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Dialogues Clin Neurosci. 2002 Dec;4(4):449-62.

Development of neuroleptic agents: pharmacogenetics and current safety issues of regulatory concern.

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  • 1Senior Medical Officer, Medicines Control Agency, London, UK.


The development of safe and effective new drug treatments for schizophrenia poses a challenging task. This class of drugs is known to be associated with a wide range of serious and troublesome safety problems that include neurological, cardiac, endocrine, and metabolic side effects. Many of these drugs have a narrow therapeutic index and generate metabolites that often have their own unique pharmacological profile different from the parent compound. These features make it imperative that the optimal dose schedules for neuroleptic drugs are carefully characterized. Many of these drugs are metabolized by cytochrome P450 enzymes, which show genetic polymorphism and a bi modal distribution within the population, A significant subset of the population cannot eliminate these drugs as effectively as the majority. This brings an added dimension of complexity in characterizing the dose and individualizing therapy. Many neuroleptic agents are proarrhythmic with an adverse effect on cardiac repolarization. They are prone to prolonging the QT interval and inducing torsade de pointes. Given the potentially fatal outcome of this ventricular tachyarrhythmia, drug development programs need to ensure that the proarrhythmic potential of any new neuroleptic agent is thoroughly explored and its proarrhythmic risk characterized. The clinical use of many of these drugs is further troubled by their high potential for drug-drug interactions. These too need to be adequately investigated during development The approval and the labeling of a new neuroleptic agent require a careful regulatory assessment of its risk/benefit ratio in comparison with the available alternatives. Their safe and effective use in routine clinical practice depends on careful attention to prescribing information, especially the contraindications, precautions, and patient-monitoring requirements.


CYP2D6; QT interval; cardiotoxicity; dose schedule; drug interactions; pharmacogenetics; polypharmacy; prescribing label; prescribing patterns; torsade de pointes

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