Antipsychotic-induced hyperprolactinemia in Tourette syndrome

Introduction

Tourette syndrome (TS) is a common neuropsychiatric disorder characterized by motor and vocal tics, with a prevalence of 6 cases per 1000 school-aged children in the United States. ¹ The mainstay of pharmacologic management of tics has been the use of antipsychotic drugs. ² In psychotic disorders, hyperprolactinemia is one of the most common adverse effects associated with antipsychotics, occurring in 40–50% of subjects. ³ Symptoms of hyperprolactinemia include gynecomastia, galactorrhea, sexual dysfunction, infertility, oligomenorrhea and amenorrhea. To our knowledge, the prevalence of symptomatic hyperprolactinemia in TS is unknown, although clinical trials in early psychosis report symptomatic hyperprolactinemia in 2.2–9.8% ⁴ of patients treated with olanzapine, quetiapine and risperidone, at doses that are also used in TS. In this paper, we describe two patients with TS who experienced antipsychotic-induced hyperprolactinemia, and we discuss the management of antipsychotic-induced hyperprolactinemia in TS in relation to pathophysiology and pharmacology.

Case A

Patient A is a 19-year-old male diagnosed with TS at the age of 9 at our outpatient clinic. In The Netherlands, ethics approval for reporting individual cases is not required. Written consent was obtained for publication of his medical history in an international medical journal. Initially, treatment with pipamperone (up to 60 mg/day) was started, but this did not lead to a reduction of tics. Subsequently, pimozide (2 mg/day) was started but, following excessive weight gain, treatment was discontinued. In 2009, at the age of 11, treatment with risperidone 1 mg/day was initiated in combination with psychostimulants (methylphenidate 54 mg/day). Despite improved control of the tic disorder, after 4 weeks, the patient developed a unilateral swelling of the right mammary gland without galactorrhea. Prolactin level at that time was 902 mU/l (ref. 53–360 mU/l). After cessation of risperidone, prolactin levels returned to 21 mU/l. A few months later, he developed a unilateral swelling of the left mammary gland under use of sulpiride (50 mg/day), with a prolactin level of 919 mU/l. Sulpiride was discontinued, and prolactin levels returned to normal (116 mU/l) and the swelling disappeared. Swelling reoccurred during treatment with tetrabenazine (25 mg/day), now with a relatively mild increase of prolactin levels (290 mU/l), which returned to baseline after cessation of medication. Since the age of 14, our patient has been treated with aripiprazole (2.5 mg/day) with a significant reduction of tics. He has no complaints of swelling of the mammary glands and his prolactin level is 26 mU/l. He has a normal sexual development. No brain MRI was performed.

Case B

Patient B was a 24-year-old woman diagnosed with TS who has been treated in our outpatient clinic for 7 years. In The Netherlands, ethics approval for reporting individual cases is not required. Patient B provided written informed consent for publication of her medical history in an international medical journal. She uses oral contraception (cyproterone acetate 2.0 mg/ethinylestradiol 0.035 mg). Her medical history reveals a hemolytic anemia due to glucose phosphate isomerase enzyme deficiency. She has been treated with pimozide (4 mg/day), but this was ceased due to limited clinical effect. Treatment with tiapride (200 mg/day) was initiated but subsequently ceased due to akathisia. Finally, an acceptable tic-reducing effect was reached using pipamperone (120 mg/day), risperidone (4 mg/day) and topiramate (150 mg/day). In addition, citalopram 10 mg daily was started because of depressive mood. She developed galactorrhea [prolactin level 1001 mU/l (ref. 40–530 mU/l)]. Underlying neurologic processes causing hyperprolactinemia were excluded by normal brain MRI. Pipamperone was stopped and the galactorrhea disappeared. Her tics became more severe and risperidone was increased to 5 mg/day. Since that time, she has had frequent periods of galactorrhea (not related to menstrual cycle). A switch to aripiprazole (instead of risperidone) was tried, but due to limited effect and the occurrence of adverse effects (headache and dizziness), it was stopped. Recently, she again had complaints of galactorrhea and her prolactin level was 1072 mU/l. Decreasing the dose of risperidone was tried, but this resulted in an unacceptable increase of tics.

Discussion

Dopamine-receptor antagonists are the most effective pharmacologic treatment of tics. More specifically, high-affinity D₂-receptor antagonists such as haloperidol and pimozide have been shown to be effective in reducing tics. ⁵ The only D₂-receptor antagonists that are formally registered for TS are pimozide [by the Food and Drug Administration (FDA) for adolescents > 12 years] and haloperidol (by the FDA for TS in adults, and for children > 3 years in Germany). ⁶ The main effect on tics seems to be mediated by the blockade of the striatal dopamine D₂ receptors. ⁷ The stronger the blockade of the dopamine receptor, the more effective the drug is at reducing psychotic syndromes and tics.^8,9 The degree of blockade of the dopamine receptor depends on receptor affinity, residence time of the drug on the receptor, and dose (higher doses lead to more antagonism).^7,10

Adverse effects occur due to blockade of other dopamine pathways in the brain, such as the nigrostriatal pathway. Blockade of the tuberoinfundibular pathway results in hyperprolactinemia owing to reduction of the negative feedback of prolactin release (dopamine inhibits prolactin release in the pituitary).

Typical antipsychotics such as pimozide and pipamperone are strong dopamine D₂-receptor, and to a lesser extent, D₁-receptor antagonists. Consequently, they have a high association with adverse effects, including prolactin elevation.^10,11 Risperidone, sulpiride and tiapride are atypical antipsychotics. The pharmacologic mechanisms that constitute atypicality are debated. It has long been argued that atypical antipsychotics are characterized by antagonism at both D₂ receptors and serotonin 5-HT₂ receptors, ¹² but more recently, it has been hypothesized that clozapine (which is the prototype for this class) and many other atypical antipsychotics generally share a lower residence time at the D₂ receptor. This blunts the effects of pathologically high dopamine concentrations, while still allowing a certain level of physiological activation by endogenous dopamine release, thus reducing adverse extrapyramidal and neuroendocrine effects (like hyperprolactinemia). ¹³ Aripiprazole is another atypical antipsychotic drug used in TS, but it is based on a different pharmacologic principle. ¹⁴ Aripiprazole is a partial dopamine D₂-receptor agonist that acts as an agonist at low endogenous dopamine levels, and as an antagonist when levels are high.

As previously mentioned, prolactin elevation is one of the adverse effects of antipsychotics. Hyperprolactinemia, which may occur in up to 40–50% of patients, is due to blockade of dopamine D₂ receptors in the anterior pituitary gland.^10,15 Factors that contribute to elevation of prolactin level are age of the patient (higher sensitivity in younger people), sex (more frequent in women) and previous antipsychotic use. ³ In addition, the role of genetic factors is uncertain. Variants of the gene encoding the dopamine D₂ receptor also seem to influence the propensity for antipsychotic-induced hyperprolactinemia. ¹⁵ Symptoms of hyperprolactinemia include gynecomastia, galactorrhea, sexual dysfunction, infertility, oligomenorrhea and amenorrhea. ¹⁶

In a randomized, double-blind trial comparing the efficacy and tolerability of olanzapine, quetiapine and risperidone (all atypical antipsychotics) in early psychosis (400 patients, mean age 24.5 years, 27% female) gynecomastia was present in 9.8% of patients in the risperidone group (0.5–4 mg/day), in 6.8% in the olanzapine group (2.5–20 mg/day) and in 2.2% in the quetiapine group (100–800 mg/day). Indeed, patients in the risperidone group had greater increases in prolactin levels than those in the olanzapine or quetiapine groups at weeks 12 and 52. ⁴

There are no prevalence rates of symptomatic hyperprolactinemia in patients with TS treated with antipsychotic drugs, but doses of risperidone and olanzapine used in TS ⁹ are comparable with doses used in the abovementioned study.

In TS, the concomitant use of psychostimulants, melatonin and selective serotonin reuptake inhibitors (SSRIs) is not uncommon. The concomitant use of psychostimulants possibly has a protective effect, owing to their dopamine-receptor agonist activity. ¹⁹ Melatonin and SSRIs have a prolactin-elevating effect.^17,18

Patients with TS who require treatment are often in the age range in which the growth-inhibiting effect of chronically elevated prolactin levels, either directly or via delay of pubertal development, may result in short stature. ¹⁶ There is convincing evidence that hyperprolactinemia results in a reduction in bone mineral density. ¹⁹ Particularly in young patients (<25 years) who have not reached peak bone mass, elevation of prolactin levels seems to be particularly detrimental. ²⁰

Management

In most patients treated with neuroleptics, newly developing hyperprolactinemia will be drug-induced. Although clinically overt pituitary tumors are rare, small [median 1.2 mm (range 0.1–6.0 mm)] prolactinomas are found in 4% of autopsies ²¹ and neuroleptics may stimulate the growth of a previously asymptomatic tumor. ²² Therefore, tumors in the hypothalamic–pituitary area should be considered in patients with stable antipsychotic treatment who develop clinically overt and biochemically confirmed hyperprolactinemia. Dopamine-receptor agonists such as bromocriptine or cabergoline are the first step in the medical treatment of prolactinomas. As far as we know, there are no studies reporting effects of bromocriptine or cabergoline in TS, but because of the opposing pharmacologic effects of antipsychotics and prolactin inhibitors, this combination can be expected to aggravate tics.

In our opinion, there are several options to consider in symptomatic hyperprolactinemia in TS. Behavioral therapy should be considered as an alternative treatment for tics. Several randomized controlled trials in behavioral therapy on tics and TS have shown behavioral therapy to be an effective and promising treatment in tic reduction. ² Recently, a randomized, single-blind trial comparing risperidone with behavioral therapy in tic disorders was conducted; the data are currently being analyzed. ²³

Other options to treat drug-induced hyperprolactinemia are reducing the dose of the involved antipsychotic or eliminating the most typical antipsychotic if the patient is treated with a combination of D₂-receptor antagonists. Also, a switch to a compound with a more atypical profile can be considered. However, this may lead to an exacerbation of symptoms and may not always be preferable.

Currently, the most viable option is switching to or adding aripiprazole, which is a partial dopamine D₂-receptor agonist and is an efficacious and safe treatment for children and adolescents with TS. ¹⁴ It is interesting that aripiprazole caused a sustained prolactin reduction with positive effect on tics in our adolescent patient, but not in the adult female patient. In a review by Safer et al, ²⁴ 60% of children and 30–32% of adolescents were found to have subnormal prolactin levels during treatment with aripiprazole. No subnormal levels of prolactin have been reported in adults. This may be related to the maturation of central dopaminergic signaling. ²⁴ The clinical consequences of these differences remain to be established. Also, in view of the limited alternatives, there are no reasons to discourage a switch to aripiprazole in a young adult with hyperprolactinemia, although it seems prudent to critically assess the effects.

Conclusion

Children and adolescents with TS are frequently treated with antipsychotics, either as monotherapy or in combination with psychostimulants, melatonin and SSRIs. Hyperprolactinemia is a common adverse effect of antipsychotic use that can lead to delayed pubertal development, short stature and reduction in bone mass density, particularly among children and adolescents. Therefore, it is important to be alert to various clinical manifestations. Antipsychotics with a strong dopamine D₂-receptor antagonistic effect, such as amisulpride, risperidone and paliperidone, should probably be avoided in younger patients. If such drugs are required for the treatment of TS, we suggest determining baseline levels of prolactin before the start of the therapy and subsequently monitoring them annually. In symptomatic hyperprolactinemia in TS, dose reduction should be attempted. If this is not possible, consider adding or switching to aripiprazole (partial dopamine D₂-receptor agonist) or a low-affinity dopamine D₂-receptor antagonist (quetiapine or one of the new atypical antipsychotics). In asymptomatic hyperprolactinemia in TS, it is important to monitor growth and sexual maturation. Presently, there is insufficient scientific evidence to support routine bone densitometry for screening in children and adolescents undergoing psychotropic treatment. ¹⁹ The use of combined oral contraceptives in female patients could be considered in the presence of symptoms of estrogen deficiency, but the use of oral contraceptives is associated with an increased risk of thromboembolism and breast cancer, so these risks should be carefully assessed and discussed. ¹⁶