Dr. Jerrell: I have been working with adult clients with schizophrenia in some capacity for most of my career. Early on, my research focused on psychosocial treatments and then antipsychotic medications, but I’ve always focused on cost effectiveness comparisons. Then, around the early 2000s, psychiatric investigators really started looking into the cardiometabolic effects of taking antipsychotic medications in adults.
CCPR: And how did this segue into studying the same issues in children?
Dr. Jerrell: I had done observational database studies using our state Medicaid database for adults with schizophrenia, and at a certain point, with all the children and adolescents who were being prescribed psychiatric medications, I thought that the adverse effects of antipsychotics in this young patient population were worth examining.
CCPR: And what did you learn?
Dr. Jerrell: For the children’s studies, I requested a 10 year data file to study, because I really didn’t expect to find many kids in the South Carolina Medicaid database that were prescribed antipsychotics. I certainly didn’t expect the more than 4,000 kids that I did find who were taking antipsychotic medications during this decade. Then, we started looking at specific side effects and the results really became interesting.
CCPR: Did you find a high incidence of those same cardiometabolic effects in children that you had seen in adults?
Dr. Jerrell: Yes, very much so. In one study, we found that cardiac events including arrhythmias, ischemic, and pulmonary events were more likely to occur in children prescribed multiple antipsychotic medications than in those who were prescribed only one antipsychotic (McIntyre RS and Jerrell JM, Arch Pediatr Adolesc Med 2008;162(10):929–935).
CCPR: And were these instances very high among the children on these medications?
Dr. Jerrell: Relatively speaking, they were. The cardiovascular event incidence rates were only about eight to nine percent in the antipsychotic treated group, but that’s still higher than in the child and adolescent control group, which was about three percent.
CCPR: And were there any long-term sequelae of these events? Did anyone die, for example?
Dr. Jerrell: In the data we examined, there were very few deaths in either the control group or the antipsychotic treated groups. And that is noteworthy because many of these kids were on antipsychotic medications for an average of about seven years.
CCPR: What did you learn about metabolic effects?
Dr. Jerrell: There was a significantly higher risk of incidence of weight gain or obesity and diagnosis of type 2 diabetes in children treated with antipsychotics (McIntyre and Jerrell ibid). For example, in the control group, obesity and weight gain was diagnosed in 8.6% of the children, whereas it was diagnosed after the start of an antipsychotic medication in 13.9% of the children. Similarly, type 2 diabetes mellitus was diagnosed in 1.9% of children in the control group and in 3.1% of those started on antipsychotics.
CCPR: So there was a clear risk that if a child took an antipsychotic, he or she was more likely to have weight gain or diabetes?
Dr. Jerrell: Yes, and it was significantly higher if they were prescribed more than one antipsychotic medication, which many kids were.
CCPR: Were there any medications that were implicated more than others?
Dr. Jerrell: Our results were not drug-specific, primarily because risperidone (Risperdal) was the most commonly prescribed antipsychotic medication, either as monotherapy (39.5% of those in the antipsychotic treated group), or as one of the “multiple antipsychotics” prescribed to 42.3% of the treated group.
CCPR: What have you learned about neurological side effects?
Dr. Jerrell: Similar to the neurological adverse effects found in the few randomized controlled trials that have been done with kids, we found diagnoses of seizures, sedation, and involuntary movement disorders, such as extrapyramidal symptoms and akathisia types of issues were more common in antipsychotic-treated cohorts. [For example, see Vitiello B et al, Eur Neuropsychopharmacol 2009;19(9):629–635.] Exposure to risperidone, multiple antipsychotics (which was usually risperidone plus something else), or an antipsychotic co-prescribed with an SSRI antidepressant consistently elevated the risk of developing a range of these neurological side effects (Jerrell JM et al, J Child Neurology 2008;23(12):1392–1399). In terms of SSRIs, although we know that Prozac inhibits the metabolism of Risperdal, we didn’t do a subanalysis of specific SSRIs taken with specific antipsychotics, so I can’t say if this drug combination is associated with a higher incidence of neurological adverse events.
CCPR: In your research on antipsychotic side effects, you have specifically included children with developmental disabilities and mental retardation. I certainly see a lot of these kids in my practice. What have you learned about them?
Dr. Jerrell: We thought it was important to study these kids, because they’re being seen by psychiatrists and, quite often, doctors have to base their care decisions for these children on research from treatment groups that are not representative of the developmentally disabled. The results showed what you would expect—that these kids already have impaired brain functioning, which is also reflected in a higher risk of having neurological side effects when exposed to antipsychotic agents (Jerrell JM, et al, J Child Neurology 2008;23(12):1392–1399). However, we did not find any differences for cardio-metabolic effects among the developmentally disabled (McIntyre and Jerrell ibid).
CCPR: You also have looked specifically at African American kids. Any difference there?
Dr. Jerrell: Slightly fewer than 50 percent of the kids in this study were African American, and when we examined the results for this subgroup, we found that they don’t respond any differently to antipsychotics than anyone else, but they do demonstrate the same risk for adverse events (Jerrell JM, J Natl Med Assoc 2010;102(5):375–383). Typically, fewer African American kids enter randomized controlled trials, so this study was useful for gaining more information on a particular subgroup of patients.
CCPR: Did you learn anything about hyperprolactinemia and prolactin levels in children and adolescents taking antipsychotics?
Dr. Jerrell: Unfortunately, Medicaid data do not capture lab values, so I can’t speak to changes in prolactin levels per se. And even if they did, I’m not sure how many doctors would be ordering prolactin levels on their adolescent patients, when these results don’t correlate highly with sexual and reproductive problems. So, we were dependant on diagnostic codes entered for some type of sexual or reproductive problem. We did not find a difference in the development of sexual or reproductive conditions between the antipsychotic treated cohort and the control group. However, females, adolescents, and those with comorbid metabolic or endocrine conditions did experience more sexual or reproductive problems, which are commonly thought to result from hyperprolactinemia (Jerrell JM et al, J Adolesc Health 2009;45(1):70–76).
CCPR: What is the take-home message from your research? What should practicing psychiatrists like myself keep in mind when prescribing antipsychotics?
Dr. Jerrell: Well, I’d like to emphasize that coprescribing multiple antipsychotics appears to significantly raise the risk of many adverse side effects, as opposed to canceling out each other’s side effects, as some people have thought in the past. That’s a myth I’d like to dispel. Of those prescribed multiple antipsychotics, only about one third of kids were cross-tapered down to one drug. The rest were treated long-term on multiple medications, which frankly, is risky for individual patients, given these results.
CCPR: That’s helpful, considering I think many doctors do prescribe multiple medications. Anything else?
Dr. Jerrell: Monitoring cardiometabolic indices is particularly important. Keeping track of immediate weight, blood glucose, and lipid changes, and those things over time, and monitoring the occurrence of cardiovascular events can help the practitioner know when the treatment plan or medication might need to be changed.
CCPR: Thank you, Dr. Jerrell.