Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines

Abstract

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20 – 50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines – chlorpromazine, fluphenazine and haloperidol – belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualise therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library – one that enlists the ‘essential biomarkers’ required for optimal pharmacotherapy – may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.

Keywords::

• antipsychotics
• bioethics
• biomarker
• CYP1A2
• CYP2D6
• DRD3
• essential medicines policy
• HTR2A
• pharmacogenetics
• tardive dyskinesia
• World Health Organization

Acknowledgments

Supported in part by the VISN 22 Mental Illness Research, Education, and Clinical Center (MIRECC), the Southern California Institute for Research and Education (SCIRE), the UCSD Psychopharmacology Research Initiatives Center of Excellence (PRICE) and a VA Career Development Award (S Mee). JE Graham holds the CIHR Canada Research Chair in Bioethics at Dalhousie University and is supported in part by grants from the Canada Foundation for Innovation and the Nova Scotia Research and Innovation Trust. The authors thank RH Friis and K Papageorgiou for their helpful discussions.