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Haloperidol

Classification: C

Drug products: Haldol, Haldol Depot, Haldol®, Haldol® Depot, Haldol®-Janssen, Haloperidol Ebb, Haloperidol ratiopharm, Haloperidol WZF, Haloperidol-Grindeks, Haloperidol-neuraxpharm, Haloperidol-ratiopharm®, Serenase

ATC code: N05AD01

Substances: haloperidol, haloperidol decanoate

Summary

Haloperidol, an antipsychotic agent of the first generation that blocks dopamine D2-receptors, is equally effective in both men and women.

Haloperidol is associated with QT prolongation and thus a risk of potentially fatal arrhythmia of the type Torsade de Pointes (TdP). No difference in risk between men and women has been shown for haloperidol but a known risk factor for Torsade de Pointes is female sex.

Since haloperidol blocks dopamine receptors in the pituitary, prolactin levels increase, which leads to decreased libido, gynecomastia, erectile and ejaculatory disturbances in men and amenorrhea/menstrual disturbances in women.

Additional information

Pharmacokinetics and dosing

Two pharmacokinetic studies addressed possible sex differences in pharmacokinetics of oral haloperidol. Neither a four-week study in patients treated with haloperidol 2-20 mg/day (10 men, 16 women) [1] nor a single dose study (haloperidol 10 mg) in healthy poor and extensive metabolizers of CYP2D6 (8 men, 8 women) could detect a statistically significant difference between man and women with respect to clearance or half-life [2]. Due to the low statistical power of these two studies it is hard to draw any conclusion on sex differences of haloperidol pharmacokinetics.

Effects

The optimal dosing of haloperidol may be as low as 4 mg/day [3], but many clinical trials on haloperidol used doses up to 20 mg/day.   

In general, possible sex differences of haloperidol have not been studied to any larger extent.  The results of a 6 week randomized clinical trial of haloperidol versus olanzapine in patients with schizophrenia spectrum disorder (426 men, 233 women in the treatment arm with haloperidol (5-20 mg/d)) [4] have been analysed with regard to sex differences in efficacy in two publications [5, 6]. Men and women were not found to significantly differ on any of the clinical outcome measures (Brief Psychiatric rating scale, BPRS) total score or positive or negative subscale. When the data was analyzed in women only after stratifying by age group < 47 years versus > 47 years (as a proxy for menopausal status), there was a significant overall difference in treatment response between pre- and postmenopausal women (BPRS, respectively: 22.8 ± 1.3 vs. 27.7 ± 2.1) [6].

Postoperative nausea and vomiting (PONV) can be treated by intravenous haloperidol 0.5 mg. In a register-based study of 2617 surgical procedures haloperidol was administered (523 men, 749 women. The results indicate a reduced risk of PONV by haloperidol in men but not in women [7].

A Cochrane meta-analysis noted that haloperidol decreased aggression among patients with agitated dementia. However, the data were insufficient to examine response to treatment in relation to patient’s sex and cause of dementia [8].

Adverse effects

The optimal dosing of haloperidol may be as low as 4 mg/day [3], but many clinical trials on haloperidol used doses up to 20 mg/day.   

An analysis of reported adverse effects of haloperidol, compiled by Johnson & Johnson, identified 229 cases of abnormally long QTc intervals, among which were 73 cases of Torsade de Pointes (TdP). Eleven (15%) of the TdP cases were fatal, and 8 (73%) of these deaths occurred after haloperidol had been given intravenously. However, the data provided in this review did not analyse the risk for adverse events separately in men and women. But female sex is among known risk factors for drug-induced ventricular arrhythmias [9, 10].

Haloperidol elevates serum prolactin levels to 20–40 ng/ml when used at therapeutic doses and sexual dysfunction is reported by 45% of men and 25% of women treated with haloperidol [11, 12]. Reduced libido (in around 31% of men and 24% of women) is the most commonly reported disturbance. In men, reports of erectile dysfunction varies between 30–50% [11-13] and gynecomastia has been reported in 3.3% [12]. In women, amenorrhea/menstrual disturbances has been reported in 14% in one clinical trial and in 54% in another trial [13].

The effect of haloperidol on prolactin levels in men and women was analysed in the above mentioned randomized clinical trial of haloperidol versus olanzapine [4]. Haloperidol administered to women increased the average serum prolactin levels from 24 ng/ml at baseline to 53 ng/ml during week 1-8 and to 66 ng/ml at week 34-52 respectively. Administration of haloperidol to men increased average baseline prolactin levels from 11 ng/ml to 24 ng during week 1-8 and 23 during week 34-52 respectively [14, 15].

In a study of children and adolescents with a mean age of 13 years (9 boys, 6 girls) an average dose of 15.3 mg/d of haloperidol increased prolactin from 10.2 ng/ml to 67.7 ng/ml in girls and from 8.5 ng/ml to 34.7 ng/ml in boys [16].

Due to an inhibition of dopamine-transmission in basal ganglia first generation antipsychotic drugs have been linked to an increased risk of extrapyramidal side effects (parkinsonism).  A cross-sectional study in patients with or without antipsychotic-related parkinsonism (47 men, 103 women) suggests that carriership of the j759 T allele of the HTR2C gene in women may be protective against development of parkinsonism in elderly patients during treatment with haloperidol [17].

According to a Korean cross-sectional study of 51 patients (30 men, 21 women) treated with haloperidol and 57 normal controls a decreased bone mass density (BMD) was detected in 86% of women and 50% of men treated with haloperidol. Among women with decreased BMD, 17 of 18 had hyperprolactinemia. In the control group, BMD was not correlated with patient’s sex [18].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Updated: 2019-09-24

Date of litterature search: 2019-07-20

References

  1. de Leon J, Diaz FJ, Wedlund P, Josiassen RC, Cooper TB, Simpson GM. Haloperidol half-life after chronic dosing. J Clin Psychopharmacol. 2004;24(6):656-60. PubMed
  2. Desai M, Tanus-Santos JE, Li L, Gorski JC, Arefayene M, Liu Y et al. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6. Pharmacogenomics J. 2003;3(2):105-13. PubMed
  3. McEvoy JP, Johnson J, Perkins D, Lieberman JA, Hamer RM, Keefe RS et al. Insight in first-episode psychosis. Psychol Med. 2006;36(10):1385-93. PubMed
  4. Tollefson GD, Beasley CM, Tran PV, Street JS, Krueger JA, Tamura RN et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry. 1997;154:457-65. PubMed
  5. Ascher-Svanum H, Stensland M, Zhao Z, Kinon BJ. Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia. BMC Psychiatry. 2005;5:3. PubMed
  6. Goldstein JM, Cohen LS, Horton NJ, Lee H, Andersen S, Tohen M et al. Sex differences in clinical response to olanzapine compared with haloperidol. Psychiatry Res. 2002;110:27-37. PubMed
  7. Brettner F, Janitza S, Prüll K, Weninger E, Mansmann U, Küchenhoff H et al. Gender-Specific Differences in Low-Dose Haloperidol Response for Prevention of Postoperative Nausea and Vomiting: A Register-Based Cohort Study. PLoS One. 2016;11(1):e0146746. PubMed
  8. Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev. 2002;1(2):CD002852. PubMed
  9. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011;108:687-93. PubMed
  10. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-22. PubMed
  11. Baggaley M. Sexual dysfunction in schizophrenia: focus on recent evidence. Hum Psychopharmacol. 2008;23(3):201-9. PubMed
  12. Bobes J, Garc A-Portilla MP, Rejas J, Hern Ndez G, Garcia-Garcia M, Rico-Villademoros F et al. Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study. J Sex Marital Ther. 2003;29(2):125-47. PubMed
  13. Dossenbach M, Dyachkova Y, Pirildar S, Anders M, Khalil A, Araszkiewicz A et al. Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study. Eur Psychiatry. 2006;21(4):251-8. PubMed
  14. David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther. 2000;22(9):1085-96. PubMed
  15. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials. Psychoneuroendocrinology. 2003;28 Suppl 2(1):69-82. PubMed
  16. Wudarsky M, Nicolson R, Hamburger SD, Spechler L, Gochman P, Bedwell J et al. Elevated prolactin in pediatric patients on typical and atypical antipsychotics. J Child Adolesc Psychopharmacol. 1999;9(4):239-45. PubMed
  17. Knol W, van Marum RJ, Jansen PA, Strengman E, Al Hadithy AF, Wilffert B et al. Genetic variation and the risk of haloperidol-related parkinsonism in elderly patients: a candidate gene approach. J Clin Psychopharmacol. 2013;33(3):405-10. PubMed
  18. Jung DU, Conley RR, Kelly DL, Kim DW, Yoon SH, Jang JH et al. Prevalence of bone mineral density loss in Korean patients with schizophrenia: a cross-sectional study. J Clin Psychiatry. 2006;67(9):1391-6. PubMed
  19. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-08-19.] länk

Authors: Carl-Olav Stiller, Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson