Primum non nocere ("First, do no harm"), one of the oldest principles of medical ethics, is the plea that medical interventions should not do damage to patients. Novel interventions are often associated with burgeoning hope in severely affected patient groups. Pharmaceutical marketing adds to this general expectancy and therefore many parents and children are prepared to take the risk of new interventions in order to gain relief from a serious and chronic condition. Patients as well as parents in controlled clinical trials usually say that despite the increased risks, if they had the choice they would prefer to be in the drug arm compared to the placebo arm of the study. Harm avoidance and risk reduction does not seem to be the first aim of either doctors or patients. From an ethical point of view, as long as the effects of a certain intervention are not well established by sound scientific studies, the first consideration should not be whether it works but whether it harms. It has only been possible to discuss some of the substance classes currently used in child psychopharmacology here. With respect to all inter ventions mentioned in this chapter, there remain open questions of drug safety. Stimulants, for example, have now been used for more than half a century, but fundamental questions of preclinical mechanisms and long-term safety remain unanswered and even unasked. This demonstrates that once a drug is widely accepted due to its high efficacy in short-term trials, long-term safety questions in general will not be addressed because there are no research sponsors interested in long-term safety studies and a correspondingly low public interest in these questions. It is only in the last few years that long-term safety has become a political issue and some funding has been provided to create clinical networks for pharmacovigilance and pharmacoepidemiological procedures, in order to establish and monitor safety in everyday practice. The standard voluntary reporting systems currently in place are not reliable because they depend on the patients' and doctors' willingness to report side effects, and are skewed by a tendency to report exotic rather than common side effects. Furthermore, patients often have no access to side effect reporting systems whilst doctors often shy away from reporting because this is associated with considerable paperwork. When the FDA invited The Paediatric Expert Panel in summer 2005 to comment on possible serious side effects like hallucinations and cardiac side effects of stimulant treatment, the only indications the agency could refer to were sporadic spontaneous reports. There is no way of quantifying the relationship between these spontaneous reports and the prescriptions, so relative risk cannot be calculated, and the magnitude of the serious side effects of a widely-used drug remains unknown. This is an example of how interventions that could have an impact on the developing organism and the maturating brain need careful long-term follow up, and not only of patients in clinical trials.
There are inherent problems associated with extrapolating interventional trial study results to the clinical setting. Study patients are usually a highly select population with lower co-morbidity and profiles of symptomatology that are easier to treat as compared to clinic patients. Co-morbidity and co-medication are much more frequent in real life situations than in trials. That leads to a general underestimation of risks due to the combination of different interventions. Research programmes are usually targeted at the detection of an effective intervention, while documenting possible risks at the same time. This has nothing to do with safety in clinic situations, where patients are treated for months or even years not only with one drug, but with combinations of drugs or different drugs in turn. These patients are not usually followed up. This lack of studies leads to ever more debates on the safety of stimulant treatments, often sponsored by lobby groups like the Scientologists who have vested interests, and many obscure theories have even found their way into scientific journals, causing additional harm and anxiety to families and patients. Only the scientific investigation of the long-term consequences of a medical intervention in the maturating brain, not only in ani mal models but in real life situations, can answer these questions and provide a reliable evidence base for treatment decisions. In contrast, the current discussions of evidence based treatments centre on pharmaco-economic considerations with respect to effectiveness rather than to safety and not at all on long-term safety. It is clear that the industry has no direct motivation for studying the long-term safety of their compounds (Vitiello et al. 2004), particularly if they are being widely used. When drugs manufactured by different patent holders are combined, there are no commercial sponsors willing to study the consequences of the combinations. It is clear that the state or health insurance systems must sponsor research in this field in order to protect patients from risks of novel interventions. Another question that is related to the potential harm of stimulants is the question of whether the burden of illness justifies any pharmacological intervention. Comparing the diagnostic manuals in the United States and the rest of the world (DSM-IV vs. ICD-10) one can easily see that the American criteria allow for the inclusion of many more children under the diagnosis of ADHD than the much stricter ICD-10 criteria. Santosh applied an ICD-10 diagnostic algorithm to the well-known MTA sample and found that only about a third of the patients fulfilled ICD-10 criteria. In this subgroup with more clearcut symptoms, the effects of medication were even more convincing than in the DSM-IV sample. So we can ask the question whether early intervention with a drug is justified in the mild cases. This question is particularly pertinent to treatment in the very young. In Europe the stimulant treatment of preschoolers is still rare. In contrast, Zito and Safer (2005) showed that in the United States a considerable proportion of children in the preschool age range is treated with stimulants, and there are even children under the age of 3 treated for ADHD. There must be concern with respect to long-term consequences because these interventions in preschoolers occur in a phase of massive brain development. All the animal literature leads us to suspect long lasting effects of these interventions. This must not mean that these interventions will be harmful; it is conceivable that they are even curative at this age whilst they can induce only symptomatic changes in older children. However, who studies this question, and is it ethically permissible to conduct prospective trials on this in humans? In any case, in the interests of safety, we should follow up the children treated very early with stimulants as a naturalistic study of a high risk cohort.
Turning to SSRIs, the SSRI debate demonstrates that medications generally thought to be safe, and demonstrated to be safe in adults, can nevertheless carry specific risks to other age groups. The side effect of "activation" is well known in adults but its significance as a signal of behavioural activation and suicidal thinking is only found in children and adolescents. There is even a different side effect profile of SSRIs, with most side effects appearing in smaller children (Safer and Zito 2006). What the SSRI debacle underscores is the importance of age-specific safety considerations. It is worth not ing that at the same time there is no debate about the older antidepressants, which have well-known but much higher safety risks. It is difficult to kill oneself with overdoses of SSRIs, but this can easily be done with a tricyclic antidepressant. Obviously these debates on safety also are connected with marketing of the drugs and the stockholder interests involved. One does not have to wholly subscribe to the provocative conspiracy theories of David Healy (2004), expounded in a polemic written by the British psychopharma-cologist, physician and medical historian ("Let Them Eat Prozac"), to accept that there was a clear publication bias (Whittington et al. 2003) that resulted in prescribers only being aware of the positive studies of efficacy. In the United States, John March is now setting up a nationwide psychopharmacol-ogy pharmacovigilance network, sponsored by the NIMH (March 2005 and March et al. 2004). One can conclude that the SSRI debacle shows that the political rules of the game (that is, the current drug regulatory environment) need to change in order to prioritise the public health value of clinical trials above their profitability for the pharmaceutical industry and academic medical centres (March 2005).
In general, the methods of collecting data on side effects have to be improved, validated and standardised. It is incredible that up to now, in general verbatim reports of patients are "translated" by agencies not involved in clinical care, resulting in verbatim references such as "hung", "hang", "cut", "self-harm" and so on being translated into sweeping, inaccurate labels such as "emotional lability".
For every new intervention in the brain, there should not only be a debate about the secure way of scientifically measuring the effects of the treatment but also a scientifically sound measure of expected and unexpected side effects, such as in the Columbia recording system of suicidal behaviour and thinking. Inter-rater reliability for different criteria must be established if we wish to collect reliable data concerning potential harm of interventions in the brain.
A last example in our plea for a stronger emphasis in safety is the use of atypical neuroleptics and the recent discussion of the appropriateness of their use in general in adults and in comparison to older drugs (Lieberman et al. 2005). Atypical neuroleptics are a new substance class of medication with potential use for children and adolescents that has been introduced to the market without any relevant studies in adolescents suffering from schizophrenia. Children and adolescents tolerate typical antipsychotics less well than adults and often react with early-onset dyskinesia. As a result, the new alternatives are widely used in the treatment of childhood schizophrenia. In a preventive study, Risperidone has even been used in adolescents to prevent schizophrenia; but there is no labelling of any of these substances for the use in children or adolescents for the indication of schizophrenia due to the lack of clinical trials in this age group. Some studies, especially with Risperidone, address the problem of disruptive behaviour (Findling et al. 2001; Fegert
2003; Croonenberghs et al. 2005). From these studies we have learned that children have a different side effect profile with atypical neuroleptics as compared to adults, with more weight gain in smaller children and some adverse events related to high prolactin levels. In general the problem of weight gain for some of these second generation antipsychotic drugs increasingly seems to be a limiting factor of their use. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study in adult patients with chronic schizophrenia (Lieberman et al. 2005) showed that treatment with Olanzapine was particularly associated with more discontinuation for weight gain or metabolic effects, whilst the use of first generation antipsychotics was associated with more discontinuation due to extra-pyramidal side effects. Olanzapine was superior to the other drugs with respect to treatment adherence. At present, there is controversy about the possible safety of atypical drugs because of their propensity to induce weight gain and alter glucose and/or lipid metabolism in the young, with possible longer-term consequences for physical health. Given the higher proportions of extra-pyramidal reactions in adolescents and the higher importance of hormonal changes in a developing metabolism there is no sound database for a cost-benefit evaluation of novel antipsychotics in the treatment of schizophrenia in children and adolescents. This situation will change in the next few years because the FDA has issued a written request to all the pharmaceutical companies marketing atypical antipsychotics, requiring studies for the indication of schizophrenia and/or hypomania/mania in children and adolescents. These studies have start in 2006, be conducted on a worldwide base and take into account gender differences and national differences. Up to now, most of the studies have addressed a small number of mostly male and predominantly Caucasian children. The study of girls and children from ethnic minority backgrounds, who might have a different reaction with respect to the side effect profile, is still rare.
With respect to the three most important psychopharmacological substance classes used in children and adolescents, we have to conclude that most of the safety issues remain unaddressed. There is sensible change in progress with respect to study policies and the acceptance of the risks related to off-label use, but these changes will take a long time. With respect to novel interventions in the brain, one can draw the general conclusion that there is also an initial focus on their therapeutic effects in adult patients with severe diseases. Clinical trials tend to be performed in highly selected monosymp-tomatic populations to prove the effectiveness of the compound; side effects are only observed opportunistically but there is often no standardised way of studying potential side effects. Questions of long-term safety and long-term vigilance of the consequences of the intervention, especially in the developing brain, are usually not addressed. This constitutes a remarkable risk in the treatment of children and adolescents, that we would find intolerable in adult medicine.
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