Central D2 Receptor Occupancy Research Articles

Reversal of Symptomatic Hyperprolactinemia by Aripiprazole

Back to table of contents Previous article Next article Letter to the EditorFull AccessReversal of Symptomatic Hyperprolactinemia by AripiprazoleREBECCA WAHL, M.D., and ROBERT OSTROFF, M.D., REBECCA WAHLSearch for more papers by this author, M.D., and ROBERT OSTROFFSearch for more papers by this author, M.D., New Haven, Conn.Published Online:1 Aug 2005https://doi.org/10.1176/appi.ajp.162.8.1542-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Hyperprolactinemia is a well-recognized complication of treatment with antipsychotics, causing multiple endocrine and sexual side effects, including the risk for osteoporosis and possibly breast cancer (1). We report a case of successful treatment of risperidone-induced hyperprolactinemia by the partial dopamine agonist aripiprazole.Anne was a 17-year-old adolescent diagnosed with schizophrenia complicated by medication noncompliance. She was admitted to the inpatient service while acutely psychotic. She had mild asthma but no other medical problems. Her periods had been normal since menarche. Her maternal grandfather also has schizophrenia but had been asymptomatic for many years while taking haloperidol.Risperidone was started because of the option for a long-acting formulation. Anne accepted the idea of an intramuscular injection because of her grandfather’s history. Her oral dose was titrated up to 4 mg/day over 2 weeks, after which she received her first injection of 25 mg. She reported a decrease in psychotic symptoms but began to complain of bilateral breast pain, swelling, and galactorrhea. Serum prolactin was drawn and found to be elevated, at 119 μg/ml (normal range 0–25 μg/ml). Aripiprazole (15 mg/day) was added to her drug regimen because of its partial agonism at the dopamine receptor (2), making it a theoretically useful tool in lowering prolactin. Anne remained taking oral risperidone, 4 mg/day, and had a gradual resolution of her breast pain and galactorrhea. Another prolactin level taken 12 days later was 18 μg/ml. Anne was discharged from the hospital much improved while taking a combination of a long-acting intramuscular injection of risperidone, 25 mg every 2 weeks, and aripiprazole, 15 mg/day.Aripiprazole lowers serum prolactin below placebo when it is used as a single agent (3). To our knowledge, this is the first case report of aripiprazole used in combination with another antipsychotic expressly to treat symptomatic hyperprolactinemia. Risperidone causes more marked elevations in prolactin than other atypical antipsychotics because it does not fully cross the blood-brain barrier (4). Dopamine D2 receptor occupancy is therefore higher at the level of the pituitary than in the striatum. Aripiprazole has a greater affinity for the D2 receptor than risperidone, with central D2 receptor occupancy around 90% at a dose of 15 mg/day (5). The partial agonist property of this compound means that in the presence of dopamine hypoactivity, as induced by risperidone, aripiprazole will function as a dopamine agonist with roughly 30% intrinsic activity at postsynaptic receptors (5), restoring tonic inhibition to anterior pituitary lactotrophs. Spontaneous prolactin decline in this case would be unlikely because the time since risperidone exposure was short. However, normalization after longer-term treatment (1 year) has been reported (6).It may be advantageous to avoid the use of directly acting dopaminergic agents in psychotic patients because of the risk for worsening psychosis. Whether this risk is really any lower for aripiprazole when combined with a direct D2 receptor antagonist is not clear and would need to be answered in a controlled trial.

Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients.

Previous studies of the relationship between plasma prolactin and clinical effects in patients treated with antipsychotic drugs have yielded inconsistent results. A possible explanation may be that most studies have not included subtherapeutic or low doses of antipsychotics. In this exploratory, double-blind study, the relationship between plasma prolactin concentration and central D2 receptor occupancy was examined in 13 schizophrenic patients treated with the experimental antipsychotic drug raclopride (2, 6, or 12 mg daily). D2 receptor occupancy was determined by positron emission tomography and was related to antipsychotic effect as measured by the Brief Psychiatric Rating Scale. Plasma prolactin concentration was increased in eight of nine patients with a D2 receptor occupancy greater than 50%, whereas it was normal among patients with a D2 receptor occupancy less than 50% (p < 0.01). Plasma prolactin concentration measured 4 hours after the morning dose of raclopride correlated significantly with plasma raclopride concentration (r = 0.92, p < 0.01), the degree of D2 receptor occupancy (r = 0.81,p < 0.01), and the antipsychotic effect (r = 0.79, p < 0.01). Further controlled studies that include low doses of antipsychotic drugs may warrant a reconciliation of plasma prolactin as a useful tool in clinical monitoring of antipsychotic drug treatment.

Central D2 receptor occupancy and effects of zuclopenthixol acetate in humans.

Repeated positron emission tomography (PET) measurements of D2 receptor occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 receptor occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 receptor occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 receptor occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 receptor occupancy calls for careful assessment of acute extrapyramidal symptoms.