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Home , Breast engorgement, Paliperidone

Cases That Test Your Skills

Psychosis resolves, but menses stop Nicole Renee Graham, MD, Mustafa Pirzada, MD, Almari Ginory, DO, Laura Mayol-Sabatier, MD, and Mathew Nguyen, MD

Ms. S, age 30, says her classmates are ‘working against her.’ How would you relieves her psychotic symptoms, but she misses 2 handle this case? Answer the challenge menstrual cycles while taking the drug. What is your next step? questions throughout this article

CASE Paranoid and hallucinating tory testing during hospitalization. Ms. S, age 30, is an unmarried graduate stu- As an outpatient, Ms. S is continued on the dent who has been given a diagnosis of same medications until she has to be switched , paranoid type, during inpatient because she cannot afford the out-of-pocket hospitalization that was prompted by impair- cost of the , ($80 ment in school functioning (difficulty turning a month). is recommended, but Ms. in assignments, poor concentration, making S refuses because of the mandatory weekly careless mistakes on tests), paranoid delu- blood monitoring. She briefly tries fluphen- sions, and multisensory hallucinations. She azine, 2.5 mg/d, but it is discontinued because says that her roommate and classmates are of malaise and lightheadedness without working together to make her leave school, . and recalls seeing them “snare and smirk” as Clozapine is again recommended, but she passes by. Ms. S says that she feels her Ms. S remains suspicious of the necessary classmates are calling her names and talking blood draws and refuses. After several trials badly about her as soon as she is out of sight. of , Ms. S starts paliperidone Ms. S is antipsychotic-naïve and has a base- using samples from the clinic, titrated to 6 mg line body mass index of 17.8 kg/m2, indicat- at bedtime. Once tolerance and therapeutic ing that she is underweight. We believe that improvement are observed, she is continued , 20 mg/d, is a good initial treat- on this medication through the manufactur- ment because of its propensity for weight er’s patient assistance program. gain; however, she experiences only marginal Within 3 months, Ms. S and her fam- improvement. Ms. S does not have health ily find that she has improved signifi- insurance, and cannot afford a brand name cantly. She no longer reports hallucinatory medication; therefore, she is cross-tapered to experiences, is less guarded during ses- perphenazine, 8 mg, and , 0.5 Dr. Graham is a Child and Adolescent Psychiatry Fellow, Dr. Pirzada mg, both taken twice daily (olanzapine was is Chief Child and Adolescent Psychiatry Fellow, Dr. Ginory is not available as a generic at the time). Assistant Professor, Dr. Mayol-Sabatier is a Child and Adolescent Psychiatry Fellow, and Dr. Nguyen is Assistant Professor, At discharge, Ms. S does not report Department of Psychiatry, University of Florida, Gainesville, any hallucinatory experiences, but is guarded, Florida. voices suspicions about the treatment team, Disclosure and asks “What are they doing with all my The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of Current Psychiatry blood?”—referring to blood draws for labora- competing products. Vol. 13, No. 5 25 Cases That Test Your Skills

Figure 1 Figure 2 Pituitary gland and role in synthesis HPA axis and its effects on and ejection of milk the ovaries and

– + + hypothalamus hypothalamus suckling – DA mechanoreceptors

DA GnRH

anterior – posterior pituitary anterior pituitary pituitary – +

Clinical Point prolactin oxytocin A prolactin level of FSH, LH + breasts + >25 μg/L is considered milk gland myoepithelial effects on ovary cells cells abnormal; however, (contraction) prolactin levels >200 μg/L milk milk synthesis ejection effects on have been observed DA: ; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing in patients taking an DA: dopamine hormone; LH: luteinizing hormone antipsychotic

sions, and has followed through with paid >200 µg/L have been observed in patients and volunteer job applications and inter- taking an antipsychotic.1 Given Ms. S’s views. She soon finds a job teaching clinically significant elevation of prolactin, entry-level classes at a community college she is referred to her primary care physi- and is looking forward to a summer trip cian. We decide to augment her regimen abroad. with , 10 mg/d, because this During a follow-up appointment, Ms. S drug has been noted to help in cases of reports that she had missed 2 consecutive hyperprolactinemia associated with other menstrual cycles without or frac- antipsychotics.2,3 tures. A urine test is negative; the Prolactin serves several roles in the prolactin level is 72 µg/L. body, including but not limited to lacta- tion, sexual gratification, proliferation of Hyperprolactinemia in women is defined as a oligodendrocyte precursor cells, surfac- plasma prolactin level of tant synthesis of fetal lungs at the end of a) >2.5 µg/L pregnancy, and neurogenesis in maternal b) >5 µg/L and fetal brains (Figure 1 and Figure 2). A c) >10 µg/L 2004 review reported secondary amenor- Discuss this article at d) >20 µg/L rhea, galactorrhea, and osteopenia as com- www.facebook.com/ e) >25 µg/L mon symptoms of hyperprolactinemia.5 CurrentPsychiatry Hyperprolactinemia has been seen with most antipsychotics, both typical and The authors’ observations atypical. Although several studies docu- A prolactin level >25 µg/L is considered ment prolactin elevation with , abnormal.1 A level of >250 µg/L may fewer have examined the active metabolite Current Psychiatry 26 May 2014 identify a prolactinoma; however, levels (9-hydroxyrisperidone) paliperidone.5-7 Cases That Test Your Skills

Table Effects of hyperprolactinemia by organ system Organ system Effects Bone Decreased bone density mediated by relative or absolute deficiency of (women) or testosterone (men) Reproductive Infertility (women); reduced spermatogenesis, erectile dysfunction, ejaculatory dysfunction Endocrine Galactorrhea, menstrual abnormalities (women), (men), possible increased risk of cancer (breast, endometrial in women) needs to be further studied Cardiovascular Possible higher risk of cardiovascular disease Mental health Risk of depression Clinical Point

In women, a high prolactin level can cause is 21 µg/L, and she reports having a normal In women, a) menstrual disturbance menstrual period. She continues treatment hyperprolactinemia b) galactorrhea with paliperidone, 3 mg/d, and aripiprazole, can cause menstrual c) breast engorgement 10 mg/d, experiences regular menses, and abnormalities, sexual d) sexual dysfunction continues teaching. dysfunction, breast e) all of the above Pharmacotherapy of hyperprolactinemia engorgement, and includes galactorrhea The authors’ observations a) Acutely, hyperprolactinemia can cause b) perphenazine menstrual abnormalities, decreased libido, c) breast engorgement, galactorrhea, and d) olanzapine sexual dysfunction in women.8 In men, the e) risperidone most common symptoms of hyperprolac- tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas- The authors’ observations tia. Osteoporosis has been associated with Our goal in treating Ms. S was to address chronic elevation of the prolactin level8 her schizophrenia symptoms and improve (Table). her overall functioning. Often, finding an effective treatment can be challeng- ing, and there is little evidence to support TREATMENT Adjunctive aripiprazole the of one antipsychotic over After 8 weeks of adjunctive aripiprazole, another.4 In Ms. S’s case, our care was Ms. S’s prolactin level decreases to 42 µg/L, stymied by the cost of medication, chal- but menses do not return. Because her lenges related to delusions intrinsic family and primary care providers are eager to the illness (she refused clozapine to have the prolactin level return to nor- because of required blood draws), and mal, reducing her risk of complications, we adverse effects. When Ms. S developed decide to decrease paliperidone to 3 mg at amenorrhea while taking paliperidone— bedtime. the only medication that showed sig- Eight weeks later, Ms. S shows functional nificant improvement in her psychotic improvement. A repeat test of prolactin is 24 symptoms—our goal was to maintain her µg/L; she reports a 4-day period of spotting 1 functional level without significant long- Current Psychiatry week ago. One month later, the prolactin level term adverse effects. Vol. 13, No. 5 27 continued Cases That Test Your Skills

trial, aripiprazole had a lower rate of prolac- Related Resources tin elevation compared with placebo.12 • Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a Aripiprazole’s ability to reduce an comprehensive review [published online March 28, 2014]. CNS elevated prolactin level caused by other Drugs. doi: 10.1007/s40263-014-0157-3. antipsychotics has been demonstrated in • Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for 13 antipsychotic-induced hyperprolactinemia: meta-analysis of several studies with haloperidol, olan- randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: zapine,14,15 and risperidone.15-17 There has 10.1371/journal.pone.0070179. been 1 case report,18 but no controlled stud- Drug Brand Names ies, of aripiprazole being used to decrease Aripiprazole • Abilify Haloperidol • Haldol Benzatropine • Cogentin Olanzapine • Zyprexa the prolactin level in patients treated with Bromocriptine • Parlodel Paliperidone • Invega paliperidone. • Dostinex Perphenazine • Trilafon Clozapine • Clozaril Risperidone • Risperdal In Ms. S’s case, adding aripiprazole, Clinical Point • Prolixin 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud- Aripiprazole is ies have shown that adjunctive aripipra- considered to be a zole with a D2 antagonist normalizes the prolactin-sparing Managing hyperprolactinemia prolactin level,19 it is reasonable to con- agent; it has been Management of iatrogenic hyperprolac- clude that adding aripiprazole facilitated shown to reduce an tinemia includes decreasing the dosage reduction of her prolactin level and might of the offending agent, using a prolactin- have continued to do so if given more time. elevated prolactin sparing antipsychotic, or initiating a dopa- Regrettably, because of patient and fam- level mine agonist, such as bromocriptine or ily concerns, paliperidone was reduced cabergoline, in addition to an antipsy- before this could be determined. It is chotic.1,4 Aripiprazole is considered to be a unclear whether normalization of Ms. S’s prolactin-sparing agent because of its pro- prolactin level and return of her menstrual pensity to increase the prolactin level to less cycle was caused by adding aripiprazole of a degree than what is seen with other or by reducing the dosage of paliperidone. antipsychotics; in fact, it has been shown to Although additional randomized con- reduce an elevated prolactin level.9-11. trolled trials should be conducted on the Most typical and atypical antipsychotics utility of this approach, it is reasonable to are dopamine—specifically D2—receptor consider augmentation with aripiprazole antagonists. These antipsychotics prevent when treating a patient who is stable on dopamine from binding to the D2 recep- an antipsychotic, including paliperidone, tor and from inhibiting prolactin release, but has developed hyperprolactinemia therefore causing hyperprolactinemia. secondary to treatment. Aripiprazole differs from other antipsychot- References ics: It is a partial D2 receptor agonist with 1. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis high affinity, and therefore suppresses pro- and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol lactin release.8 In a randomized controlled Metab. 2011;96(2):273-288. Bottom Line Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or Current Psychiatry 28 May 2014 discontinuation of the offending agent and augmentation with aripiprazole. Cases That Test Your Skills

2. Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia 11. Aihara K, Shimada J, Miwa T, et al. The novel antipsychotic associated with psychotropics—a review. Hum aripiprazole is a partial agonist at short and long isoforms Psychopharmacol. 2010;25(4):281-297. of D2 receptors linked to the regulation of adenylyl cyclase 3. Hanssens L, L’Italien G, Loze JY, et al. The effect of activity and prolactin release. Brain Res. 2004;1003(1-2):9-17. antipsychotic medication on sexual function and serum 12. Bushe C, Shaw M, Peveler RC. A review of the association prolactin levels in community-treated schizophrenic between antipsychotic use and . J patients: results from the Schizophrenia Trial of Aripiprazole Psychopharmacol. 2008;22(2 suppl):46-55. (STAR) study (NCT00237913). BMC Psychiatry. 2008;8:95. 13. Yasui-Furukori N, Furukori H, Sugawara N, et al. Dose- doi: 10.1186/1471-244X-8-95. dependent effects of adjunctive treatment with aripiprazole 4. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical on hyperprolactinemia induced by risperidone in female Antipsychotic Trials of Intervention Effectiveness (CATIE) patients with schizophrenia. J Clin Psychopharmacol. Investigators. Effectiveness of antipsychotic drugs in 2010;30(5):596-599. patients with chronic schizophrenia. N Engl J Med. 14. Lorenz RA, Weinstein B. Resolution of haloperidol- 2005;353(12):1209-1223. induced hyperprolactinemia with aripiprazole. J Clin 5. Haddad PM, Wieck A. Antipsychotic-induced Psychopharmacol. 2007;27(5):524-525. hyperprolactinaemia: mechanisms, clinical features and 15. Aggarwal A, Jain M, Garg A, et al. Aripiprazole for management. Drugs. 2004;64(20):2291-2314. olanzapine-induced symptomatic hyper prolactinemia. 6. Knegtering R, Baselmans P, Castelein S, et al. Predominant Indian J Pharmacol. 2010;42(1):58-59. role of the 9-hydroxy metabolite of risperidone in elevating 16. Byerly MJ, Marcus RN, Tran QV, et al. Effects of aripiprazole blood prolactin levels. Am J Psychiatry. 2005;162(5): on prolactin levels in subjects with schizophrenia during 1010-1012. cross-titration with risperidone or olanzapine: analysis Clinical Point 7. Berwaerts J, Cleton A, Rossenu S, et al. A comparison of of a randomized, open-label study. Schizophr Res. 2009; serum prolactin concentrations after administration of 107(2-3):218-222. paliperidone extended-release and risperidone tablets in 17. Chen CK, Huang YS, Ree SC, et al. Differential add-on It is unclear whether patients with schizophrenia. J Psychopharmacol. 2010; effects of aripiprazole in resolving hyperprolactinemia 24(7):1011-1018. induced by risperidone in comparison to adding aripiprazole 8. Holt RI, Peveler RC. Antipsychotics and antipsychotics. Prog Neuropsychopharmacol Biol hyperprolactinaemia: mechanisms, consequences and Psychiatry. 2010;34(8):1495-1499. or reducing the management. Clin Endocrinol (Oxf). 2011;74(2):141-147. 18. Chen CY, Lin TY, Wang CC, et al. Improvement of serum 9. Friberg LE, Vermeulen AM, Petersson KJ, et al. An agonist- prolactin and sexual function after switching to aripiprazole paliperidone antagonist interaction model for prolactin release following from risperidone in schizophrenia: a case series. Psychiatry risperidone and paliperidone treatment. Clin Pharmacol Clin Neurosci. 2011;65(1):95-97. dosage caused Ther. 2009;85(4):409-417. 19. Rocha FL, Hara C, Ramos MG. Using aripiprazole to 10. Skopek M, Manoj P. Hyperprolactinaemia during attenuate paliperidone-induced hyperprolactinemia. normalization of treatment with paliperidone. Australas Psychiatry. 2010; Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(6): 18(3):261-263. 1153-1154. Ms. S’s prolactin level

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