Low-Dose Amisulpride and Elevation in Serum Prolactin

Clinical Question

At low doses, substituted benzamides such as sulpiride, levosulpiride, and amisulpride preferentially block the higher affinity dopamine autoreceptors that are located on the presynaptic neuron1,2; this results in increased release of dopamine,1,2 an effect that is useful for the treatment of depression,3 somatoform disorders,4 and negative symptoms of schizophrenia.3 At high doses, these drugs also block the lower affinity dopamine postsynaptic receptors,1,2 effectively ameliorating positive symptoms of schizophrenia.5 Given that dopamine inhibits the release of prolactin, would low doses of these drugs lower serum prolactin and high doses lead to hyperprolactinemia?

High and Low Doses of These Drugs Both Increase Serum Prolactin

Curiously, even though low and high doses of these substituted benzamides have opposite dopaminergic effects in the brain, both low and high doses increase serum prolactin. For example, high doses of these drugs are used for the treatment of psychosis, and the resultant hyperprolactinemia and its consequences are well-recognized adverse effects.1,4 And, when low doses of these drugs are used for depression, negative symptoms of schizophrenia, or other indications, hyperprolactinemia is again observed.6-11

In a recent study, for example, Lee et al11 found that the mean serum prolactin level was clinically elevated at 76.1 ng/mL in (mostly) young men (n = 12) and women (n = 8) who were receiving low-dose amisulpride for different indications. The dose of amisulpride was 300 mg/d in 2 patients and 100-200 mg/d in the remaining patients. The duration of treatment ranged from 1 week to more than 2 years. No patient was receiving any other medication that could explain the prolactin elevation. Even within this low dose range, higher doses of amisulpride were associated with significantly higher serum prolactin levels. The hyperprolactinemia was more marked in women (mean level = 110.7 ng/mL) than in men (mean level = 53.1 ng/mL) despite comparable amisulpride dosing (mean doses, 200 mg/d vs 188 mg/d, respectively).

These findings are in conformity with the scientific literature. For example, other authors8,10 have reported prolactin elevation with low-dose amisulpride. Prolactin elevation has also been reported with low doses of sulpiride9,12 and levosulpiride.7 Finally, dose-dependent prolactin elevation and greater prolactin elevation in women than in men has been described with other antipsychotic drugs, such as paliperidone, as well.13

Reason Why Even Low Doses of These Drugs Increase Serum Prolactin

These drugs penetrate the blood-brain barrier poorly and therefore achieve lower concentrations inside the brain than outside it.14 The pituitary is located outside the blood-brain barrier; so, what constitutes low-dose amisulpride in the brain might effectively be high-dose amisulpride outside the brain, as in the pituitary. Such an uncoupling or dissociation in the magnitude of amisulpride activity between the striatum and the pituitary has been demonstrated in animals14 as well as humans.15

Expressed otherwise, a 100-mg dose of amisulpride may achieve concentrations in the brain that are too low to do anything more than block the high-affinity dopamine autoreceptors, thereby increasing dopaminergic neurotransmission. However, the same dose may achieve sufficient concentrations outside the blood-brain barrier, such as in the pituitary, to efficiently block the dopamine receptors there, thus raising serum prolactin.

Clinical Consequences of Hyperprolactinemia

The hyperprolactinemia induced by dopamine receptor antagonists may be therapeutically exploited, such as to induce lactation in nonlactating women after childbirth; for example, low doses of sulpiride have been used for this indication.12,16 Hyperprolactinemia, however, more usually causes adverse effects such as decreased libido (and its consequences), amenorrhea and infertility, breast engorgement and lactation, and gynecomastia. Hyperprolactinemia may also be associated with reduced bone mineral density, especially in women. Finally, hyperprolactinemia may rarely be associated with breast cancer and pituitary tumors.17-20

Management

Regardless of dose, sulpiride, levosulpiride, and amisulpride should be used with caution or not at all in patients who are at risk of or already have conditions that might be aggravated by prolactin elevation. Examples of such patients are women with preexisting menstrual irregularities, women who are trying to conceive, and persons with prolactin-dependent tumors. Other patients at risk of prolactin-related adverse effects are women who are postmenopausal and at risk of osteoporosis and those who already have osteoporosis.

In such patients, if a substituted benzamide drug is considered necessary, a baseline prolactin level may be desirable to guide the interpretation of levels obtained after the initiation of therapy. In other patients, it may suffice to assess prolactin levels only if problems that are possibly prolactin-related emerge, because patients with hyperprolactinemia do not necessarily experience adverse effects related to the condition, as clinical trial data show.13

There are few ways to address clinically significant hyperprolactinemia that arises from the use of low-dose substituted benzamide drugs. Switching to prolactin-sparing antipsychotics such as aripiprazole21,22 will not help, because other antipsychotics, even those that are prolactin-sparing, are not prescribed for the same indications as low doses of substituted benzamides. For the same reason, aripiprazole augmentation23,24 is unlikely to be a viable strategy. Using dopamine agonists such as bromocriptine25 would probably be only a temporary expedient and not a long-term solution because it could worsen psychosis.26

Decreasing the dose of medication is a possibility, given that Lee et al11 found that lower doses of amisulpride occasioned less hyperprolactinemia; the risk, of course, is that lowering already low doses of a drug may compromise the efficacy of the drug. Hormone replacement26 may be attempted if the drug responsible for prolactin elevation clearly benefits the patient and if suitable alternatives are unavailable. In the worst-case scenario, in which the adverse consequences of unresolved hyperprolactinemia outweigh the observed benefits of treatment, the drug is best discontinued.

J Clin Psychiatry 2013;74(6):e558-e560 (doi:10.4088/JCP.13f08510)

© Copyright 2013 Physicians Postgraduate Press, Inc.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India ([email protected]).
Financial disclosure and more about Dr Andrade.

REFERENCES

1. McKeage K, Plosker GL. Amisulpride: a review of its use in the management of schizophrenia. CNS Drugs. 2004;18(13):933-956. PubMed doi:10.2165/00023210-200418130-00007

2. Racagni G, Canonico PL, Ravizza L, et al. Consensus on the use of substituted benzamides in psychiatric patients. Neuropsychobiology. 2004;50(2):134-143. PubMed doi:10.1159/000079104

3. Pani L, Gessa GL. The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia. Mol Psychiatry. 2002;7(3):247-253. PubMed doi:10.1038/sj.mp.4001040

4. Mucci A, Nolfe G, Maj M. Levosulpiride: a review of its clinical use in psychiatry. Pharmacol Res. 1995;31(2):95-101. PubMed doi:10.1016/1043-6618(95)80053-0

5. Curran MP, Perry CM. Amisulpride: a review of its use in the management of schizophrenia. Drugs. 2001;61(14):2123-2150. PubMed doi:10.2165/00003495-200161140-00014

6. Rüther E, Degner D, Munzel U, et al. Antidepressant action of sulpiride. Results of a placebo-controlled double-blind trial. Pharmacopsychiatry. 1999;32(4):127-135. PubMed doi:10.1055/s-2007-979218

7. Greco E, Polonio-Balbi P, Speranza JC. Levosulpiride: a new solution for premature ejaculation? Int J Impot Res. 2002;14(4):308-309. PubMed doi:10.1038/sj.ijir.3900901

8. Kopecek M, Bares M, Svarc J, et al. Hyperprolactinemia after low dose of amisulpride. Neuroendocrinol Lett. 2004;25(6):419-422. PubMed

9. Uchida H, Takeuchi H, Suzuki T, et al. Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder. J Clin Psychopharmacol. 2005;25(6):545-551. PubMed doi:10.1097/01.jcp.0000185425.00644.41

10. Raj R, Sidhu BS. Hyperprolactinaemia with amisulpride. Indian J Psychiatry. 2008;50(1):54-56. PubMed doi:10.4103/0019-5545.39761

11. Lee B-H, Kang S-G, Kim T-W, et al. Hyperprolactinemia induced by low-dosage amisulpride in Korean psychiatric patients. Psychiatry Clin Neurosci. 2012;66(1):69-73. PubMed doi:10.1111/j.1440-1819.2011.02296.x

12. Ylikorkala O, Kauppila A, Kivinen S, et al. Sulpiride improves inadequate lactation. Br Med J (Clin Res Ed). 1982;285(6337):249-251. PubMed doi:10.1136/bmj.285.6337.249

13. Meltzer HY, Bobo WV, Nuamah IF, et al. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies. J Clin Psychiatry. 2008;69(5):817-829. PubMed doi:10.4088/JCP.v69n0515

14. Kapur S, Langlois X, Vinken P, et al. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther. 2002;302(3):1129-1134. PubMed doi:10.1124/jpet.102.035303

15. Bressan RA, Erlandsson K, Spencer EP, et al. Prolactinemia is uncoupled from central D2/D3 dopamine receptor occupancy in amisulpride treated patients. Psychopharmacology (Berl). 2004;175(3):367-373. PubMed doi:10.1007/s00213-004-1826-6

16. O’ Leary RM. Sulpiride improves inadequate lactation. Br Med J (Clin Res Ed). 1982;285(6344):807. PubMed doi:10.1136/bmj.285.6344.807

17. Szarfman A, Tonning JM, Levine JG, et al. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy. 2006;26(6):748-758. PubMed doi:10.1592/phco.26.6.748

18. Byerly M, Suppes T, Tran QV, et al. Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives. J Clin Psychopharmacol. 2007;27(6):639-661. PubMed doi:10.1097/jcp.0b013e31815ac4e5

19. Bostwick JR, Guthrie SK, Ellingrod VL. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy. 2009;29(1):64-73. PubMed doi:10.1592/phco.29.1.64

20. Cookson J, Hodgson R, Wildgust HJ. Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis. J Psychopharmacol. 2012;26(suppl):42-51. PubMed doi:10.1177/0269881112442016

21. Lu ML, Shen WW, Chen CH. Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1978-1981. PubMed doi:10.1016/j.pnpbp.2008.09.016

22. Lee BH, Kim YK. Resolution of amisulpride-associated amenorrhea by switching to aripiprazole. Psychiatry Invest. 2006;3(1):102-106.

23. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164(9):1404-1410. PubMed doi:10.1176/appi.ajp.2007.06071075

24. Yasui-Furukori N, Furukori H, Sugawara N, et al. Dose-dependent effects of adjunctive treatment with aripiprazole on hyperprolactinemia induced by risperidone in female patients with schizophrenia. J Clin Psychopharmacol. 2010;30(5):596-599. PubMed doi:10.1097/JCP.0b013e3181ee832d

25. Yuan HN, Wang CY, Sze CW, et al. A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J Clin Psychopharmacol. 2008;28(3):264-370. PubMed doi:10.1097/JCP.0b013e318172473c

26. Inder WJ, Castle D. Antipsychotic-induced hyperprolactinaemia. Aust N Z J Psychiatry. 2011;45(10):830-837. PubMed doi:10.3109/00048674.2011.589044