Anchoring on Risperidone: A Case-Based Discussion of Managing Hyperprolactinemia With Dual Antipsychotics

Antipsychotic‑induced hyperprolactinemia results from dopamine-2 receptor (D2R) blockade in the tuberoinfundibular pathway. Risperidone and other antipsychotics with high D2R affinity commonly cause substantial prolactin (PRL) elevation.¹ Recovery of normal PRL levels after antipsychotic discontinuation is expected over days to weeks.² The following case illustrates an attribution pitfall during treatment with 2 high-potency antipsychotics (each of which could be culpable in the genesis of hyperprolactinemia) and provides a pragmatic sequence for management, including brief guidance on when to consider macroprolactin testing.

Case Example

“Rachel,” a 35-year-old woman with schizoaffective disorder, bipolar type, was transferred to inpatient psychiatry on day 0 for conservatorship evaluation after being found incompetent to stand trial. She had a chronic severe psychotic illness with substantial functional impairment despite multiple prior antipsychotic trials, including clozapine. Collateral history and chart review documented prior state hospitalizations, grave disability, severe hygiene neglect, and poor attention to basic medical needs. She did not report any other medical history and did not take any medications other than risperidone and fluphenazine. The physical exam was notable only for obesity. Her mental status exam showed no positive psychotic symptoms; however, she displayed negative features, including restricted social relatedness, mild speech latency, and concrete thought processes. She had been receiving risperidone 6 mg nightly and fluphenazine 25 mg nightly for at least 2 months prior to admission. On day 13, the patient’s PRL was found to be 72 ng/mL (normal level < 25 ng/mL). Her risperidone was discontinued on day 26 due to suspected risperidone-induced hyperprolactinemia. However, repeat PRL on day 48 was 76 ng/mL.

At this time (day 49), she reported a 3-month history of amenorrhea but denied any galactorrhea, vision changes, headache, or hot flashes. Rachel was started on aripiprazole and clozapine, which were respectively titrated to 25 mg and 300 mg nightly. Fluphenazine was then tapered off and completely discontinued on day 56. By day 97, the PRL had normalized (9.1 ng/ml). Shortly thereafter, her amenorrhea resolved, and she was ready for transfer to a lower level of care.

Discussion

When Rachel was diagnosed with hyperprolactinemia on day 13 of admission, she had been on stable doses of risperidone and fluphenazine for over 2 months. Both of these antipsychotics are potent antagonists at the D2R (Table),^3-5 hence it is not possible to know if the presenting hyperprolactinemia was due primarily to the risperidone, the fluphenazine, or synergistically to both. The persistence of the hyperprolactinemia 3 weeks following the discontinuation of the risperidone supports fluphenazine as the likely etiology of her prolonged hyperprolactinemia. In the context of the well-established association between risperidone and hyperprolactinemia, it can be difficult to escape anchoring bias, or the tendency to overemphasize an initial impression despite later evidence suggesting an alternative explanation, for a patient who presents with hyperprolactinemia on risperidone.

Oral risperidone is among the antipsychotics most strongly associated with hyperprolactinemia, with reported rates varying across studies and reaching 70% to 100% in some series.^1,6 Although prolactin elevation with risperidone is generally dose-related, clinically significant elevations may still occur even at relatively low doses.⁶ In addition, risperidone has been reported to produce marked prolactin elevations, in some cases exceeding 200 µg/L (ng/mL), whereas prolactin elevations associated with many other antipsychotics more commonly remain below 100 µg/L.^1,6,7 Furthermore, in large-scale meta-analyses, risperidone consistently has one of the most potent dose-dependent effects on PRL levels.^8,9 The association between fluphenazine and hyperprolactinemia has been much less studied in the literature than that of risperidone, but a review of basic pharmacology provides insight into why fluphenazine was likely the primary culprit in this case, at least after the discontinuation of risperidone.

Prolactin synthesis is largely mediated by the inhibition of D2Rs on lactotrope cells in the anterior pituitary. Most antipsychotics act as antagonists at these D2Rs, and the D2R binding affinity, also known as Ki (inhibitory constants), of these antagonists correlates with the likelihood of hyperprolactinemia. For pure antagonists, the stronger the binding affinity, the lower the Ki, because a lower concentration of a potent drug is required to affect the receptor it binds to. For example, clozapine has a low binding affinity to D2Rs and a high Ki (Ki = 144-431 nM), resulting in a low incidence of hyperprolactinemia. In contrast, haloperidol has a high binding affinity and a low Ki (Ki = 1.2-2.0 nM), resulting in a high incidence of hyperprolactinemia.^3-5 Fluphenazine has a higher binding affinity (lower Ki) for D2Rs than risperidone. In retrospect, for this patient, the fluphenazine, which was dosed at 25 mg compared with 6 mg of risperidone, likely outcompeted the risperidone and occupied a greater percentage of the D2Rs. Unsurprisingly, discontinuation of Rachel’s risperidone had little effect on the PRL levels as more D2Rs were occupied by the fluphenazine.

Of note, D2R binding affinity alone is not sufficient to predict the likelihood of developing hyperprolactinemia. Indeed, risperidone, despite having a lower binding affinity than several other antipsychotics, has a seemingly higher risk of clinically significant hyperprolactinemia.^8,9 The reasons for this paradox are speculative. Some suggest that it is the rate of receptor-ligand dissociation that is more instrumental in predicting hyperprolactinemia, while others hypothesize that the antipsychotic’s blood-brain barrier permeability determines how much of a drug will be shunted to the anterior pituitary.² Nondopamine pathways likely also indirectly affect prolactin secretion. Finally, as will be discussed hereafter, the full functional activity of a drug’s binding to the D2R can greatly impact PRL levels, as is the case for the 3 antagonist/partial agonists, of which aripiprazole is one. Regardless, the binding affinities of fluphenazine and risperidone provide a compelling explanation for the disease course observed in this patient.

Endocrine Society guidelines for the management of hyperprolactinemia recommend discontinuing the ostensible precipitating agent before pursuing further workup.¹⁰ This case example illustrates that each D2R-blocking agent must be considered independently before pursuing a noniatrogenic attribution of increased PRL. Subclasses of antipsychotics, those with low D2R binding affinities as well as D2R partial agonists (AKA antagonist/partial agonists), are much less likely to cause hyperprolactinemia than those with high D2R binding affinities. For these agents, physicians should consider the patient’s entire clinical presentation before deciding to substitute antipsychotics.

If substitution is indicated, aripiprazole augmentation or clozapine substitution of high-potency antipsychotics are both effective methods of normalizing PRL while maintaining antipsychotic efficacy.^5,11 Again, binding affinities provide some insight into why aripiprazole is effective at normalizing prolactin. Aripiprazole is one of the most potent antipsychotics available, with a D2R Ki of 0.34 nm, meaning that it is effective at outcompeting most other antipsychotics at the D2R.⁴ It is slightly less potent than brexpiprazole, which has a D2R Ki of 0.3 nm, and slightly more potent than cariprazine, which has a D2R Ki of 0.49. These 3 antipsychotics are classified as partial agonists due to their highly potent antagonism at D2Rs with simultaneous agonism, resulting in an intracellular functional antagonism that determines the functional activity of the D2R. Consequently, despite all 3 of these partial agonists binding to D2Rs significantly more potently than even haloperidol and risperidone, the partial agonism determines the clinical effect. As a generalization, aripiprazole antagonizes D2Rs sufficiently to provide an antipsychotic effect at 10 mg/day, but its partial agonism creates intracellular intrinsic antagonism below the level of D2R antagonism required to increase prolactin release in the tuberoinfundibular tract.¹² These 3 partial agonists have shown a similar normalizing effect on PRL,^4,8 although current published data is most convincing for aripiprazole. Two additional atypical antipsychotics, clozapine and quetiapine, also demonstrate minimal prolactin elevation, albeit for a different pharmacological property: they both bind very weakly to the D2R, consistent with their high Ki’s.

No specific recommendations exist on the substitution or discontinuation of multiple D2R antagonists in cases of antipsychotic-associated hyperprolactinemia. In most cases, it is not feasible to substitute both antipsychotics simultaneously, which might disrupt control of the patient’s psychotic symptoms. Therefore, clinicians should consider substituting antipsychotics using a stepwise approach. Case reports on risperidone-induced hyperprolactinemia have shown that prolactin typically normalizes 1 to 2 weeks after risperidone discontinuation.^13-16 Thus, it is reasonable to wait 2 weeks before rechecking prolactin levels and determining whether the second high potency antipsychotic should also be substituted. In this case example, prolactin remained elevated 3 weeks following risperidone discontinuation, necessitating substitution of Rachel’s fluphenazine as well.

If prolactin remains elevated following iatrogenic exclusion, macroprolactinemia should be considered. Macroprolactinemia is a benign phenomenon occurring in 10% to 25% of patients with hyperprolactinemia.¹⁷ It occurs when prolactin molecules complex with IgG immunoglobulin, forming a bulky structure that artificially increases measured serum prolactin. Macroprolactinemia has been demonstrated to be biologically inert.¹⁸ In line with these findings, patients with macroprolactinemia are usually clinically asymptomatic and do not experience symptomatic progression longitudinally.¹⁹ For this reason, there is no indication for treatment of asymptomatic macroprolactinemia, and the purpose of macroprolactinemia screening is primarily to prevent unnecessary additional diagnostic workup, such as neuroimaging. In the present case example, it would have been reasonable to pursue macroprolactin screening if Rachel’s prolactin had remained elevated after fluphenazine substitution. Importantly, macroprolactinemia can coexist with another precipitating factor, such as a prolactinoma.²⁰ Therefore, additional workup, including consultation with endocrinology, can be considered in symptomatic patients whose symptoms might be driven by true hyperprolactinemia.

Concluding Thoughts

This case highlights antipsychotic-associated hyperprolactinemia during concurrent treatment with risperidone and fluphenazine. Although risperidone was initially suspected to be the culprit, prolactin levels remained elevated after its discontinuation and normalized only after fluphenazine was also withdrawn, underscoring the difficulty of establishing causality during dual antipsychotic therapy. When hyperprolactinemia develops in this setting, a gradual transition to prolactin-sparing agents such as aripiprazole or clozapine may help normalize prolactin levels while maintaining psychiatric stability.

Dr Wobig is a resident in the combined internal medicine/psychiatry residency at UC Davis Health in Sacramento, CA.

Dr DeMartini is the training director of combined internal medicine/psychiatry residency and an associate professor at UC Davis Health in Sacramento, CA.

Dr Bourgeois is vice chair of Hospital Psychiatry Services and a professor at UC Davis Health in Sacramento, CA.

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