This is a program on the recognition and treatment of bipolar disorders in children and adolescents. My name is Robert Kowatch. I'm a child psychiatrist at Cincinnati Children's Hospital and the University of Cincinnati Medical Center, Cincinnati, Ohio.

Pediatric bipolar topics covered during this talk include diagnosis, differential diagnosis, comorbidity, a short case presentation, and treatment options, including behavioral, mood stabilizers, and atypical antipsychotics.

Age of onset, according to a National Depressive and Manic Depressive Association (NDMDA) survey of approximately 500 subjects: in this survey they asked subjects, "When did you first notice bipolar symptoms; not when you were first diagnosed, but when did you first think you might be bipolar?" As illustrated, in 59% of subjects this was before age 20, with a peak around ages 15 to 19. Unfortunately, the lag to diagnosis was 8 years. So despite the fact that many preadolescents and adolescents had symptoms, it still took them 8 to 10 years to be diagnosed.

Are we seeing a younger age of onset? Previously these disorders were undiagnosed or they were misdiagnosed as borderline child, oppositional-defiant conduct, or schizophrenia. There are also some data emerging from the adult literature that increased rates of substance use can cause younger ages of onset, at least in young adult populations.

A big question in child psychiatry is: what about the use of stimulants? Many times we see children who were exposed to stimulants at a young age (4, 5, or 6 years), appropriately, to treat attention deficit hyperactivity disorder (ADHD). Several years later the stimulants wear off, and they do a lot of mood cycling. We're still not sure if that's a result of being exposed to stimulants or if it's totally coincidental.

Lastly, there's the issue of genetic anticipation. This is a vague genetic mechanism whereby in each generation we may be seeing an earlier age of onset for bipolar disorders. The exact mechanism of this is unknown.

This is from Perlis' data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program. When they asked subjects, "at what age did you first become bipolar," in two thirds of patients, it was before the age of 18. Only in a third was the age of onset greater than age 18. So with these more modern data, we start to see that bipolar disorder emerges before age 18 in many cases.

This is a study from Carter and colleagues of 320 bipolar I and II patients. They reported that those with an onset of first mood episode at less than 18 years of age had more frequent suicide ideations and attempts; more Axis I comorbidity, including substance abuse; and more rapid cycling. They're at approximately twice the risk for rapid cycling. They had an age of onset less than age 18.

The effects of pediatric bipolar disorder are listed here. They include school failure. Many of these patients have undiagnosed learning disabilities that go unrecognized, which cause them to fail or do poorly in school. There are a lot of entanglements with the legal system, particularly in adolescents, as they tend to have comorbid conduct disorder and substance use disorder.

Hypersexuality can be a real problem for adolescent patients, and females tend to get pregnant, mainly when they're in a depressed phase. Low self-esteem leads to many problems. There is a lot of family tension and chaos and impairment; loss of job time for the parents, and frequently divorce because of the stress caused by having and raising a bipolar child.

Many of these patients have poor peer relationships. They're very moody and irritable, and this leads them to be ostracized. And, lastly, they can have increased rates of suicide attempts and completions. Their suicide rate is 3 to 4 times what you'd expect in the normal population.

The prevalence of bipolar disorder in adolescents was defined by Lewinsohn in a 1995 study published in the Journal of the American Academy of Child Psychiatry. This group at the Oregon Research Institute did diagnostic interviews with approximately 1700 high school students aged 14 to 18 years. They found a prevalence of bipolar I, bipolar II, and cyclothymia of approximately 1%. It's important to recognize that this is not a clinical population; it's kind of a pseudoepidemiologic population.

They also found 5.7% with bipolar not otherwise specified (BP NOS) or what they called "core positive." These are patients who didn't have enough symptoms to really qualify for bipolar I, bipolar II, or cyclothymia, but experienced a couple of days of mood symptoms.

In the Lewinsohn study, the distribution of bipolar subjects is shown. You can see 84% really fit into the core positive or BP NOS category, 2% for bipolar I, 10% for bipolar II, and 4% for cyclothymia.

It's important to keep in mind that the majority of subjects you're going to see in clinical practice probably fit into the BP NOS category; 2 percent with bipolar I, who you tend to see mostly on inpatient services, then 10% with bipolar II. Bipolar II is about 5 times more prevalent than bipolar I, particularly in adolescents.

This shows the treatment utilization and suicide attempts from the Lewinsohn study. Illustrated here is the number who received mental health treatment and the number who attempted suicide. It compares the 4 different groups seen in this study: the never mentally ill; the group with bipolar disorder (bipolar I, bipolar II, and cyclothymia); the group with major depressive disorder, which is a comparison group; and the core-positive group. You can see very high rates of bipolar disorder in the received-treatment group (56%) and in the attempted-suicide group (44%). Major depression was seen in about 33% in the received-treatment group and 22% in the attempted-suicide group.

What's important here is that in the core-positive group, 39% had received mental health treatment and 14% had attempted suicide. So, these are very high rates of receiving treatment and attempting suicide for the core-positive group.

Once again from the Lewinsohn data, look at the percentage with impairment across these 3 diagnostic groups. This is based upon the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) social functioning data criteria. There are very high rates of impairment for the bipolar disorder group. The same is not only true for the group with major depressive disorder, but also for the core-positive group; very high rates of impairment -- 48% in social, 54% in family, 53% for school. Despite the fact that children may not fit clearly into the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) categories of bipolar I, II, or cyclothymia, they still may fit in as BP NOS. I think they still need aggressive recognition and treatment to prevent these impairments.

These are data from a study published by Bowring and Kovacs in the Journal of the American Academy of Child Psychiatry in 1992. They identified 4 factors detailing why it is difficult to diagnose bipolar disorders in children and adolescents. These include a low base rate of approximately 1% and variable clinical presentation. Depending on when you see these subjects, they can be either euthymic, manic, depressed, or mixed, which makes it sometimes very difficult to discern what their mood state is.

High comorbidity, or overlap with other disorders, is another factor. We'll talk more about that later, but many of these subjects have comorbid anxiety, ADHD, oppositional-defiant, or other behavior disorders.

Lastly, the effects of development on symptom expression; mania tends to express itself differently in a 6-year-old vs a 12-year-old vs an 18-year-old.

If you look at general mood and you compare, adults and adolescents mainly tend to be euphoric or irritable, but children tend to be mostly irritable. This is seen in multiple studies.

The question is whether or not they have clear episodes: in adults, somewhat; in adolescents, sometimes; in children, no. The episodes tend to be more chronically cycling. You don't tend to see as many clear episodes.

Clear episodes of mania in adults tend to be euphoric; adolescents, mostly irritable; children have rages.

Clear episodes of depression in adults tend to be a dominant feature. In adolescents they tend to also be present. Many times they'll have clear periods of major depression. In children they can also be present, but it's not as clear as many times; they're more of a mixed picture.

What is the prevalence of ADHD? In adults, the prevalence of comorbid ADHD is felt to be less than we see in children and adolescents. It's about 30% to 40% in adolescents. About 60% to 70% of children have comorbid ADHD.

Lastly, lithium responsiveness. Adults are somewhat responsive to lithium. In adolescents, sometimes they'll respond to lithium. In children, this tends to be less so.

Dr. Geller took the standard Kaufman K-SADS and elaborated on the 16 mania items to make them more developmentally appropriate. For example, with grandiosity, adults may give advice on matters about which they have no knowledge. Children might tell the school principal that they could run the school better and could they please do so. This is really pathologic grandiosity. It's not normal. And you see many examples of this in children, but sometimes it's hard to tease out. But it's generally more than you'd expect for a child their age.

Examples of elation from the Washington University (WASH-U) K-SADS: in a normal child, they're going to be super happy on days that they do special things such as going to Disneyland, on Christmas mornings, and during grandparents' visits. The child's joy is generally appropriate to context, and it's not impairing.

This is in contrast to the manic child. Here we have examples of a 7-year-old boy who was repeatedly taken to the principal for clowning and giggling in class when no one else was, and he was suspended from school. He had to leave church with his family for similar behaviors.

Another case is of a 9-year-old girl who continually danced around the house stating, "I'm high, over the mountain high," after suspension from school, showing no insight into the seriousness of her behaviors.

In contrast, the adult manic: a 50-year-old man in the emergency room was infectiously amusing as he described multiple hospitalizations, losing jobs, and losing family ties.

According to the American Psychiatric Association (APA) Practice Guidelines, a dysphoric mania or mixed episode is where you have criteria met for both a manic episode and for a major depressive episode, except for duration; duration for a major depressive episode is generally 2 weeks, whereas this can occur nearly every day during at least a 1-week period.

It occurs in about 40% of bipolar I adults. Symptoms are depressed mood, a lot of irritability and hostility, mood lability, anhedonia, hopelessness and helplessness, suicidal ideation/attempts, guilt, and fatigue. The reason that this is important is many children and adolescents seem to present with mixed or dysphoric mania.

This introduces a study done by Geller, which is the first longitudinal study of children and adolescents with bipolar disorder. This study was published in the Archives of General Psychiatry in May 2004. Dr. Geller followed over 90 subjects. The study reports on 86 subjects, with a mean age of 10.8 years when they were first assessed. They were assessed every 6 months out to 48 months, and they were assessed using the WASH-U K-SADS and evaluated by a research nurse.

Dr. Geller has modified the criteria for mixed mania according to what she sees in these patients. Mixed is mania or hypomania with depression. An episode was defined as the entire length of the illness, because in many of these patients, phenomenology really is different; you don't see clear episodes if a patient has chronic cycling and mood swings every day. So she defined the episode as the entire length of the illness.

Cycling was defined in the study as mood changes during an episode. Ultrarapid is every few days, and will change, going from depression to mania. Ultradian is daily cycling. Many of these patients may have 2 or 3 major mood swings per day. These are not simple temper tantrums. These are very severe mood swings where a patient will be euphoric and happy for a couple of hours and then suddenly switch to being very depressed or irritable.

The phenomenology of the Geller sample is illustrated here. For the intake episode of mania, the mean age of onset was 7.4 years, plus or minus 3.5 years. What this really means is that some of these subjects had the onset of mania when they were 3 years old. This has been found by multiple investigators.

Duration of the intake episode was 3.5 years; ie, they tend to be chronically sick. Eighty-eight percent had mixed or dysphoric mania. The cycling pattern was predominantly ultradian, with 3.5 major mood cycles per day.

None of these subjects fits the DSM-IV criteria for rapid cycling, which is 4 or more mood episodes per year. They're really having daily or weekly cycling.

This once again is from the Geller and colleagues 4-year longitudinal study. Illustrated here are the subjects who recovered after the index episode and the subjects who relapsed after recovery. Eighty-seven percent had recovered by the end of 48 months. But of that 87%, 64% had relapsed after recovery.

What this illustrates is that bipolar disorder tends to be a chronic disorder, and that even though subjects will recover, they then tend to relapse.

Once again, these are data from Geller and colleagues 4-year longitudinal study. Shown here is the survival curve, the proportion of time with mania or hypomania in the subjects with baseline psychosis vs the subjects without baseline psychosis.

Basically, the patients with baseline psychosis did not recover as well as the subjects without baseline psychosis. Psychosis seems to be a marker for severity of the illness.

Clinicians should consider bipolarity in children when they see acute dramatic worsening of apparent ADHD with severe mood swings, or a lack of response or a negative response to stimulants with frequent mood swings. Other symptoms include grandiosity and elated mood; inappropriate sexual behavior; severe mood swings (generally 3 or 4 times per day, lasting more than 3 or 4 hours in total); and a lot of aggressive behavior that's not predatory in nature. Mixed features are predominant with a lot of irritability and belligerence. Euphoria is not as common. Many people in the Geller sample saw mainly euphoria, but you have to remember that that sample is a research sample that was selected out due to elation or grandiosity.

In adolescence, the picture becomes a little bit clearer; markedly labile moods with a lot of mixed features and extreme irritability, and other deterioration in behavior, including grades slipping and social relationships deteriorating.

There is a lot of substance abuse, usually including drugs and alcohol. If the mania progresses, they can get psychotic. Paranoia and a thought disorder emerge, and they may wind up being hospitalized.

The differential diagnosis of pediatric bipolar disorder includes intermittent explosive disorder; fetal alcohol syndromes, including alcohol-related neurodevelopmental disorder; severe ADHD with irritability, pervasive developmental disorders, and psychotic spectrum disorders.

Intermittent explosive disorder in DSM-IV is defined as several discrete episodes of failure to resist aggressive impulses that result in serious assaultive acts or destruction of property. The degree of aggressiveness expressed during the episodes is grossly out of proportion to any precipitating psychosocial stressors.

I think what makes it difficult in children is that the aggressive episodes are not better accounted for by another mental disorder, ie, a manic episode, conduct disorder, or ADHD.

Here we compare the symptoms of IED vs bipolar disorder in children and adolescents. Intermittent explosive disorder has discrete episodes, bipolar disorder not as much. Assaultiveness and destructiveness tend to occur during IED, whereas not during bipolar disorder. Reaction out of proportion to the stimulus occurs in both.

Where you really see the differences are in the mood symptoms. Euphoria and irritability you'll see much more in the bipolar disorder, less so in the IED. Inflated self-esteem and grandiosity are much greater in bipolar disorder, as are decreased need for sleep, more talk/pressured speech, flight of ideas/racing thoughts, distractibility, increased goal-directed activity, and excessive involvement in pleasure activities. Basically what you're going to see is a lot more than mood symptoms in the bipolar disorders as opposed to IED.

The fetal alcohol syndrome occurs following maternal alcohol use during pregnancy. You generally tend to see short stature with growth deficiencies, and permanent brain damage resulting in neurologic abnormalities, delays in development, intellectual impairment, and learning or behavioral disabilities. Many times you'll see abnormal facial features, including a short eye opening, short nose, flat midface, thin upper lip, and small chin.

This shows the faces seen in typical fetal alcohol syndrome. Discriminating features include short palpebral fissures, flat midface, a short nose, indistinct philtrum, and a thin upper lip. Associated features include the presence of epicanthal folds, a low nasal bridge, minor ear abnormalities, and micrognathia, ie, small chin. Many times these children are described as being pixie-faced or funny-looking kids.

Alcohol-related neurodevelopmental disorder is a variant of fetal alcohol syndrome. The full dysmorphia is absent, but there's generally a history of alcohol exposure. They'll show mood and behavior problems; problems in social perception; deficits in higher-level receptive and expressive language (but not as much as you'd see in autism); problems in memory, attention, or judgment (many times they'll also have associated ADHD); many difficulties in school; and poor capacity for abstraction or metacognition.

These children look different than children with bipolar disorder. They'll have some of the mood symptoms, but these kids have a lot more learning and cognition problems than what you would normally see in children with bipolar disorder. So it's very important to get a history if they've been exposed to alcohol in utero because that changes the prognosis and the treatment plan.

Attention deficit hyperactivity disorder is probably the most common comorbid disorder, occurring in 49% of patients with pediatric bipolar disorder. This is followed by conduct or oppositional defiant disorder (ODD) occurring in 30% to 76%, substance use disorders in approximately 40%, and anxiety disorders in approximately 36%.

It is difficult for clinicians to differentiate mania vs ADHD, and the real problem is comorbidity. ADHD is primarily a disorder of attention, not mood, with an onset before 7 years of age. It tends to be persistent, not episodic. The real problem is that many patients with mania--children and adolescents--tend to also have ADHD.

This illustrates a number of studies of mania in both children and adolescents and the incidence of ADHD. What's important here is the mean age vs the percentage of ADHD. In the study by West and colleagues, at a mean age of 15 years, the percentage of subjects who had comorbid ADHD was 57%. Compare this with the Faraone and colleagues study with a mean age of 6 years, where the percentage of ADHD was 93%. Generally in adolescents you'll find about 30% to 40% of subjects have comorbid ADHD. In children less than age 12 years, anywhere from 70% to 90% have a comorbid ADHD.

This is a study done by Geller that was published in 1998. She compared 60 bipolar subjects, mean age of 11 years with comorbid ADHD vs 60 subjects with ADHD, no mood disorder (either bipolar or unipolar), and a mean age of about 10 years. She compared these 2 groups on the WASH-U K-SADS and looked specifically at the 16 mania items.

For the WASH-U K-SADS items, no differences were apparent between the ADHD and the bipolar group. On these 2 items -- hyperenergetic behavior and distractibility (ie, do they run around a lot and are they distractible?) -- there were very high rates, greater than 90% in both groups. You could not tell the difference between these 2 items.

Once again this is from the Geller data. The differences between the bipolar and the ADHD groups are seen in the mood symptoms. The bipolar group has much higher reports of elevated mood, grandiosity, flight of ideas, decreased need for sleep, and hypersexuality.

This is the case of Deckard, a 12-year-old boy. His mother brings him in because of increasing problems with behavior in the last several months at home and in school -- intensifying irritability, dysphoria, and euphoria. He has a history of staying up all night on the Internet, phoning friends, and doing projects; outbursts of rage occur with increasing frequency (3 to 4 times per day); he demonstrates moderate grandiosity, including telling his soccer coach and teachers how to do their jobs; and he shows inappropriate sexual behavior, including kissing and touching peers.

Deckard's personal and family medical history includes anxiety symptoms beginning around age 7 years, with no history of sexual abuse. Family psychiatric history is significant for the biologic mother's history of anxiety and depression. The biologic father had a history of mood swings and substance abuse.

Developmentally, Deckard is a bright and artistic child with good academic performance. His peer relationships have been satisfactory but not excellent.

Based upon interviews with Deckard, his parents' review of school records, and his presentation, he is diagnosed as nonpsychotic, early-onset bipolar disorder. His presentation includes irritability and euphoric moods, and rapid and intrusive speech. He's intrusive, bossy, and flirtatious.

When you view this case, you need to think about whether pharmacotherapy is appropriate; and, if so, which agent should be used -- traditional mood stabilizers (such as lithium, valproate, and carbamazepine) vs atypical antipsychotics, or combinations of these agents?

Nonpharmacological management techniques: pediatric bipolar disorder tends to be a chronic disorder, much like diabetes. And despite the fact that medications are many times used as first-line treatment, it's usually a combined approach that works best.

You have to work with the family along the lines of stress management. They have to understand these children don't do well around exam times, or around Christmas when there's less structure. They don't do well in large areas such as malls.

Sleep hygiene is really important. It's very important that these patients go to bed at the same time, get up at the same time. They generally like to live like farmers.

Their diet is really important. They don't do well with large amounts of caffeine. You have to counsel the adolescents about caffeine and alcohol, and if they start to gain a lot of weight, it can make their moods worse because nobody likes to be fat.

Support groups for these patients are critically important. The Child and Adolescent Bipolar Foundation, which can be found at www.bpkids.org, has a wealth of resources for parents and children and adolescents with bipolar disorder.

There are also 2 books I think are excellent. The first is Raising a Moody Child: How to Cope with Depression and Bipolar Disorder by Mary Fristad and Jill Goldberg Arnold. The second is New Hope for Children and Teens with Bipolar Disorder: Your Friendly, Authoritative Guide to the Latest in Traditional and Complementary Solutions by Dr. Boris Birmaher of Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

School interventions are critical here. Many times the schools just see these children as being bad kids or conduct disorders. The schools need to be educated about the fact that these kids have a mood disorder. These kids need individualized education programs (IEPs). It's important to intervene with the school so they get the correct placement and have their learning disabilities diagnosed.

Psychotherapy is also very important. This is a chronic disorder. Fristad and Miklowitz have done some very nice work recently with both single and multifamily psychoeducational groups. It's important for the families to understand that this is a medical disorder. It's not something that they're causing, but it's something they can make worse if they don't understand it and manage it correctly.

Lastly, mood charting can be very helpful for patients and families. It allows them to see that this is a disorder where there are mood swings. It's a biologic disorder. Also, they can bring these charts in to their physicians and go over how their treatment course has been since they were last seen. An example of these mood charts can be found at www.manicdepressive.org.

This summarizes the extent of knowledge we have in terms of randomized, placebo-controlled trials of mood stabilizers in children and adolescents. We don't have many.

With lithium, there are 2 controlled trials. With valproate, there are none. With carbamazepine (Tegretol) there are none. There are 2 trials with atypical antipsychotics.

We generally tend to break these up into 2 groups: the traditional mood stabilizers and the newer ones. The traditional include lithium, valproate, and carbamazepine. The newer novel antiepileptic agents with mood stabilizer properties include gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide.

A double-blind and placebo-controlled study of lithium for adolescent bipolars with secondary substance dependency was done by Geller and published in 1998. It was the first controlled study we have of lithium. There were 25 subjects with a mean age of 16 years randomized to 6 weeks of either lithium or placebo.

Their mean age of onset of the bipolar disorder was about 10 years. The mean age of onset for substance abuse was about 15 years. So it's a very typical picture of what you'll see; the mood symptoms begin about the ages of 9 or 10 years. Substance abuse occurs about age 14 or 15 years. In the majority of cases, the substance abuse included alcohol and marijuana.

This illustrates the outcome of the Geller and colleagues lithium study. At the end of 6 weeks, the group that was on active treatment had much better urine drug assays as opposed to the group that was on placebo. In this study they found that the addition of lithium decreased the amount of substance abuse.

On the Children's Global Assessment Scale, the 0-to-100 scale, the same pattern emerges. The group that was on lithium had much better improved global assessment of function than the group that was on placebo.

Lithium use in children and adolescents is generally similar to adults. The target dose is 30 mg/kg/day. We'll start our outpatients at a slightly lower dose of 25 mg/kg/day. We shoot for serum levels of roughly 0.9 to 1.1 mEq/L.

It takes a while to have a full onset of action, anywhere from 6 to 8 weeks. Side effects of lithium include weight gain, exacerbation of acne, enuresis, or hypothyroidism. Because of these side effects, it makes it particularly problematic to keep adolescents on this medication because you're giving them medicine that's going to make them fat and give them pimples.

Baseline labs include complete blood count (CBC) with differential analysis, pregnancy test in females, electrocardiogram (EKG), renal and thyroid functions, and calcium levels. Every 6 months you should repeat the thyroid-stimulating hormone (TSH) to check for hypothyroidism, the blood urea nitrogen (BUN), and serum creatinine.

This illustrates the results of an adult study done by Bowden. It was the classic lithium, valproate, and placebo study. This 21-day study was done in adult inpatients. Approximately 50% of the valproate group and 50% of the lithium group got better vs 24% in the placebo group. This means that half the people did not respond to lithium or valproate as monotherapy. The same is true in children and adolescents with bipolar disorder.

An open-label trial of divalproex in children and adolescents with bipolar disorder -- this was a small, multisite study that was led by Wagner at the University of Texas (UT) Medical Branch at Galveston. The patients were a mean age of 12 years and bipolar, manic, mixed, or hypomanic. Their mean Young Mania Rating Scale (YMRS) at randomization was 26.3, which is very high. It was an open-label study; the plan was to stabilize everyone openly on divalproex and then discontinue to either divalproex or placebo once they were stable.

The mean change from baseline on the mania rating scale is illustrated here. At baseline, there were very high scores. The mean change at the end of 56 days was significant. But by the end of the study, only 12 patients remained, which is a problem more with the discontinuation strategy. Once people get better and they're told they're going to be discontinued and placed on placebo at the end of the study, they tend to withdraw from the study.

This illustrates the results of the Wagner and colleagues open-label trial of divalproex that was previously mentioned. Sixty-one percent of subjects saw a greater than 50% improvement on the YMRS. The mean duration of treatment was 33 days. Fifty-eight percent had discontinued the study. About 70% had comorbid diagnosis, including ADHD and anxiety disorders.

A randomized placebo-controlled trial of Adderall (mixed salts of dextroamphetamine) for the symptoms of comorbid ADHD and pediatric bipolar disorder was done by myself and Scheffer at UT Southwestern in Dallas, Texas. It was funded by the Stanley Foundation. Forty bipolar children and adolescents with comorbid ADHD entered a 3-phase treatment study.

During this study there were 3 phases. During the first phase, they were openly treated with valproate for about 8 weeks. Second, they remained on valproate, and they were randomized to 2 weeks of Adderall and then crossed over to placebo. The third phase was a follow-up phase for 12 weeks during which they were followed on a combination of valproate plus Dexedrine (dextroamphetamine).

Phase I open treatment with valproate: there were 40 subjects, mean age of 9.4 years, mostly bipolar I. The mean YMRS score was 29. Eighty-two percent were male.

During this phase they were treated for 8 weeks; 80% responded to valproate in terms of their manic symptoms, 7.5% had a positive ADHD response as well to the valproate (3 out of 40) vs 32 out of 40 who responded to valproate for the mania.

In the phase II, double-blind crossover phase of dextroamphetamine, 31 subjects randomized to receive Adderall and then placebo or vice versa. The mean age was 9.8 years, mostly bipolar I. They remained on valproate. If they had a positive mood response, they entered the crossover phase with 5 mg of Adderall twice daily or placebo.

The group that received the combined valproate plus Dexedrine had a 90% response rate in terms of their ADHD symptoms on the Clinical Global Impression (CGI) scale. This is in comparison to the group that received divalproex plus placebo, which had a 10% response towards their ADHD -- a significant difference between the group that had the combined treatment, valproate plus Dexedrine, vs the group that had valproate plus placebo.

This slide illustrates the change in the YMRS scores throughout this study. At baseline, the very high YMRS scores were approximately 27, while those treated with divalproex had a significant decrease in the YMRS -- a drop to about 10.

What we wanted to illustrate was the group that had the combined divalproex plus Adderall also had a decrease in their YMRS scores that was significant vs when they were on divalproex alone. It seemed like the addition of the Adderall did not actually make their moods worse; in many cases, their moods got better.

There were 23 out of 29 patients who elected to continue on open treatment with a combination of Adderall plus the valproate. Their mean YMRS score was 5.6.

Open consecutive treatment was given for 12 additional weeks. The average dose of the Adderall was 14.5 mg/day. One patient out of 23 had a manic exacerbation while on the combination. When the Adderall was discontinued, the mania resolved. They continued on their valproate.

On the whole what this illustrates is that the combination of a mood stabilizer with this stimulant was safe. It seemed as though we had to stabilize their moods first as many of these patients had been on stimulants before and had not done well. When they were first mood stable on valproate and then Adderall was added, both their mania and ADHD seemed to do very well and respond.

Divalproex sodium use in children: this is a good agent, and we generally target a dose of 20 mg/kg/day. You can start outpatients at a slightly lower dose. We shoot for serum levels of 80 to 120 mg/mL. Generally divalproex works a little bit faster than lithium. We get full responses in about 4 to 6 weeks. Side effects include nausea, sedation, and weight gain.

In terms of laboratory measures, you have to remember to check pregnancy tests in females, CBCs, platelets, and liver function tests (LFTs). Platelets and LFTs should be repeated every 6 months.

Polycystic ovary syndrome (PCOS): the signs and symptoms of PCOS include changes in hair growth (hirsutism), acne, alopecia (hair loss), menstrual abnormalities, obesity, and changes of endocrine measures such as testosterone and follicle-stimulating hormone (FSH). The pathogenesis of this disorder is still unknown. We're not sure if PCOS is related to the weight gain, the hyperinsulinemia that you frequently see following weight gain, hyperandrogenism, or if there is a genetic predisposition.

What's really important is to ask female patients about their menstrual cycle, to chart their height and their weight, and look for changes in hair growth.

This is a difficult disorder to diagnose. It's not diagnosed by ultrasound. It's diagnosed by the endocrine measures. If you suspect this disorder, it's generally best to get endocrine consultation.

There are now 2 controlled adult trials demonstrating efficacy of carbamazepine for adult mania. There's only 1 open study in childhood that suggests that it may be helpful. It does require laboratories: generally get the serum levels about every 6 months of the carbamazepine. Onset of action is generally at about 2 weeks. You target serum levels of 9 to 11 mcg/mL. But there are many cytochrome P450 interactions, which makes this medication difficult to use in children and adolescents because most bipolar patients will end up on 4 or 5 different medications.

This lists the newer antiepileptic drugs with mood stabilizing properties, including gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide. I'll discuss each one of these drugs.

Gabapentin (Neurontin) is a medication that mimics gamma-aminobutyric acid (GABA) in the central nervous system. Psychiatrists really like this medication as patients do not mind it; there are low side effects, and they seem to feel better. The problem was there were 2 controlled adult studies that did not demonstrate efficacy in acute mania. Therefore, it was no better than placebo.

But it may be useful for anxiety. There have been some studies that report success in adults with social anxiety disorder and panic disorder. Unfortunately in younger children below the ages of 10 years, it causes some disinhibition, not infrequently. You can start at 150-300 mg/day. Your target range is 900-2400 mg/day. We've had good luck with this agent as an adjunct to other mood stabilizers, atypicals, in those patients with anxiety disorders -- usually in adolescents.

Lamotrigine (Lamictal) is an agent used in neurology. It blocks voltage-sensitive sodium channels. It's used for seizures. In adult bipolar disorder, there are 2 controlled studies demonstrating efficacy for bipolar depression. It's now indicated for maintenance treatment of bipolar I in adults. There are serious rashes or serum sicknesses that can occur with the use of this agent, so there's a US Food and Drug Administration (FDA) black box warning that says, "Do not use if less than age 16 years."

Lamotrigine rash incidence can be the most common reason for discontinuation. Most rashes are benign and self-limited, but some may progress to a Stevens-Johnson syndrome. The earlier data, from March 1998, showed that in pediatrics, any rash occurred in about 13% of patients vs 11% in adults. Stevens-Johnson syndrome occurred in about 1% of children vs 0.3% in adults. This is about 3 times more common.

But there are later, more modern German registry data for lower dosing that show that the incidence of rash was about 3 in 10,000 in children for Stevens-Johnson syndrome. So the incidence of rash seems to be much lower with the revised dosing schedule.

Revised lamotrigine dosing: this is from the company. It shows, basically, that you want to dose at weeks 1 and 2, 25 mg/day; weeks 3 and 4, 50 mg/day; week 5, 100 mg/day; week 6, the target dose of 200 mg/day. This is in adults. For valproate, you want to go twice as low and twice as slow.

What we found in our adolescent patients is that if you follow this dosing regimen, they seem to do quite well. You also have to remind them not to change any shampoos, lotions, or not to use any other new medications while they're being started on lamotrigine.

Lamotrigine for pediatric bipolar depression or mixed mania: This was a study presented by Saxena of Stanford University, Stanford, California, at the Fall 2004 American Academy of Child Psychiatry meetings. This was an outpatient study with 18 patients with a mean age of 15 years. They're bipolar I, II, NOS. Open lamotrigine was given as monotherapy or as an add-on. This was an 8-week study.

The majority of patients here had bipolar I, 39%; this was followed by bipolar II, 33%; or NOS, 27%. High rates of comorbidity included ADHD and ODD of 66%; anxiety disorders, 50%; and psychosis, 17%.

At baseline, the Child Depression Rating Scale score was 57, which is high and clinically significant. The YMRS score was 16, which indicates hypomania. And overt aggression scales were all very high for aggression, irritability, and suicidality. The mean weight was 161 pounds.

The results in the completed subjects: 1 dropout and 17 completers out of 18, and an 88% response on the Clinical Global Impression of Change (CGI-C) score, which is a very good rate. Responders on the Child Depression Rating Scale were 65%. There were no weight gains or rashes during this study.

This illustrates the Child Depression Rating Scale decrease in scores by week on lamotrigine. It started out at about 57, and decreased down to about 28, which is a significant clinical drop in terms of the depression scores.

Here you can see YMRS scores dropping from about 16 down to about 10, once again, a significant drop.

Topiramate (Topamax)is an antiseizure agent that blocks voltage-gated sodium channels as 1 of its mechanisms. Half-life is about 21 hours. Start at a generally low dose, 25 mg at bedtime or 25 mg twice daily in older adolescents. Unfortunately, the controlled adult studies were negatives. There was 1 adolescent study that was stopped prematurely. So we still don't know if it's better than placebo. The one thing about topiramate is it does suppress appetite, so people tend to lose weight on it. Unfortunately, it does cause some memory problems with word finding difficulty, which can be problematic for children and adolescents who are in school.

Tiagabine (Gabitril) is once again is an agent used for seizures, a selective GABA-reuptake inhibitor. Open adult trials have indicated limited efficacy. Side effects include sedation, fatigue, dizziness, and tremor. These tend to occur at the higher dosages, which were 40-50 mg/day. There are no studies in children with bipolar disorder using this agent to date.

Oxcarbazepine (Trileptal)was the analog of carbamazepine, or the "son" of carbamazepine. It has lower adverse effects than carbamazepine. There are 2 smaller adult studies suggesting efficacy but no controlled studies. Dosing in children/adolescents can start at either 150 or 300 mg/day. The effective range is 900-1800 mg/day. Mean dose is generally about 1200 mg/day.

There have been reports of hyponatremia, mainly in the adults and older adults, with this agent; we've not seen this in children and adolescents. There are no controlled studies with this agent for pediatric mania.

Levetiracetam (Keppra) is also an antiseizure agent that is sometimes used in adult mood disorders. It affects GABAergic transmission. There are no controlled adult studies nor are there any controlled pediatric studies with this agent.

Zonisamide (Zonegran) is another antiseizure agent that affects sodium and T-type calcium channels. It has multiple mechanisms of action. There's 1 open-label study in adults suggesting some effect; 80% of 15 patients had at least moderate improvement. Responders tend to have a lower final dose of about 180 mg/day. The poor responders tend to have a higher dose of 470 mg/day.

It's important to recognize that in adults there are no controlled trials, nor are there any controlled trials of this agent in mania for children or adolescents. There was dose-dependent weight loss in the epilepsy trials.

In all these agents, I think we really need to see the controlled data before we can make any conclusions about their efficacy in child and adolescent mania.

The atypical antipsychotics are probably the biggest boom in psychiatry in the last 10 years. They include Clozaril (clozapine), Risperdal (risperidone), Zyprexa (olanzapine), Seroquel (quetiapine) Geodon (ziprasidone), and Abilify (aripiprazole). They're very powerful, but they do have strong adverse effects as well.

What I'll do now is review the data we have in children and adolescents with bipolar disorders for the use of atypicals. The first study is risperidone treatment for bipolar disorder in children. This is a study by Frazier. It was a retrospective chart review.

There were 28 outpatient children and adolescents with bipolar disorder with a mean age of 10 years, mostly male. Risperidone was added on during the current treatment. The mean dose is 1.7 mg/day. The period of evaluation was across 6 months. The results of the study show that 82% were much improved. Side effects included weight gain, sedation, and some drooling.

This illustrates once again the results from the Frazier and colleagues study. What's important here is to realize that the agent, risperidone, is also effective for mania, psychosis, and aggression. Eighty-two percent were rated as much improved in terms of their aggression ratings. The atypical agents do seem to be very effective for aggression in children and adolescents.

This is a second study by Frazier. This is an open perspective study of olanzapine in 23 children with bipolar disorder, ages 5 to 14 years.

The results showed a 61% response rate, and greater than 30% improvement on the YMRS. The significant side effects were minor except for weight gain with an average of 5 kg across this 8-week study.

This is a study carried out by DelBello and colleagues, published in the Journal of the American Academy of Child Psychiatry in 2002. This is an inpatient study with 30 hospitalized bipolar I adolescents, ages 12 to 18 years. It's a 6-week study in which they were randomized to either divalproex (valproate) plus placebo or divalproex plus quetiapine.

Patients received valproate, 20 mg/kg/day. The mean valproate levels were about 100 mcg/mL in both groups. Quetiapine was titrated from 50 mg/day to 450 mg/day by day 7. The mean dose of quetiapine was 432 mg/day.

This illustrates the difference between the 2 groups. The group that had the combined valproate plus quetiapine was significantly better than the group that had valproate by itself on their YMRS scores. This is at day 42.

There are no serious adverse effects in either group. No patients discontinued due to adverse effects. The most common adverse effects include sedation, nausea, and headaches. No significant change in lab values. The weight change was equivalent in both groups, about 2 to 3 kg. On the whole, the combination of valproate plus quetiapine was very well tolerated and was efficacious.

Aripiprazole is a partial dopamine agonist. It's shown some efficacy for schizophrenia and acute mania in adults. It's now indicated for the treatment of acute mania in adults.

Side effects include nausea, which can be significant. Generally you start this agent at about 2.5 mg/day. It can be given once a day because of its very long half-life. There can be significant cytochrome P450 (CYP450) drug interactions with agents such as fluoxetine, Paxil (paroxetine), or carbamazepine. It may be weight neutral.

This summarizes a number of studies and looks at the overall response rates between lithium, valproate, and atypicals.

Lithium, in the 3 studies listed here, has response rates of 42% to 55%. Valproate -- 4 studies with response rates of 46% to 56%; the atypicals have response rates of anywhere from 62% to 84%.

This illustrates the overall difference in response rates between lithium, valproate, and the atypical antipsychotics. It's important to realize this is based on a limited data set, but the trend we are starting to see is that lithium and valproate have response rates of about 50% as opposed to the atypical agents that have response rates anywhere from 60% to 80%. On the whole, the atypical antipsychotics are more powerful and in some ways easier to use than the traditional mood stabilizers.

Concerns with atypical antipsychotics include metabolic effects (production of type 2 diabetes, hyperlipidemia) and tardive dyskinesia (TD). We still don't know if long-term use of these agents will produce TD.

Hyperprolactinemia is mainly a concern with risperidone. Levels tend to go up, but then they tend to come down to what may not be clinically significant at about 1 year. But we still don't know if this is really true. The levels are slightly above what you'd expect in normal children and adolescents.

Cardiac effects are mainly a concern with ziprasidone, which may produce a prolongation of the QT interval corrected for heart rate (QTc). We are recommending that you get baseline EKGs when you use this agent; these should be repeated when you get to about 3 mg/kg/day, or if you start to see any symptoms.

Sexual dysfunction can occur with some of these agents, and there have been reports of strokes in the elderly. There are no reports of this in children or adolescents.

This was a study published in the American Academy of Child Psychiatry in 2002. It was an Israeli study by Ratzoni and colleagues. There were 50 adolescents with schizophrenia. They compared olanzapine, risperidone, and Haldol (haloperidol) across 12 weeks of prospective treatment. Mean dose of olanzapine was 12 mg/day; risperidone, 3 mg/day; haloperidol, 7 mg/day.

Mean proportional weekly weight change with these 3 agents: illustrated here, the highest rate of weight gain with olanzapine at week 12 was about an 11% mean proportional weight change from baseline, which is a lot of weight to gain. Risperidone was about half that at about 6%, and haloperidol was much lower, at about 1%. On the whole with these agents, particularly with olanzapine and clozapine, the real problem is the massive weight gain that you'll get in some kids.

American Diabetes Association (ADA) consensus on antipsychotic drugs: what this illustrates is the propensity for weight gain, the risk for diabetes, and worsening lipid profile across 6 agents. The highest risk for weight gain is with clozapine and olanzapine. Greatest risk for diabetes is with clozapine and olanzapine. Worsening lipid profile, once again, with clozapine and olanzapine. There's not as much data on aripiprazole or ziprasidone. Risperidone and quetiapine tend to be in the middle.

Illustrated are the recommendations from the ADA and the APA for any patients on atypical agents. This includes children and adolescents. At baseline they recommend a personal family history of obesity, heart disease, or hyperlipidemia; height and weight for calculation of body mass index (BMI); waist circumference measurement; blood pressure; a fasting plasma glucose; and a fasting lipid profile. The height and weight should be repeated every time the patient's seen or at least every 4 weeks. At 12 weeks, they recommend repeating all the laboratory measures, including the fasting plasma glucose and the fasting lipid profile. If you start to see an increase in any of these measures, you should consider switching to a different atypical antipsychotic that may cause less weight gain.

In the treatment of pediatric mania, it's really important to assess any medications that may be making the mania worse, to taper stimulants or antidepressant medications, and to re-evaluate mood and behavior in about a week to determine if these medications were making the moods worse.

If they still have mood symptoms, then in the minority of cases, if it's purely a euphoric picture, you can go ahead and treat with lithium if they have not been on this agent. A majority of patients will require a combination treatment with mood stabilizers such as valproate or lithium and an atypical agent. For those who have partial response, you may need to use 1 or 2 mood stabilizers with an atypical agent.

Once they're stable, you want to reevaluate the ADHD. If they have ADHD symptoms on the Connors' Teacher Rating Scale, for example, treat with low-dose, long-acting stimulants. Generally use Concerta (methylphenidate), Adderall XR (extended-release), or Ritalin LA (extended-release methylphenidate).

Treatment of pediatric mania with psychosis: in this case, the atypical antipsychotics become first line for mixed, euphoric, or mixed/manic/depressed. For those who don't respond, you can use combinations of things such as valproate plus lithium plus an atypical, or lithium plus oxcarbazepine, or sometimes we see efficacy with the use of 2 atypical agents, although there are no data on this combination.

With pediatric bipolar disorder maintenance treatment, it's important to recognize that there are no good controlled maintenance data. There's 1 older, 18-month naturalistic prospective study done by Strober at University of California, Los Angeles (UCLA) with 37 bipolar adolescents who had been inpatients. This study showed that the relapse rate was 3 times higher in those who had discontinued their lithium.

Our general recommendations are to continue mood-stabilizing atypical antipsychotics during the school year and then re-evaluate at the end of school. Generally if patients have had a very rough course and have been hospitalized and/or psychotic, it's probably best to continue on at least with the atypical antipsychotic. If necessary, you can taper the mood stabilizer gradually and see how they respond. If symptoms don't re-emerge, then you can see about tapering other agents. Our clinical experience has been that the majority of patients need these agents at least through young adulthood.

There's only 1 retrospective study, carried out by Biederman at Harvard University, Cambridge, Massachusetts, that looked at the addition of selective serotonin reuptake inhibitors (SSRIs) to the treatment course of patients with bipolar disorder. This is in children and adolescents. It showed that in the short term, the addition of SSRIs seemed to be effective, but over the long term, they have mood-destabilizing effects. We are starting to use more lamotrigine in those patients who require an antidepressant agent. If you go low and slow with this agent, it seems to work very well.

These disorders are often difficult to diagnose and to manage. We don't have any magic bullets, ie, one thing that seems to cure the disorder. We need much more research into the use of both single agents and combination agents, and combination of pharmacotherapy with cognitive behavioral therapy.

Treatment guidelines would be beneficial to the field. There'll be practice parameters that'll be published next year in the Journal of the American Academy of Child Psychiatry. There are also treatment guidelines put together by a consensus group that'll be published in the March 2005 Journal of the American Academy of Child Psychiatry.

The Storm in My Brain is a pamphlet put together by the people at the Child and Adolescent Bipolar Foundation. It's a very nice pamphlet for children that you can download off their Web site and give to patients. It goes over some of the problems of having this disorder in children. This Web site also has a variety of resources for parents. I highly recommend it.