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- bipolar I disorder 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 risperidone, prolactin level—is a common endocrinologic 3 mg/d, lamotrigine, 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 prazosin, 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 ziprasidone (mild abnormal decreased bone mineral density and osteo- lip movement), olanzapine (ineffective and porosis, although available evidence has con- drowsy), valproic acid (tremor and abdomi- flicting findings.1 nal discomfort), lithium (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 • Antipsychotics, antidepressants, 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 • Antipsychotic-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 aripiprazole or a Current Psychiatry whose products are mentioned in this article or with manufacturers of dopamine agonist. 42 March 2018 competing products. Savvy Psychopharmacology reference range.3 Various hormones and brexpiprazole, and cariprazine are partial D2 neurotransmitters can impact inhibition or receptor agonists, 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, haloperidol), can Except for aripiprazole, brexpiprazole, car- cause significant elevation without evidence iprazine, and clozapine, 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 serotonin hyperprolactinemia (Table 1,1,3,5-11 page 44). reuptake inhibitors (SSRIs) inducing hyper- These medication classes increase prolactin prolactinemia.6 Fluoxetine and paroxetine 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, escitalopram, sertraline, fluvoxamine, hormones, such as serotonin or estrogen.5 milnacipran, and venlafaxine. In comparison, Antipsychotics are the most common there were only 11 reports of hyperprolac- medication-related cause of hyperprolac- tinemia associated with tricyclic 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 paliperidone, 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: serotonergic 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 Mirtazapine and bupropion have been transient D2 receptor association, clozapine found to be prolactin-neutral.5 Bupropion and quetiapine 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: Chlorpromazine, Antipsychotic-associated D2 receptor haloperidol, thioridazine, thiothixene5 antagonism5 Prolactin-raising atypical antipsychotics: Paliperidone, risperidone1 Antidepressants Serotonin reuptake inhibitors: May release prolactin-regulating Citalopram, escitalopram, fluoxetine, factors, such as vasoactive intestinal fluvoxamine, milnacipran, paroxetine, polypeptide or oxytocin7 6 sertraline, venlafaxine May inhibit the tuberoinfundibular Tricyclic antidepressants: Amitriptyline, dopamine system through the amoxapine, clomipramine, 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 Methyldopa,5 reserpine,5 Methyldopa inhibits the conversion should be referred tetrabenazine,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