Tuesday, November 25, 2008

Another excerpt from the upcoming new edition of my Med Guide

The psychostimulants, as a class, have been around for a long time. These were some of the first drugs to be used in psychiatry, and so physicians feel fairly comfortable with these medications--some would say too comfortable. In children, stimulants are by far the most commonly prescribed psychoactive medications, primarily for the treatment of attention deficit/hyperactivity disorder (ADHD). Stimulants are also used, with questionable effectiveness, as appetite suppressants to promote weight loss. They can be valuable for people with narcolepsy, since their stimulating properties can help narcoleptics stay awake and function through the day. Some adults with ADHD also seem to benefit from stimulant medication.
Currently, there is a bit of controversy about the frequency with which stimulants are used; many people (this author included) feel that these medications are overprescribed and that ADHD is overdiagnosed. It is likely that the ability to attend, as a biological trait, exists on a continuum: some individuals are designed to focus narrowly on the task at hand, while others are always open to input from the environment, and are thus "easily distractable". It is also likely that many children and adults nowadays are labeled as having ADHD when they simply are normal individuals at one end of the spectrum. Viewed this way, medicating these individuals constitutes cosmetic psychopharmacology.
This argument certainly does not apply to Fragile X, however. Children with Fragile X have a well-defined, single-gene disorder which causes attentional deficits along with other characteristic symptoms. They (along with a fair number of children who really do have neurologically-based ADHD) have symptoms which offer a clear-cut rationale for the use of psychostimulants to enhance attention. The only reasonable question is whether these medications work for children with Fragile X.
To answer this question we must first consider how these drugs work. Although the mechanism of action is by no means fully understood, the conventional wisdom is that psychostimulants work by promoting release of certain neurotransmitters, especially dopamine (but also norepinephrine, as well as other things secreted along with them). The primary effect of psychostimulants, the enhancement of attention and concentration, is thought to result from the increased release of dopamine in the frontal areas of the brain. But, of course, the drug is present in other areas, too, and exerts effects there as well. The areas of the brain which regulate level of arousal, blood pressure, heart rate and other "autonomic" functions are also stimulated, while the area controlling appetite is inhibited. Under normal circumstances, most people are much more sensitive to the primary effect of facilitating dopaminergic transmission in the frontal lobes, and at most therapeutic doses will experience an enhancement of attention, concentration, and overall cognitive performance (which is why these medications were initially touted as "smart drugs").
As attention and concentration (referred to by some as "focus") increase with increasing doses of a stimulant, physical activity tends to decline, accounting for the paradoxical decrease in hyperactivity (which is ususally the objective of treatment). However, the primary and secondary effects of stimulants, enhancement of attention and reduction of hyperactivity, are known to occur at different dosages. Lower doses of a stimulant are likely to enhance attention optimally and improve cognitive performance, but may not control hyperactivity. Higher doses are likely to reduce hyperactivity, but may actually result in "overfocus", in which attention is focused so narrowly that actual cognitive performance declines. Still higher doses will cause psychiatric symptoms in virtually anyone, including irritability, aggression, anxiety, agitation, paranoia, or hallucinations. Fortunately, for most people the dose required to cause trouble is much higher than usual therapeutic doses. However, the situation is somewhat different for Fragile X individuals.
Fragile X predisposes one to anxiety, aggression, and agitation. On an intuitive level, it seems obvious that care should be taken with any substance which could aggravate these. On a biochemical level, psychostimulants are "sympathomimetic": they mimic the effects of adrenaline in the central nervous system, heightening arousal as well as increasing heart rate and blood pressure. Since Fragile X individuals often have problems with hyperarousal, stimulants may make matters worse in some cases. Many Fragile X individuals are able to achieve significant improvements in attention and cognitive performance with low doses of stimulants, though, and any potential adverse effects are readily reversible should they arise. Therefore, a trial of a stimulant is rational and safe for a Fragile X individual with particular attentional problems, but should be done with caution. Dosages should be relatively low, and it cannot be expected that significant reduction of hyperactivity will occur, at least compared to the sometimes dramatic response seen in "garden variety" ADHD. Careful monitoring for emergence or exacerbation of anxiety or aggression must occur throughout treatment. Many Fragile X parents are not informed of this risk, are unaware of the connection between stimulants and worsening of aggression or anxiety, and therefore continue administering the medication even when adverse psychiatric side-effects occur--despite the fact that these effects readily reverse upon discontinuation of the drug.
Psychostimulant medications can cause uncommon, but serious, medical problems. Most worrisome is the development of motor tics. This can start as a subtle, almost undetectable twitch, and progress to severe involuntary muscle movement. It usually stops soon after the stimulant is discontinued or the dosage decreased, but sometimes is frighteningly persistent. The key is to catch the tics early on; more persistent tics usually occur following longer treatment in which early signs were ignored. This side-effect is usually dose related, so reducing the dose can be helpful and allow for uninterupted treatment. Also, since most Fragile X children are treated with lower doses of stimulants, this may be less likely to occur in the first place (there are no reliable statistics on the frequency of this side-effect in Fragile X). Tics can also be treated with clonidine if they persist, or if the clinical judgment is made not to interrupt stimulant therapy.
Since they can be potent appetite suppressants, psychostimulants can cause some growth delays during long-term administration. Several studies have shown, however, that children will eventually catch up, even if the medication is continued. Often, "drug holidays" are taken during non-critical times (such as summer vacation) to expedite this process. In any case, growth charts should be carefully monitored for all children on stimulant medications, and significant growth delay is an appropriate reason for discontinuing the medication.
Specific side effects and their medical management are discussed in the individual reviews of medications.

Update 2008: The caveats concerning stimulants noted in this book have proven to be well founded, and just as frequently ignored as ever. Stimulants are nearly irresistable for all concerned, offering the promise of an instant fix for the disabling inattentiveness and the disruptive hyperactivity seen in nearly all children with fragile X. Teachers love stimulants because they help so many kids participate in class. Parents love them because they start working right away, and because they want their kids to get the most out of school. Pediatricians love them because they’re easy to prescribe and have a long safety record. The only problem is that they don’t work very well in kids with fragile X! At least half of all stimulant trials in fragile X kids end abruptly because of immediate psychiatric side effects---usually extreme irritability or increased aggression. Seizures and tics are also seen with alarming frequency in this population following the start of a new stimulant medication. However, these are all fairly obvious and easily recognized, and when the drug is discontinued the adverse effects dissipate rapidly. Perhaps more concerning are the psychiatric side effects which develop insidiously over much longer time frames; I have consulted on many cases in which a fragile X child has an excellent initial response to a stimulant with no apparent side effect, only to have multiples problem emerge months or years later. Most commonly, obsessive-compulsive symptoms worsen over time, as mood deteriorates and tantrums increase. Because stimulants cause significant physiological dependence, everything gets worse if any attempt is made to discontinue the drug, and this is often seen as evidence the stimulant is not to blame. In fact, this is only evidence that stimulants are potentially addictive, and demonstrates why they are highly controlled substances. The appropriate response is a gradual taper of the stimulant dose over the course of many months.
The entire field of Child Psychiatry appears to have come to the realization that excessive and indescriminate use of stimulants has led to an increase in childhood Bipolar Disorder, Anxiety Disorders, and psychoses. Indeed, the current fad is for overdiagnosis of Bipolar Disorder, after ignoring for decades that this condition can present in childhood. So, the most important lesson is to be vigilant over the long term; most medications which work right away have serious side effects which develop much later.

Saturday, November 15, 2008

Trends in Psychiatry

The medical field is just like any other kind of human endeavor: subject to fads and herd mentality. While we’d all like to think that doctors rely only on science and only care about the best available evidence, doctors are people, too. Like everyone else, doctors are heavily influenced by what other people think, and the opinions of their medical peers are very important in determining practice patterns. In addition, doctors must function in an environment where information is usually insufficient. We don’t know enough about how any part of the body works, yet all these parts can have problems, and doctors are expected to fix them when they do. Filling in these knowledge gaps is more art than science, and in this artistic facet of medicine, most doctors seek the consensus of their peers---medicine is a field for creative renegades only on TV.

So, each medical specialty has its own trends, which vary over time and by geographic region. This is by no means peculiar to psychiatry; all areas of medicine experience this same phenomenon, but here we are concerned with the effect of psychiatric fads on treatment of people with developmental disorders.

Major Tranquilizers: The Original Fad

The field of psychopharmacology didn’t really exist until the first antipsychotic drugs became available in the 1950’s. The first generation of antipsychotics, like Thorazine and Mellaril, revolutionized psychiatry by allowing direct biomedical treatment of psychosis. These “major tranquilizers” were powerful drugs with a wide range of effects (good and bad) which could actually treat schizophrenia and other major thought disorders for the first time. Unfortunately, the enthusiasm for these drugs was a bit overdone, and many people who were never psychotic were prescribed antipsychotics anyway. Why? As an old professor of mine used to say, “When all you have is a hammer, everything starts to look like a nail!” Nowhere did this megatrend of the 50’s cause more problems than in the medical management of developmental disorders. Enormous numbers of people with DD were prescribed major tranquilizers for a wide range of symptoms. In some cases, the drugs had genuine benefits, but in many others, the main effect was non-specific sedation. Decades later, the chickens finally came home to roost, as thousands of people with developmental disorders were diagnosed with irreversible, drug-induced movement disorders.

Nowadays, these older antipsychotics are rarely used, and seldom prescribed to children. However, we may be seeing a similar phenomenon in our time. The newest generation of antipsychotics, usually called “atypical antipsychotics”, are being prescribed in vast quantities to children and adults with developmental disorders. In part, this is because this class of drugs represents a significant advance compared to the older antipsychotics, though some critics argue that the differences in practice are not that great, and the real push is coming from pharmaceutical companies. Indeed, while the new drugs are more easily tolerated by patients, and they appear to be somewhat more effective in their primary indication, the treatment of schizophrenia, they are not the “silver bullet” many had hoped for. Risperdal (risperidone) became the first atypical antipsychotic actually marketed for the treatment of autism after a large and well-done study showed efficacy in treating the irritability and behavior problems associated with autism. The multicenter trial described below led to FDA approval of Risperdal for this indication, the first formal approval of any treatment for autism.

N Engl J Med. 2002 Aug 1;347(5):314-21.

Risperidone in children with autism and serious behavioral problems.

McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D; Research Units on Pediatric Psychopharmacology Autism Network.
University of California, Los Angeles, USA.

BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.

This would seem to be good news, and in most ways it is. A commonly used treatment for autism spectrum disorders was shown to be efficacious in autistic children; this is good evidence that this drug and other atypical antipsychotics treat some of the most difficult symptoms of developmental disorders. However, all drugs have side effects, and antipsychotics have more than most. Some of these are well known and well described. For example, a number of movement disorders, some irreversible, can occur with these medications. Fortunately, newer drugs are less likely to cause these problems, especially at the lower doses usually prescribed in developmental disorders. However, they seem to have some special problems of their own, like pronounced weight gain in younger patients, and unusual side effects such as this:

J Child Adolesc Psychopharmacol.

Risperidone-induced enuresis in two children with autistic disorder.

Herg√ľner S, Mukaddes NM.
Department of Child and Adolescent Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

INTRODUCTION: Risperidone appears to be effective in treating behavioral problems in children with autistic disorder. Although increased appetite, weight gain, and sedation are among the most common side effects, risperidone-induced enuresis is rarely reported. METHOD: We will present two cases with risperidone-induced enuresis, and discuss our findings in the context of current literature. RESULTS: Two children aged 11 and 10 years, diagnosed with autism and mental retardation, have developed new-onset diurnal and nocturnal enuresis respectively on their first and second weeks of risperidone monotherapy (1.5 and 1 mg/day). They did not experience sedation, and their medical history and workup were unremarkable. As enuresis did not resolve spontaneously, we decided to substitute risperidone with olanzapine. Enuresis ceased rapidly after discontinuation of risperidone with no emergence when patients were treated with olanzapine 5 mg/day for a period of 6 months and 1 year, respectively. DISCUSSION: Although the pathophysiology of antipsychotic-induced enuresis remains unclear, a number of mechanisms including alpha(1)-adrenergic blockade, dopamine blockade, and antimuscarinic effects has been proposed. Olanzapine has lower alpha(1)-adrenergic and dopaminergic blockade properties, thus changing risperidone to olanzapine may be an alternative modality in risperidone-induced enuresis when antipsychotic treatment is crucial. Clinicians should be more vigilant about screening for this side effect, especially in younger population with developmental disabilities.

Urinary incontinence is not usually associated with treatment with older antipsychotics, yet the newer drugs can cause this with surprising frequency in younger patients with DD.
By itself, this isn’t a show-stopper, but this illustrates an important point. When a drug which is useful, but perhaps not the first choice in most cases, becomes the only drug actually officially approved for that indication, it suddenly becomes the first choice of many risk-averse doctors. Thus, Risperdal became the first choice for the treatment of all autism spectrum disorders, in the eyes of many physicians. That could be a big problem in the end, with atypical antipsychotics becoming more popular than their first-generation cousins ever were. While we’d like to think that these are simply better drugs, and their popularity is well-deserved, we may not know the whole story. People with MRDD suffer from a wide range of symptoms, and many are better treated with other classes of medications. Risperdal and other atypical antipsychotics may be the first choice for some of these symptoms, but they’re certainly not the first choice for most.