Antipsychotic Tied to Dose-Related Weight Gain, Higher Cholesterol

Batya Swift Yasgur, MA, LSW

June 02, 2022

Increases in use of the antipsychotic risperidone (Risperdal) are associated with small dose-related increases in both weight and blood cholesterol levels, new research suggests.

Investigators analyzed 1-year data for more than 400 patients who were taking risperidone and/or its metabolite paliperidone (Invega). Results showed increments of 1 mg of risperidone-equivalent doses were associated with an increase of 0.25% of weight within a year of follow-up.

In addition, 1-mg dose increments were also associated with increases in total cholesterol level by .05 mmol/L (1.93 mg/dL) and LDL cholesterol level by .04 mmol/L (1.54 mg/dL).

"Although our findings report a positive and statistically significant dose-dependence of weight gain and cholesterol, both total and LDL, the size of the predicted changes of metabolic effects is clinically nonrelevant," lead author Marianna Piras, PharmD, Centre for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland, told Medscape Medical News.

"Therefore, dose-lowering would not have a beneficial effect on attenuating weight gain or cholesterol increases and could lead to psychiatric decompensation," said Piras, who is also a PhD candidate in the Unit of Pharmacogenetics and Clinical Psychopharmacology at the University of Lausanne.

However, she added that because dose increments could increase risk for significant weight gain in the first month of treatment — the dose can be increased typically in a range of 1 to 10 grams — and strong dose increments could contribute to metabolic worsening over time, "risperidone minimum effective doses should be preferred."

The findings were published online May 11 in the Journal of Clinical Psychiatry,

"Serious Public Health Issue"

Compared with the general population, patients with mental illness present with a greater prevalence of metabolic disorders. In addition, several psychotropic medications, including antipsychotics, can induce metabolic alterations such as weight gain, the investigators note.

Antipsychotic-induced metabolic adverse effects "constitute a serious public health issue" because they are risk factors for cardiovascular diseases such as obesity and/or dyslipidemia, "which have been associated with a 10-year reduced life expectancy in the psychiatric population," Piras said.

"The dose-dependence of metabolic adverse effects is a debated subject that needs to be assessed for each psychotropic drug known to induce weight gain," she added.

Several previous studies have examined whether there is a dose-related effect of antipsychotics on metabolic parameters, "with some results suggesting that [weight gain] seems to develop even when low off-label doses are prescribed," Piras noted.

She and her colleagues had already studied dose-related metabolic effects of quetiapine (Seroquel) and olanzapine (Zyprexa).

Risperidone is an antipsychotic with a "medium-to-high metabolic risk profile," the researchers note, and few studies have examined the impact of risperidone on metabolic parameters other than weight gain.

For the current analysis, they analyzed data from a longitudinal study that included 438 patients (mean age, 40.7 years; 50.7% men) who started treatment with risperidone and/or paliperidone between 2007 and 2018.

The participants had diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, depression, "other," or "unknown."

Clinical follow-up periods were up to a year, but were no shorter than 3 weeks. The investigators also assessed the data at different time intervals at 1, 3, 6, and 12 months "to appreciate the evolution of the metabolic parameters."

In addition, they collected demographic and clinical information, such as comorbidities, and measured patients' weight, height, waist circumference, blood pressure (BP), plasma glucose, and lipids at baseline and at 1, 3, and 12 months and then annually. Weight, waist circumference, and BP were also assessed at 2 and 6 months.

Doses of paliperidone were converted into risperidone-equivalent doses.

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 timepoint," the investigators report.

Treatment month Weight gain value
1 1.58% < .001
3 1.20% < .001
6 .80% < .001
12 .57% < .001

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 timepoint.

Treatment month Weight gain value
1 0.16% .002
3 0.29% < .001
6 0.21% < .001
12 0.25% < .001

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.

Age group Treatment month Weight gain P value
Adolescents (≤ 17 years) 6









Adults (> 17 to < 65 years) 3









Older adults (≥ 65 years) 1










< .001


< .001

< .001

< .001

Dose was shown to have a significant effect on weight gain for women at all four timepoints (P ≥ .001), but for men only at 3 months (P = .003).

For each additional 1-mg dose, there was a .05 mmol/L (1.93 mg/dL) increase in total cholesterol (P = .018) after 1 year and a .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.

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 for Medscape Medical News, Erika Nurmi, MD, PhD, associate professor in the Department of Psychiatry and Biobehavioral Sciences at UCLA's Semel Institute for Neuroscience in Los Angeles, said the study is "unique in the field."

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 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," 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," Nurmi cautioned.

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. Nurmi reports 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.

J Clin Psychiatry. Published online May 11, 2022. Abstract

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