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 .
the antipsychotic drugs differ in their side effect profiles , as they affect different neuroreceptors ( histamine , -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 .
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
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 .
there is also a marked circadian variation with maximum secretion ~4 hours from sleep onset and minimum ~6 hours after waking .
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 .
prolactin levels are higher during menstrual midcycle and the 2nd half of the cycle . during pregnancy ,
levels rise 1020-fold , reaching 200  g / l at term and 300  g / l during nursing .
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 d2 receptors on lactotrophs , inhibiting prolactin gene transcription .
estrogens , binding to specific intracellular receptors in lactotrophs , enhance prolactin gene transcription and synthesis .
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 .
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 . 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 .
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 .   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 .
aripiprazole , a relatively new atypical antipsychotic , also does not appear to increase prolactin levels .
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 .
a report of 35 patients aged 919 years found no prolactin elevation with clozapine , but in 9 of 10 with haloperidol and 7 of 10 with olanzapine . in another study of 11 outpatients
aged 417 years treated with risperidone , 9 developed hyperprolactinemia of whom one had amenorrhea , and one had gynecomastia .
a further study reported that prolactin levels were increased in all 34 patients aged 514 years treated with risperidone .
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   and in one case with galactorrhea that resolved after drug discontinuation .
two studies of the effects of quetiapine led to slightly differing results : one showed no increase in prolactin levels in 10 1215-year - old children while the other study of 15 1317-year - olds found a slight increase of no clinical significance , from a mean of 11.3 to 14.4  ng / ml . 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 .
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% .
these relatively benign findings have been attributed to low drug dosage for behavioral rather than psychiatric disorders and decreasing compliance over time .
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 .
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 . 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 .
sixteen adolescents aged 1317 years with subaverage intelligence and disruptive behavior disorders treated with olanzapine for 8 weeks had significant elevations in serum prolactin levels , from baseline 9.7  6.1 to 24.8  19.8  ( sd )  g / l without any symptoms or signs of hyperprolactinemia .   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 .
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 1518-year - old adolescents with new - onset psychosis found prolactin elevation in 91% of those treated with risperidone versus 9% of those treated with quetiapine .
dutch investigators have recently conducted an extensive literature review of studies of antipsychotic medication effects on prolactin level and associated side effects in children and adolescents .
twenty of these were concerning risperidone , 7 olanzapine , 5 quetiapine , 4 haloperidol , 3 pimozide , 2 clozapine , and 1 ziprasidone .
they found that all antipsychotics with the exception of clozapine , ziprasidone , and quetiapine increased the mean prolactin level from 8 to 2528  ng / ml .
the incidence of hyperprolactinemia was 90% with haloperidol , 80% with pimozide , 62% with risperidone , 31% with olanzapine , and 12% with quetiapine .
risperidone , olanzapine , and pimozide were seen to induce a persistent elevation in prolactin levels .
associated gynecomastia , galactorrhea , or irregular menses were reported in 4.8% of the children and adolescents .
interpretation of the numerous studies is confounded by variation in study design , diagnoses , dosages , and age distribution , varying use of concomitant medication , short duration of some studies , compliance uncertainty , lack of prolactin baseline values ( one fourth of the studies analyzed by roke et al . ) , and other missing data as noted in the table .
there may also be publication bias , as all data on prolactin values from manufacturers ' files have not been published .
the effects of hyperprolactinemia may be underestimated because they depend on self - report , and may be mistaken for common adolescent problems of gynecomastia and irregular menstrual cycles .
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 .
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
.   found a positive correlation of the fourfold elevation in serum prolactin level at 8 and 24 weeks with dose per kilogram body weight ( r = 0.65 , p < .001 ) , number of functional cyp2d6 genes , serum 9-hydroxyrisperidone concentration ( r = 0.66 , p < .001 ) and negative correlation with the risperidone/9-hydroxyrisperidone ratio ( r = 0.57 , p = .004 ) but not with risperidone concentration ( r = 0.24 , p = .26 ) .
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 . 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 .
subjects were 153 419-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 .
antipsychotic - induced hyperprolactinemia in adults with schizophrenia has been associated with reduced bmd and increased fracture risk [ 36 , 37 ] .
the initial report of the effect of psychotropic drugs on bmd in children was a cross - sectional study that involved 83 boys aged 7 to 17 years treated with risperidone for an average of 3 years and selective serotonin reuptake inhibitors ( ssris ) .
with adjustment for the stage of sexual maturation , height , and body mass index , a negative association was found between serum prolactin level and trabecular volumetric bmd at the distal radius . furthermore , treatment with ssris was associated with lower trabecular bmd at the radius and bmd z - score at the lumbar spine .
lumbar spine bmd z - score did not correlate with prolactinemia . in females with prolactin secreting tumors ,
hyperprolactinemia effects on bmd are mediated by hypogonadism . however , in this study , serum testosterone concentrations , adjusted for maturational stage , were not affected by hyperprolactinemia , suggesting a direct effect of the hyperprolactinemia on bone turnover .
prolactin receptors have been found in osteoblasts , and animal studies indicate that hyperprolactinemia activates the phosphoinositide 3-kinase pathways via the prolactin receptors to suppress alkaline phosphatase activity .
the finding that ssri treatment was associated with reduced bmd could reflect an effect on prolactinemia .
however , no independent effect of ssris on prolactin concentration was found in an earlier study by these authors , and the negative association between ssris and bmd was found after adjustment for numerous covariates including prolactinemia .
the study of calarge et al .   is limited by the dependence on a single measurement of serum prolactin which can vary by time of day and stress level , and absence of measures of bone turnover .
the authors recognize that it is premature to make any definitive conclusions about the effect of psychotropic medications on bone mineralization . noting higher - than - expected postmarketing reports of pituitary tumors associated with risperidone , szarfman et al .  
analyzed patterns of these tumors in the united states food and drug administration adverse event ( ae ) reporting system database .
they sought disproportionate reporting patterns of pituitary tumor reports for antipsychotics with different affinities for blocking d2 receptors ( aripiprazole , clozapine , olanzapine , quetiapine , risperidone , ziprasidone , and haloperidol ) .
the rank order of the strength of the association between the drug and the development of pituitary tumors corresponded to the affinity of these 7 drugs for the d2 receptor . in children
718 years of age , there was 1 ae of pituitary tumor associated with olanzapine and 3 with risperidone .
the authors note the importance of these findings for children because the symptoms of a pituitary expanding mass may not be as readily evaluated in those with mental illness or serious behavioral problems and that delayed detection can result in hemorrhage or optic nerve compression .
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 .
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
the author is a consultant to a law firm pursuing litigation with manufacturers of second - generation antipsychotic drugs .
 there is increasing use of antipsychotic drugs in pediatric and psychiatry practice for a wide range of behavioral and affective disorders . 
 these drugs have prominent side effects of interest to pediatric endocrinologists , including weight gain and associated metabolic risk factors and hyperprolactinemia . 
 the drugs block dopamine action , thus disinhibiting prolactin secretion . 
 hyperprolactinemia is especially prominent with first - generation antipsychotics such as haloperidol and the second - generation drugs , most commonly risperidone , with some patients developing gynecomastia or galactorrhea or , as a result of prolactin inhibition of gonadotropin releasing hormone from the hypothalamus , amenorrhea . with concern about the long - term effects of antipsychotics on bone mass and pituitary tumor formation , 
 it is prudent to monitor serum prolactin levels in antipsychotic drug - treated pediatric patients and consider treatment with an agent less likely to induce hyperprolactinemia . 
1. Introduction
2. Physiology
3. Effects of Hyperprolactinemia
4. Effects of Psychotropic Drugs on Prolactin Secretion
5. Potential Long-Term Effects of Psychotropic Drugs
6. Conclusion
 Disclosure