Hyperprolactinemia with Antipsychotic Drugs in Children and Adolescents

The practice of psychiatry and the shift to noninstitutional care of severe psychiatric disorders are the result of antipsychotic medications, beginning with chlorpromazine in the early 1950s. Approximately 10 other drugs, known as first-generation or typical antipsychotics, followed over the subsequent 30 years. These drugs were effective in treating positive symptoms of psychosis such as hallucination and delusion but did not alleviate the negative symptoms of withdrawal, apathy, cognitive impairment, or loss of affect. Furthermore, they were associated with frequent extrapyramidal symptoms, including acute dystonia, akinesia, akathisia, tardive dyskinesia, and parkinsonism. A series of newer drugs began emerging in 1989, referred to as second generation or atypical antipsychotics, thought to be more effective than the older agents in alleviating the negative, cognitive, and affective symptoms, with fewer extrapyramidal adverse effects [1].

The antipsychotic drugs differ in their side effect profiles, as they affect different neuroreceptors (histamine, α-adrenergic, muscarinic, dopamine, or serotonin). The principal concern for endocrinologists with the newer drugs has been the metabolic effects of weight gain, glucose intolerance, hyperlipidemia, and hypertension [2]. This is particularly important with the increasing use of these agents in pediatrics to treat bipolar disorder, schizophrenia, autism, oppositional and other behavior disturbances, Tourette disorder, and pervasive developmental disorder. In 2003-2004, 1% of all pediatric visits resulted in the prescription of atypical antipsychotic medication [3]. The importance and implications of the metabolic side effects of atypical antipsychotics for pediatric patients have been recently reviewed [1, 4].

This paper will examine the side effect of hyperprolactinemia in children and adolescents treated with antipsychotic drugs.

Prolactin, a 198-amino acid polypeptide, is secreted by the anterior pituitary lactotroph cells in a pulsatile manner with 13-14 peaks per day, the peak amplitude 60% above nadir [5]. There is also a marked circadian variation with maximum secretion 4 hours from sleep onset and minimum 6 hours after waking [6]. Thus, there can be as much as a fourfold variation in level depending on the time of day or night sampling is done; there are also transient mild increases related to meals, stress, and sexual activity [7]. Prolactin levels are higher during menstrual midcycle and the 2nd half of the cycle. During pregnancy, levels rise 10–20-fold, reaching 200  g/L at term and 300  g/L during nursing [8]. Normal upper limit range is 15–25  g/L [7].

Prolactin stimulates breast enlargement during pregnancy and milk production during lactation, while reducing libido and fertility, which may have evolutionary/survival significance.

Secretion of prolactin is inhibited predominantly by dopamine produced in the tuberoinfundibular neurons of the hypothalamus, released from nerve endings in the median eminence and carried through the portal hypophyseal circulation to the pituitary, there binding to dopamine receptors on lactotrophs, inhibiting prolactin gene transcription [9]. Antipsychotic drugs are thought to disinhibit prolactin secretion by receptor blockade. Serotonin stimulates prolactin secretion via serotonin and 5- receptors. Estrogens, binding to specific intracellular receptors in lactotrophs, enhance prolactin gene transcription and synthesis [6]. They also inhibit dopamine synthesis in the tuberoinfundibular neurons and reduce D₂ receptor levels on lactotrophs in animal models [10, 11].

Gonadotropin releasing hormone (GnRH), released in a pulsatile manner from the hypothalamus, stimulates release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary. Prolactin inhibits the release of GnRH in the hypothalamus. The positive feedback of estradiol on LH secretion in women is also blocked. Consequently, estrogen levels in women and testosterone levels in men are suppressed, with marked individual variability in the prolactin level causing gonadal hypofunction.

In children and adolescents, hyperprolactinemia resulting from prolactinomas, which are rare, can result in galactorrhea, amenorrhea, gynecomastia, and maturational delay with growth failure [12]. Of concern is the potential effect of the induced hypogonadotropism state on the critical peak bone formation of adolescence and the maintenance of bone density through adulthood.

Psychiatric disorders may be associated with modest elevations in serum prolactin concentrations as a stress phenomenon [13]. Further prolactin elevation can be measured within minutes to hours after the start of treatment with first-generation antipsychotic drugs, with levels up to 10-fold after several weeks at therapeutic dosages. Levels typically fall to normal within 2 to 4 days of stopping the drugs but may take up to 3 weeks to return to normal [14].

In adult psychiatric patients clozapine and quetiapine did not raise plasma prolactin levels at any dosage. Olanzapine only did so at higher dosages, but risperidone and amisulpride caused marked, sustained increase in serum prolactin levels in a substantial number of patients [14]. Aripiprazole, a relatively new atypical antipsychotic, also does not appear to increase prolactin levels [15]. Ziprasidone caused only transient elevations in psychiatric patients and healthy volunteers [16].

A review published in 2004 of 14 reports of the effects of both first- and second-generation antipsychotic agents in children and adolescents included 276 patients of whom 49 had prolactin elevations [17]. A report of 35 patients aged 9–19 years found no prolactin elevation with clozapine, but in 9 of 10 with haloperidol and 7 of 10 with olanzapine [18]. In another study of 11 outpatients aged 4–17 years treated with risperidone, 9 developed hyperprolactinemia of whom one had amenorrhea, and one had gynecomastia [19]. A further study reported that prolactin levels were increased in all 34 patients aged 5–14 years treated with risperidone [20]. Hyperprolactinemia was also noted in pediatric patients using ziprasidone and olanzapine. As with adults, ziprasidone- associated prolactin elevation was mild and transient, but associated with mild gynecomastia [21] and in one case with galactorrhea that resolved after drug discontinuation [22]. Two studies of the effects of quetiapine led to slightly differing results: one showed no increase in prolactin levels in 10 12–15-year-old children while the other study of 15 13–17-year-olds found a slight increase of no clinical significance, from a mean of 11.3 to 14.4 ng/mL [17]. Clozapine was not associated with increased prolactin levels, and the single patient who developed galactorrhea with risperidone had resolution of the problem when switched to clozapine [23].

A retrospective study analyzed prolactin levels and hyperprolactinemia attributable side effects from 5 clinical trials involving 592 children and adolescents of subaverage intelligence with conduct or other disruptive behavior disorders aged 5 to 15 years treated with risperidone. There was a weak effect of risperidone on prolactin concentrations during short-term treatment and lesser effect with long-term treatment, with side effects of gynecomastia, amenorrhea, or galactorrhea in only 2.2% [24]. These relatively benign findings have been attributed to low drug dosage for behavioral rather than psychiatric disorders and decreasing compliance over time [25].

Quite different findings emerged from a small double-blind placebo-controlled study of the effect of relatively low dose risperidone on prolactinemia in 10 children and adolescents with mental retardation and pervasive developmental disorders. Prolactin levels approximately tripled, and this increase was sustained for a mean 33 weeks of treatment [26].

Three adolescents were reported with risperidone-induced hyperprolactinemia resulting in gynecomastia in one boy that cleared and did not recur with olanzapine, gynecomastia with galactorrhea in another boy with comparable prolactinemia that resolved when he was switched to clozapine, and amenorrhea and galactorrhea in the third patient that resolved when she was changed to quetiapine. Their prolactin levels were 2100, 1670, and 1990 mIU/L (58, 46, and 55  g/L) when they were hyperprolactinemic and reduced to 63, 90, and 191 mIU/L (2, 2.5, and 5.3  g/L) after resolution [27]. Among 10 psychotic adolescents treated with risperidone, Holzer and Eap had 3 males developing gynecomastia and 2 females developing galactorrhea, along with 3 others having hyperprolactinemia without symptoms [25].

Sixteen adolescents aged 13–17 years with subaverage intelligence and disruptive behavior disorders treated with olanzapine for 8 weeks had significant elevations in serum prolactin levels, from baseline to  (SD)  g/L without any symptoms or signs of hyperprolactinemia [28].

A study from Italy compared short- and long-term effects on prolactin of risperidone and olanzapine in 42 children and adolescents treated for a year [29]. They found that after adjusting for dose and the greater potency of risperidone, the increase in prolactin levels during risperidone treatment was 10.7 times higher than that during olanzapine treatment. Only one subject had a symptom of hyperprolactinemia, transient mild galactorrhea with risperidone which resolved without a change in therapy. Similarly, a randomized comparison of quetiapine and risperidone in 22 15–18-year-old adolescents with new-onset psychosis found prolactin elevation in 91% of those treated with risperidone versus 9% of those treated with quetiapine [30].

The degree of hyperprolactinemia induced by short-term risperidone treatment in children and youth is dose dependent [17, 33]. This dose dependency is linked to plasma concentrations of both risperidone and its active metabolite 9-hydroxyrisperidone [33]. CYP2D6 is primarily responsible for the conversion of risperidone to 9-hydroxyrisperidone. In an examination of the possible role of activity of this enzyme in risperidone-induced prolactin release in children, Troost et al. [34] found a positive correlation of the fourfold elevation in serum prolactin level at 8 and 24 weeks with dose per kilogram body weight ( , ), number of functional CYP2D6 genes, serum 9-hydroxyrisperidone concentration ( , ) and negative correlation with the risperidone/9-hydroxyrisperidone ratio ( , ) but not with risperidone concentration ( , ). Thus, more rapid CYP2D6 metabolism may be a risk factor for hyperprolactinemia with risperidone. Polymorphic variation in the dopamine D2 receptor may be another pharmacogenetic factor determining risk for risperidone-induced hyperprolactinemia in children and adolescents. Two variants were identified that were associated with higher prolactin concentration in a study of 107 patients treated for up to 3 years [32].

Because second-generation antipsychotics are being increasingly prescribed for children and adolescents with conditions that are not psychoses and that are also treated with stimulants, the potential mitigating effect of the stimulants on the side effects of the antipsychotics has been examined [35]. Stimulant drugs have opposite effects on the dopamine receptor than do the antipsychotics. Subjects were 153 4–19-year-olds treated with antipsychotics, 71 of whom were coprescribed stimulants. The antipsychotic drugs included risperidone (33%), aripiprazole (30%), quetiapine (18%), olanzapine (12%), and ziprasidone (6%). In addition to no effect of cotreatment with stimulants on the side effect of hyperprolactinemia, there was no effect on body composition, metabolic parameters, sedation, or overall efficacy of the antipsychotic agent.

Second-generation antipsychotics are being increasingly prescribed for children and adolescents with a wide range of behavioral disturbances in addition to psychoses, resulting in metabolic and hormonal changes of importance to the consulting pediatric endocrinologist. In addition to weight gain and associated comorbidities of insulin resistance, hyperprolactinemia is a common side effect resulting from the inhibition of dopamine action. First-generation antipsychotics, particularly haloperidol, and the second-generation antipsychotic drugs, most prominently risperidone, appear to be associated with the greatest risk for hyperprolactinemia; some treated individuals developing hyperprolactinemia will have galactorrhea, amenorrhea, or gynecomastia. Hyperprolactinemia may have a deleterious effect on peak bone mass attainment and increase long-term osteopenia risk, even in the absence of overt symptoms or signs of hyperprolactinemia. This adverse effect may be enhanced by the commonly associated treatment with SSRIs. The effect of psychotropic drugs on bone mass accrual needs further study. The suggestion of a greater risk for pituitary tumors related to drug affinity for D2 receptors also requires continued study. Thus, in addition to surveillance for signs and symptoms of hyperprolactinemia in children and adolescents taking antipsychotic medications, monitoring serum prolactin concentrations is warranted. In the presence of hyperprolactinemia, cessation of antipsychotic therapy or changing to a formulation less likely to raise prolactin levels should be considered.

The author is a consultant to a law firm pursuing litigation with manufacturers of second-generation antipsychotic drugs.