COMPLICATIONS OF AN ABRUPT SWITCH FROM A FULL ANTAGONIST TO A PARTIAL D2 AGONIST

Abrupt switching between antipsychotic medications remains a common yet highrisk practice among mental health providers. While partial agonists at dopamine type 2 (D2) receptors such as aripiprazole offer valuable options, particularly in a long-acting injectable (LAI) form to support adherence, they require careful transition protocols to avoid dopaminergic instability. When switching from a full D2 receptor antagonist to a partial agonist, dopaminergic instability may occur due to differences in binding affinity and adaptive D2 receptor upregulation. These dynamics can precipitate rebound psychosis, withdrawal symptoms, and clinical deterioration if proper overlap protocols are not followed. This presentation highlights a clinically significant case demonstrating the consequences of an abrupt switch from a full D2 antagonist to a partial agonist LAI, and to advance safer switching practices through improved understanding of receptor pharmacodynamics. Case presentation: We describe a 27-year-old Hispanic female with bipolar I disorder, previously stable on oral risperidone 2 mg twice daily. Her risperidone was abruptly discontinued, and she was transitioned directly to aripiprazole 400 mg intramuscular LAI without oral supplementation. Within several days, she experienced worsening command auditory hallucinations and suicidal ideation, prompting emergency hospitalization. Toxicology screening was negative. She also reported brief transient vision loss that resolved spontaneously. Medical and neurological work-up were unremarkable. She was restarted on oral risperidone with clinical stabilization prior to transfer to outpatient transfer.

Discussion

LAI antipsychotics reduce relapse risk and improve medication adherence, but their safe use requires an appreciation of pharmacokinetics and receptor interactions. In this patient, the history of long-term exposure to a full D2 antagonist likely led to compensatory upregulation and increased sensitivity of dopamine receptors. When risperidone was abruptly discontinued, these now sensitized receptors were suddenly exposed to endogenous dopamine, resulting in the abrupt worsening of command auditory hallucinations and suicidal ideation. An additional challenge in this transition arises from the difference in receptorbinding affinity. Aripiprazole binds to D2 receptors with almost a tenfold higher affinity than risperidone, and when introduced, it can competitively displace the residual risperidone that was present on the receptor sites. In this particular case report, because aripiprazole LAI requires time to reach therapeutic concentrations, its early displacement of risperidone was likely minimal, making the abrupt cessation of risperidone the primary driver of the patient’s withdrawal and rebound symptoms. The exhibited discontinuation syndrome may have been preventable with oral supplementation–had the transition involved any agent other than a partial agonist, as oral aripiprazole would have accelerated displacement even further. This case therefore illustrates how abrupt switching from a full D2 antagonist to a partial agonist can increase risk of dopaminergic dysregulation and instability.

Conclusion

Understanding receptor dynamics and implementing appropriate cross-titration strategies are essential when switching from full D2 antagonists to partial agonists, particularly with LAI initiation. This case illustrates a preventable cause of clinical deterioration and reinforces the need for evidence-based protocols that account for receptor pharmacology, pharmacokinetics, and adherence history to ensure safe antipsychotic transitions in practice.