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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 Trihexyphenidyl decreased bone mineral density, damage to car- was withdrawn in October 2001 and flurazepam was discontinued in January 2002.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 and management. Drugs, 64, 2291–2314.
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 lactinemia and bone mineral density: the potential 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 5. Kinon BJ, Gilmore JA, Liu H, Halbreich UM (2003) Prevalence of hyperprolactinemia in schizophrenic patient is believed to have been largely induced by patients treated with conventional antipsychotic the addition of risperidone. Although increasing medications or risperidone. Psychoneuroendocrinology, quetiapine doses have been associated with higher prolactin levels (21), quetiapine has a higher Ki, 6. Wahl R, Ostroff R (2005) Reversal of symptomatic and therefore less affinity, for the D2 receptor than hyperprolactinemia by aripiprazole. American Journal risperidone (3, 22). Quetiapine has also been thought of as prolactin-sparing (3): It has been 7. Lin S, Chen C (2006) Reversal of antipsychotic- shown to elevate prolactin less than risperidone induced hyperprolactimemia, weight gain, and (21, 23); decrease prolactin levels (25); and reverse dyslipidemia by aripiprazole: a case report. Journal of hyperprolactinemia when substituted for other neuroleptics (23, 24). Because doses of all other 8. Lee B, Lim Y (2006) The relationship between psychiatric medications were held constant dur- prolactin response and clinical efficacy of risperi-done in acute psychotic inpatients. Progress in ing treatment with aripiprazole, the decrease in Ó 2009 The Authors. Journal compilation Ó 2009 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 34, 595–598 Neuro-Psychopharmacology & Biologic Psychiatry, 30, 17. Fowlie S, Burton J (1987) Hyperprolactinemia and nonpuerperal lactation associated with clomipr- 9. Brunelleschi S et al. (2003) Risperidone-associated amine. Scottish Medical Journal, 32, 052.
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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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