Vol 4 n° 4 - Drug Development
Past issues Contributors How to publish Contributions and comments Home
 
chizophrenia is a mental disease that affects approx- imately 1% of the population with distressing long-term consequences for the patient and society. There is con- sistent evidence that the principal etiology of schizo- phrenia involves predisposing genetic factors. However, the search for the susceptibility genes with a view to any form of gene therapy has proved elusive. Furthermore, it is not clear whether the genes of familial schizophrenia are also involved in sporadic cases, which represent the overwhelming majority of patients with schizophrenia. For sporadic cases, genetic association studies comparing the distribution of allelic frequencies of candidate genes in patients with schizophrenia and controls have been performed, but the outcome of such C l i n i c a l   r e s e a r c h 4 4 9 Development of neuroleptic agents: pharmacogenetics and current safety issues of regulatory concern Rashmi Shah, MD, FRCP, FFPM Keywords: pharmacogenetics; CYP2D6; dose schedule; cardiotoxicity; QT inter- val; torsade de pointes; drug interactions; polypharmacy; prescribing label; pres- cribing patterns Author   affiliations:   Senior   Medical   Officer,   Medicines   Control   Agency, London, UK Address for correspondence: Rashmi Shah, MD, FRCP, FFPM, Senior Medical Officer,  Medicines  Control  Agency,  Market  Towers,  1  Nine  Elms  Lane, London, SW8 5NQ, UK (e-mail: rashmi.shah@mca.gsi.gov.uk) S 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, car- diac, endocrine, and metabolic side effects. Many of these drugs have a narrow therapeutic index and generate metabo- lites 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 bimodal distribution within the pop- ulation. 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 proar- rhythmic with an adverse effect on cardiac repolarization. They are prone to prolonging the QT interval and inducing tor- sade 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 proar- rhythmic 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 alter- natives. Their safe and effective use in routine clinical practice depends on careful attention to prescribing information, especially the contraindications, precautions, and patient-monitoring requirements. Dialogues Clin Neurosci. 2002;4:449-462.