 1-2% of adults worldwide have bipolar disorder. However, studies are lacking on the exact figures for children. According to the Academy of Child and Adolescent Psychiatry, up to one-third of the 3.4 million children and adolescents with depression in the United States may actually be experiencing the early onset of bipolar disorder.

Evidence is emerging that bipolar disorder beginning in childhood or early adolescence may be a different, possibly more severe form of the illness than older-adolescent and adult-onset bipolar disorder. When the illness begins before or soon after puberty, it is often characterized by a continuous, rapid-cycling, irritable, and mixed symptom state that may co-occur with disruptive behavior disorders, especially ADHD or conduct disorder. In contrast, later adolescent- or adult-onset bipolar disorder tends to begin suddenly, often with a classic manic episode, and to have a more episodic pattern with relatively stable periods between episodes.

The mood of bipolar children is most often irritable and prone to destructive outbursts than to be elated or euphoric as in adults. These youths tend to be inflexible and oppositional and almost all experience periods of explosive rage. These tantrums last for hours at a time with holes getting kicked in walls, and parents, siblings and pets being threatened or hurt. Bipolar children do not often show this rageful side to the outside world and because parents do not wish the outside world to see the child in this light, or to learn of their lack of control over the child, the illness stays behind closed doors as the parents try desperately to find some solutions.

Beyond the oppositionality and extreme irritability, the majority of bipolar children cycle rapidly from depression to mania and back again. Some cycle over a period of days; others seem to alternate mood states several times throughout the day. Because the mood shifts are so rapid, it is easy to see how children may become trapped in the switch process between depression and mania and develop what is called a mixed state. They exhibit marked agitation, high energy, and constant restlessness. At the same time, they feel worthless and self-destructive. While mixed states are not as common in adults unless induced by antidepressant treatment, they are a hallmark of the ultra-rapid cycles found in childhood-onset bipolar disorder.

When depressed, bipolar children may complain of headaches, muscle aches, stomachaches or tiredness. They are frequently absent from school or perform poorly in school. They talk of running away from home and exhibit irritability, unexplained crying, social isolation, poor communication, and extreme sensitivity to rejection or failure. Other manifestations of manic and depressive states may include alcohol or substance abuse and difficulty with relationships. They also have a decreased need for sleep (not insomnia as with adults) and can actually function well on much less sleep than normal. Psychotic symptoms are also extremely common in children and adolescents with mania, which is why they are often misdiagnosed with schizophrenia.

The most common comorbid conditions with child-onset bipolar disorder are ADHD and conduct disorder. (See "What Features Can Help Distinguish Bipolar Disorder from ADHD?). Anxiety disorders, substance abuse, and personality disorders can also occur together. Studies have indicated between 40-90% of children with bipolar disorder also have ADHD, and around 50% have comorbid conduct disorder.¹

Although ADHD and bipolar disorder share several characteristics--hyperactivity, distractibility, irritability, decreased need for sleep, and temper tantrums--there are characteristic differences in the presentation of the two. In children with ADHD, from the time they start walking, they are wearing out the soles of their tennis shoes. With bipolar, the hyperactivity is much more episodic.

Another key to differentiating bipolar illness from ADHD is the child's response to medications. Children with ADHD do not respond to a mood stabilizer, but for children with true bipolar disorder, mood stabilizers are usually wonder drugs. Conversely, a stimulant, which helps patients with ADHD, pushes a bipolar child into in-creased symptoms of mania.

Conduct disorder is a complicated group of behavioral and emotional problems in youngsters. Children and adolescents with this disorder have great difficulty following rules and behaving in a socially acceptable way. Many factors may contribute to a child developing conduct disorder, including brain damage, child abuse, genetic vulnerability, school failure, and traumatic life experience.

Conduct disorder is distinguished from bipolar by a characteristic lack of guilt--children with conduct disorder will do something wrong, but have no remorse, whereas bipolar children often feel guilty, even for no reason. Children with conduct disorder also often feel paranoid, as do children with bipolar illness, but paranoia in children with conduct disorder is not evidence of psychosis because it's justified, they did something wrong, and now someone is out to get them.

Several research studies have found that approximately half of the bipolar group they studied had overlapping mania or hypomanic episodes with conduct disorder. This raises questions whether bipolar and conduct disorder co-occur or are they oppositional behaviors motivated by the mood disorder and expressed mainly during full episodes of mania or hypomania. Dr. Joseph Biederman of Harvard University, a recipient of a NARSAD Distinguished Investigator award in 2002, stated at the 1997 International Conference for Child and Adolescent Psychiatry in Toronto, "There is a group of children whose entire clinical picture of conduct disorder may evaporate if you treat the manic symptoms."

Two main strategies have been used to investigate how bipolar disorder affects the brain: (1) examination of brain tissue after people with bipolar disorder have died and (2) brain imaging in people who have bipolar disorder.

Studies have found several changes in the brains of people with bipolar disorder:

• Decreases in the number and density of glial cells in the prefrontal cortex.
• Decreases in the number of neurons in part of the hippocampus.
• Increases in the levels of some neuropeptides in the hypothalamus.
• White matter hyperintensities: small abnormal areas in the white matter of the brain (especially in the frontal lobe) as seen using magnetic resonance imaging. These abnormalities may be caused by the loss of myelin or axons.
• Decreases in the size of the cerebellum.
• Reduced activity in the prefrontal cortex during the depressive stage.

Strong evidence exists for a genetic component in the susceptibility to develop bipolar disorder. Controversy exits among experts on how to interpret extreme volatility of mood, temper, and behavior in children. The presence of bipolar disorder in other biologically related members of the family is an important element to be considered in formulating a bipolar diagnosis.
(See Chart: "Risk of Developing Bipolar Disorder in Relatives of Bipolar Patient.")

Because many children meet full criteria for both disorders--ADHD and bipolar--some researchers be-lieve the disorders can co-occur. A recent study by Drs. Janet Wozniak, a 1993 NARSAD Young Investigator, and Joseph Biederman found that parents and siblings (first-degree relatives) of manic children not only had increased risk for mania and ADHD but these two conditions occurred together in those same relatives. In their study, they found a 16% rate of bipolar disorder among relatives of bipolar-ADHD cases indicating that co-occurring bipolar-ADHD has a genetic link. Some other researchers speculate that ADHD may be, for many, an early stage on a de-velopmental path that culminates in full-blown bipolar disorder.

Researchers have noted that mood disorders seem to be increasing in incidence among the age group, or cohort, born since 1940, with younger people being affected. Recently, Dr. Raymond DePaulo's (a 1998 NARSAD Distinguished Investigator and a member of NARSAD's Scientific Council) laboratory at Johns Hopkins University reported a ten-year earlier age of onset of bipolar illness in affected children compared with their bipolar parent. This trend was noted in the 1980s by Dr. Gerald Klerman at Yale and by Dr. Elliot Gershon (NARSAD Scientific Council member) and his colleagues at the National Institute of Mental Health. They found that each successive generation of individuals born since World War II appears to have a higher incidence and earlier age of onset of both major depression and bipolar disorder.

Although there is no clear explanation for this so-called cohort effect, genetic researchers have begun to explore the possibility that this increase in disease severity, coupled with a decrease in the age of onset in succeeding generations, may be due to a known inheritance pattern within families called "anticipation." An example of how anticipation works can be found in Huntington's chorea. While there are a variety of patterns within the genes, those genes that mutate and have a successively repeating number of sequences through the generations lead to a progressively earlier and more severe expression of the illness. A small study by Drs. Melvin McInnis (recipient of a NARSAD Young Investigator award in 1992 and Independent Investigator award in 1999) and Raymond DePaulo at Johns Hop-kins University point to the possibility that anticipation may be at play in bipolar disorder.

As molecular genetic studies progress, bipolar disorder is looking more and more like a multiple-gene disorder. It appears to be an illness with at least a single important genetic mutation, modified by other variations in the genetic makeup and greatly influenced by interactions with the environment.

VCFS is a relatively common congenital disorder affecting approximately one in 2,000 to 3,000 children. Children with VCFS suffer a variety of anomalies: nasal speech (usually cleft palate), cardiac problems, learning disabilities, and a characteristic facial appearance that includes a vertically long face, a long nose with a widened nasal bridge, small ears whose uppermost sections are overfolded, long tapering fingers, narrow "squinting" eyes, and a flat facial expression. Drs. Demitri Papolos (recipient of NARSAD's Young Investigator award in 1990 and Independent Investigator award in 1997) and Janice Papolos at Albert Einstein College of Medicine have found that more than 90% of VCFS children over the age of 12 have some form of bipolar disorder. Unraveling the specific effects of the loss of genetic material in VCFS may provide important clues in understanding the genetic basis of childhood-onset bipolar disorder.

Approximately 85% of patients with VCFS have a mutation on the short arm of chromosome 22. The enzyme catechol-O-methyltransferase (COMT) breaks down three important neurotransmitters--norepinephrine, dopamine, and epinephrine--all of which have been implicated in mood disorders for many years. The allele pattern for COMT has 3 variations, depending on the alleles inherited from the parents. "H" can stand for high activity and "L" for low activity. Several studies have found that COMT LL is strongly associated with aggressive and violent behavior as well as adult alcoholism. Noteworthy is that the breakdown of 3 neurotransmitters previously mentioned is associated with two cardinal features of childhood-onset bipolar disorder -- ultra-rapid cycling and aggression --and one comorbid feature of the adult form of bipolar disorder, alcoholism.³

The treatment of children and adolescents is based mainly on experience with adults, since as yet there is very limited data on the efficacy and safety of mood stabilizing medications in youth. The essential treatment in adults involves the use of appropriate doses of mood stabilizers, most typically lithium and/or valproate, which are often very effective for controlling mania and preventing recurrences of manic and depressive episodes.

If possible, a board-certified child psychiatrist who has completed a specialized child psychiatry fellowship program should diagnose and treat a bipolar child. Unfortunately, there is a severe shortage of child psychiatrists, and few have extensive experience treating early-onset bipolar disorder.

Teaching hospitals affiliated with reputable medical schools are often a good place to start looking for an experienced child psychiatrist. A pediatrician is also a good source for a referral. If your community does not have a child psychiatrist with expertise in mood disorders, then look for an adult psychiatrist who has a broad background in mood disorders, and experience in treating children and adolescents.

Other specialists who may be able to help, at least with an initial evaluation, include pediatric neurologists. Neurologists have experience with the anticonvulsant medications often used for treating juvenile bipolar disorder. Pediatricians who consult with a psychopharmacologist can also provide competent care if a child psychiatrist is not available.

Some families take their child to nationally-known doctors at teaching hospitals for diagnosis and stabilization. They then turn to local professionals for medical management of their child's treatment and psychotherapy. The local professionals consult with the expert as needed.

Researchers are investigating light therapy, electroconvulsant therapy, and transcranial magnetic stimulation as possible supplemental treatments for bipolar disorder. Also, nutritional supplements, such as Omega-3 oil (fish oil) are being studied. Some reports caution however, that the herb, St. John's Wort, can trigger mania and, therefore it should not be administered to children (see "Drugs to be Avoided by Children with Bipolar Disorder".)

Continuous treatment has been shown to be more effective than an on-off approach since episodes left untreated will generally worsen and become more frequent. Treatment is complicated because individuals respond differently to various medications, so a trial-and-error approach is used. The following is a brief overview of mood stabilizers and the newer anticonvulsants:

• Lithium: A salt that occurs naturally in the earth. Used for treating manic phase of bipolar disorder with a proven anti-suicidal effect. An estimated 70-80% of adult bipolar patients respond positively to lithium treatment. But patients who have four or more cycles in one year (i.e. rapid cycles) may not do as well on lithium as they do on other mood stabilizers. Since children typically have a rapid-cycling condi-tion, there is a question about lithium's effectiveness in the pediatric population. However, despite the rapid-cycling, some children do have an excellent response to the drug or to its use in combination with another mood stabilizer.

• Valproate (Depakote): Anti-convulsant used for children who have rapid-cycling between mania and depression.
Note: According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who begin taking the medication before age 24. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician.4

• Carbamazepine (Tegretol): Anti-convulsant with anti-manic and anti-aggressive properties, useful in treating frequent rage attacks.

• Gabapentin (Neurontin): Newer anti-convulsant which seems to have fewer side effects than other mood stabilizers, but doctors do not know how effective it is, and some parents report activation of manic symptoms in young children.

• Topiramate (Topamax): Newer anti-convulsant that may control rapid-cycling and mixed bipolar states in patients who have not responded well to valproate or carbamazepine. Unlike other mood stabilizers, it does not cause weight gain but its efficacy in children has not been established.

• Lamotrigine (Lamictal): Newer anti-convulsant that can cause a rare but life-threatening rash.

Although mood stabilizers and anti-convulsants are the mainstay of treatment, there is increasing interest in the newer antipsychotics such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) for use during manic states. These medications can be particularly beneficial when children experience delusions or hallucinations and when rapid control of mania is needed. Some of the newer antipsychotics are very effective in controlling rages and aggression.

Recently, calcium channel blockers have received attention as potential mood stabilizers. Verapamil, nimodipine, and isradipine are being investigated for the treatment of acute mania, ultra-ultra-rapid-cycling, and recurrent depression.