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Guidelines for Antipsychotic-Induced Hyperprolactinemia

Brigitta E. Miyamoto; Martha Galecki, MD; and Dimitry Francois, MD

ABSTRACTTreatment with antipsychotic medi-

cation can be associated with hyperpro-lactinemia, which may be asymptomatic or associated with a wide variety of side effects. Determining a baseline prolactin level before beginning antipsychotic ther-apy can assist the clinician in determining whether or not a patient’s elevated level is due to medication-induced hyperpro-lactinemia. If other causes of hyperpro-lactinemic can be ruled out, then careful consideration must be given to the risks and benefits of maintaining the patient on the therapeutic antipsychotic regimen. It is suggested that prolactin levels in patients taking antipsychotics should be moni-tored, but there is no consensus regarding frequency. Management of antipsychotic-induced hyperprolactinemia should be conducted on a case-by-case basis. [Psy-chiatr Ann. 2015;45(5):266-272.]

Treatment with antipsychotic medication may be correlated with a rise in prolactin level due

to hypothalamic dopamine blockade. Hyperprolactinemia associated with an-tipsychotic use can be asymptomatic or associated with a number of adverse effects. Irregular menses, male gyneco-mastia, osteoporosis, sexual dysfunction,

and infertility in both genders are among the potential risks, necessitating that psychiatrists monitor and manage del-eterious effects in patients being treated with antipsychotics. This article includes a discussion of evidence for baseline prolactin screening, suggested work-up in the event that hyperprolactinemia is detected, and possible courses of action.

Brigitta E. Miyamoto is a third-year Medi-

cal Student, Weill Cornell Medical College.

Martha Galecki, MD, is a second-year Resident

in Psychiatry, Weill Cornell Medical College.

Dimitry Francois, MD, is an Assistant Professor

of Psychiatry, Weill Cornell Medical College.

Address correspondence to Dimitry

Francois, MD, 21 Bloomingdale Road,

White Plains, NY 10605; email: dif9013@

med.cornell.edu.

Disclosure: The authors have no relevant

financial relationships to disclose.

doi: 10.3928/00485713-20150501-09

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SHOULD A BASELINE PROLACTIN LEVEL BE MEASURED PRIOR TO INITIATING ANTIPSYCHOTIC THERAPY?

The guidelines are not clear on this question; some clinicians recommend no screening or propose screening for higher-risk medications and patients, whereas others endorse universal pre-treatment screening.1 The strongest predictors of hyperprolactinemia are the type and dose of the antipsychotic prescribed, with increased levels ob-served at higher doses.2 In the case of typical antipsychotics, antipsychotic efficacy correlates with elevation in prolactin level. Therefore, haloperidol gives rise to the greatest prolactin lev-el increase. Risperidone is among the highest elevators of the atypical anti-psychotics. Olanzapine and quetiap-ine are less commonly associated with hyperprolactinemia. Clozapine and aripiprazole rarely elevate prolactin.2 Age of the female patient is also a fac-tor in developing hyperprolactinemia. Women of reproductive age, particu-larly parous women, appear to be at higher risk of hyperprolactinemia than postmenopausal women.1

Nonetheless, pretreatment prolac-tin screening in a patient started on an antipsychotic regimen allows for less diagnostic confusion in the event of potential hyperprolactinemia, permit-ting greater confidence in a diagnosis of medication-induced hyperprolac-tinemia.1 For example, if it is clear that an increase in prolactin level fol-lows the initiation of antipsychotic therapy, and no features of pituitary disease (such as headache and visual disturbances) are present, then further investigation is unnecessary.1 The Pi-tuitary Society recommends retesting the prolactin level 72 hours after tem-porarily discontinuing antipsychotic medication.3 Often, however, drug dis-continuation is not feasible because of the patient’s clinical condition.1 Some

authors propose not only establishing a baseline prolactin level, but also de-termining baseline menstruation and psychosexual function.4 The latter information is useful because inquir-ing about these more private topics provides a good segue to explaining potential antipsychotic side effects to the patient and sets the stage for revis-iting these types of questions during follow-up appointments.

WHICH EVALUATION SHOULD BE PERFORMED WHEN AN ELEVATED PROLACTIN LEVEL IS DETECTED IN A PATIENT RECEIVING ANTIPSYCHOTIC THERAPY?

One must first examine the tempo-ral relationship between prolactin lev-el elevation and initiation of antipsy-chotic therapy.4 As mentioned above, unnecessary work-up can be avoided when the temporal relationship is clear.1 This is why establishing a pre-treatment prolactin level is valuable. If the time course is unclear, however, a full set of testing must be conducted, including assessing liver, renal, and thyroid function. One may consider performing magnetic resonance imag-ing of the pituitary gland, particularly if the patient displays symptoms of a sellar space-occupying lesion, sug-gested by the presence of headache and visual field defects,5 or if the prolactin level is more than 4 times greater than the upper range of nor-mal1 (ie, 300-500 mIU/L, correspond-ing to ~14-24 ng/mL).4 One may also consider determining sex steroid lev-els to assess for risk of osteoporosis.1 In addition to time course and symp-tomatology, the degree of rise in pro-lactin level is helpful in determining whether the elevation can best be at-tributed to use of antipsychotic drugs or another cause. If the prolactin level is less than 2,000 mIU/L (~95 ng/mL), elevated numbers are more likely due to the use of antipsychotic medica-

tion; if the level is greater than 2,500 mIU/L (~118 mg/mL), in the absence of breast-feeding or pregnancy, a pitu-itary tumor may be suspected.4

WHAT SHOULD BE DONE IF THE PATIENT IS ASYMPTOMATIC OR MILDLY SYMPTOMATIC?

The risks and benefits of discon-tinuing or changing an antipsychotic regimen versus the possibility of psy-chiatric illness relapse must be care-fully weighed.6 The presence and se-verity of clinical symptoms, and not a rise in prolactin level alone, should dictate treatment strategy.6 In an as-ymptomatic female patient having regular periods, it is unnecessary to make changes in antipsychotic medi-cation.1 Similarly, in the case of a female patient experiencing mild ga-lactorrhea with regular periods, treat-ment may continue.7 The recommen-dation to discontinue antipsychotic therapy in asymptomatic patients with medication-induced hyperprolac-tinemia is weakly made, according to the Endocrine Society Clinical Prac-tice Guideline.8 Nevertheless, known or postulated side effects from long-standing hyper-prolactinemia, such as osteoporosis and an elevated risk of pituitary adenomas, may present a justifiable reason to reevaluate estab-lished antipsychotic therapy despite a lack of symptoms.6

WHAT COURSE OF ACTION SHOULD BE TAKEN WHEN SYMPTOMS ARE SIGNIFICANT?

One must weigh the benefit the pa-tient is obtaining from antipsychotic therapy, predicted length of time the patient will continue on medication, and risk of relapse in the case of dose reduction or change in medication.6 Side effects (such as galactorrhea, gynecomastia, oligomenorrhea, amen-orrhea, infertility, sexual dysfunc-tion, and osteoporosis) and the level

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of patient distress must be monitored. In patients who rely on depot admin-istration of antipsychotics, benefits may outweigh the risks of switching medications.5 Two relatively new de-pot antipsychotics have recently come onto the market: (1) aripiprazole9 and (2) olanzapine.10 These drugs may provide clinicians with more options should they wish to change treatment to a prolactin-sparing depot antipsy-chotic medication.

TREATMENT OPTIONS Change to a Prolactin-Sparing Antipsychotic

This class of drugs includes olan-zapine, quetiapine, ziprasidone,4 and clozapine. Unfortunately, the cross-titration period poses a significant risk of relapse of psychiatric symptoms.4

The decision to switch to a prolactin-sparing antipsychotic must be made individually for each patient.

Addition of Sex SteroidsIn women undergoing antipsychot-

ic therapy, a combined oral contracep-tive will prevent estrogen-deficiency symptoms, possibly including bone mineral density (BMD) loss.2 How-ever, symptoms of hyperprolactinemia will be unaffected.5

Addition of Dopamine Receptor Agonist

Because the addition of a dopamine receptor agonist such as amantadine or bromocriptine may cause a psychotic relapse, this option is typically not recommended.6 Although dopamine receptor agonists have been shown to increase BMD, they may also give rise to orthostatic hypotension, gastroin-testinal side effects, and exacerbation of psychosis.7 Addition of the recep-tors should therefore be considered a third-line strategy, after changing an-tipsychotics and supplementing with sex steroids.2 In such cases, the lowest

possible dose of dopamine receptor ag-onist should be used, with close moni-toring.2 However, in the absence of the option to alter the antipsychotic medi-cation, addition of a dopamine receptor agonist is the only approach to improve infertility and galactorrhea symptoms.2

Decrease Current Dose of Medication

As the risk of hyperprolactinemia is dose-dependent, a reduction in an-tipsychotic dose may theoretically be helpful,1 but effectiveness of such a reduction has not been systematically studied.4 It is unclear whether dose lowering has significant effects on prolactin levels, prolactinemia symp-toms, or recurrence of psychiatric symptoms.4

Is Adding Aripiprazole Safe and Effective?

Some studies have suggested treat-ment strategies using aripiprazole as an adjunct to reduce the prolactin level in patients treated with antipsy-chotics. Particularly in patients who are clinically stable on antipsychotic treatment, discontinuing current med-ication and switching to an atypical antipsychotic may be inappropriate, so adjunctive therapy may be a better strategy.11 The rationale of aripipra-zole’s use as an adjunct may be attrib-uted to its dual agonism/antagonism at the dopamine D2 receptor, which may mitigate the effects of other an-tipsychotic medications on the pitu-itary gland.12 Meta-analysis of five randomized controlled trials showed a prolactin level normalization rate of 79%.13 No significant differences in psychiatric symptoms or side ef-fects between control and adjunctive aripiprazole-treatment groups were detected.13 However, an increase in sedation, insomnia, and headache was present if the administered dose was higher than 15 mg/day. Thus, the au-

thors suggest an aripiprazole dose of 5 mg/day.13

How Should the Side Effects of Osteopenia and Osteoporosis Be Addressed?

If amenorrhea has lasted 12 months or longer in a female patient on an antipsychotic regimen, BMD mea-surements should be undertaken. If osteopenia or osteoporosis is discov-ered, Haddad and Wieck5 recommend referring the patient to a specialist for further management. Others suggest the approach to treating bone loss is to lower prolactin, which will normal-ize the sex steroids, or alternatively, to provide exogenous sex steroids.6 Hyperprolactinemia alone is not a di-rect risk factor for the development of osteoporosis; data appear to point toward a prolonged decrease in sex steroid levels as the cause of osteo-porosis due to hyperprolactinemia.6 BMD loss is possible in both genders. Monitoring BMD for 2 years after osteoporosis detection allows the cli-nician to determine whether one of the aforementioned interventions has been successful. If BMD level does not respond, only then should one consider alternative treatments such as bisphosphonates.2 On the other hand, some sources recommend the introduction of bisphosphonates im-mediately upon discovery of osteo-porosis.7 Therefore, there is no clear recommendation on how to prevent or treat osteoporosis in this population.

Does Prolonged Hyperprolactinemia due to Long-Term Antipsychotic Therapy Increase the Risk of Breast Cancer, Pituitary Tumors, or Sexual Dysfunction?

Breast Cancer. More data are needed to answer this question. Some authors cite lower rates of breast can-cer in women with schizophrenia,

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PSYCHIATRIC ANNALS • Vol. 45, No. 5, 2015 271

whereas others claim higher rates.2 A study of female patients with operable breast lesions showed the presence of hyperprolactinemia in comparable proportions in the case of breast can-cer and benign breast conditions.2 Similarly, a Dutch investigation of women with idiopathic hyperprolac-tinemia or prolactinomas demonstrat-ed no increase in breast cancer rates when compared with national breast cancer incidence.2 However, two stud-ies have lent support to a potential as-sociation between hyperprolactinemia and breast cancer. A prospective anal-ysis found a 2-fold increase in breast cancer in women having prolactin lev-els in the 75th percentile compared to those with levels in the lower 25% range. In addition, a retrospective co-

hort study demonstrated that the use of prolactin-raising antipsychotics was associated with a 16% increase in breast cancer.6

Pituitary Tumors. There is an in-creased prevalence of prolactinoma in patients receiving risperidone and haloperidol, but not in those receiving ziprasidone, olanzapine, clozapine, or quetiapine. This finding, however, may be attributed to surveillance and reporting bias.1 In fact, patients receiv-ing antipsychotic therapy, particularly when taking medications more likely to induce hyperprolactinemia, such as risperidone and haloperidol, are more likely to undergo pituitary imaging screening.1 Although the relationship is currently unclear, correlations have been shown between affinity for the

dopamine D2 receptor and strength of association with pituitary tumor, with risperidone having the highest recep-tor affinity and strength of associa-tion, followed by haloperidol, ziprasi-done, and olanzapine.6

Sexual Dysfunction. Research on this topic has been limited by the confounding factors of patients tak-ing more than one medication and the difficulty of distinguishing sexual dysfunction attributed to medication versus the effect of the psychiatric ill-ness itself.14

Studies have demonstrated higher rates of sexual dysfunction in patients with prodromal signs of psychosis as well as first-episode psychosis com-pared with healthy controls,14 suggest-ing that sexual dysfunction may be

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inherent to the illness itself. Neverthe-less, observations have been made on the association between antipsychotic medications known to significantly increase prolactin and the incidence of sexual dysfunction. For instance, risperidone is well known to increase prolactin levels, and its use has also been correlated with some of the high-est rates of anorgasmia.15 The risks of medication nonadherence are par-ticularly high when patients develop sexual dysfunction as a side effect,15 indicating the importance of screening for sexual side effects over the course of antipsychotic treatment.

How Often Should Prolactin Be Measured in Patients Taking Antipsychotics?

Monitoring of prolactin is “gen-erally not recommended” in clinical guidelines.4 Thus, an elevated prolac-tin level will frequently be detected only after inquiring about the patient’s side effects to medication. It is impor-tant to ask about them, as patients will not often reveal symptoms of a more personal nature.4 Despite the fact that no guidelines exist for routine pro-lactin monitoring, some symptoms, such as osteoporosis and infertility, are silent, and guidelines for routine monitoring in patients on antipsy-chotic regimens should perhaps be implemented.16 Some authors suggest testing prolactin levels 3 months after initiation of an antipsychotic, because blood will be drawn for diabetes and dyslipidemia monitoring at this time, followed by subsequent testing as un-

desirable symptoms appear.1 Other au-thors propose annual testing.7

CONCLUSION Treatment with antipsychotic medi-

cation can be associated with hyperp-rolactinemia, which may be asymptom-atic or associated with a wide variety of side effects. Prior to initiating antipsy-chotic therapy, determining a baseline prolactin level may assist the clinician in determining whether a patient’s el-evated level is due to medication-in-duced hyperprolactinemia or another cause. One must conduct a thorough work-up of hyperprolactinemic patients to rule out other causes, and then care-fully consider the risks and benefits of maintaining the patient on the therapeu-tic antipsychotic regimen, altering the dose, changing the medication, or add-ing other medications to specifically address adverse effects. It is suggested that prolactin levels in patients taking antipsychotics should be monitored, although no consensus as to frequency has been reached. Management of anti-psychotic-induced hyperprolactinemia should be on a case-by-case basis.

REFERENCES 1. Holt RI, Peveler RC. Antipsychotics and

hyperprolactinaemia: mechanisms, conse-quences and management. Clin Endocrinol (Oxf). 2011;74(2):141-147.

2. Inder WJ, Castle D. Antipsychotic-induced hyperprolactinaemia. Aust N Z J Psychiatry. 2011;45(10):830-837.

3. The Pituitary Society. Prolactinoma. http://www.pituitarysociety.org/public/specific/prolactinoma/prolactin.aspx. Accessed April 17, 2015.

4. Walters J, Jones I. Clinical questions and uncertainty--prolactin measurement in

patients with schizophrenia and bipolar disorder. J Psychopharmacol. 2008;22(2 Suppl):82-89.

5. Haddad PM, Wieck A. Antipsychotic-in-duced hyperprolactinaemia: mechanisms, clinical features and management. Drugs. 2004;64(20):2291-2314.

6. Byerly M, Suppes T, Tran QV, Baker RA. Clinical implications of antipsychotic-in-duced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and cur-rent perspectives. J Clin Psychopharmacol. 2007;27(6):639-661.

7. Madhusoodanan S, Parida S, Jimenez C. Hy-perprolactinemia associated with psycho-tropics--a review. Hum Psychopharmacol. 2010;25(4):281-297.

8. Melmed S, Casanueva FF, Hoffman AR, et al.; Endocrine Society. Diagnosis and treat-ment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273-288.

9. Otsuka America Pharmaceutical. Abilify Maintena. http://www.abilifymaintena.com/. Accessed April 9, 2015.

10. Eli Lilly and Company. Zyprexa relprevv (olanzapine) for extended release. http://pi.lilly.com/us/zyprexa_relprevv.pdf. Ac-cessed April 9, 2015.

11. Ajmal A, Joffe H, Nachtigall LB. Psycho-tropic-induced hyperprolactinemia: a clini-cal review. Psychosomatics. 2014;55:29-36.

12. Lieberman JA. Dopamine partial agonists. CNS Drugs. 2004;18(4):251-267.

13. Li X, Tang Y, Wang C. Adjunctive aripip-razole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179.

14. De Hert M, Detraux J, Peuskens J. Second-generation and newly approved antipsy-chotics, serum prolactin levels and sexual dysfunctions: a critical literature review. Expert Opin Drug Saf. 2014;13(5):605-624.

15. Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychophar-macol. 2011;26(3):130-140.

16. Citrome L. Current guidelines and their rec-ommendations for prolactin monitoring in psychosis. J Psychopharmacol. 2008;22(2 Suppl):90-97.