February 2013

Innov Clin Neurosci. 2013;10(2):10–16

Dear Editor:

In response to the article by Arcari et al, which was published in the September 2012 issue of Innovations in Clinical Neuroscience,[1] we wish to clarify the following:

• The mechanism of antipsychotic-induced hyperprolactinemia
• The lack of evidence that antipsychotics induce pituitary tumors in patients
• That pharmacovigilance disproportionality analyses are not evidence of a cause and effect relationship
• That the authors’ recommendation to monitor prolactin concentrations in asymptomatic patients treated with antipsychotics is not supported.

The mechanism of action of antipsychotics for schizophrenia treatment, although not fully understood, is thought to be related to central dopamine D2 receptor blockade. The resulting loss of tonic inhibition of prolactin production in the anterior pituitary is the most likely cause of antipsychotic-induced hyperprolactinemia, as also endorsed in the articles[2–7] cited by Arcari et al, and counter to their assertion that a serum prolactin increase is often due to a drug-induced benign pituitary tumor (prolactinoma). The statement that risperidone is a leading cause of antipsychotic-induced pituitary tumors is based on a single reference involving a disproportionality analysis of the United States Food and Drug Administration’s (FDA) Adverse Event Reporting System.[8] That analysis was the topic of the Wall Street Journal article (June 17, 2005), which triggered treatment decisions in the authors’ case report of an asymptomatic patient, including discontinuing her from effective psychiatric treatment.

Experts view disproportionality analyses as a hypothesis-generating tool that can identify potential risks to be further evaluated in the context of other relevant data.[9] In the cited article,[8] Szarfman et al state, “A high score…for a drug-adverse event association cannot prove causality.” A high drug-event pairing score may be attributed to an underlying disease and its treatment or confounders by indication, among other considerations. In a recently completed study by the manufacturer of risperidone,[10] no increased risk of pituitary tumors with mass effects was found in patients treated with risperidone versus other atypical antipsychotics (hazard ratio=1.0; 95% confidence interval [CI] 0.5–2.0). The elevated number of pituitary tumor cases in adverse event reports might be explained by detection bias.10 We are not aware of any published literature that establishes a causal relationship between antipsychotics and pituitary tumor.

As described in the United States Package Insert, risperidone may cause hyperprolactinemia. However, it has never been demonstrated that hyperprolactinemia can cause a pituitary adenoma, including in normal states of hyperprolactinemia and pituitary hyperplasia, such as pregnancy.[11] Arcari et al[1] cite two articles to demonstrate that prolactinomas may regress after risperidone withdrawal. Neither case demonstrates that. Both patients were also managed with dopamine agonist therapy to shrink the mass. In the first example,[12] the patient had a macroadenoma before risperidone was started. While the patient used risperidone, biannual magnetic resonance imaging (MRI) scans were stable for two years before the mass grew from 11mm (at baseline) to 12mm. Risperidone was discontinued; subsequent MRIs showed no change in tumor size. Therefore, tumor regression after risperidone withdrawal is not evidenced.

In the second example,[13] a female patient experienced galactorrhea and amenorrhea while using risperidone. She had increased prolactin (124ng/mL) and a 3 to 4mm microadenoma on a subsequent computed tomograhy (CT) scan. Risperidone was discontinued and no adenoma was seen on the MRI one month later. MRI is the gold standard for pituitary evaluation: a false positive on the initial CT cannot be excluded.

In Arcari et al’s case report,[1] a 57-year-old woman with a 21-year history of thioridazine treatment for schizoaffective disorder had been switched to risperidone because of suspected tardive dyskinesia. The authors state that the patient experienced “great emotional stability” on risperidone. No hyperprolactinemia or extrapyramidal symptoms were reported. However, a serum prolactin level was drawn and revealed an elevation (100.1ug/L). A 2mm area on MRI was suspicious for pituitary microadenoma. Approximately six months after switching to ziprasidone, both prolactin and MRI were normal. The authors do not consider plausible alternative etiologies for the initial MRI finding, notably thioridazine history, pituitary enlargement associated with the underlying illness, a clinically insignificant adenoma (occurring in 10–20% of the general population14), or a radiographic detection bias associated with the elevated prolactin. Arcari et al do not provide compelling evidence linking risperidone and pituitary adenoma. The natural history of the transient pituitary finding, had the patient continued risperidone, cannot be predicted. The authors refer to Gianfrancesco et al[15] in recommending annual prolactin screening in patients taking risperidone or other antipsychotics. However, similar to McCarren et al,[10] Gianfrancesco concluded that investigation and reporting biases may influence the disproportional reporting of pituitary tumor in patients on risperidone, and that prolactin evaluation is indicated only for clinically symptomatic patients.[15] We concur with this position.

1. Arcari GT, Mendes AK, Sothern RB. A risperidone-induced prolactinoma resolved when a woman with schizoaffective disorder switched to ziprasidone: a case report. Innov Clin Neurosci. 2012;9(9):21–24.
2. Popli A, Gupta S, Rangwani SR. Risperidone-induced galactorrhea associated with a prolactin elevation. Ann Clin Psychiatry. 1998;10:31–33.
3. Dickson R, Glazer W. Neuroleptic induced hyperprolactinemia. Schizophr Res. 1999;35:S75–86.
4. Hariharan J, Moshin J. Risperidone induced galactorrhea: a case analysis. WMJ. 2002;101:41–43.
5. Halbreich U, Kahn LS. Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J Psychiatr Pract. 2003;9:344–353.
6. Holzer L, Eap CB. Risperidone induced symptomatic hyperprolactinemia in adolescents. J Clin Psychopharmacol. 2006;26:167–171.
7. Kopecek M, BaresM, Horacek J, Mohr P. Low dose risperidone augmentation of antidepressants or anxiolytics is associated with hyperprolactinemia. Neuro Endocrinol Lett. 2006;27:803–806.
8. Szarfman A, Tonning JM, Levine JG, et al. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy. 2006;26(6):748–758
9. Almenoff J, Tonning JM, Gould AL, et al. Perspectives on the use of data mining in pharmaco-vigilance. Drug Saf. 2005;28(11):981–1007.
10. McCarren M, Qiu H, Ziyadeh N, et al. Follow-up study of a pharmacovigilance signal: no evidence of increased risk with risperidone of pituitary tumor with mass effect. J Clin Psychopharmacol. 2012;32(6):743–749.
11. Foyouzi N, Frisbaek Y, Norwitz ER. Pituitary gland and pregnancy. Obstet Gynecol Clin North Am. 2004;31:873–892.
12. Pal JK, Sarino WA. Effect of risperidone on prolactinoma growth in a psychotic woman. Psychosom Med. 2000;62:736–73.
13. Mendhekar DN, Jiloha RC, Srivastava PK. Effect of risperidone on prolactinoma—a case report. Pharmacopsychiatry. 2004;37:41–42.
14. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101(3):613–619.
15. Gianfrancesco FD, Pandina G, Mahmoud R, et al. Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: a claims-based study. Ann Gen Psychiatry. 2009;8:5.

With regards,
Danielle Coppola, MD; Shanker Thiagarajah, BSc, MB ChB, MRCP, MFPM; Hong Qiu; David Hough, MD
Drs. Coppola, Qiu, and Hough are with Janssen Research and Development, LLC, Raritan, New Jersey; Dr. Thiagarajah is with Janssen-Cilag, Ltd, High Wycombe, United Kingdom.

Funding/financial disclosures: Janssen Research and Development, LLC (formerly Johnson & Johnson Pharmaceutical Research and Development, LLC) in Raritan, New Jersey developed risperidone. Drs. Coppola, Qiu, and Hough are employees of Janssen Research and Development. Dr. Thiagarajah is an employee of Global Medical Safety, Janssen-Cilag Ltd. in High Wycombe, United Kingdom, which is also a Johnson & Johnson company.

Acknowledgment: Wendy P. Battisti, PhD (Janssen Research and Development, LLC) provided additional editorial and administrative support for this letter.


Dear Editor:

We note the concerns of Coppola et al in this issue pointing out some proposed limitations of our case report regarding an association between antipsychotic drugs and occurrence of a prolactinoma in a woman using thioridazine for approximately 21 years followed by risperidone for 10 years.[1] After learning from a June 2005 newspaper article about a possible link between prolactinemia and use of risperidone, the patient sought medical advice whereupon her prolactin level (PRL) was elevated (83.8µg/L) and a magnetic resonance imaging (MRI) scan detected an area in the pituitary consistent with a microadenoma. After PRL was noted to be at a higher level on August 31 (100.1µg/L), risperidone was replaced with an alternative drug (ziprasidone), whereupon there was a return to normal PRL within eight weeks and complete disappearance of the suspected adenoma in a six-month follow-up MRI. Ensuing PRL determined once or twice a year for 5.5 years were all below the upper normal limit for female subjects (24.1µg/L) and our patient’s PRL remained normal (9.2µg/L) when checked on September 27, 2012.

Although the course of onset of the pituitary microadenoma and hyperprolactinemia was unknown, it appeared conceivable that risperidone was somehow involved with the microadenoma development and its complete disappearance after the drug substitution, since the only change in medication regimen was switching to a different antipsychotic. Thus, the goal of our report was to add more information into the literature about a prolactinemia that may have resulted from a medication-induced pituitary prolactinoma[2] and suggest that PRL be periodically tested in individuals using antipsychotic drugs in order to consider management options, including a change to a prolactin-sparing drug. We wish to note the following additional representative literature supporting points mentioned in our case report and that address the concerns of Coppola et al:

1. Following use of four antipsychotics by patients with schizophrenia, risperidone clearly had “the most robust effect” on PRL that appeared to be dose-dependent.[3]

2. A review of 17 studies found that PRL increased by up to 272 percent in psychotic patients using haloperidol or risperidone, and noted that certain individuals may be more sensitive to elevated prolactin and/or prolactin-secreting pituitary tumors by risperidone or other antipsychotic medications.[4]

3. A review of hyperprolactinemia and psychotropics noted that risperidone is one of “the most frequent and significant offenders” and that more marked elevations in PRL are caused by risperidone than other atypical antipsychotics since it does not fully cross the blood-brain barrier, resulting in higher D2 receptor occupancy of the pituitary than the striatum.[5] To manage hyperprolactinemia, they suggested that PRL be measured “in all symptomatic patients on antipsychotics and routinely in patients on conventional antipsychotics or risperidone.”

4. In a review of atypical antipsychotics, Ali et al[6] found up to a 91-percent prevalence of increased PRL in risperidone-treated patients and presented a case report of a man with schizophrenia who developed a pituitary macroadenoma and hyperprolactinemia while using risperidone. The authors recommended that PRL “should be measured regularly,” which “is particularly important if the patient is receiving risperidone or a typical antipsychotic agent.”[6]

5. A double-blind study of patients with schizophrenia found that after six weeks of daily treatment, mean PRL was not significantly changed for ziprasidone (-3.5ng/mL), but significantly increased for risperidone (+61.1ng/mL) compared to baseline.[7]

6. For a female patient who had a residual adenoma and hyperprolactinemia after prolactinoma resection, a change in treatment from risperidone to aripiprazole resulted in reductions in PRL, tumor size, and visual field effect with no psychotic decompensation.[8]

7. Additional information from an article by Szarfman et al[9] cited in our case report noted that 1) knocking out the D2 receptor in mice resulted in a striking progressive increase in pituitary lactograph cells and pituitary tumors, PRL levels were six times higher in females, and females developed tumors much earlier than males; and 2) subchronic toxicity studies of mice with risperidone for 18 to 24 months produced a statistically significant increase in pituitary adenomas and adenocarcinomas, as well as a four-fold elevation in PRL levels.

Thus, accumulating case reports and reviews highlight the role of risperidone on PRL, discuss alternative methods of treating psychosis when the etiology is unclear, and indicate that additional studies regarding the relationship between the occurrence of prolactinemia and prolactinoma and atypical antipsychotics would be worthwhile. Coppola et al end their commentary with a paraphrase from Gianfrancesco et al[10] that “PRL evaluation is indicated only for clinically symptomatic patients,” to which they concur, yet in a recent article they do not rule out a small risk that a pituitary tumor may develop with years of risperidone exposure.[11] In guidelines provided by the Clinical Guidelines Subcommittee of the Endocrine Society[12] where “even minimal prolactin elevations may be consistent with the presence of a prolactinoma,” annual PRL monitoring for patients taking anti-psychotics and diagnosed with hyperprolactinemia is recommended, even after any management intervention, especially since the prevalence of hyperprolactinemia is still underestimated.[5]

Also, symptoms of a pituitary expanding mass may not be evaluated promptly in patients with mental illness, and delayed detection could lead to complications, such as hemorrhage or optic nerve compression.[9] Our patient was asymptomatic, and if the recommendation of no annual PRL had taken place, she would never have known of her high PRL levels that subsequently led to an MRI and diagnosis of a pituitary microadenoma, which completely disappeared after transitioning from risperidone to an alternative antipsychotic drug.

In reaction to the comments regarding our case report, we asked for a second reading of the original MRIs of our subject’s brain by an unaffiliated neuroradiologist who agreed with the initial report seven years earlier that there was a “decreased signal in the pituitary gland consistent with a microadenoma.”

1. Arcari GT, Mendes AK, Sothern RB. A risperidone-induced prolactinoma resolved when a woman with schizoaffective disorder switched to ziprasidone: a case report. Innov Clin Neurosci. 2012; 9(9):21–24.
2. Doraiswamy PM, Schott G, Star K, et al. Atypical antipsychotics and pituitary neoplasms in the WHO database. Psychopharmacol Bull. 2007;40(1):74–76.
3. Volavka J, Czobor P, Cooper TB, et al Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry. 2004;65(1):57–61.
4. Hoffer ZS, Roth RL, Mathews M. Evidence for the partial dopamine-receptor agonist aripiprazole as a first-line treatment of psychosis in patients with iatrogenic or tumorogenic hyperprolactinemia. Psychosomatics. 2009;50(4):317–324.
5. Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics—a review. Human Psychopharmacol. 2010;25(4):281–297.
6. Ali S, Miller KK, Freudenreich O. Management of psychosis associated with a prolactinoma: case report and review of the literature. Psychosomatics. 2010;51(5):370–376.
7. Zhang H, Li H, Shu L, et al. Double-blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia. Neuropsychiatr Dis Treat. 2011;7:77–85.
8. Broekhof R, Gosselink MJ, Pijl H, Giltay EJ. The effect of aripiprazole and quinagolide, a dopamine agonist, in a patient with symptomatic pituitary prolactinoma and chronic psychosis. Gen Hosp Psychiatry. 2012;34(2):209.e1–3.
9. Szarfman A, Tonning JM, Levine JG, Doraiswamy PM. Atypical antipsychotics and pituitary tumors: a pharmacovigilence study. Pharmacotherapy. 2006;26:748–758.
10. Gianfrancesco FD, Pandina G, Mahmoud R, et al. Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: a claims-based study. Ann Gen Psychiatry. 2009;8:5.
11. McCarren M, Qiu H, Ziyadeh N, et al. Follow-up study of a pharmacovigilance signal: no evidence of increased risk with risperidone of pituitary tumor with mass effect. J Clin Psychopharmacol. 2012;32(6):743-749.
12. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–288.

With regards,
Gail T. Arcari, MEd; Asante K. Mendes, MD; and Robert B. Sothern, PhD
Ms. Arcari is from Cromwell, Connecticut; Dr. Mendes is from Tufts University School of Medicine, Boston, Massachussetts, and University of Connecticut Health Center, Farmington, Connecticut; and Dr. Sothern is Research Assistant Professor, College of Biological Sciences, University of Minnesota, St. Paul, Minnesota.

Funding/financial disclosures: No funding was received for the preparation of this article. The authors have no conflicts relevant to the content of this article.