Hyperprolactinemia in Patients with Psychiatric Illness: A Therapeutic Dilemma

Received: 25-Feb-2021 Accepted Date: Mar 23, 2021 ; Published: 30-Mar-2021

Introduction

Hyperprolactinemia in patients with psychosis is a common finding in daily clinical practice [1]. A potential bias was noted for testing hyperprolactinemia in patients undergoing neuroleptic treatment [2]. The said patients are also more likely to undergo MRI/CT in this association [2]. It has been recognized, from previous studies, that psychotropic medications are among the most common causes of hyperprolactinemia in general practice [3,4]. Hyperprolactinemia and prolactinomas can cause complications such as irregular menstrual cycles, galactorrhea, and bone loss. Additionally, it can cause specific problems in males such as erectile dysfunction, decreased libido, and gynecomastia. The treatment of hyperprolactinemia, using DAs in patients suffering from psychiatric conditions, has been held accountable for exacerbating or worsening the illness [5]. This review addresses the possible ways to manage hyperprolactinemia observed in psychiatric patients while maintaining the pharmacological psychiatric treatment at the same time.

Case Presentation

A 48-year-old female, diagnosed as a schizophrenic for 20 years, was admitted to the psychiatry ward of King Khalid University Hospital, Riyadh, to manage her active relapses. The patient has kept off her antipsychotic medications. On admission, she complained of galactorrhea and oligomenorrhea. She was started with risperidone-2 mg orally at night for 4 days and then increased to 4 mg daily. Injectable risperidone (Risperdal Consta-37.5 mg) was also given every 2 weeks. Her initial prolactin level was 6314 miu/l (N 55-425 miu/l), FSH-4.65, LH-2.29, with normal thyroid and renal function tests. A Magnetic Resonance Image (MRI) of the sella turcica revealed a 4 × 8 mm focal pituitary hemorrhagic adenoma. Given the active psychiatric illness and the small-sized macroprolactinomas, the treatment of hyperprolactinemia was postponed until the stabilization of her schizophrenia. Her prolactin level remained almost the same, in the 6000 miu range, during her stay of 4 weeks. She was discharged after the stabilization of her schizophrenia. After 2 months, cabergoline, an ergot derivative, was introduced at a small dose of 0.25 mg weekly. It was subsequently increased to 0.25 mg twice weekly. Her prolactin level dropped to 610 miu/l within 6 weeks, while her menstrual cycle returned to normal and the condition of galactorrhea improved as well.

Discussion

The co-existence of hyperprolactinemia and psychosis is commonly observed in psychiatric patients on antipsychotic drugs. Hyperprolactinemia is presumed to be related to dopamine receptor blockade, mediated by D2 receptors [6-8].

Indeed, it has been documented that the degree of hyperprolactinemia correlates with the degree of occupation of D2 receptors, exceeding by 50% [9]. Many neuroleptic drugs, including risperidone, have been attributed to high prolactin levels [10-12]. It has been reported that the condition is more frequent and severe with regards to first-generation antipsychotic medications [11,12]. These include haloperidol, chlorpromazine, thioridazine, pimozide, thiothhxene, trifluoperazine, and fluphenazine. Second-generation antipsychotics leading to hyperprolactinemia are generally unheard of [11,12]. These include clozapine, lurasidone, asenapine, quetiapine, ziprasidone, and aripiprazole. Be that as it may, of the second-generation antipsychotic medications, risperidone and paliperidone have been associated with prolactin elevation [11,12]. With relevance to risperidone, which was given to the patient in the case study, persistent elevation of prolactin for periods up to 2 years has been documented with maintenance treatment [13]. It is encountered in both men and women and is dose-dependent [11,14]. The hyperprolactinemia in female patients can lead to the emergence of undesirable conditions like galactorrhea, menstrual irregularities, and premature bone loss [4,13]. Concerning men, it might lead to gynecomastia and erectile dysfunction [15,16]. Risperidone-associated hyperprolactinemia was found to adversely affect the patient’s health and compliance with the medication [16]. Furthermore, it has been established that the severity of the condition differs based on sex. Women were observed to be more receptible to hyperprolactinemia than men, even with the same dosage [17]. Genetically, risperidone-induced hyperprolactinemia is linked to Taq1A A1 and the A-241G allele of the D2 receptor gene [18].

Prolactin Secreting Adenomas in Patients with Psychiatric Illness

The illustrative case presents the example of a patient who needs to be maintained on antipsychotic medications, which could require treatment with DA for prolactinoma.

Prolactin secreting adenomas account for about 40% of all pituitary adenomas, making them the most common one [19]. The clinical sequelae of prolactinomas could be related to the elevated prolactin level, or to the mass effect of the tumor, particularly when it is more than 1 cm in size (macroprolactinoma). The serum prolactin level correlates with the size of the tumor. Small micro-prolactinomas (<1 cm) are usually treated medically with DAs [20,21]. Generally, these medications are effective in normalizing prolactin levels for up to 70% of cases. Along with that, they can also shrink the size of the adenoma in both micro-prolactinomas and macroprolactinomas [20,21]. Macroprolactinomas can also be treated pharmacologically with the help of Das [20,21]. Surgical treatment or radiotherapy for residual tumor post-surgery is reserved for patients who do not respond to the medical treatment or are intolerant towards dopamine agonists. DAs have many side effects such as nausea, vomiting, orthostatic hypotension, and valvular heart disease (cabergoline doses which are used for the treatment of Parkinson’s disease). They have been held responsible for the exacerbation of psychiatric illnesses [22-24].

Pharmacovigilance studies and some case reports have raised concern about the association of antipsychotic drugs especially risperidone with the emergence or enlargement of prolactin-secreting adenomas [25-28]. In the case of a patient with coexisting prolactin-secreting adenoma and active psychosis, the psychiatrist and the endocrinologist must work together in an attempt to manage the clinical consequences of the tumor mass and the resultant hyperprolactinemia, while avoiding the aggravation of the psychiatric disease, which might be instigated due to dopamine agonists. In the circumstance that the prolactinoma is very small while the psychiatric illness is active and severe, it would be wise to give the psychiatric illness the priority of treatment, while observing the hyperprolactinemia and its clinical consequences. For symptomatic patients, a cautious dosage of DA was recommended [29]. On the flip side, this approach has to be undertaken under very close supervision. Others have discouraged this approach due to the possibility of exacerbation of the psychiatric illness during the procedure except if antipsychotic treatment is maintained and under very close supervision [30]. More recently, other countermeasures have been recognized. It is deemed possible to switch to another antipsychotic medication that wouldn’t cause an opposing effect on the action of the DA. In a report by Pal and Sarino, olanzapine was successfully used to treat a patient suffering from macroprolactinoma with coexistent bromocriptine therapy [31]. Clozapine combined with quinazoline a DA has also been recommended to treat such patients [32]. In like manner, Quetiapine has also been suggested for the treatment of symptomatic hyperprolactinemia related to antipsychotics [33]. Galactorrhea with normal prolactin levels has rarely been reported with its use [34]. Lately, there have been many reports recommending the use of aripiprazole for treating hyperprolactinemia associated with psychosis and in patients with prolactinomas as well [35-39]. Aripiprazole has unique pharmacological effects of being a potent partial agonist for dopamine D2 and 5-HT1 receptors, but antagonist to 5-HT2A receptors [35-39]. The advantage of using aripiprazole in treating schizophrenia without affecting the prolactin level appears to be due to this partial agonist at D2 receptors. Aripiprazole has a greater affinity for the D2 receptor than risperidone with central D2 receptor occupancy of 90%-95% at doses of 15 mg/day [36,40,41]. On the occurrence of hypodopaminergic activity caused by risperidone, aripiprazole will function as a dopamine agonist at postsynaptic receptors [41]. In a report by Casey, et al. it was possible to safely switch patients to aripiprazole with the help of three different strategies. The first option is immediate initiation of 30 mg/day and discontinuation of the current antipsychotic medication. The second option is tapering down the antipsychotic treatment over 2 weeks while immediately initiating aripiprazole at 30 mg/ day dosage. The third is by gradually building up the dose of aripiprazole over 2 weeks while simultaneously tapering down the dose of the current antipsychotic medication [42]. Careful monitoring of the psychiatric and endocrine status is warranted for all three approaches. In some case reports, prolactin elevation was also found with aripiprazole treatment, particularly at a higher dosage [43,44]. A dose of 5 mg was suggested as an appropriate starting dose for this setting, with the increment of 5 mg by week 4 of treatment as tolerated [45].

Use of Dopamine Agonists in Psychiatric Illness

If the antipsychotic medication-induced hyperprolactinemia is asymptomatic, there is no need to discontinue the treatment [29,46]. If in any case, hypogonadal symptoms are discovered, replacement with estrogen or testosterone may be needed [29]. Regardless, there have been reports of safe and successful treatment of hyperprolactinemia with dopamine agonists while the patients were on antipsychotic medications as well.

Risperidone-induced hyperprolactinemia in children was successfully reversed with cabergoline [47]. Furthermore, the effective and safe use of cabergoline and bromocriptine in adult patients suffering from risperidone-induced hyperprolactinemia was also reported with no worsening of the psychiatric illness [48-50]. This approach can be considered as the last option when a drug that does not cause hyperprolactinemia cannot be substituted for the asymptomatic hyperprolactinemic patient [29]. However, this issue is still a matter of debate as it has not been endorsed by other investigators [51].

Conclusion

The treatment of hyperprolactinemia in a psychiatric patient requires proper judgment; taking into account the clinical backdrop of the patient, the presence or absence of symptoms, and the formation of the prolactinoma tumor. For patients that suffer from prolactinoma and psychosis simultaneously, special attention should be paid to tackle the psychiatric illness while managing the prolactin-secreting adenoma and its consequences at the same time. Cooperation between the psychiatrist and the endocrinologist is necessary, and a few feasible therapeutic options are available. A small asymptomatic microadenoma can be monitored without intervention whilst priority is given to psychiatric treatment [30]. In the case of symptomatic prolactinoma or more sizable adenomas, switching to another medication such as aripiprazole might be favorable while either maintaining or tapering down the antipsychotic treatment. Careful and small doses of dopamine agonists preferably cabergoline can be considered while conducting a close follow-up of the psychiatric illness [30]. In antipsychotic-induced hyperprolactinemia, the first step to undertake is reducing the dosage or switching to a prolactin-sparing antipsychotic medication. Only if that is not possible, the smallest feasible dose of DA can be contemplated with a very close observation of the psychiatric illness. If hyperprolactinemia is mild and the patient is asymptomatic, treatment with the antipsychotic drug can be continued. As stated above, some issues in managing such cases are still controversial. More studies are required to guide practicing clinicians for the safe management of these patients.

Declarations

Acknowledgement

We would like to thank Dr. Rabie Hawari for his help in providing the illustrative case.

Conflict of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

1. Kinon, Bruce J., et al. "Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone." Psychoneuroendocrinology, Vol. 28, No. Suppl 2, 2003, pp. 55-68.
2. Gianfrancesco, Frank D., et al. "Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: A claims-based study." Annals of General Psychiatry, Vol. 8, No. 1, 2009, pp. 1-10.
3. Molitch, Mark E. "Disorders of prolactin secretion." Endocrinology and Metabolism Clinics of North America, Vol. 30, No. 3, 2001, pp. 585-610.
4. Wieck, Angelika, and Peter Haddad. "Hyperprolactinaemia caused by antipsychotic drugs: This common side effect needs more attention." 2002, pp. 250-52.
5. Chang, Shen-Chieh, Chun-Hsin Chen, and Mong-Liang Lu. "Cabergoline-induced psychotic exacerbation in schizophrenic patients." General Hospital Psychiatry, Vol. 30, No. 4, 2008, pp. 78-380.
6. Molitch, Mark E. "Medication-induced hyperprolactinemia." Mayo Clinic Proceedings, Vol. 80, No. 8, 2005, pp. 1050-57.
7. Haddad, Peter M., and Angelika Wieck. "Antipsychotic-induced hyperprolactinaemia." Drugs, Vol. 64, No. 20, 2004, pp. 2291-314.
8. Wieck, A., and P. M. Haddad. "Antipsychotic-induced hyperprolactinaemia in women: Pathophysiology, severity and consequences: Selective literature review." The British Journal of Psychiatry, Vol. 182, No. 3, 2003, pp. 199-204.
9. Nordstrom, Anna-Lena, and Lars Farde. "Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients." Journal of Clinical Psychopharmacology, Vol. 18, No. 4, 1998, pp. 305-10.
10. Pappagallo, Mia, and Raul Silva. "The effect of atypical antipsychotic agents on prolactin levels in children and adolescents." Journal of Child and Adolescent Psychopharmacology, Vol. 14, No. 3, 2004, pp. 359-71.
11. David, Stacy R., et al. "The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia." Clinical Therapeutics, Vol. 22, No. 9, 2000, pp. 1085-96.
12. Rummel-Kluge, Christine, et al. "Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis." Schizophrenia Research, Vol. 123, No. 2-3, 2010, pp. 225-33.
13. Roke, Yvette, et al. "Antipsychotic medication in children and adolescents: A descriptive review of the effects on prolactin level and associated side effects." Journal of Child and Adolescent Psychopharmacology, Vol. 19, No. 4, 2009, pp. 403-14.
14. Cohen, David, et al. "Adverse effects of second-generation antipsychotics in children and adolescents: A Bayesian meta-analysis." Journal of Clinical Psychopharmacology, Vol. 32, No. 3, 2012, pp. 309-16.
15. Park, Yeon Won, Yooseok Kim, and Jun Ho Lee. "Antipsychotic-induced sexual dysfunction and its management." The World Journal of Men's Health, Vol. 30, No. 3, 2012, pp. 153-59.
16. Kearns, Ann E., et al. "Risperidone-associated hyperprolactinemia." Endocrine Practice, Vol. 6, No. 6, 2000, pp. 425-29.
17. Bushe, Chris, and Michael Shaw. "Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics." Journal of Psychopharmacology, Vol. 21, No. 7, 2007, pp. 768-73.
18. Calarge, Chadi A., et al. "Variants of the dopamine D2 receptor and risperidone-induced hyperprolactinemia in children and adolescents." Pharmacogenetics and Genomics, Vol. 19, No. 5, 2009, pp. 373-82.
19. Molitch, Mark E. "Diagnosis and treatment of pituitary adenomas: A review." JAMA, Vol. 317, No. 5, 2017, pp. 516-24.
20. Mann, W. Alexander. "Treatment for prolactinomas and hyperprolactinaemia: A lifetime approach." European Journal of Clinical Investigation, Vol. 41, No. 3, 2011, pp. 334-42.
21. Gillam, Mary P., et al. "Advances in the treatment of prolactinomas." Endocrine Reviews, Vol. 27, No. 5, 2006, pp. 485-534.
22. Taylor, Jacob, et al. "Neuropsychiatric complications of Parkinson disease treatments: Importance of multidisciplinary care." The American Journal of Geriatric Psychiatry, Vol. 24, No. 12, 2016, pp. 1171-80.
23. Chang, Shen-Chieh, Chun-Hsin Chen, and Mong-Liang Lu. "Cabergoline-induced psychotic exacerbation in schizophrenic patients." General Hospital Psychiatry, Vol. 30, No. 4, 2008, pp. 378-80.
24. Ceravolo, Roberto, et al. "A review of adverse events linked to dopamine agonists in the treatment of Parkinson’s disease." Expert Opinion on Drug Safety, Vol. 15, No. 2, 2016, pp. 181-98.
25. Koves, I. H., F. C. Jarman, and F. J. Cameron. "Antipsychotic medication and marked hyperprolactinaemia: Iatros or true prolactinoma?" Acta Pædiatrica, Vol. 93, No. 11, 2004, pp. 1543-47.
26. Perroud, Nader, and Philippe Huguelet. "A possible effect of amisulpride on a prolactinoma growth in a woman with borderline personality disorder." Pharmacological Research, Vol. 50, No. 3, 2004, pp. 377-79.
27. Akkaya, C., et al. "Hyperprolactinemia and possibly related development of prolactinoma during amisulpride treatment; three cases." Journal of Psychopharmacology, Vol. 23, No. 6, 2009, pp. 723-26.
28. Mendhekar, D. N., R. C. Jiloha, and P. K. Srivastava. "Effect of risperidone on prolactinoma." Pharmacopsychiatry, Vol. 38, No. 01, 2004, pp. 41-42.
29. Melmed, Shlomo, et al. "Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline." The Journal of Clinical Endocrinology and Metabolism, Vol. 96, No. 2, 2011, pp. 273-88.
30. Ali, Shirin, Karen Klahr Miller, and Oliver Freudenreich. "Management of psychosis associated with a prolactinoma: Case report and review of the literature." Psychosomatics, Vol. 51, No. 5, 2010, pp. 370-76.
31. Pal, Jayanta K., and Wilbur A. Sarino. "Effect of risperidone on prolactinoma growth in a psychotic woman." Psychosomatic Medicine, Vol. 62, No. 5, 2000, pp. 736-38.
32. Melkersson, Kristina, and A-L. Hulting. "Prolactin-secreting pituitary adenoma in neuroleptic treated patients with psychotic disorder." European Archives of Psychiatry and Clinical Neuroscience, Vol. 250, No. 1, 2000, pp. 6-10.
33. Keller, R., and F. Mongini. "Switch to quetiapine in antipsychotic agent-related hyperprolactinemia." Neurological Sciences, Vol. 23, No. 5, 2002, pp. 233-35.
34. Mushtaq, Saira, Sadaf Khan, and Harshad Patel. "Quetiapine-induced galactorrhea with normal prolactin level in an adult female patient." The Primary Care Companion to CNS Disorders, Vol. 14, No. 2, 2012.
35. Shim, Joo-Cheol, et al. "Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: A placebo-controlled trial." American Journal of Psychiatry, Vol. 164, No. 9, 2007, pp. 1404-10.
36. Hamamura, Takashi, and Toshiki Harada. "Unique pharmacological profile of aripiprazole as the phasic component buster." Psychopharmacology, Vol. 191, No. 3, 2007, pp. 741-43.
37. Tuplin, Erin W., and Matthew R. Holahan. "Aripiprazole, a drug that displays partial agonism and functional selectivity." Current Neuropharmacology, Vol. 15, No. 8, 2017, pp. 1192-207.
38. Wahl, Rebecca, and Robert Ostroff. "Reversal of symptomatic hyperprolactinemia by aripiprazole." American Journal of Psychiatry, Vol. 162, No. 8, 2005, pp. 1542-43.
39. Bakker, Ilse CA, Chris D. Schubart, and Pierre MJ Zelissen. "Successful treatment of a prolactinoma with the antipsychotic drug aripiprazole." Endocrinology, Diabetes and Metabolism Case Reports, Vol. 2016, No. 1, 2016.
40. Tuplin, Erin W., and Matthew R. Holahan. "Aripiprazole, a drug that displays partial agonism and functional selectivity." Current Neuropharmacology, Vol. 15, No. 8, 2017, pp. 1192-207.
41. De Bartolomeis, Andrea, Carmine Tomasetti, and Felice Iasevoli. "Update on the mechanism of action of aripiprazole: Translational insights into antipsychotic strategies beyond dopamine receptor antagonism." CNS Drugs, Vol. 29, No. 9, 2015, pp. 773-99.
42. Casey, Daniel E., et al. "Switching patients to aripiprazole from other antipsychotic agents: A multicenter randomized study." Psychopharmacology, Vol. 166, No. 4, 2003, pp. 391-99.
43. Joseph, Sam Padamadan. "Aripiprazole-induced hyperprolactinemia in a young female with delusional disorder." Indian Journal of Psychological Medicine, Vol. 38, No. 3, 2016, pp. 260-62.
44. Saraf, Gayatri, et al. "Hyperprolactinemia with aripiprazole: Understanding the paradox." American Journal of Therapeutics, Vol. 21, No. 3, 2014, pp. e80-e81.
45. Tewksbury, Ashley, and Amy Olander. "Management of antipsychotic-induced hyperprolactinemia." Mental Health Clinician, Vol. 6, No. 4, 2016, pp. 185-90.
46. Madhusoodanan, Subramoniam, Suprit Parida, and Carolina Jimenez. "Hyperprolactinemia associated with psychotropics-A review." Human Psychopharmacology: Clinical and Experimental, Vol. 25, No. 4, 2010, pp. 281-97.
47. Cohen, Louise Glassner, and Joseph Biederman. "Treatment of risperidone-induced hyperprolactinemia with a dopamine agonist in children." Journal of Child and Adolescent Psychopharmacology, Vol. 11, No. 4, 2001, pp. 435-40.
48. Cavallaro, Roberto, et al. "Cabergoline treatment of risperidone-induced hyperprolactinemia: A pilot study." The Journal of Clinical Psychiatry, Vol. 65, No. 2, 2004, pp. 187-90.
49. Tollin, Steven R. "Use of the dopamine agonists bromocriptine and cabergoline in the management of risperidone-induced hyperprolactinemia in patients with psychotic disorders." Journal of Endocrinological Investigation, Vol. 23, No. 11, 2000, pp. 765-70.
50. Lee, Moon‐Soo, et al. "Effect of bromocriptine on antipsychotic drug‐induced hyperprolactinemia: Eight‐week randomized, single‐blind, placebo‐controlled, multicenter study." Psychiatry and Clinical Neurosciences, Vol. 64, No. 1, 2010, pp. 19-27.
51. Grigg, Jasmin, et al. "Antipsychotic-induced hyperprolactinemia: Synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research." Psychopharmacology, Vol. 234, No. 22, 2017, pp. 3279-97.