Atypical antipsychotics and pituitary tumors: a pharmacovigilance study.
OBJECTIVE
To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs.


METHODS
Retrospective pharmacovigilance study.


METHODS
United States Food and Drug Administration's Adverse Event Reporting System (AERS) database.


METHODS
We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D2-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D2 receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol.


RESULTS
To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event. Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (>10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors.


CONCLUSIONS
Treatment with potent D2-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies.
Szarfman
Ana
A
Office of Pharmacoepidemiology and Statistical Sciences, Immediate Office, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. szarfman@cder.fda.gov
Tonning
Joseph M
JM
Levine
Jonathan G
JG
Doraiswamy
P Murali
PM
D000293:Adolescent; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000568:Amenorrhea / Q000139:chemically induced; D014150:Antipsychotic Agents / Q000009:adverse effects*; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000009:adverse effects; D002648:Child; D003024:Clozapine / Q000009:adverse effects; D003987:Dibenzothiazepines / Q000009:adverse effects; D005260:Female; D005687:Galactorrhea / Q000139:chemically induced; D006177:Gynecomastia / Q000139:chemically induced; D006220:Haloperidol / Q000009:adverse effects; D006801:Humans; D006966:Hyperprolactinemia / Q000139:chemically induced; D008297:Male; D000077152:Olanzapine; D010879:Piperazines / Q000009:adverse effects; D010911:Pituitary Neoplasms / Q000139:chemically induced*; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000009:adverse effects; D012189:Retrospective Studies; D018967:Risperidone / Q000009:adverse effects; D012737:Sex Factors; D013844:Thiazoles / Q000009:adverse effects; D014481:United States; D014486:United States Food and Drug Administration
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D015363:Quinolones; D013844:Thiazoles; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; C092292:ziprasidone; D000068180:Aripiprazole; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine