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analysis
EMBO reports 4, 11, 1022–1024 (2003)
doi:10.1038/sj.embor.7400022


Analyse this

Many psychiatrists claim that children are undertreated for depression and ADHD, but critics charge abuse

Vicki Brower
This June, the UK government warned physicians in the UK against prescribing the anti-depressant drug Paxil® (Seroxat®; GlaxoSmithKline, Uxbridge, UK) to children under 18. The Committee on the Safety of Medicines (CSM), the UK's regulatory body, reacted to several reports of suicides and suicidal thoughts by adolescents taking the drug to treat depression. Immediately after the CSM's warning, GlaxoSmithKline also sent letters to healthcare professionals in the UK to warn about both withdrawal symptoms and the suicide risk for children. These events triggered renewed concerns in the USA about the safety of using anti-depressant drugs in children and adolescents. In July, the Connecticut Department of Children and Families (DCF) removed Paxil from the DCF Psychotropic Medication Formulary for six months and urged physicians to reassess the risks and benefits of the medication. New York Senator Charles E. Schumer sent a letter to Mark McClellan, Commissioner of the US Food and Drug Administration (FDA), asking him to investigate the adverse effects of the drug and to put a hold on GlaxoSmithKline's request to sell Paxil for children's use pending the outcome of the study. The FDA also began to review the side effects of Paxil and other anti-depressants and stated in September that it found a threefold higher rate of suicidal ideation—suicide-related thoughts—compared with a placebo. More recently, the CSM recommended on 19 September not to prescribe Wyeth-Ayerst's (Madison, NJ, USA) anti-depressant Effexor® to children under the age of 18. Indeed, the company had already sent warning letters to physicians in the USA before the CSM's warnings, stating that Effexor might cause suicidal thoughts in children.

This flurry of investigations and warning letters and the resultant press coverage have provided new ammunition for critics who have sounded alarms over the use of anti-depressant drugs in children and charged that they are being over-medicated with drugs that can cause serious side effects. Vociferous critics, such as Peter Breggin, author of Talking Back to Prozac (St Martin's, New York, NY, USA), has warned Congress and others of the dangerous side effects—suicide and violence, the potential for abuse and addiction, and "the capacity of these drugs to drastically and permanently change brain chemistry." Others, such as neurologist Fred Baughman, in private practice (El Cajon, CA, USA), assert that diagnoses of attention deficit hyperactivity disorder (ADHD) are "fraudulent" and that drug companies are pushing the unnecessary use of drugs in children to fill their coffers. Indeed, since selective serotonin re-uptake inhibitors (SSRIs), such as Prozac® (Ely Lilly & Co., Indianapolis, IN, USA), Effexor, Paxil, Luvox® (Solvay S.A., Brussels, Belgium) and Zoloft® (Pfizer Inc., New York, NY, USA) began to replace older tricyclics for treating depression 10 years ago, their prescriptions have skyrocketed, particularly in the USA, where about five times more prescriptions are filled than in Europe. Although only Prozac is approved by the FDA for use in children and adolescents, other SSRIs are being tested for paediatric use. In the meantime, physicians often prescribe them for 'off-label' use in children, partly on the basis of published clinical trials. The CSM found that there are an estimated 8,000 children under the age of 18 taking Paxil in the UK.

Since selective serotonin re-uptake inhibitors [...] began to replace older tricyclics for treating depression ten years ago, their prescriptions have skyrocketed...


But the real risks of these drugs remain unclear. "It's not a clean debate," said John Walkup, Associate Professor of Psychiatry and Behavioral Science at Johns Hopkins University (Baltimore, MD, USA). "There are lots of stakeholders—drug companies, parents, those with an anti-drug bent and kids—in the mix." Disagreeing that drug companies are 'pushing' drugs on children, Walkup said that the discussion has been poorly framed, which has resulted in fewer children and teens receiving necessary treatment. He noted that only a decade ago there was virtually no testing of drugs in children. "The exact percentages change depending on the specific analysis performed, namely adolescents versus children, suicide attempts versus other suicide-related events, data from controlled trials versus data from up to 30 days after the end of trials, etc.," according to Crystal Rice, a spokesperson for the FDA Center for Drug Evaluation and Research (CDER, Rockville, MD, USA).

Critics argue that the scientific side of the debate does not provide a clear picture either. According to the FDA, "three well-controlled clinical trials carried out in children (under 18) with major depressive disorder ... found that Paxil did not work any better than placebo." But another study with Zoloft showed that the drug had more efficacy and decreased the rate of suicidal thoughts in adolescents when compared with placebo (Wagner et al., 2003). The public was left to speculate even more when it emerged that Paxil's manufacturer had not disclosed all clinical trial results to the FDA, some of which indicated negative side effects. "The higher incidence of suicide ideation in adolescents on Paxil versus placebo in one trial was leaked to the public from an unpublished study," observed Richard Friedman, director of the psychopharmacology clinic at Weill Medical College, Cornell University (New York, NY, USA). "I am amazed that the company tried to hide it by not publishing the study, and I am amazed that the FDA didn't pick up on it." Companies should therefore not be able to choose the studies submitted to the FDA, he maintains, because "when potentially bad news about a drug is leaked from an unpublished study, the public is left to speculate about the true risks of a drug." Paxil's manufacturer did not respond to requests for comment.



In the view of supporters, however, this does not diminish the usefulness of Paxil and other SSRIs for treating various mental disorders. Child psychiatrist Harold Koplewicz, founder and director of the New York University (NYU) Child Study Center (NY, USA), observed that, before the development of SSRIs, there were no effective drugs to treat adolescent depression. And, he added, over the past decade, suicide among white male adolescents has dropped steeply. "Until the late 1980s and the advent of the SSRIs, placebo was as effective as the older tricyclics, and in some cases, more effective," he said. Walkup and Koplewicz also stressed that one of the main risk factors in depression itself is suicidal thoughts and action, and that depressed patients—whether treated with drugs or not—always have some risk of suicide, and therefore must be monitored carefully. "Doctors always try to sort out if a patient's reaction to a drug is related to the drug or not," said Walkup. But it is difficult to determine whether suicidal thoughts are a result of a drug or the depression, unless the patient is in a placebo-controlled trial.

Furthermore, the problems of depression and ADHD in young children have grown to "epidemic proportions," according to Koplewicz and others. Both conditions are huge public-health problems with serious, life-altering consequences if left untreated, they maintain. According to the US National Institute of Mental Health (NIMH; Bethesda, MD, USA), anywhere between 2.5% and 8.3% of adolescents in the USA suffer from depression, with girls exceeding boys by about 2:1 at the age of 14 years. As many as 7% of adolescents with major depression commit suicide, which is the third leading cause of death among 10–24-year-olds, and this results in 2,000–3,000 suicides each year in the USA alone. "Although it used to be thought that depression didn't occur in children and adolescents, it turns out that it's actually quite common. About one in 20 kids will have a major depressive episode," said John March, Chief of Child and Adolescent Psychiatry at Duke University Medical Center (Durham, NC, USA). Apart from the suicide risk, untreated adolescent depression can lead to academic and social fallout and might contribute to future episodes and the severity of depression, said Koplewicz. Scientific data also show that depression can modify brain structures and result in fewer viable neurons, whereas treatment with anti-depressants might actually further neuron production (Santarelli et al., 2003) and protect the hippocampus, which is involved in memory and learning and is often damaged by depression (Sheline et al., 2003).

The NIMH also estimates that 3.0–7.5% of school-age children are affected by ADHD, or about 1 or 2 in every classroom. Characterized by inattention, hyperactivity and impulsivity, ADHD is associated with impaired academic functioning, antisocial conduct, substance abuse, higher rates of arrest by the police and other social problems. Koplewicz pointed out that although in the USA fivefold more children are diagnosed with ADHD than in Europe, the country also has a higher rate of high-school graduation than in Europe, where children are less likely to be tested for ADHD and where stimulants such as Ritalin® (Novartis International AG, Basel, Switzerland) and Adderall® (Shire US Inc., Newport, KY, USA) are less often used to treat them.

As many as 7% of adolescents with major depression commit suicide, which is the third leading cause of death among 10–24-year-olds, and this results in 2,000–3,000 suicides each year in the USA alone


For depression, there is still no hard evidence for whether medication or psychotherapy or a combination of both is the most effective treatment. This must await the results of the ongoing Treatment for Adolescents with Depression (TADS) study to determine which treatment(s) are best (TADS Study Team, 2003). TADS began in 1998 and should help to pin down the answer, according to Christopher Kratochovil, associate professor of psychiatry at the University of Nebraska (Omaha, NE, USA). But there is no question among traditional mental health professionals that drug treatment is effective with ADHD. A 600-child NIMH-sponsored study, published in December 1999, showed that long-term treatment with either medication alone or medication and therapy was significantly more effective in reducing ADHD symptoms than behavioural treatments. Most child psychiatrists in the USA now think that not treating ADHD carries far more dangers than the side effects of drug treatment. For the 20–30% of children who do not respond to stimulants, a new, non-stimulant drug, Strattera® (Eli Lilly and Company) might be beneficial, because it works on noradrenaline (norepinephrine) rather than dopamine—two neurotransmitters that are important in regulating attention, impulsivity and activity levels.

Although rates of ADHD and treatment have soared in the past decade, some psychiatrists and psychologists are concerned that many children still remain undiagnosed or improperly diagnosed and put on drug therapy. Opponents, such as Breggin, see the marked increase in rates as an example of over-medication, whereas proponents, including Koplewicz, see it as a combination of both, too much and too little—some are incorrectly diagnosed with ADHD and many are not diagnosed at all. Indeed, opponents believe that the problem with depressed and hyperactive children lies with the schools, parents and the drug companies. According to Breggin,

Part of the problem, therefore, is to take mental disorders as seriously as, say, an infectious disease and remove the social stigma for those children who need medication
"children become diagnosed with ADHD when they are in conflict with the expectations or demands of parents and/or teachers. ... The ADHD diagnosis is simply a list of behaviours that most commonly cause conflict or disturbance in the classroom, especially those that require a high degree of conformity." Instead of examining the child's life, the problem is attributed to the child's "faulty brain," he said, and "both the classroom and the family are exempt from criticism." Breggin calls medicating children with anti-depressants "a coercive response to conflict in which the weakest member of the conflict, the child, is drugged into a more compliant or submissive state." However, in the view of supporters, the scientific picture is clear: diagnoses of ADHD and depression are real and require treatment. Scientists such as Xavier Castellanos, Director of the Institute for Neuroscience at the NYU Child Study Center and formerly at the NIH, point to studies from the NIH and other US researchers that have documented changes in the brains of children with ADHD in particular. And stimulants, such as Ritalin, can activate certain 'sluggish' brain areas in part by allowing dopamine to be better utilized, which allows children to slow down and focus.

Although there is no consensus yet on what causes ADHD and depression and how children can overcome it, most acknowledge that there is an understandable bias against categorizing children with mental disorders—which might work towards an under-diagnosis of children with depression or ADHD. "Kids shouldn't be sick, they should be healthy and happy, that's the way we all think," said Koplewicz. But "the 'pull yourself together' or 'kindness first' approach misses the point: that someone who has a real neurochemical imbalance in the brain needs effective treatment, not a pep talk." Part of the problem, therefore, is to take mental disorders as seriously as, say, an infectious disease and remove the social stigma for those children who need medication. "If you give a child penicillin, you're giving him 'medication'," Koplewicz said, "but if you give a child Ritalin you're giving him 'drugs'."

References

Santarelli, L. et al. ( 2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805−809. | Article | PubMed  | ISI | ChemPort |

Sheline, Y.I., Gado, M.H. & Kraemer, H.C. ( 2003) Untreated depression and hippocampal volume loss. Am. J. Psychiatry, 160, 1516−1518. | Article | PubMed  | ISI |

Treatment for Adolescents with Depression Study Team ( 2003) Treatment for Adolescents With Depression Study (TADS): rationale, design, and methods. J. Am. Acad. Child Adolesc. Psychiatry, 42, 531−542. | ISI |

Wagner, K.D., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M.S., Childress, A., Donnelly, C. & Deas, D. (Sertraline Pediatric Depression Study Group) ( 2003) Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. J. Am. Med. Assoc. 290, 1033−1041. | Article | ISI | ChemPort |
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