Significant weight gain over time
The mean duration of follow-up for the participants, of whom 374 were being treated with risperidone and 64 with paliperidone, was 153 days. Close to half (48.2%) were taking other psychotropic medications known to be associated with some degree of metabolic risk.
Patients were divided into two cohorts based on their daily dose intake (DDI): less than 3 mg/day (n = 201) and at least 3 mg/day (n = 237).
In the overall cohort, a “significant effect of time on weight change was found for each time point,” the investigators reported.
When the researchers looked at the changes according to DDI, they found that each 1-mg dose increase was associated with incremental weight gain at each time point.
Patients who had 5% or greater weight gain in the first month continued to gain weight more than patients who did not reach that threshold, leading the researchers to call that early threshold a “strong predictor of important weight gain in the long term.” There was a weight gain of 6.68% at 3 months, of 7.36% at 6 months, and of 7.7% at 12 months.
After the patients were stratified by age, there were differences in the effect of DDI on various age groups at different time points.
Dose was shown to have a significant effect on weight gain for women at all four time points (P ≥ .001), but for men only at 3 months (P = .003).
For each additional 1-mg dose, there was a 0.05 mmol/L (1.93 mg/dL) increase in total cholesterol (P = .018) after 1 year and a 0.04 mmol/L (1.54 mg/dL) increase in LDL cholesterol (P = .011).
There were no significant effects of time or DDI on triglycerides, HDL cholesterol, glucose levels, and systolic BP, and there was a negative effect of DDI on diastolic BP (P = .001).
The findings “provide evidence for a small dose effect of risperidone” on weight gain and total and LDL cholesterol levels, the investigators note.
Ms. Piras added that because each antipsychotic differs in its metabolic risk profile, “further analyses on other antipsychotics are ongoing in our laboratory, so far confirming our findings.”
Small increases, big changes
Commenting on the study, Erika Nurmi, MD, PhD, associate professor in the department of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience, University of California, Los Angeles, said the study is “unique in the field.”
Dr. Erika L. Nurmi
It “leverages real-world data from a large patient registry to ask a long-unanswered question: Are weight and metabolic adverse effects proportional to dose? Big data approaches like these are very powerful, given the large number of participants that can be included,” said Dr. Nurmi, who was not involved with the research.
However, she cautioned, the “biggest drawback [is that] these data are by nature much more complex and prone to confounding effects.”
In this case, a “critical confounder” for the study was that the majority of individuals taking higher risperidone doses were also taking other drugs known to cause weight gain, whereas the majority of those on lower risperidone doses were not. “This difference may explain the dose relationship observed,” she said.
Because real-world, big data are “valuable but also messy, conclusions drawn from them must be interpreted with caution,” Dr. Nurmi said.
She added that it is generally wise to use the lowest effective dose possible.
“Clinicians should appreciate that even small doses of antipsychotics can cause big changes in weight. Risks and benefits of medications must be carefully considered in clinical practice,” Dr. Nurmi said.
The research was funded in part by the Swiss National Research Foundation. Piras reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Nurmi reported no relevant financial relationships, but she is an unpaid member of the Tourette Association of America’s medical advisory board and of the Myriad Genetics scientific advisory board.
A version of this article first appeared on Medscape.com.