OTTAWA—Patients with ADHD, depression, anxiety disorders, and other psychiatric illnesses have been helped by a wealth of new and effective stimulants, antidepressants, anxiolytics, and antipsychotics in the past two decades. However, such advances in the field of psychopharmacology have also meant more choices for physicians and patients, while creating a fair share of controversy. Jefferson B. Prince, MD, an Instructor in Psychiatry at the Massachusetts General Hospital in Boston, provided an overview on some of these topics at the 33rd National Meeting of the Child Neurology Society.

TREATING ADHD

For clinicians who are treating patients with ADHD, it is important to understand the pharmacodynamics of medications, according to Dr. Prince. Stimulant medications such as methylphenidate increase the release of or block the reabsorption of dopamine and norepinephrine. Amphetamines inhibit the storage of dopamine in vesicles as well as the destruction of dopamine by enzymes. “The effect of that amphetamine and dopamine is that it opens the transporter and more dopamine goes out,” explained Dr. Prince. “Now, this may be better; it may be worse. It may be better in situations with very severe, noncomorbid ADHD. This may be more difficult in situations where you have comorbid ADHD, tic disorders, mood disorders, and anxiety disorders.”

Dopamine systems also seem to decline over time, said Dr. Prince, which is another factor to consider before selecting an ADHD drug. “The amphetamines are actually wonderful antidepressants” in adults, he said. In the pediatric population, however, “they are lousy antidepressants” that can exacerbate depression, manias, etc. “We can use whatever we feel is the most appropriate, based on our own inclination, and based on efficacy. There’s really not a way to distinguish these compounds.... We always want to ask the questions: Are [patients] tolerating it? How much is it helping?”

Atomoxetine, the first nonstimulant to be approved by the FDA for treating ADHD, is also effective, despite the fact that it often takes longer to work, acknowledged Dr. Prince. “We need to really give anywhere from four to 10 weeks to make a judgment about the efficacy of it,” he noted. “I still use stimulants as my first treatment.” He added that he reserves prescribing sertraline, an antidepressant, primarily for children of families who come in and “want that new thing that’s not a stimulant. We always have to meet the families where they are. With a stimulant, we can make a judgment within weeks whether it is tolerated and effective. Use them first, but in stimulant nonresponders, I would use atomoxetine.”

Dr. Prince also advises using atomoxetine for patients who experience adverse effects of stimulants, such as tics and sleep and mood problems. “If there is ADHD plus anxiety, I’d say that atomoxetine has been very helpful for reducing anxiety in children,” he stated. “I have been underwhelmed by its impact in improving mood. The only thing I’ve seen in terms of mood is actually making it worse.”

STIMULANT CONTROVERSIES

One of the biggest concerns regarding stimulants has been reports of growth suppression. For patients who take methylphenidate, data have shown that during the first six months or so weight reduction can occur. “After that it seems to pick up, and it doesn’t seem to be a problem,” noted Dr. Prince. Regarding height, during the first few years, a slowing of growth velocity may also occur. One trial showed that during a two-year course of treatment with OROS methylphenidate, patients experienced a reduction of about 1.5 to 2 cm of growth. “We have to balance this with the benefit of the medication,” asserted Dr. Prince.

The impact on adult height is not clear, though some retrospective data are available. One study followed a group of children between ages 4 and 12 who were treated for a mean period of about three years and were then reexamined when they were in their early 20s. “There is absolutely no difference in their adult height compared to their twin brothers or to those with ADHD who are untreated,” said Dr. Prince. Some investigators have suggested that the growth or maturation phenomenon is part of the condition rather than part of the treatment. “Certainly, we have some patients who are sensitive, and growth is an issue,” he advised. “We consult with our pediatric and endocrinologic colleagues. But in general, we don’t worry about this terribly.”

Dr. Prince also addressed concerns that treatment of ADHD may increase a patient’s risk of developing substance abuse. He cited Wilens et al, who conducted a meta-analysis examining long-term treatment with stimulants in patients with ADHD and found that the impact of pharmacologic treatment of ADHD from childhood through adolescence and early adulthood appeared to reduce the risk of nonnicotinic substance abuse by 50%. “For people with virulent substance abuse, we don’t recommend treating their ADHD through it,” said Dr. Prince. “But if we start early and stay with it, it seems we reduce the risk considerably. This is very important information that should be reassuring to parents.”

Researchers have also been looking for alternative ways to stimulate the frontal cortex, with one possibility being the narcolepsy drug modafinil. There have been mixed results in the adult population and some positive results in the childhood population. “I would say it’s a thing that’s still of interest, but it’s really a minor player in the overall pharmacotherapy of ADHD,” said Dr. Prince. “A number of things are on the horizon. There are some cholinergic medications that are being looked at. There are longer-acting forms of alpha-adrenergic agents that are being looked at. There are other formulations of stimulants.”

ANXIETY DISORDERS

A number of medications, including clomipramine, fluvoxamine, sertraline, and fluoxetine, have been approved for treating obsessive-compulsive disorder (OCD) in children in various age-groups. In addition, studies have shown that selective serotonin reuptake inhibitors (SSRIs), over the short, medium, and long term, are quite helpful in reducing symptoms for OCD and seem to be well tolerated, according to Dr. Prince. “The response rate over time is about 50%, and it seems to get better if we enhance it with cognitive behavioral therapy,” he stated. “The medicines reduce the symptoms, and the behavioral therapy helps people learn how to cope with this. When we look at dosing in these studies, we can see that the range of dosing is very wide. With these patients, it is very important to start low and go slowly.”

Initial results from the Pediatric OCD Treatment Study (POTS), a five-year treatment outcome trial, have shown that sertraline had a very robust effect size, as did cognitive behavioral therapy, both in the short term. “However, the combination of both cognitive behavioral therapy and sertraline did much better than either one alone,” Dr. Prince pointed out. “This is really the model we have for OCD and one I would suggest is probably going to be adopted for depression.”

DEPRESSION AND SUICIDE

Treating patients with depression can be particularly difficult, because by the time most patients finally visit a physician, they are already far down the clinical path. A review of randomized controlled trials in pediatric depression shows that there have been seven positive trials on SSRIs and a number of negative trials as well. “Tricyclic antidepressants have been very thoroughly studied in children and in adolescents,” stated Dr. Prince. “They are not helpful, or they do not appear to be helpful for pediatric depression, so we have mixed data.” Results from the Treatment of Adolescents with Depression Study (TADS) earlier this year found that the combination of fluoxetine with cognitive behavioral therapy offered the most favorable trade-off between benefit and risk for adolescents with major depressive disorder.

Suicide is the third-leading cause of death in the 15- to 24-year-old age-group, with more incidents than for cancer, heart disease, congenital anomalies, stroke, influenza, and blood poisoning combined. The rate of suicide in adolescents in the United States, from the 1950s to the late 1980s, increased by about 300-fold. “No one understands that,” Dr. Prince said. Since the late 1980s, however, it has reduced by about 30%. “I would make an argument that the other thing that happened in 1988 is that fluoxetine became available in the US. If we look at teens who complete suicide, the most likely thing that they have is depression. It is usually depression that is associated with conduct problems, breaking the law, and substance abuse, as well as anxiety. The teenagers who are most likely to kill themselves are white males, more so than nonwhite males, who had a recent breakup or humiliation, who have a lack of support, and access to a firearm. That is the highest risk group. Bipolar adolescents are probably a somewhat higher risk than just single depression. Also if there is psychosis, that could be a risk factor.”

Researchers who examined suicidality in depressed teens at the time of evaluation found that 60% of this group reported suicidal ideation, and 30% reported a suicide attempt. In addition, when asked if they had thought of killing themselves in the past six months, almost 20% of US high school students between ages 15 and 19 had, and nearly 9% actually had made an attempt. “The attempts are self-defining,” said Dr. Prince. “It could be taking four Tylenol instead of two. It’s what they thought was an attempt to take their lives. Almost 3% present for medical attention; fortunately, it drops off from medical attention to actually completed suicides. Obviously, suicides are devastating events for primarily the family but also for those of us trying to take care of these kids.”

ORIGINS OF CONTROVERSY

In 2003, the Medicines and Healthcare Products Regulatory Agency—the British equivalent of the FDA—advised physicians in the United Kingdom not to prescribe paroxetine, venlafaxine, sertraline, citalopram, escitalopram, or fluvoxamine for children. Data from nine trials found that mood swings, crying spells, suicidal thoughts, and potentially suicidal behaviors occurred twice as often in children randomized to paroxetine compared with those randomized to placebo, although no patient in the studies completed suicide. “The British interpreted the results of the trials to indicate that the medications were not efficacious,” said Dr. Prince. “In Britain now, you are allowed to prescribe fluoxetine, but it is said that it will only work 10% of the time.” The FDA subsequently looked at these data, and ultimately in October of this year, it advised that there did appear to be an increased risk of suicidality, suicidal ideation, and suicidal gestures in pediatric patients and thus required a warning in the form of a black box on the labels of all antidepressants.

“If we look at it from a different perspective, using data from Texas for Medicaid prescriptions from 1999 to 2000, we find that the rate of SSRI prescription in the adolescent population increased almost sevenfold,” said Dr. Prince. “Then, using Centers for Disease Control data in the same geography, looking at the rate of completed suicide, they found that the rate of completed suicide had gone down from 6.51 per 100,000 to 6 per 100,000, which was highly statistically significant, because they had such high power. The reassuring thing for us as clinicians is that in this research group it did not go up and may have gone down, in fact. As we move from research to clinical practice, frankly, the mother of Hubert doesn’t care about the group, she cares about Hubert. And that’s what we always have to recognize and appreciate.”

Dr. Prince believes these medicines are “extraordinarily helpful” to most people. “However,” he cautioned, “they are powerful medicines. They should be treated by us with respect. Although they agree with most people, they don’t agree with everyone. We need to help families understand that.... We need to recognize that if we give antidepressants to a depressed kid, it appears that out of a hundred kids we give it to, two or three of them may experience, at the beginning of treatment or with dose changes, increases in suicidal thinking. The important thing is that families are aware of this, they know how to recognize it, and we know what to do when and if it happens. If we do this, we can then feel very good about treating the other 97 or 98 out of a hundred who really derive significant benefit from these medicines. That’s really the position I would advocate for us as clinicians.”

CHOOSING AN ANTIDEPRESSANT

Thus far, fluoxetine is the only drug that is FDA-approved for pediatric depression. When deciding which antidepressant to prescribe, clinicians should consider the fact that some medicines have a longer half-life than others, noted Dr. Prince. Fluoxetine has a very long half-life, he pointed out; on the other hand, venlafaxine has the shortest half-life, followed closely by paroxetine. Possible substance abuse should also be assessed. “We want to get informed consent, have good documentation, start low and go slowly, and educate the family,” he said. “When we start medications, I will often use a medium-acting medication. I also have to think about drug interactions, and a number of them have very potent interactions.... We try to maintain people for six to 12 months, and once we get them to a remission, if it’s a first episode, after six to 12 months, I’ll try to taper slowly. If someone has been on a medicine for a year, I’ll take three months to taper it. If this is a second, third, or fourth episode of depression, I may keep it in place for much longer. If it was a second episode and it was severe depression, I may treat for two years. I have people who are out now seven or eight years treated.”

ANTIPSYCHOTICS

Psychosis can occur in a variety of different conditions in the pediatric population, not only with affective illness but in the posttraumatic stress disorder/pervasive developmental disorder spectrum and with substance abuse as well. The Treatment for Adolescent Psychosis Study was recently undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population, in comparison with haloperidol. The authors found that risperidone and olanzapine acutely reduced psychotic symptoms in this pediatric sample and that the magnitude of the antipsychotic response with these atypical agents was comparable to that observed with haloperidol. However, children treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appeared more prevalent and severe than reported in adults. “In many respects, although olanzapine is a very effective medication, the side effects have really curtailed its use in our population,” said Dr. Prince.

In general, when prescribing psychotic drugs for patients, dosing varies widely, Dr. Prince noted. “I have a number of patients, particularly those who are not psychotic but who have resistant depressions, tic disorders, and aggressive conduct disorders, who actually do very well on low doses of these medications,” he said. “I would encourage you to check out the low doses of these medicines on your patients. We often miss things [because] we began too aggressively when we started using these to treat schizophrenia. For affective disorders, [patients] often do very well on lower doses, particularly the pervasive developmental disorder population.... If there are side effects, we always want to think about reducing the dose. We may need to think about changing the timing of the dose.... I monitor height, weight, glucose, and lipid profile in patients on long-term treatment. Consider checking an EKG, and I inquire about family history of diabetes and arrhythmias. What we are left with is doing what we can, with what we have, where we are.”

—Colby Stong

Suggested Reading
March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820.
Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;292:1969-1976.
Sikich L, Hamer RM, Bashford RA, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology. 2004;29:133-145.
Wilens T, Pelham W, Stein M, et al. ADHD treatment with once-daily OROS methylphenidate: interim 12-month results from a long-term open-label study. J Am Acad Child Adolesc Psychiatry. 2003;42:424-433.

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