Dr. Pringsheim: I have studied antipsychotic prescribing patterns of Canadian physicians over time, looking at trends in use, number of prescriptions, why people are receiving prescriptions, and how long they are taking them. In Canada, we have seen about a 120 percent increase in use over a five-year period (Pringsheim T et al, J ChildAdolesc Psychopharmacology 2011;21(6):537-543). In the United States and Canada, not only has there been large increases in use over time, but more prescribers are not specialists, so these prescriptions are being written by pediatricians and family doctors in addition to psychiatrists.
CCPR: And based on this data, you have worked with a group of physicians and other experts to create some standard antipsychotic prescribing guidelines?
Dr. Pringsheim: Yes. There was a real need to inform physicians about adverse effects of antipsychotic medications and how to monitor drug safety. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guidelines were created to provide guidance on how to monitor antipsychotic side effects and how to manage extrapyramidal and metabolic side effects in children and adolescents (Pringsheim T et al, Paediatr Child Health 2011;16(9):581-589). (The full guidelines can be seen at http://camesaguideline.org)
CCPR: Please tell us about the metabolic consequences of antipsychotics.
Dr. Pringsheim: All of the second-generation antipsychotics that are commonly used in kids, such as risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), and aripiprazole (Abilify), carry risks of metabolic, hormonal, and extrapyramidal side effects. Metabolic side effects include weight gain, increase in body mass index or waist circumference, increase in cholesterol and triglycerides, and increases in fasting glucose and liver enzymes. Usually the first thing we see is an increase in body mass index and waist circumference, so typically these children are gaining fat mass. And with a gain in fat mass we see abnormalities in laboratory markers such as an increase in low-density lipoprotein cholesterol and triglycerides, and the development of insulin resistance.
CCPR: Are some agents more metabolically difficult than others?
Dr Pringsheim: Yes, the agents with the highest risk for metabolic side effects are olanzapine and clozapine. Risperidone and quetiapine have an intermediate risk, and aripiprazole is lower risk, but children do gain weight and increase their body mass index on this drug as well, it just tends to happen a bit more slowly.
CCPR: Are some metabolic risks stronger or more common than others?
Dr. Pringsheim: Most of the metabolic laboratory abnormalities are driven by the absolute amount of weight gain; so this seems to confer the greatest risk. If a child remains lean on a treatment, they are less likely to develop problems with their cholesterol and triglycerides, for example. If the child gains weight on the treatment, the risk of all of the other metabolic abnormalities is greater. And so, because the risk of weight gain is higher with olanzapine and clozapine (Clozaril), children on these medications are more likely to develop the metabolic laboratory abnormalities as well. That being said, I treat children with risperidone and aripiprazole, and they still develop metabolic abnormalities at a rate of about 30 percent. So I screen all kids who are treated with second-generation antipsychotics regardless of type.
CCPR: What are the best interventions for metabolic side effects?
Dr. Pringsheim: The most important thing is prevention. Physicians should provide anticipatory guidance to patients and families, letting them know that these medications stimulate the appetite, so the child will want to eat more, and they will likely not make healthy choices and they will gain weight. So there should be counseling about the need to limit intake, and the need to promote exercise and an active, healthy lifestyle to try to prevent weight gain.
CCPR: What if the child has already gained weight?
Dr. Pringsheim: Our first strategy if the child has gained weight on the medication is to reevaluate the use of the medication. If a child has a very serious mental health disorder such as schizophrenia or bipolar disorder, it is very hard to stop the medications in that setting because of the seriousness of the illness. But the evidence for the use of medication is not as strong for some of the behavioral disorders and there are alternatives to antipsychotic therapy. You really need to reevaluate whether or not you should continue, since there is the risk of causing harm to the child. There is data that the side effects are dosage dependent, so we tell clinicians to try to use the lowest effective dose and that you can try decreasing the dose slightly to see if that makes a difference.
CCPR: Let’s say we can’t stop the medication or decrease the dose. What else can we do?
Dr. Pringsheim: The next line of therapy is to try dietary intervention. I recommend having the family meet with a dietitian and try some lifestyle interventions like exercise. We have a pediatric weight program at my center where we refer kids if they haven’t been successful in managing the weight gain, so you may want to do that if one of these programs is available to you.
CCPR: What does the research says about metformin?
Dr. Pringsheim: There are only four studies of metformin for antipsychotic-induced metabolic issues in children; some of them are negative, some are positive. These studies are all very short and there is a small number of kids in each study. So we don’t have a lot of good guidance. At the time that we (at CAMESA) did our evidence review, we didn’t feel there was compelling evidence to use this medication in kids. We made a weak recommendation based on the fact that the randomized controlled trials have many limitations and the benefits are closely balanced with risks and burdens. I personally wouldn’t start metformin without consulting an endocrinologist, since they have much more experience in prescribing this medication.