Antidepressant-induced hyperprolactinaemia

Antidepressant-InducedHyperprolactinaemiaIncidence, Mechanisms and Management

Flora Coker1 and David Taylor1,2

1 Pharmacy Department, Maudsley Hospital, London, UK

2 Divison of Pharmaceutical Sciences, King’s College, London, UK

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5641. Tricyclic Antidepressants (TCAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

1.1 Prospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5651.1.1 Amitriptyline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5651.1.2 Amitriptyline and Desipramine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5651.1.3 Imipramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5651.1.4 Nortriptyline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5661.1.5 Clomipramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

1.2 Case Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5662. Monoamine Oxidase Inhibitors (MAOIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

2.1 Prospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5673. Selective Serotonin Reuptake Inhibitors (SSRIs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.1 Retrospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5673.1.1 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.2 Prospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5673.2.1 Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5673.2.2 Paroxetine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5673.2.3 Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.3 Case Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5684. Serotonin-Noradrenaline (Norepinephrine) Reuptake Inhibitors (SNRIs) . . . . . . . . . . . . . . . . . . . . . . . . . 568

4.1 Prospective Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5684.1.1 Venlafaxine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

4.2 Case Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5685. Noradrenaline Reuptake Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

5.1 Prospective Studies and Case Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5695.1.1 Reboxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

6. Other Antidepressant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5696.1 Prospective Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

6.1.1 Mirtazapine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5696.1.2 Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570

7. Incidence of Antidepressant-Induced Hyperprolactinaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5708. Mechanisms and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5709. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

REVIEWARTICLECNS Drugs 2010; 24 (7): 563-574

1172-7047/10/0007-0563/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

Abstract Prolactin, a polypeptide hormone, is responsible, amongst other things,for milk production during lactation and breast enlargement during preg-nancy. Numerous drugs can affect prolactin levels. Most commonly, con-ventional antipsychotics are associated with hyperprolactinaemia but therehave also been reports of antidepressants causing hyperprolactinaemia. Thisreview sets out to establish the incidence of antidepressant-induced hyper-prolactinaemia, its possible mechanism and to determine appropriate re-medial actions. Nearly all antidepressants are reported to be associated withhyperprolactinaemia. Incidence rates were not clearly established andsymptoms were very rare. The mechanism by which antidepressants maycause hyperprolactinaemia is not fully understood, though several theorieshave been postulated, such as serotonin stimulation of GABAergic neuronsand indirect modulation of prolactin release by serotonin. Patients takingantidepressants presenting to their clinician with symptoms potentially re-lated to hyperprolactinaemia, such as galactorrhoea, should have their plas-ma prolactin level measured and their antidepressant changed if an increasedprolactin level is confirmed. Routine monitoring of prolactin levels is other-wise not appropriate.

Prolactin, a polypeptide hormone, is producedby lactotroph cells of the anterior pituitary.[1] It isreleased in a pulsatile manner, with intervals ofabout 95 minutes between peak amplitudes.During sleep, prolactin levels increase, peakingearly in the morning. Immediately after wakeninglevels begin to decline. Prolactin receptors havebeen found in humans in the mammary glands andbrain and also in the liver, kidneys, ovaries, uterus,prostate and testes.[1,2] The main function of pro-lactin in humans is stimulating breast development,to cause breast enlargement during pregnancy andmilk production during lactation. In women, ser-um prolactin levels are twice those in men afterpuberty (in childhood there are no differences be-tween the sexes in serum prolactin levels).[3]

Dopamine is the predominant inhibitor ofprolactin secretion. Regulation of prolactin bydopamine occurs through tuberoinfundibular dopa-minergic and tuberohypophyseal dopaminergicneurons.[3] Dopamine binds to the dopamine D2

receptors on the membrane of the lactotrophcells, inhibiting prolactin gene transcription andproliferation of lactotrophs.[3,4]

Hyperprolactinaemia may be seen in chronicrenal failure, primary hypothyroidism and pre-senting patients with prolactinoma; it may also bemedication induced (e.g. in patients taking anti-

psychotics).[5] Hyperprolactinaemia is not alwayssymptomatic and in patients who are symptom-atic there is great individual variation as to thethreshold at which symptoms will manifest. Thesymptoms and signs of hyperprolactinaemia arewell documented and they include galactorrhoea(spontaneously or after nipple stimulation), gy-naecomastia, infertility, menstrual irregularities(oligomenorrhoea, amenorrhoea), sexual dys-function (i.e. decreased libido, impaired arousal)and decreased bone mineral density.[6]

Prolactin levels are normally reported in unitsof ng/mL (mg/L), mU/L or nmol/L (conversionfactors vary according to assay method used).Normal ranges are generally quoted as around10–28 mg/L for women and 5–10 mg/L for men.Levels above 250 mg/L have been associated withpituitary adenomas, and hyperprolactinaemiathat is medication induced is generally associatedwith prolactin levels ranging from 25 to 100mg/L.[7,8]A single blood sample is usually adequate tomakea diagnosis of hyperprolactinaemia. However,sometimes, there may be ambiguity when theresult obtained lies between the upper limits ofnormal and 100mg/L, and in this situation furthersampling on another day is recommended.[8-10]

Hyperprolactinaemia as an adverse effectof antipsychotic treatment is well documented.

564 Coker & Taylor

ª 2010 Adis Data Information BV. All rights reserved. CNS Drugs 2010; 24 (7)

However, in patients taking antidepressants thephenomenon is less well known, although it hasoccasionally been reported with several classes ofdrug including tricyclic antidepressants (TCAs),monoamine oxidase inhibitors (MAOIs) andselective serotonin reuptake inhibitors (SSRIs).The aim of this review was to establish theincidence of antidepressant-induced hyperpro-lactinaemia, its possible mechanism and to deter-mine appropriate remedial actions. To identifyrelevant literature we searched EMBASE,MEDLINE and PubMed, up to March 2010,using the drug names amitriptyline, clomipra-mine, fluvoxamine, desipramine, imipramine,dosulepin (dothiepin), trimipramine, citalopram,fluoxetine, escitalopram, sertraline, paroxetine,fluvoxamine, phenelzine, tranylcypromine, iso-carboxazid, moclobemide, reboxetine, venlafaxine,mirtazapine, duloxetine, tricyclics, monoamineoxidase inhibitors and serotonin reuptake in-hibitors, combined with each of the terms ‘pro-lactin’, ‘antidepressants’, ‘hyperprolactinaemia’,‘galactorrhoea’ and ‘adverse effects’. In August2008, various manufacturers were contactedfor information on the incidence of hyper-prolactinaemia. Reports/studies were selected forreview if any change in prolactin level or symp-toms of hyperprolactinaemia had been reported.

1. Tricyclic Antidepressants (TCAs)

1.1 Prospective Studies

1.1.1 Amitriptyline

There have been three studies investigatingthe effect of amitriptyline on prolactin. Meltzeret al.[11] reported that, when given in dosages of150–250mg/day to five depressed patients (threemale, two female), amitriptyline showed no effecton serum prolactin levels (after a period of3–7 weeks). In a further study undertaken bythe same lead author, amitriptyline (dosage200–300mg/day) caused a 2-fold increase in pro-lactin levels during chronic treatment (exactduration of treatment not specified) in two ofnine patients.[12] In a third study, amitriptyline150mg/day administered to nine subjects (treat-ment period: 1 month) increased prolactinlevels in each subject by around 50%, although

levels largely remained within the normalrange.[13]

1.1.2 Amitriptyline and Desipramine

Each of these drugs has been shown to en-hance prolactin response to tryptophan or fen-fluramine in various studies. Tryptophan is thebiochemical precursor of serotonin. Intravenoustryptophan is known to increase serum prolactinlevels and has been used as a promoter of centralserotonin function. Fenfluramine is a sero-tonergic agonist that is also known to stimulateprolactin release.

Administration of amitriptyline and desipra-mine after intravenous tryptophan to 21 depres-sed patients enhanced the ability of tryptophan toincrease prolactin levels without marked altera-tions in baseline levels.[14] Similar findings wereseen in 24 patients treated with desipramine for4 weeks.[15] Desipramine significantly enhancedthe area under the curve and peak prolactin re-sponses to tryptophan.

1.1.3 Imipramine

The aforementioned study byMeltzer et al.,[11]

also examined the effect of imipramine on pro-lactin levels. Five depressed patients (two male,three female) received dosages of 150–250mg/dayof imipramine for 3–7 weeks. There was no sig-nificant difference between pre- and post-drugprolactin levels.[11] Shapira and colleagues[16]

examined prolactin responses to fenfluramineand placebo challenge in ten depressed patientsbefore and after treatment with imipramine200mg/day for 3 weeks. Results showed that inthe drug-free state, fenfluramine increased pro-lactin levels to a significantly greater extentthan placebo. Baseline prolactin levels were un-changed by imipramine treatment for 21 days.Prolactin response to fenfluramine was sig-nificantly increased following imipramine ad-ministration, compared with the response seenin the drug-free state. Although the prolactinresponse to placebo was also increased by imi-pramine, this was not statistically significant.

The effect of imipramine (and amitriptylineand desipramine) on prolactin levels after ad-ministration of drugs that enhance prolactin

Antidepressant-Induced Hyperprolactinaemia 565


release suggests the involvement of serotonergicpathways.

1.1.4 Nortriptyline

Meltzer and colleagues[12] evaluated the effectof nortriptyline on prolactin levels in eightpatients before (placebo period) and during4–6 weeks of treatment in dosages of up to150mg/day. Overall, serum prolactin levels werenot significantly different in the placebo andtreatment periods (mean– SD 26.9 – 14.5 mg/L vs27.5 – 11.8 mg/L). However, for one patient therewas a significant increase in the serum prolactinlevel in the first 2 weeks of treatment (from21.7– 11.9mg/L to 41.6– 16.5mg/L), although lev-els declined to that obtained in the placebo period(24.3 – 12.8 mg/L) during the last 2 weeks.[12]

1.1.5 Clomipramine

Small increases in serum prolactin levels havebeen reported in healthy volunteers or depressedpatients following the acute or chronic adminis-

tration of clomipramine. In a study by Andersonand Cowen,[17] six healthy male subjects weretested with L-tryptophan on two occasions – oneafter receiving a single dose of clomipramine20mg and the other after receiving matchingplacebo capsules. The tests were separated by 4-to 6-week intervals. The subjects received L-tryptophan by intravenous infusion; this causedsignificant increases in plasma prolactin levels.Following treatment with clomipramine therewas no change in basal levels of prolactin. Afterinfusion with L-tryptophan, the levels of pro-lactin increased in patients who had been pre-treated with clomipramine.[17]

1.2 Case Reports

Case reports of prolactin level increasesfor some of the TCAs were found in the litera-ture. The most common symptom reportedis galactorrhoea. The reports are summarized intable I.

Table I. Summary of case reports of increases in prolactin levels for tricyclic antidepressants (TCAs)

Study Drug Dosage

(mg/day)Patient

details

Concurrent

medication

Symptoms Prolactin level Outcome

Gadd

et al.[18]Dosulepin 225 28-year-old

lactating

female

None Galactorrhoea 570mU/L;160mU/L after

dosulepin withdrawal

Galactorrhoea gradually

subsided after dosulepin

was withdrawn

Anand[19] Clomipramine 150 26-year-old

female

L-tryptophan Galactorrhoea

and amenorrhoea

Onset of lactation:

prolactin 102.2 mg/L;clomipramine 50mg/LWeek 1: prolactin

25.4 mg/L;clomipramine 42mg/LWeek 4: prolactin

14 mg/L; clomipramine

36 mg/LWeek 6: prolactin

3.8 mg/L;clomipramine 30mg/L

Patient was also having

ECT. Both L-tryptophan

and ECT were stopped,

but lactation continued.

Clomipramine dose was

reduced to 25mg twice

daily and a dopamine

agonist was initiated.

Lactation became less

distressing and ceased at

6wk, following

clomipramine dose

reduction and addition of

the dopamine agonist

Fowlie

and

Burton[20]

Clomipramine 50 20-year-old

female

Oral

contraceptive

(name not

given)

Galactorrhoea

and bilateral

breast swelling

988 IU/mL; 140 IU/mL

after clomipramine

withdrawal

Oral contraceptive

stopped after 12wk but

galactorrhoea still

persisted. Within 2wk of

stopping clomipramine,

prolactin levels began to

decline and by 3mo had

normalized

ECT =electroconvulsive therapy.

566 Coker & Taylor


2. Monoamine Oxidase Inhibitors(MAOIs)


MAOIs inhibit the intracellular metabolism ofmonoamines and, therefore, increase intracerebrallevels of serotonin, dopamine and noradrenaline(norepinephrine).[12] As a result of increased dop-amine levels, it might be expected that prolactinlevels would decrease in patients taking MAOIs.However, only increased prolactin levels have beenreported with MAOIs.[12,21] Meltzer and co-work-ers[12] described the effect of phenelzine on pro-lactin levels in 11 patients.[12] In four of the subjectsprolactin level elevation was observed (prolactinlevel increase was said to be ‘‘marked’’ in one of thesubjects).[12] The increase persisted for another5 weeks of treatment in these four patients. Duringa week of placebo treatment, serum prolactin levelsreturned to baseline. On restarting phenelzine 1week later, prolactin levels rose again in all fourpatients. The mechanism of action for phenelzinecausing increased prolactin levels is uncertain.

In a further prospective study, Price and col-leagues[22] reported a small but significant increasein prolactin levels versus baseline (mean – SD3.0 – 2.5 ng/mL; p< 0.01) in nine subjects whowere administered tranylcypromine at a meandosage of 28.9mg/day (duration of treatmentnot stated).

3. Selective Serotonin Reuptake Inhibitors(SSRIs)

3.1 Retrospective Studies

Two retrospective studies have been conductedwith SSRIs. One study evaluated all SSRIs[23] andthe other examined the adverse effects caused byfluoxetine.[24]

Egberts et al.[23] carried out a retrospectiveanalysis to assess the differences in the risk of de-veloping non-puerperal lactation for patients usingdifferent antidepressants in the Netherlands. Anal-yses were restricted to women, as predominantlywomen are at risk for developing non-puerperallactation. From suspected adverse drug reactionsreported to the Netherlands Pharmacovigilance

Foundation during the 10-year study period,38 reports were for non-puerperal lactation, ofwhich 15 were attributed to the use of an anti-depressant drug. Prolactin level was measuredin five of these patients; levels were normal in four.The disorder resolved in all patients when the drugdose was reduced, continued or stopped. Therewas a clear association between using an anti-depressant and reporting of non-puerperal lacta-tion. The serotonergic antidepressants (SSRIsand clomipramine) in particular were associatedwith a higher risk (odds ratio: 12.7 [95% CI 6.4,25.4]) than were other antidepressants (odds ratio:1.6 [95% CI 0.2, 11.6]) compared with those nottreated with antidepressants. The authors con-cluded that the risk of non-puerperal lactation inwomen using serotonergic antidepressants iseight times (odds ratio: 8.2 [95%CI 1.1, 64]) higherthan in women using non-serotonergic antide-pressants.[23]

3.1.1 Fluoxetine

Coulter and Pillans[24] performed a retro-spective analysis (over a 4-year period) of adverseeffects caused by fluoxetine. Of 5555 reports ofadverse effects with the drug, there were none ofhyperprolactinaemia.


3.2.1 Sertraline

Prolactin levels were not affected by sertraline intwo studies that included 27 subjects in total(15 with major depression, 12 healthy volunteers).Dosages were generally 50mg/day or lower.[25,26]

3.2.2 Paroxetine

Paroxetine was found not to significantly af-fect prolactin levels in eight healthy male volun-teers receiving 30mg/day (mean change, +7%).[27]

3.2.3 Citalopram

Citalopram 20mg administered by intra-venous infusion over 30 minutes to eight healthymale subjects caused increased prolactin levels(from 8.81 – 3.53 to 17.80 – 4.65 ng/mL) at 80minutes after the start of the infusion.[28] Like-wise, Kapitany et al.[29] reported a pronouncedincrease in prolactin levels (by 7.1 – 14.8 ng/mL)



in control patients given 20mg of citalopramintravenously. Mondelli et al.[30] observed similarelevations in 12 women (six healthy; six with an-orexia nervosa) administered citalopram as anintravenous infusion of 20mg over 120 minutes.

In another human volunteer study, oral ad-ministration of citalopram 20mg, escitalopram10mg or placebo to 15 healthy volunteers had noeffect on prolactin levels.[31] Henning and Net-ter[32] also reported that there was no prolactinlevel change after a single oral dose of citalopram20mg in 48 healthy male patients. In a furtherstudy, acute administration of citalopram 20mgand 40mg to nine subjects had no significantstatistical effect on prolactin levels.[33] In con-trast, 19 patients receiving oral citalopram 40mgfor 4 weeks (they had received 20mg for the first4 days) showed a 2-fold increase in prolactin levels(p = 0.007; n= 13).[34]

3.3 Case Reports

Galactorrhoea as a result of SSRI therapy hasbeen recorded in several patients (table II).

4. Serotonin-Noradrenaline(Norepinephrine) Reuptake Inhibitors(SNRIs)

4.1 Prospective Study

4.1.1 Venlafaxine

Venlafaxine given as a singe dose of 75mg in-creased prolactin levels in four of six patients in asingle-blind placebo trial.[39] At lower doses (i.e.12.5mg and 25mg) one subject showed an in-crease, while at 50mg two subjects showed anincrease. Two subjects showed no increase at allcompared with placebo at any of the doses. Meanvalues for the six patients showed a 2-fold increase90 minutes after the dose was administered.[39]

4.2 Case Reports

For venlafaxine there are case reports of ga-lactorrhoea, breast pain and tenderness. Withduloxetine, there is one case report of galactor-rhoea in a patient who had received venlafaxinebefore duloxetine (see table III).

Table II. Summary of case reports of increases in prolactin levels for selective serotonin reuptake inhibitors (SSRIs)

Study Drug Dosage

(mg/day)Patient

details

Concurrent

medication


Peterson[35] Fluoxetine Not

stated

71-year-old

female

Premarin,

benazapril,

alprazolam

Unilateral

galactorrhoea for

approximately

2mo

37.4 mg/L(1.2–24.2 mg/L);6.1 mg/L post-

fluoxetine

Galactorrhoea ceased

within 10 d of stopping

fluoxetine

Morrison

et al.[36]Paroxetine 40 32-year-old

female

Trazodone 25mg

and Tylenol

(combination

product containing

paracetamol,

codeine and

caffeine)

Galactorrhoea

without

amenorrhoea

46.1 mg/L (normal

is 20mg/L); 7.4 mg/Lafter paroxetine

withdrawal

Prolactin returned to below

normal range when

paroxetine stopped

Shim

et al.[37]Escitalopram 10 36-year-old

female

Ferrous sulphate Galactorrhoea,

breast pain

200 ng/mL;

2.38 ng/mL after

escitalopram

discontinued

No abnormalities in the

patient’s blood chemistry.

As galactorrhoea occurred

after escitalopram initiation,

this was stopped. Prolactin

levels decreased after

escitalopram cessation

Aggarwal

et al.[38]Escitalopram 10 25-year-old

female

None Galactorrhoea

and bilateral

breast

tenderness

11.50 ng/mL;

10.50 ng/mL after

escitalopram

cessation

Escitalopram was changed

to amitriptyline, symptoms

were absent 2wk after

stopping escitalopram and

remained absent at 3mo

follow-up

568 Coker & Taylor


5. Noradrenaline Reuptake Inhibitor

5.1 Prospective Studies and Case Report

5.1.1 Reboxetine

In a single-blind study,[43] reboxetine wasfound to significantly (p = 0.001) enhance pro-lactin secretion in 12 healthy male subjects (therewas an approximately 150% increase in prolactinlevels at 90 minutes after reboxetine administra-tion).[43] The subjects were randomized to eitherreboxetine 4mg or placebo; each received eitherreboxetine or placebo on two different days. Asecond study using neuroendocrine challengetests obtained contrasting results. Participantsreceived reboxetine 4mg initially for the first 4

days and then the dose was increased to 8mg forthe remainder of the 4 weeks. There was no sig-nificant change compared with pre-treatmentprolactin levels (day 1: -2.76 – 3.35 mg/L; day 29:-5.32 – 4.51 mg/L; p = 0.288; n = 11).[34]

6. Other Antidepressant Drugs


6.1.1 Mirtazapine

In one study, eight healthy male subjects wererandomized to either placebo or mirtazapine15mg.[44] Each participated twice, i.e. they eitherhad placebo or mirtazapine on two differentdays. Over a 2-hour period blood samples were

Table III. Summary of case reports of increases in prolactin levels for serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs)

Study Drug Dosage

(mg/day)Patient

details

Concurrent

medication


Bhatia

et al.[40]Venlafaxine 150 50-year-old

female

Alprazolam;

bromocriptine

mesylate

Breast

tenderness

and pain with

galactorrhoea

Not obtained as

patient refused

Treatment with

bromocriptine resolved

symptoms

Sternbach[41] Venlafaxine 225 38-year-old

nonlactating

female

Buspirone Galactorrhoea 32mg/L(2.8–29.2 mg/L)

Galactorrhoea persisted

despite buspirone

discontinuation.

Venlafaxine was tapered

off and galactorrhoea

remitted 4wk later.

Citalopram was

prescribed, but was

ineffective (no

galactorrhoea reported).

Galactorrhoea reoccurred

when venlafaxine (75mg)

was restarted, though

prolactin level was normal –

10mg/L

Ashton and

Longdon[42]Venlafaxine

then

duloxetine

225/60 40-year-old

female

Bupropion Nonmenstrual

spotting and

bilateral breast

discharge

39.7 mg/L(venlafaxine

225mg);

12.5 mg/L(reduced dose

of venlafaxine,

actual dose

not given)

duloxetine

10.8 mg/L to

28.2 mg/L within

1 mo of starting;

5.1 mg/L post-

discontinuation

Venlafaxine was gradually

decreased and the dose of

bupropion increased. With

this, spotting stopped but

breast discharge

persisted. As her mood

worsened, venlafaxine

was withdrawn and

duloxetine initiated.

Breast discharge increased

again and stopped when

duloxetine was

discontinued



drawn and plasma prolactin levels determined.No prolactin stimulation was seen in the eightsubjects. Schule and colleagues[45] reported simi-lar findings. Statistical analyses did not revealany significant difference between placebo andmirtazapine; results were duplicated in six malesubjects. The same authors reported similarfindings in eight healthy subjects administeredmirtazapine 15mg.[46]

In their 2004 study, Schule et al.[47] hypothe-sized that co-administration of mirtazapine andreboxetine would result in the endocrinologicaleffects of reboxetine being antagonized. Twelvesubjects were randomized to receive either re-boxetine 4mg alone or reboxetine 4mg andmirtazapine 15mg, participating twice, on two dif-ferent days. Reboxetine alone caused an increasein prolactin levels, but the drug combination re-sulted in diminished stimulation of prolactin,which was statistically significant. The authorssuggested the diminished stimulation of prolactincould be a result of the activity of mirtazapine ata2-adrenoceptors, but no further explanation wasgiven.[47-51]

6.1.2 Bupropion

Bupropion, a noradrenaline and dopaminereuptake inhibitor, has been shown not to affectplasma prolactin levels in ten healthy volunteers.In doses of up to 100mg, it did not affectplasma prolactin levels when compared withplacebo.[52]

7. Incidence of Antidepressant-InducedHyperprolactinaemia

Information on the incidence of hyper-prolactinaemia with antidepressants is meagre. Apremarketing prevalence rate for galactorrhoeaof 0.07% (i.e. four cases in 5920 patients) afteradministration of fluoxetine has been reported.[53]

The summary of product characteristics for par-oxetine gives the incidence of hyperprolactin-aemia as rare (‡0.01%).[54] With clomipramine,the frequency of galactorrhoea and breast en-largement is given as 1% to <10%.[55] For citalo-pram and sertraline, no incidence figures forhyperprolactinaemia are available.[56,57]

8. Mechanisms and Management

Antidepressants are clearly occasionally, if in-consistently, associated with hyperprolactinaemiabut incidence, outcome and relative risk are dif-ficult to discern from the available data.

Many studies have been carried out to eluci-date the mechanism by which serotonin affectsprolactin release. It is known that serotonin is anindirect modulator of prolactin release.[58] Thiseffect is thought to occur via the paraventricularnucleus, which contains postsynaptic serotonin 5-HT1A, 5-HT2 and 5-HT2C receptor subtypes[58,59]

and possibly 5-HT3 receptors also.[60] Pharma-cological experiments have shown that the pro-lactin-releasing effects of serotonin probablyoccur via central 5-HT1C/2 receptors.[59] Forexample, administration of a selective 5-HT1C/2receptor agonist DOI [(–) -1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCL] produced asignificant elevation in prolactin levels. Thiseffect was opposed by the selective 5-HT1C/2receptor antagonist ritanserin.[59] Another pro-posed mechanism by which serotonin may causeprolactin release is through the stimulation ofGABAergic neurons[58] situated near the tubero-infundibular dopamine cells. These dopaminecells have 5-HT1A receptors on them. Stimulationby serotonin would lead to inhibition of the in-hibitory control of dopamine over prolactin, thuscausing increased prolactin levels.[58]

Stressful life events may increase prolactinlevels, which in turn may lead to psychiatric ef-fects, e.g. depression.[61] Undoubtedly then, in somecases, reported antidepressant-related hyper-prolactinaemia may have its origins in pre-treatment events.

Many practising clinicians would not antici-pate that antidepressants alone would causehyperprolactinaemia. Sexual or endocrine ad-verse effects are thus likely to be attributed toother pharmacological actions of the drugs orother causes. Moreover, antidepressant-relatedhyperprolactinaemia may occur without symp-toms or at least without the patient reportingsymptoms. Clearly, it might be considered pru-dent to monitor prolactin levels in patients takingantidepressants but, given the likely incidence of

570 Coker & Taylor


hyperprolactinaemia, this may be clinically su-perfluous, despite the possible risk of reduction inbone mineral density[62] with long-term treat-ment. So, if routine monitoring is likely to beunproductive, prolactin level testing shouldprobably only be undertaken when symptomssuch as gynaecomastia, galactorrhoea, amenor-rhoea or failure to conceive (all possibly relatedto prolactin) are present. Therefore, if a patientdoes present with symptoms, the following isrecommended:� Measure prolactin level: if <25 mg/L consider

other causes; if >25 mg/L withdraw anti-depressant slowly over 2 weeks.

� Replace the antidepressant with one less likelyto cause prolactin level elevation (e.g. mirta-zapine, reboxetine, bupropion).

� Remeasure prolactin level after 2–4 weeks andobserve for symptom change (note: symptoms

may resolve sometimes after prolactin levelshave decreased).

� If the prolactin level remains elevated, refer thepatient to an endocrinologist.

9. Conclusion

In controlled studies, the extent of prolactinlevel elevation induced by antidepressants isgenerally quite small. As a consequence, onemight expect symptoms of hyperprolactinaemiato occur only very infrequently in those receivingantidepressants. This expectation is largely borneout by what data do exist on the incidenceof prolactin-related effects in people takingantidepressants. It can be seen that hyper-prolactinaemia has been reported for almost allantidepressants. Only mirtazapine has been con-vincingly shown not to elevate prolactin levels at

Table IV. Summary of case reports excluded

Study Main finding Reason for exclusion

Klein et al.[63] 34-year-old female experienced galactorrhoea taking imipramine 75–100mg.

Also taking liothyronine. Galactorrhoea ceased when imipramine discontinued,

reoccurred on rechallenge and ceased when therapy concluded

Prolactin levels not stated

Wolfsperger

and Greil[64]31-year-old female taking trimipramine 100mg and paroxetine had

galactorrhoea. Trimipramine dosage was reduced to 50mg/day and the

galactorrhoea stopped

Prolactin level 21.8 mg/L; no level stated

for after trimipramine discontinuation

Bronzo and

Stahl[53]37-year-old female taking sertraline 100mg, no other medication, had

galactorrhoea approximately 5wk after commencing treatment with sertraline.

Lactation ceased 21 d after stopping sertraline


Bonin et al.[65] 33-year-old female taking paroxetine 20mg had galactorrhoea without

amenorrhoea. Galactorrhoea remitted on discontinuation and was absent 5mo

later


Ghosal et al.[66] 16-year-old female taking paroxetine 25mg experienced galactorrhoea. On

withdrawal of paroxetine galactorrhoea ceased within 3 d


Davenport and

Velamoor[67]24-year-old female taking paroxetine10mg complained of galactorrhoea.

Paroxetine was withdrawn and on the same night galactorrhoea ceased


Gonzalez

et al.[68]32-year-old female taking paroxetine 40mg experienced galactorrhoea.

Paroxetine was reduced to 30mg and the galactorrhoea resolved over a month


Yalug et al.[69] Reboxetine cited as the cause of amenorrhoea in a female patient with major

depressive disorder. The patient was taking 8mg/day, which she had reported

to be effective; however, she also stated that she had experienced amenorrhoea

for 3mo. Reboxetine was discontinued, and after 17 d menstruation returned

and was regular for 2mo following. She was retitrated on reboxetine until her

previous dosage of 8mg/day was reached. Amenorrhoea reoccurred,

reboxetine was stopped, menstruation returned after 15 d

Actual prolactin levels not given, but

prolactin levels reported as normal

Gulsun et al.[70] 34-yr-old female taking escitalopram 20mg. Patient experienced breast

tenderness, chest pain and galactorrhoea 2wk after dose increase from 10mg

to 20mg, escitalopram continued, symptoms began to resolve, patient symptom

free after 10 d

Prolactin levels not stated, but reported

as normal



least to some degree. The majority of the data arefrom case reports (some of these had incompleteinformation and were excluded from analysis;these are summarized in table IV for reference).Studies that have been conducted have beencharacterized by small subject numbers and rela-tively short duration. Also, within each class ofantidepressant, each drug has conflicting reportsof effects on prolactin levels; some studies re-ported prolactin level elevation and some withthe same drug reported no effect on prolactinlevels. Definite conclusions are difficult to drawfrom the limited and opposing reports.

Overall, prolactin-related effects of antide-pressants are difficult to predict but symptomaticevents are likely to be very infrequent. Routinemonitoring of prolactin level is not required.

Acknowledgements

No sources of funding were used to assist in the prepara-tion of this review. Prof. Taylor has received consultancy fees,research funding and honoraria from Servier, Lundbeck, EliLilly and Wyeth. Miss Coker has no conflicts of interest thatare directly relevant to the content of this review.

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Correspondence: Prof.David Taylor, Pharmacy Department,Maudsley Hospital, Denmark Hill, London, SE5 8AZ, UK.E-mail: [email protected]

574 Coker & Taylor


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Antidepressant-induced hyperprolactinaemia