CCPR: Dr. Pringsheim, you have a special interest in the pharmacoepidemiology of antipsychotic use, particularly within vulnerable populations like kids. Please tell us what you have learned.

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 Child Adolesc 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.

CCPR: You reviewed the results of a systematic review of other agents for this use. What did you find?

Dr. Pringsheim: Yes, a number of different agents such as d-fenfluramine, sibutramine (Meridia), topiramate (Topamax), and dextroamphetamine have been evaluated, and the conclusion of the systematic review was that there is really insufficient evidence to support any of those interventions for weight gain (Ho J et al, Paediatr Child Health 2011;16(9):575–580). 

CCPR: Let’s move on to the extrapyramidal side effects of antipsychotics. Are there differences among agents on those, as well?

Dr. Pringsheim: Yes. About 25 percent of kids on risperidone or aripiprazole will have EPS in clinical trials. The greatest risk of extrapyramidal side effects is with risperidone, olanzapine, and aripiprazole, and there is a lower risk with quetiapine and clozapine. We don’t have a lot of data on ziprasidone in kids. Certainly in adults it is associated with extrapyramidal side effects, but we are hesitant to draw conclusions on the pediatric population in the absence of data. 

CCPR: And what do you suggest for extrapyramidal side effects?

Dr. Pringsheim: Well, it depends on the type: acute dystonia, tardive dystonia, tardive dyskinesia, drug-induced Parkinsonism, acute akathisia, or tardive akathisia. Really the treatment is directed depending on which side effect you encounter.

CCPR: First, please tell us about how to address the dystonias. 

Dr. Pringsheim: Acute dystonia is a symptom that occurs early on when antipsychotic medications are initiated. Typically this is seen within days of starting or increasing the dosage of an antipsychotic. The usual manifestation is extension of the arms, extension of the neck, opening of the mouth, protrusion of the tongue, deviation of the eyes in the upward direction. While this is not a common side effect, it is quite painful and usually requires emergency room management. We saw it a lot more often with first-generation antipsychotics, but it can occur with the second-generation agents as well. 

CCPR: How is acute dystonia treated?

Dr. Pringsheim: It is easily treated with diphenhydramine, an anticholinergic, or a benzodiazepine. But typically if such a reaction occurs you need to reassess your therapy. For example reinstitute a lower dosage of the medication or co-administer it with an anticholinergic.

CCPR: How about the longer-term tardive dystonia? 

Dr. Pringsheim: Tardive dystonia is a side effect that is seen typically with longer term use of medications, and the phenomenology of the movements is usually axial extension, hyperpronation of the arms, and retrocollis (extension of the neck). This can be very difficult to treat. Typically, we use anticholinergic medications.

CCPR: And what about withdrawal dyskinesias?

Dr. Pringsheim: These are common side effects seen in children if you abruptly stop an antipsychotic medication. Children can develop choreiform-like movements that involve wiggling of the body, face, and extremities, and other extra movements. What we typically recommend is that when you decide you want to come off the medication, it needs to be tapered under the supervision of a physician. Tardive dyskinesia is not very common in children. I am not saying it never happens, but it would be much more likely that what you are seeing are withdrawal dyskinesias in a child.

CCPR: Please tell us about the side effects involving prolactin.

Dr. Pringsheim: Prolactin is affected by antipsychotic use. The drug with the greatest risk of elevation in prolactin is risperidone. If you track kids longitudinally in large groups, the biggest elevation occurs within the first three months and then it slowly starts to come down over a year, but after a year it is still higher than normal. There is also a risk of high prolactin with olanzapine and ziprasidone, but not with quetiapine or clozapine. And aripiprazole actually decreases prolactin because it is a partial dopamine agonist.

CCPR: What sort of symptoms do you see with increased prolactin?

Dr. Pringsheim: With girls, you see changes within the menstrual cycle such as amenorrhea or dysmenorrhea. Both girls and boys can develop gynecomastia (enlarged breasts) and galactorrhea (production of milk or fluid in the breasts). Males may develop erectile dysfunction and disorders of ejaculation, as well. In a prepubertal child, it is very difficult to assess symptoms of elevated prolactin. You may see failure to menstruate in girls who are on an antipsychotic long term, so if they haven’t gotten a period and are past the age of 16, you should be suspicious that elevated prolactin is suppressing the onset of menstruation. 

CCPR: What is your recommendation for addressing hyperprolactinemia?

Dr. Pringsheim: I would suggest lowering the dose or switching agents if you can. I think one of the take-home messages is that you really have to be certain that you weigh the risks and the benefits before you ever write a prescription for an antipsychotic. You should have informed consent from the patient to treat them and make sure that they are aware of the risk and side effects. 

CCPR: Thank you, Dr. Pringsheim.

Table: Risk of Side Effects of Antipsychotics in Children and Adolescents