Antipsychotics are associated with weight gain and high cholesterol

New research shows that an increase in the use of the antipsychotic risperidone (Risperdal) is associated with a small increase in dose-related weight and blood cholesterol levels.

Investigators analyzed 1-year data for more than 400 patients receiving risperidone and / or its paliperidone metabolite (Invega). The results showed that an increase in the equivalent dose of risperidone by 1 mg was associated with a 0.25% weight gain over the course of a year.

In addition, an increase in the dose of 1-mg was also associated with an increase in total cholesterol levels of .05 mmol / l (1.93 mg / dl) and LDL cholesterol levels of .04 mmol / l (1.54 mg / dl).

“Although our report found that weight gain and cholesterol, both total and LDL, were positively and statistically significant dose dependent, the magnitude of the predicted changes in metabolic effects was clinically irrelevant,” said lead author Marianna Piras, PharmD, Center for Psychiatric Neurology. This was reported by the hospital of the Swiss University of Prilli Medscape medical news.

“Therefore, dose reduction does not have a positive effect on weight gain or cholesterol increase and may lead to psychiatric decompensation,” said Piras, who is also a PhD candidate in the Department of Pharmacogenetics and Clinical Psychopharmacology at the University of Lausanne.

However, he added that increasing the dose significantly increases the risk of weight gain in the first month of treatment – the dose can usually be increased from 1 gram to 10 grams – and a strong dose increase can contribute to worsening metabolism over time, ”he added. must be.

The results were posted online on May 11 Journal of Clinical Psychiatry,

“A serious problem of public health”

Patients with mental illness are more likely to have metabolic disorders than the general population. In addition, several psychotropic drugs, including antipsychotics, can cause metabolic changes such as weight gain, investigators note.

Piras said the metabolic side effects caused by antipsychotics “pose a serious public health problem” because they are risk factors for cardiovascular diseases such as obesity and / or dyslipidemia, “associated with a 10-year decline in the psychiatric population.” he said.

“Dose dependence of metabolic side effects is a topic that should be evaluated for any psychotropic drug that promotes weight gain,” he added.

Several previous studies have examined whether antipsychotics have a dose-dependent effect on metabolic parameters, “some results [weight gain] It seems to develop even when low off-label doses are prescribed, ”Piras said.

He and his colleagues have previously studied the dose-dependent metabolic effects of quetiapine (Seroquel) and olanzapine (Zyprexa).

Risperidone is an antipsychotic with a “moderate-to-high metabolic risk profile,” the researchers note, and several studies have studied the effects of risperidone on metabolic parameters other than weight gain.

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

Participants were diagnosed with schizophrenia, schizoaffective disorder, bipolar disorder, depression, and “other” or “unknown”.

The duration of clinical observation was up to one year, but not less than 3 weeks. Investigators also evaluated data at different time intervals of 1, 3, 6, and 12 months to “assess the evolution of metabolic parameters.”

In addition, they collected demographic and clinical data, such as co-morbidities, 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 blood pressure were also measured at 2 and 6 months.

Doses of paliperidone were converted to equivalent doses of risperidone.

Significant weight gain over time

The median follow-up for participants treated with 374 risperidone and 64 paliperidone was 153 days. About half (48.2%) took other psychotropic drugs that were associated with some degree of metabolic risk.

Patients were divided into two groups based on their daily dose intake (DDI): less than 3 mg / day (n = 201) and at least 3 mg / day (n = 237).

The overall cohort “found a significant effect of time on the change in weight of each time,” investigators said.

month of treatment weight gain P value
1 1.58% <.001
3 1.20% <.001
6 .80% <.001
12 .57% <.001

The researchers looked at the changes in DDI and found that each 1-mg dose increase was associated with additional weight gain over a period of time.

month of treatment weight gain P value
1 0.16% .002
3 0.29% <.001
6 0.21% <.001
12 0.25% <.001

In the first month, patients who weighed 5% or more continued to gain more weight than patients who did not reach that threshold, which researchers called the threshold “a strong predictor of significant weight gain in the long run.” Weight increased by 6.68% in 3 months, 7.36% in 6 months, and 7.7% in 12 months.

After patients were stratified by age, there were differences in the effect of DDI on different age groups at different time points.

age month of treatment weight gain P value
Adolescents (≤ 17 years old) 6






Adults (> 17 to <65 years) 3






Older people (≥ 65 years) 1












Doses have been shown to have a significant effect on weight gain in women over all four periods of time (P ≥ .001), but only after 3 months for men (P = .003).

An increase in total cholesterol of 0.05 mmol / l (1.93 mg / dl) was observed for each additional 1 mg dose.P = .018) increase in LDL cholesterol after 1 year and 0.04 mmol / l (1.54 mg / dl) (P = .011).

Time or DDI had no significant effect on triglycerides, HDL cholesterol, glucose levels, and systolic blood pressure, and DDI had a negative effect on diastolic BP.P = .001).

According to the researchers, the results “prove that risperidone is effective in small doses” to add weight and overall LDL cholesterol levels.

Piras added that because each antipsychotic differs in its metabolic risk profile, “further analysis of other antipsychotics is ongoing in our laboratory, so far confirming our findings.”

Small growths, big changes

to comment Medscape medical newsErica Nurmi, MD, PhD, associate professor of psychiatry and bioscience at UCLA’s Semel Institute of Neurology in Los Angeles, said the study was “unique in the industry”.

This raises a long-unanswered question from the real-world patient registry: Are the negative effects of weight and metabolism proportional to the dose? The response to such large data is very strong given the large number of participants, ”said Nurmi, who did not participate in the study.

However, he warned that it was “the biggest flaw” [is that] This information is far more complex and confusing by nature. “

In this case, most people who took high doses of “critical misleading” risperidone for the study also took other medications that led to weight gain, while most people who took low doses of risperidone did not. “This difference could explain the dose relationship,” he said.

Big data in the real world is “valuable, but also confusing, so the conclusions drawn from them should be interpreted with care,” Nurmi said.

He added that it is wise to use the lowest effective dose.

“Clinicians need to understand that even small doses of antipsychotics can lead to significant weight changes. The risks and benefits of medications should be carefully considered in clinical practice,” Nurmi warned.

The study was funded in part by the Swiss National Research Foundation. Piras is accountable for the relevant financial relationships. The information of the other investigators is given in the original article. Nurmi has no relevant financial relationships, but she is an unpaid member of the American Medical Advisory Board’s Tourette Association and the Scientific Council on Miriad Genetics.

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

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