Journal of Clinical Pharmacy and Therapeutics (2009) 34, 595–598
Attenuation of risperidone-induced hyperprolactinemiawith the addition of aripiprazole
M. M. Rainka* PharmD, H. A. Capote* MD, C. A. Ross* RPA-C and F. M. Gengo* àPharmD FCP*Dent Neurologic Institute, Departments of Neurology and àPharmacy, University at Buffalo, Buffalo,NY, USA
rolactinemia in a mentally retarded patient who
had previously responded well to risperidone only.
Hyperprolactinemia can be a complication of
This seemed a reasonable alternative to the addi-
conventional neurolepics as well as risperidone.
tion of dopamine agonists, which can exacerbate
We report the third case of attenuation of ris-
psychosis and worsen impulsivity. We report the
peridone-induced hyperprolactinemia by aripip-
third case of attenuation of risperidone-induced
hyperprolactinemia by aripiprazole (6, 7); however,this is the first case in a mentally retarded patient
Keywords: antipsychotic, aripiprazole, hyperpro-
MH is a 48-year-old mentally retarded Native
American male, diagnosed with impulse control
Prolactin secretion is regulated by dopamine’s
disorder and obsessive-compulsive disorder. He
inhibitory effect on lactrotroph cells in the ante-
became aggressive in 1995 or 1996 and stabilized in
1997. When we took over his care in 2001, he was
dopamine can induce hyperprolactinemia, which
psychiatrically stable on risperidone 8 mg daily,
is a recognized complication of first-generation
antipsychotics and risperidone (2–5). Hyperprol-
150 mg daily, flurazepam 15 mg daily and tri-
actinemia can lead to gynecomastia, galactorrhea,
hexyphenidyl 2 mg twice daily. Trihexyphenidyl
decreased bone mineral density, damage to car-
was withdrawn in October 2001 and flurazepam
was discontinued in January 2002. He developed a
estrogen, progesterone, and testosterone levels
tremor by October 2002. In February 2003, risperi-
(1, 2, 5). Treatment for drug-induced hyperpro-
done was decreased to 4 mg daily and the patient
lactinemia consists of discontinuation of the
had a few behavioural outbreaks. Risperidone was
offending agent or the addition of dopamine
then increased to 8 mg in August 2003 and symp-
toms of parkinsonism developed, including tremorand cog-wheeling, while improvement was seenfrom a psychiatric standpoint by March 2004. Later
in 2004, levetiracetam and quetiapine were added.
We questioned whether combining aripiprazole
Amantadine was added for control of extrapyra-
with risperidone would be beneficial in controlling
midal symptoms in December 2004. At the same
impulse control disorder and correcting hyperp-
time, risperidone began to be tapered and waseventually withdrawn due to hyperprolactinemia
Received 25 March 2008, Accepted 1 September 2008Correspondence: Michelle M. Rainka, Dent Neurologic
and extrapyramidal symptoms. In September 2005,
Institute, 3980 Sheridan Drive, Suite 200, Amherst, NY 14226,
lamotrigine was added to the regimen. In October
USA. Tel.: +1 716 250 2038; fax: +1 716 250 2057; e-mail:
2005, when risperidone was as low as 1 mg, serum
Ó 2009 The Authors. Journal compilation Ó 2009 Blackwell Publishing Ltd
prolactin was 25Æ07 ng ⁄ mL. After discontinuation
dramatic psychiatric improvement was seen in
of risperidone in January of 2006, serum prolactin
functioning, behaviour and socialization.
was 19Æ41 ng ⁄ mL. As risperidone was decreasedand discontinued, the patient developed increased
C R I T I C A L A N A L Y S I S A N D D I S C U S S I O N
Risperidone exerts an acute and persistent effect
swearing and talking to himself. Early in 2006,
on serum prolactin to a greater extent than the
valproic acid was decreased and lamotrigine was
other atypical antipsychotics by blocking dopa-
mine D2 receptors in the anterior pituitary (1, 2, 8).
Because the patient was previously stable on
Striatal occupancy has been used as a marker for
risperidone, he was rechallenged in June 2006. At
D2 receptor saturation on the pituitary as the D2
6 mg of risperidone, improvement was noted;
receptor affinities are similar (1). It has been
however; serum prolactin was 45Æ93 ng ⁄ mL in
reported that 50–72% occupancy of the D2 receptor
August 2006. Aripiprazole 5 mg daily was then
in the striatum has resulted in hyperprolactinemia
added and increased to 10 mg. In September
(1, 3). Prolactin levels are strongly correlated with
2006, at 10 mg of aripiprazole and 6 mg of
risperidone dose (2, 5, 8). Risperidone has been
risperidone, serum prolactin had decreased to
shown to occupy the D2 receptor by 82% at 6 mg
30Æ43 ng ⁄ mL. In October 2006, aripiprazole was
and 72% at 3 mg (9). 9-hydroxy-risperidone con-
increased to 15 mg daily, and serum prolactin
centrations are strongly correlated with prolactin
was further decreased to 22Æ62 ng ⁄ mL. Serum
levels whereas risperidone concentrations are not
(10). The blood–brain barrier is absent in the
pituitary which allows neurosecretory products to
Table1). During this time the patient remained on
pass into circulation. Both risperidone and its
valproic acid 500 mg, risperidone 6 mg, aripip-
metabolite have been thought to cause marked
razole 15 mg, clomipramine 150 mg, lamotrigine
elevations in prolactin compared to other atypicals
as a result of poor penetration through the blood–
3000 mg, amantadine 200 mg, bisacodyl 10 mg,
brain barrier and greater effects in the periphery
and docusate 200 mg, which had been unchanged
due to their low lipophilicity and high affinity for
since early June 2006 (prior to the addition of
the D2 receptor (1, 10). 9-hydroxy-risperidone
risperidone). During this time there were a few
shares risperidone’s affinity for the D2 receptor
situational difficulties at work but overall a
but is even less lipophilic and has a greater half-
Table 1. Prolactin levels in response to prolactin-altering drugs and doses by date
Ó 2009 The Authors. Journal compilation Ó 2009 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 34, 595–598
Attenuation of risperidone-induced hyperprolactinemia
life than the parent compound and therefore may
prolactin levels is attributed to the addition of ari-
be mainly responsible for the sustained hyper-
Reversal of risperidone-, olanzapine-, and halo-
peridol-induced hyperprolactinemia and relatedsymptoms has been reported after 15–30 mg of
This is the third case to report attenuation of ris-
aripiprazole (6, 7, 11,12). These cases are similar to
peridone-induced hyperprolactinemia by aripip-
the case presented here in that hyperprolactinemia
razole, without discontinuing risperidone, or
was reversed while the patient was on the causa-
adding a dopamine agonist. Our report clearly
tive agent. A pilot study also evaluated the reversal
illustrates the time course of the effect of adding
of hyperprolactimemia and associated symptoms
aripiprazole as well as demonstrates a sustained
by switching from either amisulpride or risperi-
effect over 1 year. In addition, our report demon-
done to aripiprazole, in which all patients experi-
strates psychiatric improvement on this combina-
enced reversal of hyperprolactinemia and its
tion with increased socialization in a mentally
retarded individual with impulse control disorder.
Aripiprazole is a partial agonist at D2, a partial
As this clinical conundrum is often encountered in
agonist at serotonin 1A, and an antagonist at
the day-to-day care of the developmentally dis-
serotonin 2A receptors (1). It has a greater affinity
abled, a controlled clinical trial would be of great
for D2 than risperidone, with 90% occupancy at the
D2 receptor at 15 mg (9). Because of aripiprazole’spartial agonist activity, it can act as an agonist in
the presence of dopamine hypoactivity induced byrisperidone, thus inhibiting lactotroph activity and
1. Haddad P, Wieck P (2004) Antipsychotic-induced
hyperprolactinemia mechanisms, clinical features
In addition to risperidone and aripiprazole, MH
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2. Kinon B, Glimore J, Liu H, Halbreich U (2003)
was treated with two other medications reported to
Hyperprolactinemia in response to antipsychotic
increase prolactin secretion, clomipramine (14–18)
drugs: characterization across comparative clinical
and quetiapine; and amantadine (19, 20), which is
trials. Psychoneurendocrinology, 28, 69–82.
reported to cause small decreases in prolactin
3. Naidoo U, Goff D, Klibanski A (2003) Hyperpro-
levels. Doses of clomipramine and amantadine
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were constant since 2001 and 2004, respectively.
impact of antipsychotic agents. Psychoneuroendo-
MH was on 600 mg quetiapine with a prolactin
level of 19Æ41 ng ⁄ mL, before rechallanging with
4. Melkersson K (2005) Differences in prolactin eleva-
risperidone. Prior to his next prolactin level at
tion and related symptoms of atypical antipsychotics
45Æ93 ng ⁄ mL in August 2006, risperidone had been
in schizophrenic patients. Journal of Clinical Psychi-
titrated to 6 mg and quetiapine had been increased
to 700 mg, The hyperprolactinemia seen in our
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Ó 2009 The Authors. Journal compilation Ó 2009 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 34, 595–598
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