Antipsychotic drugs may increase risk of breast cancer

by Jim Dryden, Washington University School of Medicine in St. Louis

Credit: Pixabay/CC0 Public Domain

Tracking medications provided to over a half million U.S. women, researchers at Washington University School of Medicine in St. Louis have found that many commonly prescribed older antipsychotic medications, and some newer ones, are associated with a significant increase in risk of breast cancer. Antipsychotics are prescribed for a broad range of conditions, including depression, bipolar disorder, schizophrenia, dementia and autism spectrum disorders.

26 dec 2021--While earlier studies have uncovered links between antipsychotic drug use and breast cancer risk, this is the first study to compare newer antipsychotics to older drugs, and to look at how the drugs affect levels of a hormone called prolactin. Increased levels of prolactin have been associated with breast cancer.

Prolactin is an important hormone involved in puberty, pregnancy and breastfeeding. However, many antipsychotics elevate prolactin levels and can produce side effects such as menstrual cycle irregularities, abnormal breast milk production and abnormal breast tissue growth.

The findings will be published in the February issue of the Journal of Clinical Psychopharmacology but are available online.

"Many women with psychiatric illnesses such as schizophrenia and bipolar disorder will take antipsychotics for decades, and they are essential to keeping symptoms in check," said the paper's first author, Tahir Rahman, MD, associate professor of psychiatry. "But both older antipsychotic medicines and some newer drugs raise levels of prolactin and increase the risk of breast cancer, which is concerning. Our study confirms findings from a smaller European study that advised women and their doctors to first try drugs that don't affect prolactin levels. We agree with that advice and believe psychiatrists should start to monitor prolactin levels in their patients taking antipsychotics."

The researchers classified antipsychotic drugs into three categories, based on their established effects on prolactin. Category 1 included drugs associated with high prolactin levels, such as haloperidol, paliperidone and risperidone. Category 2 drugs, which had mid-range effects on prolactin, included the drugs iloperidone, lurasidone and olanzapine. Category 3 included drugs with less of an effect on prolactin levels, such as aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, quetiapine and ziprasidone.

The researchers compared the effects of all three categories of antipsychotic drugs to anticonvulsant drugs and lithium, which also often are prescribed to treat psychiatric disorders. When compared with those drugs, the relative risk of breast cancer was 62% higher for women who took Category 1 drugs and 54% higher for those taking Category 2 drugs, whereas Category 3 antipsychotics were not associated with any increase in breast cancer risk.

"Certain drugs are known to elevate prolactin, and the women taking those drugs were more likely to have breast cancer," Rahman said. "But we didn't detect any increased risk in women taking antipsychotics that don't raise prolactin levels."

In mouse models, prolactin can contribute to a weakening of cellular systems that keep precancerous lesions from becoming breast cancer. In people, prolactin levels tend to be lower in women who have had more children at a younger age than in women who have fewer children or wait until they are older to do so.

In this study using data collected from 2012 through 2016, the research team performed a retrospective, observational study of breast cancer risk in women ages 18 through 64 who took antipsychotics. The data came from the IBM MarketScan and Multi-State Medicaid databases, which contain anonymized medical information on more than 170 million people.

Rahman and his colleagues used billing codes from the databases to learn which patients were treated for breast cancer during a 12-month period. Next, they matched that information to patients taking antipsychotic drugs. Of the 540,737 women in the database taking antipsychotics, only 914 were identified as having breast cancer. But a significant number of those women were taking drugs known to increase prolactin.

"Antipsychotic medications can be lifesaving for patients who have psychotic episodes where they experience symptoms such as hallucinations and delusions," Rahman said. "In recent years, the drugs have been approved to treat other conditions, too, including depression and bipolar disorder. As those high-prolactin agents are used more widely, the number at risk could increase. We've been advising against using these high-prolactin agents in women who already have breast cancer, but we'd like to investigate whether keeping prolactin levels lower even might prevent some of these cancers."

In another recent study, his team analyzed blood samples from women who took the antipsychotic drug aripiprazole (Abilify) as an add-on treatment for depression. They found that their prolactin levels did not increase and that a few women who began the study with high prolactin levels experienced decreases in prolactin levels after 12 weeks of treatment.

Those findings—combined with preclinical evidence of the anticancer effects of some antipsychotics—have inspired Rahman and his colleagues to propose repurposing some antipsychotic drugs in the fight against breast cancer.

"We don't want to alarm patients taking antipsychotic drugs for life-threatening mental health problems, but we also think it is time for doctors to track prolactin levels and vigilantly monitor their patients who are being treated with antipsychotics," Rahman said.

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More information: Tahir Rahman et al, Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs, Journal of Clinical Psychopharmacology (2021). DOI: 10.1097/JCP.0000000000001513

Provided by Washington University School of Medicine in St. Louis 

Variable Mortality Risk for Antipsychotic Use in Elderly

Effect strongest soon after start of treatment; dose-response relationship for most drugs

27 feb 2012-- The risk of mortality associated with antipsychotic drug use among elderly residents in nursing homes in the United States varies between drugs, according to a study published online Feb. 23 in BMJ.

To investigate the mortality risks associated with use of individual antipsychotic drugs, Krista F. Huybrechts, Ph.D., from the Brigham and Women's Hospital in Boston, and colleagues conducted a population-based cohort study of 75,445 new antipsychotic users (aged 65 or older) who lived in a nursing home in the United States from 2001 to 2005. The 180-day risks of all-cause and cause-specific mortality were compared for individual drugs.

The researchers found that users of haloperidol had an increased mortality risk, and users of quetiapine had a decreased risk, compared with users of risperidone (hazard ratios, 2.07 and 0.81, respectively), The effects remained after adjustment for dose, were strongest soon after the start of treatment, and were seen for all causes of mortality. There were no clinically meaningful differences seen for other drugs. For all drugs except quetiapine, there was a dose-response relationship.

"Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need," the authors write.

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Patients Taking Antipsychotics Urged to Get Routine Physicals

15 aug 2011-- Patients who take antipsychotic medications aren't being adequately monitored for dangerous health complications, researchers have found.

Known as "metabolic complications," these conditions are common among patients taking antipsychotic drugs. For example, up to 60 percent have lipid (blood fat) abnormalities such as high cholesterol, 40 percent have high blood pressure and 30 percent have metabolic syndrome. It's believed that about 90 percent of patients who take antipsychotic drugs have at least one metabolic risk factor, the researchers said.

Metabolic syndrome is the name for a group of risk factors that raise the risk for heart disease, diabetes and stroke. The risk factors include abdominal obesity, high blood fat levels, high blood pressure and high levels of blood sugar.

The risk of metabolic complications is especially high in schizophrenia patients treated with antipsychotics, according to the report published in the Aug. 10 online edition of the journal Psychological Medicine.

Despite strong evidence of the need for regular monitoring of patients taking antipsychotic drugs, it's overlooked in many cases, the researchers from England, Belgium and the United States found.

The international team reviewed 48 studies conducted in five countries between 2000 and 2011. The studies included a total of nearly 300,000 patients.

Only blood pressure and triglycerides were checked in more than half of the patients, while cholesterol, blood sugar (glucose) and weight were checked in less than half.

"This study highlights that psychiatrists are not always considering the metabolic complications of prescribed medication," study author Dr. Alex Mitchell, of the University of Leicester, said in a university news release. "One explanation is that responsibility is often lost between psychiatry and general practice. We recommend that mental health providers schedule physical health checks as a mandatory part of routine care."

Boxed Mortality Warning Added to Older Antipsychotics Given to Elderly Demented

By John Gever
ROCKVILLE, Md., 18 june 2008 -- Old-line neuroleptic drugs have been given a boxed warning on an increased risk of death when used off-label in elderly patients with dementia, the FDA announced today. It's basically the same warning that has been carried on newer, atypical antipsychotic drugs since 2005. Thomas Laughren, M.D., director of the agency's psychiatry products division, said the move was prompted by two recent observational studies that found increased death rates with older antipsychotics, such as haloperidol (Haldol), chlorpromazine (Thorazine), and fluphenazine (Prolixin), in elderly patients with Alzheimer's disease and other advanced dementias.
Such patients may suffer delusions, hallucinations, and violent agitation, he said in a telephone news conference.
"It's a very difficult situation to manage clinically," he said.
Dr. Laughren emphasized that the label revision is a warning, not a contraindication. "We are not telling physicians they cannot use these drugs in this setting."
Earlier studies with atypical antipsychotics found a 1.6- to 1.7-fold increase in death rates compared with placebo among elderly patients with dementia-related psychosis.
"Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group," according to the warning now carried on atypical antipsychotics.
The new language, to be carried on both classes of drugs, includes:
"Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear."
Letters were sent today to manufacturers of all antipsychotic drugs with the new warning language, Dr. Laughren said.
He said the agency was comfortable that the warning was appropriate for conventional antipsychotics, despite the absence of controlled trials to confirm the excess mortality.

ADA: Metabolic Monitoring Guidelines for Antipsychotics Largely Unheeded

By Crystal Phend
SAN FRANCISCO, 11 june 2008-- Recommendations for lipid and glucose monitoring for patients on atypical antipsychotic drugs have made scarcely a dent on clinical practice, researchers found.Metabolic screening and monitoring rates rose by 5% or less since 2004, when the FDA warned of increased diabetes and cardiovascular risk with antipsychotic medications, according to two separate analyses of large insurance claim databases reported here at the American Diabetes Association meeting.Only about 20% of patients on second-generation antipsychotics received recommended glucose monitoring and just 10% had lipids monitored, reported Dan W. Haupt, M.D., of Washington University in St. Louis, and colleagues in one of the studies.
Changes in screening rates were no better than, and in some cases worse, for patients starting antipsychotics than for other commercially-insured patients, found Elaine Morrato, Dr.P.H., M.P.H., of the University of Colorado in Denver, and colleagues in the other study.
In 2004, the FDA asked manufacturers of atypical antipsychotics to add a warning of the risk of hyperglycemia and diabetes with these medications.
Around the same time, the ADA, American Psychiatric Association, and other groups issued a joint consensus statement recommending that doctors screen and monitor patients on second-generation antipsychotics for signs of rapid weight gain or other problems that could lead to diabetes, obesity, and heart disease.
Surveys have found relatively high awareness of risk, intentions to screen, and self-reported screening rates, Dr. Morrato said. "So there's a disconnect between what's happening and what they say is happening."
Her study included 18,176 adults initiating aripiprazole (Abilify), clozapine (Clozaril, FazaClo), olanzapine (Zyprexa, Zydis), quetiapine (Seroquel), risperidone (Risperdal), or ziprasidone (Geodon) from 2001 through 2006 compared with 56,522 adults likewise at high risk because of diabetes.
For patients on antipsychotics, blood sugar screening rates in 2006 in the month prior to or after initiation was 25.6% and 45.5% within 61 days. Lipid screening rates were 8.9% and 26.9%, respectively.
Glucose screening rose 0.8% per quarter among antipsychotic-treated patients before the guidelines compared with a decrease of 0.6% per quarter afterward (P=0.07 for trend).
Among diabetic control group patients, laboratory glucose screening rates rose 1.2% per quarter before the statement and decreased 1.3% per quarter afterward (P<0.01 for trend).
Likewise, lipid screening decreased 0.6% per quarter after the consensus statement among antipsychotic-treated patients (P<0.001 for trend) compared with a decrease of 1.3% per quarter (P=0.37 for trend) among control group patients.
"Whatever we're observing is just sort of background rates happening," Dr. Morrato said.
Dr. Haupt's retrospective cohort study similarly used a large national insurance database. It included 5,787 patients pre-guideline (2000 to 2003) and 17,832 post-guideline (2004 to 2006) followed from 40 days prior to and 130 days after atypical antipsychotic prescription.
Monitoring rates were:
For lipid screening, 8.25% before guidelines and 10.08% afterward (P<0.01).
For lipid monitoring, 6.78% before guidelines and 8.63% after (P<0.05).
For glucose screening, 17.23% before guidelines and 21.37% after (P<0.01).
For glucose monitoring, 14.03% before guidelines and 17.61% afterward (P<0.01).
Part of the reason for low screening and monitoring rates may be that patients don't follow up on doctor's orders, particularly because many psychiatrists offices are not set up to do onsite blood draws, Dr. Morrato said.
Adding to this challenge is an "identity crisis" in psychiatry, Dr. Haupt said. "Historically these are people who have gone to medical school but have not viewed themselves as physicians in the same way as an internist would."
After the de-institutionalization of psychiatry in the late '60s and '70s, he said, "psychiatrists have been practicing really kind of separated from the rest of the medical field."
Even when screening is done, interpreting the findings of lab results and treating based on them has been problematic, as well, Dr. Morrato noted.
"Many psychiatrists don't necessarily consider these kinds of metabolic complications associated with mental illness and its treatment to be their responsibility," Dr. Haupt said.
The APA is completing a report on these issues that should be similar to existing ADA recommendations, said Dr. Haupt, who was a member of the work group for the report.
Changing clinical behavior for any guideline is not easy, Dr. Morrato said. A disease management approach may help, she said, but Dr. Haupt saw the real shift in the future as reimbursement linked to this kind of quality of care measures comes down the pipeline.
Dr. Morrato's study was supported by Pfizer. Dr. Haupt's study was supported by funding by Bristol-Myers Squibb and Otsuka Pharmaceutical.
Dr. Morrato reported no conflicts of interest. Dr. Haupt reported receiving research support from Abbott and the National Institutes of Health; consulting for Abbott, Bristol-Myers Squibb, Pfizer, Organon, and Wyeth; and receiving royalties from Compact Clinicals for a metabolic reporting form.
Primary source: American Diabetes Association meetingSource reference:Morrato EH, et al "Metabolic screening before and after the ADA consensus statement on antipsychotic drugs and risk of diabetes and dyslipidemia" ADA Meeting 2008; Abstract 967-P. Additional source: American Diabetes Association meetingSource reference: Haupt DW, et al "Prevalence and predictors of lipid and glucose monitoring among commercially insured patients treated with atypical antipsychotic agents" ADA Meeting 2008; Abstract 1216-P.