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Savvy Psychopharmacology

Strategies for managing medication-induced hyperprolactinemia

Hilary Navy, PharmD, BCGP, and Kristen Gardner, PharmD, BCPP

s. E, age 23, presents to your office functions, including involvement in the syn- for a routine visit for management of thesis and maintenance of breast milk produc- and posttraumatic tion, in reproductive behavior, and in luteal M 1,2 stress disorder with comorbid type 2 diabetes function. Hyperprolactinemia—an elevated mellitus. She currently is taking , prolactin level—is a common endocrinologic 3 mg/d, , 200 mg/d, metformin, disorder of the hypothalamic–pituitary– 2,000 mg/d, medroxyprogesterone, 150 mg axis.3 Children, adolescents, premenopausal Vicki L. Ellingrod, every 3 months, and , 8 mg/d. Her women, and women in the perinatal period PharmD, FCCP mood has been stabilized for the last 3 years are more vulnerable to medication-induced Department Editor with this medication regimen. hyperprolactinemia.4 If not asymptomatic, Ms. E has a history of self-discontinuing patients with hyperprolactinemia may expe- medication when adverse events occur. She has rience amenorrhea, galactorrhea, hypogo- been hospitalized twice for psychosis and sui- nadism, sexual dysfunction, or infertility.1,4 cide attempts. Past psychotropic medications Chronic hyperprolactinemia may increase that have been discontinued due to adverse the risk for long-term complications, such as effects include (mild abnormal decreased bone mineral density and osteo- lip movement), (ineffective and porosis, although available evidence has con- drowsy), valproic acid (tremor and abdomi- flicting findings.1 nal discomfort), (rash), and aripipra- Hyperprolactinemia is diagnosed by a zole (increased fasting blood sugar and labile prolactin concentration above the upper mood). At her appointment today, Ms. E says she is Practice Points concerned because she has been experiencing • In the absence of a tumor, medications are frequently identified as the cause of galactorrhea for the past 4 weeks. Her prolactin hyperprolactinemia. Medication-induced level is 14.4 ng/mL; a normal level for a woman elevated prolactin levels typically range who is not pregnant is <25 ng/mL. However, a from 25 to 100 ng/mL. repeat prolactin level is obtained, and is found • , , to be elevated at 38 ng/mL. hormonal preparations, Savvy Psychopharmacology antihypertensives, and gastrointestinal is produced in partnership Prolactin, a polypeptide hormone that is agents have been associated with with the College hyperprolactinemia. of Psychiatric secreted from the pituitary gland, has many and Neurologic Dr. Navy is Clinical Pharmacy Specialist, PFC Floyd K. Lindstrom • -induced Pharmacists Outpatient Clinic, VA Eastern Colorado Health Care System, Colorado hyperprolactinemia management cpnp.org Springs, Colorado, and Dr. Gardner is Clinical Pharmacy Specialist, mhc.cpnp.org (journal) Highline Behavioral Health Clinic, Kaiser Permanente Colorado, strategies may include watching and Denver, Colorado. waiting, discontinuing the antipsychotic, Disclosures reducing the antipsychotic dose, switching The authors report no financial relationships with any company antipsychotics, or adding or a Current Psychiatry whose products are mentioned in this article or with manufacturers of . 42 March 2018 competing products. Savvy Psychopharmacology

reference range.3 Various hormones and , and are partial D2 neurotransmitters can impact inhibition or receptor , and cariprazine is the only stimulation of prolactin release.5 For exam- agent that exhibits preferential binding to D3 ple, dopamine tonically inhibits prolactin receptors.12,13 Based on limited data, brexpip- release and synthesis, whereas estrogen razole and cariprazine may have prolactin- stimulates prolactin secretion.1,5 Prolactin also sparing properties given their partial D2 can be elevated under several physiologic receptor agonism.12,13 However, one study and pathologic conditions, such as during found increased prolactin levels in some stressful situations, meals, or sexual activ- patients after treatment with brexpiprazole, ity.1,5 A prolactin level >250 ng/mL is usu- 4 mg/d.14 Similarly, another study found that ally indicative of a prolactinoma; however, cariprazine could increase prolactin levels as some medications, such as strong D2 receptor much as 4.1 ng/mL, depending on the dose.15 antagonists (eg, risperidone, ), can Except for aripiprazole, brexpiprazole, car- cause significant elevation without evidence iprazine, and , all other atypical Clinical Point 3 of prolactinoma. In the absence of a tumor, antipsychotics marketed in the United States Typical medications are often identified as the cause have a standard warning in the package of hyperprolactinemia.3 According to the insert regarding prolactin elevations.1,16,17 antipsychotics are Endocrinology Society clinical practice guide- Because antidepressants are less well- more likely to cause line, medication-induced elevated prolactin studied as a cause of medication-induced hyperprolactinemia levels are typically between 25 to 100 ng/mL.3 hyperprolactinemia, drawing definitive con- than atypical clusions regarding incidence rates is limited, antipsychotics Medication-induced but the incidence seems to be fairly low.6,18 hyperprolactinemia A French pharmacovigilance study found Antipsychotics, antidepressants, hormonal that of 182,836 spontaneous adverse drug preparations, antihypertensives, and gastro- events reported between 1985 and 2009, intestinal agents have been associated with there were 159 reports of selective hyperprolactinemia (Table 1,1,3,5-11 page 44). reuptake inhibitors (SSRIs) inducing hyper­ These medication classes increase prolactin prolactinemia.6 and rep- by decreasing dopamine, which facilitates resented about one-half of the cases; however, disinhibition of prolactin synthesis and there were also cases associated with citalo- release, or increasing prolactin stimulating pram, , , , hormones, such as serotonin or estrogen.5 , and . In comparison, Antipsychotics are the most common there were only 11 reports of hyperprolac- medication-related cause of hyperprolac- tinemia associated with antidepres- tinemia.3 Typical antipsychotics are more sants or monoamine oxidase inhibitors. likely to cause hyperprolactinemia than Although patients were not always symptom- atypical antipsychotics; the incidence among atic, the most commonly reported symptoms patients taking typical antipsychotics is 40% were galactorrhea (55%), gynecomastia (29%), to 90%.3 Atypical antipsychotics, except amenorrhea (11%), mastodynia (11%), and risperidone and , are consid- sexual disorders (4%).6 Another study of 5,920 ered to cause less endocrinologic effects patients treated with fluoxetine found masto- than typical antipsychotics through various dynia in 0.25%, gynecomastia in 0.08%, and mechanisms: receptor antago- galactorrhea in 0.07% of patients.18 Symptoms Discuss this article at nism, fast dissociation from D2 receptors, D2 occurred in an extremely low percentage of www.facebook.com/ CurrentPsychiatry receptor partial agonism, and preferential patients, and the study is >20 years old.18 binding of D3 vs D2 receptors.1,5 By having and have been transient D2 receptor association, clozapine found to be prolactin-neutral.5 Bupropion and are considered to have less also has been reported to decrease prolac- risk of hyperprolactinemia compared with tin levels, potentially via its ability to block Current Psychiatry other atypical antipsychotics.1,5 Aripiprazole, dopamine reuptake.19 Vol. 17, No. 3 43 continued Savvy Psychopharmacology

Table 1 Medication-induced hyperprolactinemia Class Medications Mechanism(s) of action Antipsychotics Typical antipsychotics: , Antipsychotic-associated D2 receptor haloperidol, , thiothixene5 antagonism5 Prolactin-raising atypical antipsychotics: Paliperidone, risperidone1 Antidepressants Serotonin reuptake inhibitors: May release prolactin-regulating , escitalopram, fluoxetine, factors, such as vasoactive intestinal fluvoxamine, milnacipran, paroxetine, polypeptide or oxytocin7 6 sertraline, venlafaxine May inhibit the tuberoinfundibular Tricyclic antidepressants: , dopamine system through the , , desipramine5 stimulation of GABAergic neurons8 Monoamine oxidase inhibitor: May cause indirect modulation Clinical Point Clorgyline5 of prolactin release by increasing serotonin8 A patient with Hormone Antiandrogens,5 combined oral Estrogen-stimulated lactotroph a prolactin level preparations contraceptives,3 estrogens3 hyperplasia, which stimulates prolactin release9 >100 ng/mL Antihypertensives ,5 ,5 Methyldopa inhibits the conversion should be referred ,10 verapamil5 of levodopa to dopamine and can decrease dopamine synthesis by to Endocrinology acting as a false neurotransmitter5,9 to rule out Reserpine can inhibit the storage of hypothalamic catecholamines in prolactinoma secretory granules, which can lead to depletion of dopamine and other sympathetic biogenic amines5 Tetrabenazine is thought to be a reversible depletor of dopamine10 Verapamil blocks hypothalamic production of dopamine9 Gastrointestinal ,9 prochlorperazine11 antagonism9 medications GABA: γ-aminobutyric acid

Managing medication-induced review the patient’s prescribed medica- hyperprolactinemia tions and past medical history (eg, chronic Screening for and identifying clinically renal failure, hypothyroidism) for poten- significant hyperprolactinemia is critical, tial causes or exacerbations, and address because adverse effects of medications can these factors accordingly.3 Order a mea- lead to nonadherence and clinical decompen- surement of prolactin level. A patient sation.20 Patients must be informed of poten- with a prolactin level >100 ng/mL should tial symptoms of hyperprolactinemia, and be referred to Endocrinology to rule out clinicians should inquire about such symp- prolactinoma.1 toms at each visit. Routine monitoring of If a patient’s prolactin level is between prolactin levels in asymptomatic patients is 25 and 100 ng/mL, review the patient’s not necessary, because the Endocrine Society medications (Table 11,3,5-11), because prolac- Clinical Practice Guideline does not recom- tin levels within this range usually signal mend treating patients with asymptomatic a medication-induced cause.3 For patients medication-induced hyperprolactinemia.3 with antipsychotic-induced hyperprolac- In patients who report hyperprolac- tinemia, there are several management Current Psychiatry 44 March 2018 tinemia symptoms, clinicians should strategies (Table 2,1,3,4,9,16,17,21-27 page 45): Savvy Psychopharmacology

Table 2 Management strategies for antipsychotic-induced hyperprolactinemia Strategy Comments Watch and wait Tolerance and a decrease in prolactin levels may occur over time but will not occur in most patients1 Discontinue Levels may return to normal 3 days after discontinuation, but medications antipsychotic with longer half-lives may require longer for prolactin levels and symptoms to normalize3,9 Reduce antipsychotic Prolactin elevations may be dose-related; however, antipsychotics with a dose higher relative risk of increasing prolactin tend to raise prolactin levels even at low doses, which may be subtherapeutic depending on the indication1 Switch antipsychotic Consider switching to a prolactin-sparing antipsychotic, such as aripiprazole, brexpiprazole, cariprazine, or clozapine.1,4 Switching antipsychotics has been shown to decrease prolactin levels, but there is limited evidence available on the timeline of symptomatic improvement of prolactin-related Clinical Point adverse events. When switching from risperidone to aripiprazole, prolactin levels and symptoms may resolve within 4 weeks.21,22 The long half-life of Switching to a aripiprazole may explain why symptoms take at least 1 month to resolve. Two case reports describe probable aripiprazole-associated symptomatic prolactin-sparing 23,24 hyperprolactinemia antipsychotic may Add aripiprazole A recent meta-analysis found that adjunctive aripiprazole increases the proportion of patients who had prolactin levels return to normal in normalize prolactin antipsychotic-induced hyperprolactinemia with prolactin-raising antipsychotics, such as risperidone or haloperidol.25 Lower doses (eg, 5 mg/d) may be levels and may be sufficient.1,25 Adjunctive therapy with brexpiprazole or cariprazine has not yet preferred when risk been studied16,17 Add a dopamine and have been shown to reduce prolactin levels of relapse is low agonist and relieve symptoms of hypogonadism in patients with risperidone-induced hyperprolactinemia.26 Patients resumed menstruation after 8 weeks of bromocriptine treatment.27 Cabergoline is taken only once or twice weekly because of a longer elimination half-life, whereas bromocriptine is dosed multiple times a day4

• Watch and wait may be warranted when if the offending medication cannot be dis- the patient is experiencing mild hyperprolac- continued or switched, or if the patient has a tinemia symptoms. comorbid prolactinoma. • Discontinue. If the patient can be main- Less data exist on managing hyperprolac- tained without an antipsychotic, discontinu- tinemia that is induced by a medication other ing the antipsychotic would be a first-line than an antipsychotic; however, it seems option.3 reasonable that the same strategies could be • Reduce the dose. Reducing the antipsy- implemented. Specifically, for SSRI–induced chotic dose may be the preferred strategy hyperprolactinemia, if clinically appropriate, for patients with moderate to severe hyper- switching to or adding an alternative anti- prolactinemia symptoms who responded to depressant that may be prolactin-sparing, the antipsychotic and do not wish to start such as mirtazapine or bupropion, could be adjunctive therapy.4 attempted.8 One study found that fluoxetine- • Switching to a prolactin-sparing anti- induced galactorrhea ceased within 10 days psychotic may help normalize prolactin lev- of discontinuing the medication.30 els and may be preferred when the risk of relapse is low.3 Dopamine agonists can treat CASE CONTINUED medication-induced hyperprolactinemia, Because Ms. E has been on the same medica- but may worsen psychiatric symptoms.28,29 tion regimen for 3 years and recently devel- Current Psychiatry Therefore, this may be the preferred strategy oped galactorrhea, it seems unlikely that her Vol. 17, No. 3 45 Savvy Psychopharmacology

hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely Related Resource because the prolactin level is <100 ng/mL. • Peuskens J, Pani L, Detraux J, et al. The effects of novel and Based on the literature, the only possible newly approved antipsychotics on serum prolactin levels: a medication-induced cause of her galactorrhea comprehensive review. CNS Drugs. 2014;28(5):421-453. is risperidone. Ms. E agrees to a trial of adjunc- Drug Brand Names tive oral aripiprazole, 5 mg/d, with close moni- Amitriptyline • Elavil Methyldopa • Aldomet Amoxapine • Asendin Metoclopramide • Reglan toring of her type 2 diabetes mellitus. Because Aripiprazole • Abilify Milnacipran • Savella of the long elimination half-life of aripiprazole, Brexpiprazole • Rexulti Mirtazapine • Remeron Bromocriptine • Cycloset Olanzapine • Zyprexa 1 month is required to monitor for improve- Bupropion • Wellbutrin Paliperidone • Invega ment in galactorrhea. Ms. E is advised to use Cabergoline • Dostinex Paroxetine • Paxil Cariprazine • Vraylar • Mirapex breast pads as a nonpharmacologic strategy Chlorpromazine • Thorazine Prazosin • Minipress in the interim. After 1 month of treatment, Citalopram • Celexa • Clomipramine • Anafranil Compazine Clinical Point Ms. E denies galactorrhea symptoms and no Clorgyline • Aurorix Quetiapine • Seroquel longer requires the use of breast pads. Clozapine • Clozaril Reserpine • Raudixin • Norpramin Risperidone • Risperdal For SSRI–induced Escitalopram • Lexapro Sertraline • Zoloft References Fluoxetine • Prozac Tetrabenazine • Xenazine hyperprolactinemia, 1. Peuskens J, Pani L, Detraux J, et al. The effects of novel and Fluvoxamine • Luvox Thioridazine • Mellaril newly approved antipsychotics on serum prolactin levels: a Haloperidol • Haldol Thiothixene • Navane comprehensive review. CNS Drugs.2014;28(5):421-453. consider adding Lamotrigine • Lamictal Valproic acid • Depakote 2. Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: Lithium • Lithobid Venlafaxine • Effexor or switching to structure, function, and regulation of secretion. Physiol Rev. Medroxyprogesterone • Verapamil • Calan 2000;80(4):1523-1631. mirtazapine or Provera Ziprasidone • Geodon 3. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and Metformin • Glucophage treatment of hyperprolactinemia: an Endocrine Society Clinical bupropion practice guideline. J Clin Endocrinol Metab. 2011;96(2):273-288. 4. Bostwick JR, Guthrie SK, Ellingrod VL. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy. 2009;29(1):64-73. 5. La Torre D, Falorni A. Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag. 2007;3(5):929-951. 20. Tsuboi T, Bies RR, Suzuki T, et al. Hyperprolactinemia and 6. Petit A, Piednoir D, Germain ML, et al. Drug-induced estimated dopamine D2 receptor occupancy in patients hyperprolactinemia: a case-non-case study from the with : analysis of the CATIE data. Prog national pharmacovigilance database [in French]. Therapie. Neuropsychopharmacol Biol Psychiatry. 2013;45:178-182. 2003;58(2):159-163. 21. Lee BH, Kim YK, Park SH. Using aripiprazole to resolve 7. Emiliano AB, Fudge JL. From galactorrhea to antipsychotic-induced symptomatic hyperprolactinemia: a osteopenia: rethinking serotonin-prolactin interactions. pilot study. Prog Neuropsychopharmacol Biol Psychiatry. Neuropsychopharmacology. 2004;29(5):833-846. 2006;30(4):714-717. 8. Coker F, Taylor D. -induced hyper­ 22. Lu ML, Shen WW, Chen CH. Time course of the changes prolactinaemia: incidence, mechanisms and management. CNS in antipsychotic-induced hyperprolactinemia following the Drugs. 2010;24(7):563-574. switch to aripiprazole. Prog Neuropsychopharmacol Biol 9. Molitch ME. Medication induced hyperprolactinemia. Mayo Psychiatry. 2008;32(8):1978-1981. Clin Proc. 2005;80(8):1050-1057. 23. Mendhekar DN, Andrade C. Galactorrhea with aripiprazole. 10. Xenazine (tetrabenazine) [package insert]. Washington, DC: Can J Psychiatry. 2005;50(4):243. Prestwick Pharmaceuticals, Inc.; 2008. 24. Joseph SP. Aripiprazole induced hyperprolactinemia in a 11. Peña KS, Rosenfeld JA. Evaluation and treatment of young female with delusional disorder. Indian J Psychol Med. galactorrhea. Am Fam Physician 2001;63(9):1763-1770. 2016;38(3):260-262. 12. Durgam S, Starace A, Li D, et al. The efficacy and tolerability of 25. Meng M, Li W, Zhang S, et al. Using aripiprazole to reduce cariprazine in acute associated with bipolar I disorder: a antipsychotic-induced hyperprolactinemia: meta-analysis of phase II trial. Bipolar Disord. 2015;17(1):63-75. currently available randomized controlled trials. Shaghai Arch 13. Das S, Barnwal P, Winston AB, et al. Brexpiprazole: so far so Psychiatry. 2015;27(1):4-17. good. Ther Adv Psychopharmacol. 2016;6(1):39-54. 26. Tollin SR. Use of the dopamine agonists bromocriptine and 14. Correll CU, Skuban A, Ouyang J, et al. 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