Prolactin A

human psychopharmacology

Hum. Psychopharmacol Clin Exp 2010; 25: 281–297.

Published online 6 May 2010 in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/hup.1116

REVIEW ARTICLE

Hyperprolactinemia associated with psychotropics—a review

Subramoniam Madhusoodanan1*, Suprit Parida2 and Carolina Jimenez2

1St. John’s Episcopal Hospital Psychiatry 327 Beach Rockaway New York United States, USA2SUNY Downstate Psychiatry Brooklyn New York United States, USA

Introduction: Different classes of psychotropics can cause hyperprolactinemia to varying degrees. Among antipsychotics, typical agentsand risperidone are the most frequent and significant offenders. In this review we discuss the pathophysiology, offending medications,assessment and management of hyperprolactinemia.Methods: We did a literature review between 1976 and 2008 using PubMed, MEDLINE, PsychINFO and Cochrane database. Search termsused were prolactin, hyperprolactinemia, psychotropics, antipsychotics, typical antipsychotics, atypical antipsychotics, antidepressants andSSRIs.Results: Prolactin elevation is more common with antipsychotics than with other classes of drugs. Typical antipsychotics are more prone tocause hyperprolactinemia than atypical agents. Management options include discontinuation of offending medication, switching to anotherpsychotropic, supplementing concurrent hormonal deficiencies and adding a dopamine agonist or aripiprazole.Conclusion: Clinicians need to be alert about the potential for hyperprolactinemia and its manifestations with these medications. Prolactinlevels need to be monitored and other causes of hyperprolactinemia ruled out in suspected cases.

Copyright # 2010 John Wiley & Sons, Ltd.

key words— Hyperprolactinemia; Psychotropics; Associated

INTRODUCTION

Hyperprolactinaemia is one of the most commonendocrinological disorders of the hypothalamic-pitu-itary axis. It may be caused by several physiologicaland pathological conditions. The clinical manifes-tations of hyperprolactinaemia primarily involve thereproductive system. Even though, several drugs cancause significant increase in serum prolactin, preva-lence of hyperprolactinaemia is still underestimated.This is possibly due to the patient’s shame of reportingembarrassing symptoms and clinician’s lack ofawareness.

Among the medications, which cause hyperprolac-tinaemia, psychotropic drugs play an important role.The typical antipsychotics are frequently responsiblefor drug-induced hyperprolactinaemia. These drugsblock D2 receptors in the hypothalamic infundibularsystem (Wieck and Haddad, 2002). The receptor

* Correspondence to: S. Madhusoodanan, St. John’s Episcopal HospitalPsychiatry 327 Beach 19 St Far Rockaway New York United States11691,USA. Fax 718-869-8532 E-mail: [email protected]


binding dynamics of atypical agents are more complex.In case of antidepressants, the relation betweenprolactin and serotonin has shown more variability.This review of literature includes a pathophysiologyframework, followed by a summary of severalpsychotropics and their effect on prolactin. Theassessment and treatment of hyperprolactinaemia arealso discussed.

PHYSIOLOGY OF PROLACTIN HORMONE

Prolactin is a 23 kDa polypeptide hormone secreted bythe lactotroph cells of the anterior pituitary gland. Itsrelease displays a circadian trend. It is secreted in 4 to14 daily pulses, which increase in amplitude after sleeponset. There is a decline shortly after waking, reachingits lowest level around noon. Prolactin secretionresponds to various physiological stimuli. It increasesafter food intake and stimulation of breast. The mainbiological role of prolactin is to induce milk productionin mammary glands. Prolactin also exerts other effectssuch as facilitating the development of mammary

Received 28 September 2009

Accepted 17 March 2010

Table 1. Causes of hyperprolactinaemia

PhysiologicalPregnancyLactationBreast stimulationSexual activitySleepStress

PathologicalPituitary Pathology

ProlactinomaAdenomasEmpty-sella syndromePituitary stalk sectionLymphoid hypophysitis

Hypothalamic diseases/ tumours / metastasesCNS disorders

CraniopharygiomaOther brain tumoursSarcoidVascular disordersSpinal cord lesionsCranial irradiationSeizures

Endocrine diseaseCushing’s diseasePolycystic ovarian diseaseAcromegalyPrimary hypothyroidismOestrogen secreting tumours

MiscellaneousChest wall lesions/ trauma/ herpes zosterCirrhosisChronic renal failureCranial and hypothalamic radiationPseudocyesisDrugs

Psychotropic drugsAntipsychotics- Typical (haloperidol, chlorpromazine, thioridazine,

thiothixene, molindone and atypical agents (risperidone, amisulpride)Antidepressants- TCAs (amitriptyline, desipramine, clomipramine,

amoxapine), MAO inhibitors (pargyline, clorgyline), SSRIs (sertraline,paroxetine, fluoxetine)

Antihypertensives—Verapamil, reserpine, alpha methyldopa, labetalolH2 receptor antagonists—Ranitidine, cimetidineAntiemetics—Metoclopramide, domperidoneHormones—Oestrogen, Oral contraceptive pills, antiandrogensMiscellaneous—Opiates and opiate antagonists, protease Inhibitors,

alcohol, fenfluramine, physostigmine

282 s. madhusoodanan ET AL.

glands, parental behaviour (Benker et al., 1990) andstimulating immune responsiveness (Halbreich andKahn, 2003).

The main physiological control of prolactinsecretion is exerted by the inhibitory action ofdopamine. Dopamine is secreted in the hypothalamicperiventricular zone (periventricular nucleus andarcuate nucleus) and released from neuronal projec-tions in the median eminence. It then reaches theanterior pituitary gland through portal vessels, asystem known as the tuberoinfundibular dopaminepathway (TIDA). The dopamine-mediated inhibitionof prolactin secretion occurs through the binding ofD2 receptors on the membrane of lactotroph cellsand involves several signal transduction systems,which result in the inhibition of prolactin genetranscription and reduction of prolactin synthesis andrelease.

Serotonin mediates nocturnal surges and suckling-induced prolactin elevations and is a strong and indirectmodulator of prolactin secretion. Serotoninergicneurons project from the dorsal raphe nucleus to themedial basal hypothalamus and exert their action via5HT1A and 5HT2 receptors. In the hypothalamus, theparaventricular nucleus, a major regulatory site ofserotonin-induced prolactin release, has diverse popu-lations of neurosecretory cells producing oxytocin,vasopressin, vasoactive intestinal peptide (VIP),thyrotropin releasing hormone (TRH) and otherneuropeptides. It is known that serotonin affectsprolactin through the action of these prolactin releasingfactors (PRFs), among which VIP pathway is the beststudied. VIP and a fragment of its precursor namedpeptide his-isoleucine, act via hypothalamic afferents,paracrine and autocrine mechanisms, through lacto-troph cell receptors binding, enhancing adenylatecyclase activity and increasing prolactin gene tran-scription. Furthermore, oxytocin seems to be involvedin the VIP-induced prolactin release and may actthrough the inhibition of TIDA. Regarding dopamine,there is little synaptic contact between serotonin-fibresand dopamine cells; so, if direct inhibition ofdopaminergic cells occurs, it is rather throughserotonin volume transmission. There is evidence ofdirect stimulation of GABAergic neurons in thevicinity of dopamine cells. This pathway, ‘tuberoin-fundibular-GABA (TI-GABA) system’, modulatesprolactin secretion, possibly through serotoninergicstimulation of GABA interneurons (that express the5HT1A membrane receptor) inhibiting TIDA cells andprolactin secretion (Emiliano and Fudge, 2004).

Other CNS derived prolactin inhibiting factorsinclude somatostatin, acetylcholine, and norepine-


phine. Prolactin also autoregulates its own releasethrough a short loop negative feedback mechanism, bybinding to prolactin receptors on the TIDA cells. At thesame time, growth hormone (GH), tumour growthfactor (TGFb1) and endothelin regulate prolactinrelease via a paracrine effect at the pituitary level.Substances that increase prolactin level in the bodyinclude serotonin, TRH, oestrogen, histamine andopioids. Several physiological and pathological con-ditions can result in increased serum prolactin levels(Table 1).

Hum. Psychopharmacol Clin Exp 2010; 25: 281–297.DOI: 10.1002/hup

Table 2. Clinical manifestations of Hyperprolactinaemia

Female Male

Menstrual function HypogonadotropicAnovulation hypogonadismShortened Lutea phase decreased libido0ligomenorrhoea decreased muscle mass andAmenorrhoea body hairOsteoporosis osteoporosis

Breast Erectile dysfunctionEngorgement InfertilityGalactorrhoea GalactorrhoeaDysplasia Behavioural and mood

Sexual dysfunction AlterationsBehavioural and mood alterations

hyperprolactinemia associated with psychotropics 283

POTENTIAL CLINICAL MANIFESTATION OFHYPERPROLACTINAEMIA (TABLE 2)

The majority of symptoms of hyperprolactinaemiainvolve the reproductive system and occur both as adirect action of prolactin on target tissues, and asindirect effects mediated by the decrease in pulsatilegonadotropin secretion, leading to gonadal dysfunc-tion. The symptoms of chronic hyperprolactinaemiainclude reproductive dysfunction (anovulation, men-strual irregularity, decreased fertility, decreased oes-trogen and testosterone production), sexual impairment(diminished libido, erectile dysfunction, retrograde orpainful ejaculation, orgasmic dysfunction, impotence),breast pathology (galactorrhoea, breast enlargement,prolactin—sensitive dysplasia with increased potentialfor breast cancer), abnormalities associated withchronic hypogonadism (decreased bone mineraldensity and osteoporosis and increased cardiovascularrisk), behavioural and mood alterations (depression,anxiety, hostility, memory deficit, psychosis) (Kinonet al., 2003b) and possible immunological depression(Halbreich and Kahn, 2003).

DRUG INDUCED HYPERPROLACTINAEMIA:PREVALENCE

The prevalence of drug-induced hyperprolactinaemiais underestimated. This is due to the frequent lack ofexternally visible symptoms, patients’ reluctance toreport due to the embarrassing nature of symptoms andlack of awareness on the part of clinicians.

Medications which can raise prolactin levels(Tables 1 and 2) include dopamine precursors,L-aromatic aminoacid decarboxylase inhibitors, dopa-mine receptor antagonists; drugs enhancing serotoni-nergic neurotransmission such as serotoninergic pre-cursors, direct and indirect serotonin agonists andinhibitors of serotonin reuptake; histamine H2 receptor


antagonists (Steiner et al., 1976; Polleri et al., 1980;Muller et al., 1983; Di Renzo et al., 1989; Molitch,2005).

Petit et al., (2003) reported 159 cases of hyperpro-lactinaemia, of which 136 were in females and 29 inmales. The mean age was 40 (range 14–85) years. Theoccurrence rate of hyperprolactinaemia for therapeuticdrug classes were as follows: neuroleptics 31%,neuroleptic-like drugs 28%, antidepressants 26%,H2-receptor antagonists 5% and other drugs 10%(Petit et al., 2003).

MECHANISM OF DRUG INDUCEDHYPERPROLACTINAEMIA

Drugs increase serum prolactin level through variousmechanisms. Decrease in dopamine, increase inserotonin and potentiation of neurotransmitters likeVIP are some of the common mechanisms associatedwith increased prolactin levels (Figure 1).

Most of the medications, which increase prolactin,act by inhibiting the dopaminergic pathways. Thisincludes dopamine receptor antagonists such asantipsychotics (Wieck and Haddad, 2002), metoclo-pramide (Tamagna et al., 1979), domperidone (Fujinoet al., 1980) and labetalol (Barbieri et al., 1982); drugsinhibiting dopamine synthesis such as opiates (Shinet al., 1988), verapamil (Kelley et al., 1996), oestrogen(Frantz, 1978) and decarboxylase inhibitors likecarbidopa and beserazide; and those inhibitingdopamine release such as H2 antagonists, opiatesand storage depletor reserpine (Lee et al., 1976).

Benzodiazepines usually decrease prolactin bypromoting GABA but alprazolam (Jarvinen et al.,1992) raises prolactin levels through unclear mechan-ism. Mood stabilizers like valproate can decreaseprolactin by increasing GABA107 while lithium(Basturk et al., 2001) act by serotoninergic pathwaysto elevate prolactin level. Oestrogen potentiates VIPmediated hypothalamic synthesis of prolactin.Additionally, oestrogen acts on the pituitary lactotrophcells directly to stimulate prolactin release.

Drugs which cause hyperprolactinaemia by increas-ing serotonin act either by increasing serotoninsynthesis and release or by increasing serotoninconcentration at the level of receptors (Emiliano andFudge, 2004). Fenfluramine and tryptophan increaseserotonin synthesis and release. Serotonin receptoragonists include buspirone (Maskall et al., 1995),aripiprazole (Lawler et al., 1999; Shapiro et al., 2003),ziprasidone (Bruins Slot et al., 2006) and fenfluraminewhile serotonin reuptake inhibitors includes SSRIs andTCAs.


GABA Catecholamines (-) (-)

(+) Serotonin

Prolac�n Releasing Factors Prolac�n Inhibi�ng Factor (Dopamine) Thyrotropin releasing hormone Vasoac�ve intes�nal polypep�de

(+) (-)

(+) Oestrogen

Note: (+) indicates s�mula�on and (–) inhibi�on of the prolac�n pathways. indicates increase of neurotransmi�er or hormone.

HYPOTHALAMUS

ANTERIOR PITUITARY

Serotoninergic pathway:Precursors -5HT ,Tryptophan H2 antagonists -Cime�dine , Rani�dine Re-uptakeblockers-TCAs, SSRIs OthersLithium, MAOinhibitors

Clonazepam, diazepam, valproate

Dopaminergic pathway: Receptor antagonists -Typical an�psycho�cs -Atypical an�psycho�cs -Buspirone, amoxapine -Metoclopramide -Domperidone -LabetalolDecarboxylase inhibitors -carbidopa, benserazide Precursor -alpha methyldopa Others Verapamil, opiates, estrogens, reserpine

PROLACTIN

Figure 1. Mechanisms of drug-induced hyperprolactinaemia.


ANTIPSYCHOTICS

Antipsychotics are the most common pharmacologicalagents which cause hyperprolactinaemia and most ofthe antipsychotic agents cause hyperprolactinaemia(Molitch, 2005). The need for long-term therapy inpsychotic disorders makes the chronic adverse effectsof antipsychotics, such as hyperprolactinaemia, amajor therapeutic problem (Halbreich and Kahn,2003).

In female schizophrenic patients, menstrual irregu-larities can be partly due to an illness-relateddysfunction of the hypothalamic-pituitary-gonadalaxis with subsequent hypoestrogenic state (Goldstein,1999b) and in part to the abnormalities of neuro-transmitters or their receptors, including D1, D2, a1, a2, histamine, serotonin, GABA and opiates (Haddad


and Wieck, 2004). However, since the secretorypatterns of prolactin in drug-free psychiatric patients,measured throughout the day, are not different fromthose observed in healthy control subjects, theelevation of baseline prolactin in drug treatedpsychiatric patients is more likely a consequence ofthe drug effects rather than the illness itself (Haddadand Wieck, 2004).

The atypical antipsychotics were developed tominimize the side effects related to the completedopaminergic blockade (extrapyramidal symptomsand hyperprolactinaemia) caused by typical antipsy-chotic drugs. So, antipsychotic drugs can also beclassified based on their prolactin elevating qualities.Typical antipsychotics are traditionally ‘prolactin-raising’, while atypicals are usually ‘prolactinsparing’.



A study of 422 psychotic patients treated withneuroleptics showed that antipsychotic therapy isstrongly associated with hyperprolactinaemia, with asignificantly higher occurrence in patients treated withtypical antipsychotics compared to atypical antipsy-chotics (Montgomery et al., 2004). Neuroleptic-induced hyperprolactinaemia is often a dose-relatedside effect (Smith et al., 2002; Montgomery et al.,2004).

The degree of prolactin increase is not onlydependent on the class of antipsychotic agents andthe dose administered, but also on the patient’s age andsex. Clinical consequences associated with hyperpro-lactinaemia are well documented in women onantipsychotics, in whom the prevalence of sympto-matic hyperprolactinaemia reaches 50% or more. Themost common symptoms are galactorrhoea andmenstrual irregularities (Wieck and Haddad, 2002;Halbreich and Kahn, 2003).

At equal doses of antipsychotics over prolongedperiod, women are more likely to develop hyperpro-lactinaemia than men, and their prolactin levels are alsosignificantly higher than men during the treatment(Smith et al., 2002; Kinon et al., 2003a). Among malepatients, prolactin concentration was not influenced byage, while in women a younger age correlated with ahigher prolactin level, as expected for their reproduc-tive status (Halbreich and Kahn, 2003; Montgomeryet al., 2004).

Data from studies regarding the influence of age onhyperprolactinaemia associated with atypical drugs inelderly patients and in youths indicated the following:olanzapine appeared to be a prolactin-sparing anti-psychotic medication in the elderly (Kinon et al.,2003c), and quetiapine produced significantly lessfrequent hyperprolactinaemic events and lower meanelevation of prolactin levels than risperidone inchildren (Stevens et al., 2005).

Typical antipsychotics

Typical antipsychotics are the most common cause ofdrug-induced hyperprolactinaemia (Molitch, 2005).These drugs act as nonselective dopamine receptorantagonists and affect all four dopamine pathways.Therapeutic effects on positive and negative psychoticsymptoms occur via the dopamine D2 and D4 receptormodulation in the mesolimbic and mesocortical areas,respectively. Extrapyramidal side effects are mediatedby D2 blockade in the nigrostriatal area while D2blockade in the hypothalamic infundibular systemcauses hyperprolactinaemia (Wieck and Haddad,2002).


Serum prolactin levels have been reported toincrease in a dose-dependent manner (Meltzer andFang, 1976; Smith et al., 2002; Montgomery et al.,2004;) but even low daily dosages of typicalantipsychotics can cause significant elevations (Wieckand Haddad, 2002). The increase begins after a fewhours of initiating antipsychotics and persists duringthe remainder of treatment. The total incrementdepends on the duration of therapy. A medium-termtreatment (3–9 weeks) can increase baseline levels upto 10-fold (Meltzer and Fang, 1976). In chronictreatment, partial tolerance may cause prolactin totrend towards normalization; however prolactin levelsremain above normal in most cases (Rivera et al.,1976).

Following discontinuation of oral treatment, pro-lactin levels return to normal range within 2–3 weeks,depending on the half-life of the drug, its metabolitesand the degree of storage in fatty tissue. However incase of intramuscular depot administration, prolactinlevels remain above pre-treatment values up to6 months after discontinuation (Wieck and Haddad,2002).

Phenothiazines. After single parenteral or oral dose ofphenothiazines, acute increases in prolactin levels of 2-to 10-fold have been observed. Prolactin elevationinduced by a single fluphenazine injection was found tolast up to 28 days. Long-term studies have documentedan initial increase in prolactin levels (three-fold abovenormal range) in the first 3 days of treatment, withadditional two-fold increase during the followingweeks of treatment. The response in this case wasnot gender-dependent (Goodnick et al., 2002).

A dose-dependent increase in prolactin was observedin 40–90% of patients treated with phenothiazines(Rivera et al., 1976; Kinon et al., 2003a). Withchlorpromazine, hyperprolactinaemia develops earlyin treatment and reaches higher levels in women than inmen (Meltzer et al., 1983). The increase begins hoursafter the first intramuscular or oral administration(Mannisto et al., 1978; Busch et al., 1979) with highlevels persisting throughout the treatment period(Kolakowska et al., 1976).

The increase in prolactin level at 2 h followingadministration of 50 mg of thioridazine was compar-able to that observed with chlorpromazine at similartime interval. (Sachar et al., 1975)

Butyrophenones. Haloperidol is used for the treatmentof schizophrenia, tics, stutter or delirium. Endocrino-logical side effects reported are amenorrhoea, galac-



torrhoea, gynaecomastia, sexual dysfunction andmastalgia.

A placebo controlled study of haloperidol (10–20 mg) showed prolactin elevation with treatment,persistent at 6th week of therapy (Crawford et al.,1997). Substantial increase, up to nine-times abovebasal levels, have been found after single i.m. injectionof haloperidol, with persistent, though less consistent,elevation (three-fold) present weeks after treatment(Goodnick et al., 2002). In a study of prolactinresponse to haloperidol in 15 patients, with prolactinlevels taken every 3 days, the prolactin concentrationwas found to rapidly increase in the initial 6–9 days,with peak levels between 30 and 50 ng/mL. Followingthis, the levels tended to plateau and remained fairlyconstant throughout the study, always staying below77 ng/mL. The pattern and amplitude of the increasewere not influenced by the dose administered (Spitzeret al., 1998).

Thioxanthenes. A study comparing the effects ofthiothixene and thioridazine on prolactin levels showedequal increase with the two drugs (Crowley andHydinger-Macdonald, 1981). In a separate case studyhowever, hyperprolactinaemic response was noted tobe more with thiothixenes. (Ash and Bouma, 1981)

Flupenthixol, although being a typical antipsychotic,displays an atypical receptor profile. It is a mixeddopamine D1/D2, serotonin and histamine H1 receptorantagonist. So flupenthixol could be regarded as a‘partial atypical’ neuroleptic (Kuhn et al., 2000). Theprolactin levels during therapy with flupenthixolincrease two- to three-folds above baseline duringthe 1st month of therapy, but show reducing trendbetween the 3rd and 6th month and normalize over thenext few months (Schlosser et al., 2002).

Indole derivatives. Molindone is another drug, whichcan cause sustained hyperprolactinaemia. In 14psychiatric patients receiving high doses of molindone,a positive dose-effect response for prolactin was noted(Pandurangi et al., 1989).

Others. Pimozide administration also increases pro-lactin levels. The mechanism seems to be the impaireddopamine secretion to portal vessels, rather than thereduction of hypothalamic dopamine production(Aguilar et al., 1985).

Atypical antipsychotics

The atypical antipsychotics are characterized by fewerneurological and prolactin related side effects com-


pared to typical antipsychotic drugs. Most of themcause minimal hyperprolactinaemic response or nohyperprolactinaemia at all.

While typical neuroleptics are complete dopamineantagonists, aripiprazole exerts a mixed dopamine-agonistic/antagonistic activity (Shapiro et al., 2003).Partial agonists have a lower intrinsic activity atreceptors than full agonists, and can act either as afunctional antagonist or agonist depending on thelevels of surrounding natural neurotransmitters. Thisfacilitates an early dissociation from the receptor,allowing for a normal dopaminergic neurotransmissionin the tuberoinfundibular pathway and thus avoidinghyperprolactinaemia (Kapur et al., 2000). The hypoth-esis of a transient blockade of D2 receptors has beensupported by PET scans. It showed that haloperidolconstantly binds to D2 for 24 h, whereas the atypicaldrugs occupy receptors for a significantly shorter timeand largely expire by 24 h (Seeman, 2002). Partialagonistic activity was observed with bifeprunox andaripiprazole. Other antipsychotics, such as olanzapine,ziprasidone and clozapine, have been associated withattenuated dopamine-induced extracellular signalregulated kinase (ERK) phosphorylation (Bruins Slotet al., 2006). Another theory is that of simultaneousbinding at D2 and 5-HT2A receptors, leading to a morephysiological serotonin-dopamine balance (Kuhnet al., 2000; Seeman, 2002;).

Pharmacokinetic studies have shown a transient D2blockade by atypical antipsychotics with an earlyhyperprolactinaemic effect after acute administration.A study with 18 patients showed that the increase inprolactin levels with atypical antipsychotics is mostpronounced in the 1–5 h period after medicationadministration and return to baseline values by 12–24 h. Risperidone is the exception to this pattern.Serum prolactin concentrations have a variable meanpeak time in relation to the specific drug (120 min forrisperidone, 180 min for clozapine and 290 min forolanzapine), All of them except risperidone return tobaseline values within 12–24 h. Clozapine and risper-idone can result in a significant elevation but clozapineinduced elevation is short lived. Olanzapine-inducedprolactin increase is always within normal range(Turrone et al., 2002).

Risperidone. Risperidone is an atypical antipsychoticagent, which frequently induces hyperprolactinaemia.It is used for the treatment of schizophrenia, bipolardisorder, irritability and aggression associated withautism and Tourette syndrome. Risperidone has a dose-dependent serotonin and dopamine antagonistic action.It binds with very high affinity to serotonin 5-HT2



receptors and to dopamine D2 receptors, with anaffinity that is relatively higher compared to otheratypical antipsychotics. Recent studies indicate that theactive metabolite of risperidone, 9-hydroxy risperi-done, is the contributory agent for hyperprolactinaemia(Knegtering et al., 2005). Risperidone causes moremarked elevations in prolactin than other atypicalantipsychotics because it does not fully cross theblood-brain barrier; hence D2 receptor occupancy ishigher at the level of the pituitary than the striatum. Thefrequency of endocrinological side effects, such asamenorrhoea, galactorrhoea, gynaecomastia andsexual dysfunction in patients on risperidone is around1–10%. With risperidone, serum prolactin concen-tration increases within a few hours after acutetreatment and can remain high for an extended period(up to 54 weeks) (Tollefson et al., 1997; Purdon et al.,2000). The results of studies comparing prolactinelevation with typical agents and risperidone areconflicting. Some of them indicate higher levels withrisperidone (Kleinberg et al., 1999; Kinon et al., 2003a)while others found higher levels with typical anti-psychotics (Kearns et al., 2000). In an analysis of threeindependent multicentre, double blind randomizedclinical trials, David et al., (2000) noted a moderateincrease in serum prolactin concentration for olanza-pine (1–4 ng/ml), intermediate for haloperidol (17 ng/ml) and high for risperidone (45–80 ng/ml). Noconsistent dose-response relationship was observedfor any of the drugs. Risperidone was found to beassociated with early peaks. The time course andgender ratio of the response differed among the clinicaltrials. In haloperidol and risperidone treated patients,the mean change in prolactin was found to be greater inwomen (David et al., 2000).

Clozapine. Clozapine is believed to selectively inter-act with D1> D2, histamine and 5HT2 receptors andalter the functioning of pre- and post-synapticdopamine elements. The hyperprolactinaemic effectis mediated by supra-pituitary action of the drug(Meltzer and Gudelsky, 1992). The lack of prolactinincrease following clozapine administration could bedue to the sparing of dopamine-mediated inhibition ofthe prolactin release and the direct stimulatory effecton TID neurons (Meltzer and Gudelsky, 1992).Additionally, clozapine does not interfere withnorepinephrine-mediated inhibition of prolactinsecretion (Lamberts et al., 1990). Clozapine at highconcentrations appeared to directly inhibit prolactinrelease and DNA content of in vitro cultured pituitarytumour cells, suggesting an anti-mitotic action on thelactotrophs (Lamberts et al., 1990). A 6 weeks trial of


clozapine therapy was found to reduce hyperprolacti-naemia by 16–80% (Goodnick et al., 2002).

Olanzapine. Olanzapine shows higher affinity for 5-HT2 than dopaminergic D2 receptors at all doses. D2receptor occupancy is dose-dependent and varies from71 to 80% at the usual clinical dose range (10–20 mg/day). However, doses greater than 30 mg/day areassociated with more than 80% D2 occupancy andinduce prolactin elevation (Kapur et al., 1998). Adouble-blind trial with haloperidol and placebo controlamong 137 patients demonstrated the temporal courseof serum prolactin in each group. After 2 weeks oftreatment, the prolactin elevation was less frequentwith olanzapine (38% with 15 mg, 24% with 10 mg)and lower in magnitude as compared to the haloper-idol-treated group (72% with 15 mg). The olanzapinegroup differed significantly from the placebo group at2 weeks only at doses of more than 10 mg/day.However, at week 6, all olanzapine-treated groupsexhibited prolactin elevation comparable to that of theplacebo group. Rates of elevation were approximatelyone-third to half of those observed with haloperidol andwere more transient (Crawford et al., 1997). Thefindings were further substantiated by another largecomparison study with haloperidol in 1996 patients,both during acute and extended treatment (up to 52weeks) (Tollefson et al., 1997). Olanzapine was foundto have a more favourable safety profile andsignificantly fewer instances of treatment discontinu-ation due to adverse events (Tollefson et al., 1997).

Five clinical trials were analyzed by Kinon et al.,(2000) to study the influence of gender, time course,age and type of treatment on prolactin increase. Inaddition, the potential reduction or reversibility of theendocrine side effect was also studied. Two studies ofolanzapine versus haloperidol (Tollefson et al., 1997)and of olanzapine versus risperidone (Tran et al., 1997)were compared. Prolactin levels were observed to besubstantially high above baseline in patients treatedwith risperidone and haloperidol compared to thosetreated with olanzapine. The highest levels wereobserved in the risperidone group and in females. Inanother study comparing olanzapine, risperidone andhaloperidol similar effects of treatment and gender onprolactin levels were observed (Purdon et al., 2000).The above studies also demonstrated the reversibilityof typical and risperidone-induced hyperprolactinae-mia when these drugs were gradually discontinued anda prolactin-sparing drug simultaneously initiated(Kinon et al., 2000). Melkersson reported incidenceof treatment-induced hyperprolactinaemia in a study of75 patients: risperidone (dosage 3 mg/day) 89%,



olanzapine (dosage 10 mg/day) 24% and clozapine(dosage 400 mg/day) 0%. Mean prolactin levels weresignificantly higher in the risperidone and olanzapine-treated subjects compared to clozapine-treated group(Melkersson, 2005).

Quetiapine. Quetiapine has a high affinity for ser-otonin 5HT2A receptors and lower affinity fordopamine D2 receptors. In addition, quetiapine appearsto be selective for mesolimbic and mesocorticaldopamine receptors, with relative sparing of TIDAsystem (Goldstein, 1999a). Quetiapine has a transientdopamine D2 occupancy and thus only temporarilyelevates prolactin levels. After a single dose, the D2receptor occupancy ranges from 58 to 64% after 2 to3 h. This decreases to 0–27% within 12 h. This propertyof short D2 occupancy can explain its lack of prolactinelevation (Kapur et al., 2000). This conclusion issupported by a comparison study with haloperidol,carried out in 35 schizophrenic patients, which showedpersistently lower prolactin concentration at the 6thweek in the quetiapine treated group (Atmaca et al.,2002). These later studies substantiated the results ofpreliminary clinical studies which had found nodifference in prolactin levels between quetiapine andplacebo at week 6 (Hamner et al., 1996). Quetiapinewas associated with significantly fewer hyperprolacti-naemic events and lower mean prolactin elevation thanrisperidone in children (Stevens et al., 2005).

Aripiprazole. This atypical antipsychotic has a partialagonistic effect at D2 and 5HT1A and completeantagonistic effect at 5HT2A receptors (Lawler et al.,1999; Shapiro et al., 2003) (Table 2). This contributesto the decreased release of prolactin in vivo comparedto typical agents. This was confirmed in a comparisonstudy involving haloperidol and aripiprazole in whichboth these drugs were administered orally (Cosi et al.,2006).

Ziprasidone. It exerts agonistic properties at serotonin5-HT1A receptors (Bruins Slot et al., 2006). In acontrolled, double blind study of ziprasidone (4–160 mg/day) versus haloperidol 15 mg/day in 90patients, only transient elevations in prolactin withziprasidone were observed. The levels returned tonormal range within the dosing interval, in all fourziprasidone administered subgroups (4,10,40,160 mg/day) (Goff et al., 1998).

OthersAmisulpride. Amisulpride is a substituted benzamidederivative, which is not FDA approved in the US but is


used in European countries. It has few extrapyramidalsymptoms (EPS) but significant prolactin elevation,similar to that of conventional antipsychotics and oftenclinically relevant (Fric and Laux, 2003). It ishypothesized that amisulpride may have a selectivelyhigher occupancy of D2/D3 receptors at the pituitarylevel than at the central regions, because of its poorbrain barrier permeability (Bressan et al., 2004).Amisulpride-induced hyperprolactinaemia is reportedafter both acute and chronic treatment and does notseem to be strongly dose-related. It is more likely tocause hyperprolactinaemia than risperidone or olanza-pine with amenorrhoea occurring in about 4% oftreated women (McKeage and Plosker, 2004). In onestudy, the mean prolactin increase was significantlygreater in women than in men (Paparrigopoulos et al.,2007).Zotepine is another atypical drug reported to cause

prolactin elevation during both acute and chronicadministration (von Bardeleben et al., 1987).

ANTIDEPRESSANTS

The role of dopaminergic antagonists and antidepress-ants on the neuroendocrine system is highly variable(Goyot et al., 1985). Antidepressants with serotoni-nergic activity, including selective serotonin reuptakeinhibitors (SSRI), monoamine oxidase inhibitors(MAO-I) and some tricyclics, can cause modest butgenerally asymptomatic hyperprolactinaemia (Wieckand Haddad, 2003) (Molitch, 2005). However whenused in combination with antipsychotics, they maycause or worsen symptoms of hyperprolactinaemia(Haddad and Wieck, 2000).

Tricyclics and tetracyclics

Tricyclic antidepressants have caused mild hyperpro-lactinaemia in some patients, but the data are limited(Molitch, 2005). Antidepressants like amitriptyline(Schlienger et al., 1980), imipramine (Nutt et al.,1987), clomipramine (Anderson and Cowen, 1986) anddesipramine (Price et al., 1989) are thought to shareserotoninergic pathways with SSRIs. A small butsignificant increase of prolactin levels has beenreported with amitriptyline (Meltzer et al., 1982;Goyot et al., 1985), nortriptyline (Nielsen, 1980) andclomipramine (Goyot et al., 1985).

In one study, amitriptyline caused a 100% increase inprolactin in 2 of 14 patients (14%) (Meltzer et al.,1982). Even though, desipramine increased prolactinby 100% in two of four patients (Meltzer et al., 1982);in another study of 24 patients no changes were



reported (Price et al., 1989). There are individual casereports of symptomatic hyperprolactinaemia forimipramine, maprotiline and amoxapine (Markenet al., 1992).

Interestingly, in the Goyot et al., (1985) study, therewas a significant increase in prolactin with clomipra-mine and decrease with amitriptyline after 28 days.Clomipramine-induced hyperprolactinaemia has beenattributed to the serotoninergic pathway as it wascorrected by pre-treatment with clozapine and olanza-pine (serotonin receptor antagonism) (Markianos et al.,2002). Another study in six normal subjects who weregiven clomipramine followed by L-tryptophan, showedthat initially the former did not affect prolactin or GH,but clomipramine did increase the level of bothhormones when L-tryptophan was added (Andersonand Cowen, 1986). Clomipramine-induced hyperpro-lactinaemia reverts within weeks of discontinuation oftreatment (Fowlie and Burton, 1987). Schlienger et al.,(1980)) showed that response of basal plasma levels ofprolactin to TRH were increased in women onclomipramine but remained unchanged with maproti-line consistent with the different pharmacologic effectof these drugs (tricyclics principally inhibit serotoninreuptake and tetracyclics norepinephrine reuptake.)

Amoxapine is an antidepressant with a receptorprofile similar to that of neuroleptics (Anton et al.,1983; Apiquian et al., 2005). It increased prolactinlevels significantly more than desipramine (Antonet al., 1983). In a comparison study of 39 patients withrisperidone, amoxapine was found to have lowerincidence of EPS and less prolactin elevation(Apiquian et al., 2005).

Selective serotonin reuptake inhibitors (SSRIs)

Hyperprolactinaemia is a potential side effect of thisclass, probably involving only serotoninergic path-ways; nevertheless interactions with other neurotrans-mitters (dopamine with sertraline and norepinephrinewith paroxetine) have been reported (Emiliano andFudge, 2004). Most serotonin reuptake inhibitorsexcept sertraline can slightly elevate prolactin (Foleyand Kast, 2006).

Sertraline has strong dopamine reuptake inhibitoryproperties which probably prevent the stimulation ofprolactin release (Foley and Kast, 2006). In 13 healthyindividuals treated with sertraline for 3 weeks, therewas no increase in prolactin (Gordon et al., 1998). In 15females on sertraline with 16 controls, no difference inprolactin level was noted. However, in another study of159 patients on different medications, 27 cases (17%)of hyperprolactinaemia were due to SSRIs, sertraline


being the most frequent SSRI causing hyperprolacti-naemia followed by fluoxetine and paroxetine (Petitet al., 2003). These conflicting results warrant furtherstudies to establish the relationship between sertralineand hyperprolactinaemia.

Citalopram did not increase prolactin significantly ina study by Petit et al., 2003. Additionally, in anotherstudy of eight patients with panic disorder, citalopramdid not affect prolactin levels (Shlik et al., 1997).However, in another study with healthy subjects, a 40%elevation after 10 days of treatment was seen withcitalopram (Laine et al., 1997).

The effect of fluoxetine on prolactin has beendocumented in various studies. In one case report of a71 year-old woman with galactorrhoea and hyperpro-lactinaemia of 37.4mg/L, discontinuation of themedication resulted in decrease of prolactin to6.1mg/L and resolution of galactorrhoea (Peterson,2001). When frequent blood sampling was done afterdaily administration of 60 mg fluoxetine for 6 days inseven female patients, a significant elevation of mean24-h serum prolactin (16% above basal level) wasnoted. This was due to an increase in maximal serumprolactin peak height, without alteration of prolactincircadian pulse frequency (Urban and Veldhuis, 1991).In clinical trials of fluoxetine in 5920 patients,galactorrhoea was reported in 0.07%, breast enlarge-ment in 0.08% and breast pain in 0.25% of subjects(Marken et al., 1992). Regarding fluvoxamine, mildhyperprolactinaemia has been reported in 30 depressedpatients after 1 and 4 weeks of treatment (Price et al.,1989) and in two out of eight healthy subjects treatedwith up to 200 mg daily for 4 weeks (Spigset andMjorndal, 1997).

In a study on 11 healthy subjects treated withparoxetine 20 mg daily, prolactin levels showed noincrease in the first week but mild elevation (35%) inthe 3rd week. This increase in prolactin level wasunrelated to the increased plasma concentration of theSSRI (Cowen and Sargent, 1997). This data suggestthat SSRIs produce a delayed increase in serotoniner-gic transmission in the brain (Cowen and Sargent,1997; Porter et al., 1999). A study of eight womentreated with paroxetine for 2 months, showedoccurrence of significant hyperprolactinaemia(Amsterdam et al., 1997). In the same studyvenlafaxine, a selective serotonin-norepinephrinereuptake inhibitor (SNRI) showed no increase inprolactin concentration after 2 months. In anotherstudy of patients with major depression, 15 of whomwere treated with paroxetine and 21 with tianeptine,prolactin levels did not differ significantly fromplacebo (Muck-Seler et al., 2002).



Monoamine oxidase inhibitors

Monoamine oxidase inhibitors produce little prolactinelevation and the mechanism is not well known(Meltzer et al., 1982; Price et al., 1985). Increase inprolactin after administration of tryptophan in a studyof patients treated with tranylcypromine confirms arelation with serotonin (Price et al., 1985). Prolactinlevels doubled in all five patients treated with pargylineand in all five patients with clorgyline (Slater et al.,1977).

Other antidepressants

The atypical antidepressants mirtazapine and bupro-pion are prolactin neutral (Foley and Kast, 2006) thelatter being previously reported to even decrease serumprolactin, maybe through a dopamine re-uptakeblockade (Meltzer et al., 1982). The effect of trazodoneon prolactin is still unclear as significantly increasedprolactin levels were found in one study (Otani et al.,1995) and decreased levels in another (Rolandi et al.,1981). No elevation of prolactin level was noted withlong-term use of nefazodone (Walsh and Cowen,1994), bupropion (Whiteman et al., 1983) or venla-faxine (Amsterdam et al., 1997).

MOOD STABILIZERS

Lithium and prolactin interactions are complex andseem to be related but not limited to dopamine andserotonin pathways (Basturk et al., 2001). The effectsof lithium on prolactin secretion are controversial.Initially, lithium was purported to increase prolactin bydecreasing dopamine receptor sensitivity (Meltzeret al., 1982). However, studies showing lithiumenhancement of hyperprolactinaemia after clomipra-mine but not after metoclopramide or haloperidol,suggest that serotoninergic pathways could be involved(McCance et al., 1989). Additionally, a recent studyshowed that lithium affects prolactin secretion indifferent ways depending on treatment length; thus intherapy of less than 6 months there was elevation butover 6 months there was decrease in prolactin (Basturket al., 2001).

Hyperprolactinaemia as a side effect of carbamaze-pine has not been reported. In a study by Bonuccelliet al., (1985), in normal and epileptic subjects, noappreciable change in prolactin levels were observed,though a small increase in early sleep values wasreported. These changes in prolactin were interpretedas being mediated by carbamazepine’s serotoninergicactivity.


Short-term treatment with valproic acid in eighthealthy male volunteers did not affect hypothalamic orpituitary 5-HT1A or dopamine receptor function(Delva et al., 2002). Whereas, in studies on tuber-oinfundibular-GABA system, valproate was found todecrease prolactin concentrations in 20 healthy womenand none in schizophrenic patients; supporting thehypothesis of a defect of this system in chronicschizophrenic patients (Monteleone et al., 1985).

ANXIOLYTICS

Clonazepam and diazepam are reported to decreaseprolactin levels, possibly through a direct action on theanterior pituitary gland (Jarvinen et al., 1992).Buspirone is an anxiolytic drug that acts as a partialagonist at dopamine type 2 receptors and 5-HT1Areceptors. After acute buspirone administration,hyperprolactinaemia was reported in both depressiveand healthy subjects with significantly higherresponses in women than in men (Meltzer and Maes,1994). Also, a dose-dependent pattern was seen, up to320% of basal value, after administration of a dosehigher than what is required for anxiolytic effect(100 mg) (Seppala et al., 1987). Nevertheless, it has notbeen clear as to how the dopaminergic or theserotoninergic systems are involved in buspironerelated hyperprolactinaemia (Maskall et al., 1995).

OTHER DRUGS

Prokinetic drugs

Two prokinetic drugs: metoclopramide and domper-idone induce symptomatic hyperprolactinaemia viadopamine antagonism. Metoclopramide, blocks dopa-mine and, at higher doses, also serotonin receptors inchemoreceptor trigger zone of CNS. Domperidonedoes not cross the blood brain barrier and is a selectiveperipheral (extra cerebral) dopamine antagonist(Tamagna et al., 1979; Fujino et al., 1980). Underchronic administration of domperidone, prolactin tendsto decrease significantly, even though still above thenormal range (Brouwers et al., 1980).

Antihypertensives

Antihypertensive medications that can cause hyper-prolactinaemia are alpha methyldopa (Steiner et al.,1976), reserpine (Lee et al., 1976), labetalol (Barbieriet al., 1982) and verapamil (Kelley et al., 1996). Alphamethyldopa is an alpha-adrenergic inhibitor, which islikely to decrease dopamine synthesis by inhibitingaromatic-L-amino-acid decarboxylase, which converts



L-Dopa into dopamine, and by acting as a falseneurotransmitter (Steiner et al., 1976). Reserpinedepletes biogenic amines by inhibiting their hypo-thalamic storage in secretory granules (Lee et al.,1976). Verapamil seems to affect the N-calciumchannels, though no other calcium channel blockerhas been related to hyperprolactinaemia (Kelley et al.,1996).

Estrogens

Physiological amounts of oestrogen in women causeminimally increased basal serum prolactin (Frantz,1978), which may explain their greater prolactinresponse to physiological and pharmacological stimuli.There is conflicting data regarding oral contraceptivesand hyperprolactinaemia (Torre and Falorni, 2007).Some studies have documented that oral contraceptivescontaining oestrogen can increase prolactin levels in12% (Luciano et al., 1985) to 30% (Reyniak et al.,1980) of patients; while other studies have showneither minimal or no increase (Abu-Fadil et al., 1976;Hwang et al., 1986; Josimovich et al., 1987; De Leoet al., 1991). Studies regarding hormone replacementtherapy in naturally or surgically menopausal womenhave shown minimal (Schlegel et al., 1999) or noelevation of prolactin levels (Grasso et al., 1982;Perrone et al., 1994; Castelo-Branco et al., 1995; Fothand Romer, 1997).

Opioids

Studies on animals and humans demonstrated thatendogenous opioids administered either intravenouslyor intraventricularly led to a rapid and dose-dependentplasma prolactin increase (Van Vugt and Meites, 1980;Risch et al., 1982). Opioids may indirectly stimulateprolactin release by inhibiting Prolactin InducingFactors (PIFs) (i.e., dopamine) release and/or bystimulating PRFs production (Shin et al., 1988).Morphine and morphine analogues increase prolactinrelease in short-term (Tolis et al., 1975; Zis et al., 1984)and long-term studies (Chan et al., 1979; Afrasiabiet al., 1979). m receptor is predominantly involved inprolactin release and k is implicated to a lesser extent(Panerai et al., 1985; Pfeiffer et al., 1986; Leadem andYagenova, 1987). Methadone produces a transientincrease 2-4 h after intake (Bart et al., 2003). Cocaineabuse can cause mild chronic hyperprolactinaemia(Mendelson et al., 1989; Lee et al., 1990;).

Miscellaneous

Other drugs that have been reported to causehyperprolactinaemia are fenfluramine, cholinomi-


metics and chemotherapy. Fenfluramine, a sympatho-mimetic amine used as an appetite suppressant, causeshyperprolactinaemia by inducing the release ofserotonin and blocking its neuronal uptake (Newmanet al., 1998). Physostigmine and arecoline (cholino-mimetics) administration increased prolactin levelsand this increment was correlated with the elevation ofplasma concentrations of beta-endorphin immunor-eactivity, possibly representing that cholinergic stimu-lation of hypothalamic beta-endorphin has a peptider-gic modulation of hypothalamic-pituitary hormonalregulation (Risch et al., 1982). Chemotherapy fre-quently induces hypogonadism in both men andwomen by a direct toxic action on the gonad (Fairleyet al., 1972; Shamberger et al., 1981), but significantprolactin increases are not frequent and are usuallymild (Kauppila et al., 1998).

Other drug interactions that can lead to hyperpro-lactinaemia have been reported. One case reportdocumented hyperprolactinaemia during chronic antic-onvulsant therapy with phenytoin and phenobarbitalafter the addition of oral fluoresone 750 mg daily. Themechanism is unclear (Rossi et al., 1983). Hyperpro-lactinaemia in four patients on protease inhibitorspresenting with galactorrhoea likely resulted from theenhancement of dopamine antagonistic effects of othersimultaneously administered drugs (prokinetics andfluoxetine) through inhibitory action on cytochrome P450 system (Hutchinson et al., 2000).

ASSESSMENT OF PATIENT WITHPSYCHOTROPIC - INDUCEDHYPERPROLACTINAEMIA

The normal serum levels of prolactin are 10–25m/L inwomen and 10–20m/L in men (Henderson andDoraiswamy, 2008). Levels should be measured undernon-stressful condition and in fasting state. Clinicalmanifestations can appear at levels of 60 to 100m/L(Hamner and Arana, 1998).

Screening for hyperprolactinaemia is not routinelydone (Maguire, 2002; Bushe and Shaw, 2007).Currently, this screening is limited to questioningthe patient about possible signs and symptoms ofhyperprolactinaemia on initiation of treatment and thenannually, and measuring randomly the ones withpositive clinical manifestations (Compton and Miller,2002; Marder et al., 2004). However, it is important tonote that physicians may under estimate sexual sideeffects, as it has been shown that patients rate thesehigher than psychiatrists (Cutler, 2003). It is alsoimportant to determine the severity of the symptoms(Molitch, 2005).



It is critical to confirm that medication is the cause ofhyperprolactinaemia (Molitch, 2005; Molitch, 2008)and rule out prolactin-secreting microadenomas andespecially large lesions that can cause hypothalamic/stalk dysfunction. (Molitch and Reichlin, 1985; Bevanet al., 1987; Arafah et al., 1995; Molitch, 2005;Molitch, 2008). So it is useful to take a historyestablishing symptoms and time sequence of events(Molitch, 2005; Molitch, 2008) and discontinue thepsychotropic under psychiatric supervision. Prolactinlevel usually returns to normal within 3 or 4 days, atleast with phenothiazines (Meltzer and Fang, 1976),though some antidepressants may take longer time(Molitch, 2005). If a patient cannot stop themedication, an alternative one should be given for ashort period of time to determine if levels decrease(Molitch, 2005; Molitch, 2008). If substitution is notfeasible, MRI or CT scan should be considered(Naidich and Russell, 1999).

MANAGEMENT OFHYPERPROLACTINAEMIA

First, it is necessary to determine whether the patienthas symptoms related to hyperprolactinaemia and whatis their severity (Molitch, 2005; Molitch, 2008). In awoman with regular menses, if mild galactorrhoea wasthe only reason for prolactin measurement, onlyreassurance is needed. On the contrary, if the patienthas amenorrhea, bothersome galactorrhoea, decreasedlibido, impotence or osteoporosis, active treatment isindicated (Molitch, 2005; Molitch, 2008). Also,measures to normalize prolactin level should beattempted in women with amenorrhea or men withtestosterone deficiency (Haddad and Wieck, 2004;Miller, 2004). In the case of antipsychotics, they can beswitched to prolactin sparing medications (Kim et al.,2002; Kinon et al., 2006) (Takahashi et al., 2003;Madhusoodanan et al., 2007) like olanzapine (Kinonet al., 2000; Kim et al., 2002), quetiapine (Kunwar andMegna, 2003) and aripiprazole (Casey et al., 2003;Anghelescu and Wolf, 2004; Lee et al., 2006; Cassanoet al., 2007; De Hert et al., 2007) or clozapine (Bunkeret al., 1997; Breier et al., 1999). In antidepressant-induced hyperprolactinaemia, switching to anotherantidepressant may be successful (Molitch, 2005).

If the patient is symptomatic and cannot be switchedto another medication, other treatments can beattempted. If oestrogen or testosterone levels aredecreased, these hormones can be substituted. If thereis osteoporosis, a bisphosphonate can be prescribed(Molitch, 2005; Molitch 2008).


The most difficult treatment is to give a dopamineagonist while continuing the current medication(Molitch, 2005; Molitch, 2008). Although dopamine-agonists have been successful in the treatment ofantipsychotic-induced hyperprolactinaemia, bromo-criptine treatment is reported to be associated withexacerbation of the acute psychotic state in women.Discontinuation of bromocriptine and increase inantipsychotic dosage resulted in complete remission(Frye et al., 1982; Dorevitch et al., 1991). Bromo-criptine has been shown to increase bone density(Klibanski and Greenspan, 1986) but can causeorthostatic hypotension and gastrointestinal sideeffects (Haddad and Wieck, 2004). So, caution isrecommended when prescribing it (Dorevitch et al.,1991).

Bromocriptine (5.0 to 7.5 mg daily) was investigatedin patients with schizophrenia on conventional anti-psychotics presenting with amenorrhoea, galactor-rhoea and impotence. Menstrual cycles returned in 7 of10 patients with amenorrhoea and a decrease inlactation was observed in 5 of 6 patients withgalactorrhoea and a significant increase in the serumlevels of testosterone after 8 weeks of treatment in sixout of six male patients; while, no worsening ofpsychotic symptoms was noted (Matsuoka et al.,1986). In one series of seven patients with hyperpro-lactinaemia and galactorrhoea, bromocriptine cor-rected the galactorrhoea in all and decreased prolactinin four and to normal levels in two (Beumont et al.,1975). In another study (Smith, 1992) of six females,one patient had worsened psychiatric symptoms whiletaking bromocriptine (5 to10 mg daily) and had to stopit. Bromocriptine was useful in one case of amisul-pride-induced hyperprolactinaemia without exacer-bation of psychosis (Bliesener et al., 2004).

Cabergoline (0.125 mg to 0.250 mg/week) alsoshowed significant reduction or normalization ofprolactin, improvement of side effects and nodeterioration of psychotic symptoms in a study of 19schizophrenic patients with risperidone-induced symp-tomatic hyperprolactinaemia (Cavallaro et al., 2004).Normalization of prolactin levels in four male childrenwith risperidone-induced hyperprolactinaemia treatedwith cabergoline (initial mean dose 2.13 þ/� 0.09 mg/week and maintenance dose of 1 mg/week) wasreported by Cohen and Biederman, (2001). No adverseevents were noted during the 13–21 months oftreatment. In another series, four patients withhyperprolactinaemia secondary to risperidone, bromo-criptine or cabergoline decreased prolactin andhypogonadism in three patients without exacerbationof psychosis (Tollin, 2000).



Combination therapy with aripiprazole for risper-idone-induced hyperprolactinaemia was effective inone case. Aripiprazole has dopamine receptor affinityand partial agonist properties, which may restore tonicinhibition of lactotrophs and correct dopaminehypoactivity induced by risperidone (Wahl and Ostroff,2005). The safety and efficacy of the combined use ofaripiprazole with other antipsychotics for treatment ofhyperprolactinaemia are still unclear and need to beexplored in clinical trials (Cassano et al., 2007). In aplacebo controlled trial Shim et al., studied 55 patientswith haloperidol-induced hyperprolactinaemia andfound that addition of aripiprazole (up to 30 mg/day)corrected the levels of 88.5% of patients in 8 weekscompared to 3.6% patients on placebo (Shim et al.,2007).

Management of hyperprolactinaemia should includemonitoring of prolactin levels to decrease clinicalmanifestations and optimize adherence (Torre andFalorni, 2007). A safe approach would be to measureprolactin levels in all symptomatic patients onantipsychotics and routinely in patients on conven-tional antipsychotics or risperidone (Miller, 2004).Patients with hyperprolactinaemia >100 ng/ml shouldget an MRI to exclude prolactinoma (Haddad andWieck, 2004; Miller, 2004).

DISCUSSION

The effects of antipsychotic medications on serumprolactin seem to be multifactorial. Some factors areinherent to the medication, while others to the patient.Typical antipsychotics and risperidone are more likelyto induce hyperprolactinaemia than olanzapine.Women are more sensitive to drug induced prolactinelevation than men (Kinon et al., 2003b). Similarly,advanced age seems to influence prolactin response,leading to a blunted reaction to conventional anti-psychotics (Street et al., 2000) when compared withsubjects aged 28.87� 8.36 (Purdon et al., 2000).Among antipsychotics, risperidone and typical drugssuch as haloperidol, chlorpromazine, thioridazine andthiothixene induce sustained hyperprolactinaemia.

Serum prolactin levels have been reported toincrease in a dose-dependent manner with typicalantipsychotics (Meltzer and Fang, 1976; Smith et al.,2002; Montgomery et al., 2004;). The length oftreatment is also significant. For instance, in chronictreatment, partial tolerance may cause prolactin totrend towards normalization; however prolactin levelsremain above normal in most cases (Rivera et al.,1976). The route of medication administration isimportant as well. Intramuscular depot injections keep


the prolactin levels high even after 6 months ofdiscontinuation (Wieck and Haddad, 2002).

Atypical drugs show a better pharmacological profilein this respect, even though risperidone, amisulprideand zotepine induce hyperprolactinaemia with fre-quencies and levels similar to those observed withtypical antipsychotics. Other atypical drugs, such asolanzapine, clozapine or aripiprazole can be con-sidered ‘prolactin-sparing’ and are used in switchingprotocols to correct antipsychotic-induced hyperpro-lactinaemia.

Antidepressant drugs with serotoninergic activity,including SSRI, monoamine oxidase inhibitors (MAO-I) and some tricyclics, can also cause hyperprolacti-naemia. Fluoxetine is the best documented andsertraline the most controversial. The mechanismseems to involve serotoninergic pathways and themultiple neuropeptides and hormones that are influ-enced by it (Emiliano and Fudge, 2004). Nonetheless,other neurotransmitters may be involved (Emilianoand Fudge, 2004). So far, mirtazapine and bupropionare prolactin neutral (Foley and Kast, 2006) and thelatter can even decrease prolactin (Meltzer et al.,1982).

Among other psychotropics, lithium and buspironecan produce hyperprolactinaemia. Interactionsbetween lithium and prolactin seem to be associatedwith but not limited to dopamine and serotoninpathways (Basturk et al., 2001). Buspirone is a partialagonist of D2 and 5HT1A receptors (Meltzer andMaes, 1994). Other medications like prokinetics,antihypertensives, opioids and oestrogens can producehyperprolactinaemia by different methods.

Assessment of psychotropic-induced hyperprolacti-naemia starts with the discussion of side effects, theirmagnitude and the time-line of events (Molitch, 2005;Molitch, 2008). Measurement of prolactin levels at theinitial presentation and then annually is a thoughtfulapproach. The other approach is measuring prolactinlevels in patients with clinical manifestations (Comp-ton and Miller, 2002; Marder et al., 2004). Anti-psychotic-induced hyperprolactinaemia may revertwhen the responsible drug is discontinued (Meltzerand Fang, 1976). It is important to emphasize the needfor close psychiatric supervision with these treatmentapproaches. When medication discontinuation is notpossible (Naidich and Russell, 1999) or prolactin levelsdo not revert back, other causes of hyperprolactinaemialike pituitary microadenoma and masses of pituitarystalk should be ruled out, preferably with an MRI.Other treatment strategies of psychotropic-inducedhyperprolactinaemia include: switching to anotherpsychotropic, supplementing concurrent hormonal



deficiencies and adding a dopamine agonist oraripiprazole.

CONCLUSION

Hyperprolactinaemia is a common side effect ofpsychotropics and is caused by diverse mechanisms.The understanding of drug characteristics and inter-actions guide the assessment and management ofpatients and decrease the frequency of side effects.Assessment of signs and symptoms and prolactin levelmeasurements in symptomatic patients should be done.During management it is important to provide closepsychiatric supervision and be alert about the othercauses of hyperprolactinaemia. In the absence of anideal medication, the current knowledge may beenhanced by controlled trials comparing varioustreatment options like dopamine agonists, antipsycho-tic switches and combination therapies for manage-ment of psychotropic-induced hyperprolactinaemia.Future antipsychotic medications should be designedto have fewer of these side effects.

ACKNOWLEDGEMENTS

This study was not funded by any agency. Dr. Madhusoo-danan, Dr. Parida and Dr. Jimenez do not have any conflict ofinterests in connection with the preparation of this manu-script.

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