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A link may exist between the development of pituitary tumors and the use of some drugs commonly used to treat schizophrenia, according to research from Duke University Medical Center and the U.S. Food and Drug Administration (FDA). Although a connection has been suspected for more than 20 years, this is the first systematic study to document an association between specific antipsychotic medications and adverse reports of pituitary tumors in humans.
Of seven antipsychotic medications, risperidone (trade name Risperdal), was linked to 70 percent of pituitary tumors reported to the FDA's Adverse Events Reporting System database. Risperidone is the most widely used medication within the class of drugs called atypical antipsychotics, which are used to treat schizophrenia, paranoia and manic-depressive disorders, according to the study authors.
The findings appear in the June 2, 2006 issue of Pharmacotherapy. The study was funded by the author's respective research departments. Coauthors include lead author Ana Szarfman, Joseph Tonning and Jonathan Levine, all of the FDA.
The researchers cautioned that the study, although suggestive, does not prove that the medications actually cause pituitary tumors.
"Our findings do not prove a causal relationship between antipsychotic medications and pituitary tumors, but health professionals and patients should be aware of such potentially adverse effects," said P. Murali Doraiswamy, M.D., a psychiatrist at Duke and co-author of the study.
"Atypical antipsychotics are lifesaving medications for a lot of people. By no means are we advocating that people stop using them, especially risperidone," he said. "But we do need to learn more about possible differences in their long-term side-effects, and I believe this should be a high priority for investigation."
Doraiswamy cautions that the study merely suggests an association between the drugs, pituitary tumors and several other side-effects – not a true causal relationship. Further studies are needed to offer such conclusive evidence. If future studies confirm the findings, stronger warning labels should be considered for these drugs, he said.
"The actual numbers of people known to have developed pituitary tumors as a possible side-effect due to any of these medications remains unclear because many adverse drug reactions are not reported to the FDA," Doraiswamy cautioned. "We also don't have exact numbers of how many people currently take these drugs. Another caveat is that pituitary tumors can occur incidentally among the population in general."
The team chose six atypical antipsychotics and one typical antipsychotic to examine in a "data mining" analysis using a sophisticated software algorithm. The algorithm, called the Multi-item Gamma Poisson Shrinker (MGPS), was used to "mine" data contained in the FDA's Adverse Event Reporting System (AERS) database. Using the algorithm software, the researchers looked for disproportionate reporting patterns of pituitary tumors linked to use of risperidone, aripiprazole, clozapine, olanzapine, quetiapine, ziprasidone and haloperidol, the typical antipsychotic.
They found 77 reports of pituitary tumors associated with the seven antipsychotics. Risperidone was associated with 54 (70 percent) of those reports and had the highest adjusted reporting ratio for pituitary tumors, followed by haloperidol and ziprasidone. Complications included nine reports of visual problems, two reports of convulsions, four reports of headaches, three reports of cerebrovascular events and seven reports of patients who needed surgical intervention.
The antipsychotic drugs in question are all dopamine D2 receptor antagonists that work by blocking dopamine, a neurotransmitter. A key function of dopamine is to suppress the release of prolactin, a hormone, from the pituitary gland.
Elevation of blood prolactin levels is a well known side-effect of potent dopamine D2 blocking antipsychotics and, because antipsychotic medications vary in their potency, some medications appear to increase prolactin levels more intensely than other medications in their class, Doraiswamy said.
Increased cellular production of prolactin can cause enlargement of the pituitary gland and disrupt production of other hormones, creating hormonal imbalances in the body. It can also lead to the development of pituitary tumors. Most pituitary tumors are benign, and pituitary cancer is extremely rare.
Enlargement of the pituitary can cause other problems as well. The gland is located close to the optic nerve, so its enlargement can compress the nerve and cause visual problems, including partial blindness. Any swelling or abnormal growth within the pituitary can press on the brain and lead to headaches, bleeding, and, in some cases, convulsions, Doraiswamy added.
Indeed, reported side-effects to the FDA database included 796 reports of increased blood levels of the hormone prolactin (hyperprolactinemia); 503 reports of the cessation of menses in women (amenorrhea); 630 reports of production of breast milk in adults and children of both sexes (galactorrhea); and male breast development. Ninety of the reports of hyperprolactinemia and 96 of the reports of galactorrhea occurred in children and adolescents. According to Doraiswamy, these symptoms can be indicative of a pituitary disturbance but not necessarily of a pituitary tumor.
All reported side-effects were most strongly associated with risperidone, which also accounted for 82 percent of all reported occurrences of side-effects in children and adolescents, Doraiswamy said.
The researchers are concerned that development of pituitary tumors following chronic use of potent antipsychotics may pose a problem in mentally ill patients, particularly children.
"In this population, we worry that symptoms may not be evaluated quickly enough, which, if due to a tumor, could lead to complications such as visual problems or localized bleeding near the pituitary gland," Doraiswamy said. "Although such serious side-effects are quite rare, prescribing physicians, patients and their family members should watch for them because they can be controlled."
Doraiswamy noted that the patterns of reported side-effects contained in a database as large as the FDA's may never have been fully appreciated without the use of the MGPS algorithm method, which was developed in part by Szarfman, the study's lead author.
More than 1,000 adverse drug events are added to the FDA's drug safety database every day, and the system now holds more than 2.5 million entries. The large numbers suggest millions of possible combinations between medications and side-effects that no human could ever compute, monitor or contextualize on their own, Doraiswamy said.
Doraiswamy has previously received funding and consulting fees from all companies that manufacture the antipsychotic medications examined in this study. They are Janssen Pharmaceutica, the manufacturer of risperidone (Risperdal); Bristol-Myers Squibb Company/Otsuka America Pharmaceuticals, manufacturers of aripiprazole (Abilify); Novartis Pharmaceuticals, manufacturer of clozapine (Clozaril); Eli Lilly and Company, manufacturer of olanzapine (Zyprexa); AstraZeneca Pharmaceuticals LP, manufacturer of quetiapine (Seroquel); and McNeill Laboratories/Janssen Pharmaceutica, manufacturer and developer of the typical antipsychotic haloperidol (Haldol).
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