It has been 12 years since the first atypical neuroleptic was approved for use in the United States. Since that time, 4 additional drugs have entered the marketplace. Several more are in the late stage of clinical development and should be submitted for approval in the near future. All of these compounds have in common qualities that differentiate them from first generation neuroleptics. They all share affinity for the dopamine (d2) receptor, but they bind with much lower affinity. They are all less selective in that they also bind with high affinity to serotonin receptors. All of these new compounds were developed in schizophrenic patients but because of their effects on improving positive symptoms were approved for the broader claim of treatment of the "manifestations of psychotic disorders." New rating scales such as the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS) were employed to further elucidate the effects on the negative symptoms, and product labeling includes mention of these effects in the clinical trial section. Although it has been debated whether these new drugs offer greater efficacy, it is well accepted that this class has significantly fewer extrapyramidal adverse effects than typical neuroleptics. Because of this greater safety margin, atypicals are being used in much broader patient populations today, resulting in a $5 billion market.
This presentation will highlight the clinical development of these compounds. Strengths and weaknesses of the individual study designs will be reviewed, as well as hurdles of using new rating scales in drug trials. Discussion will also include attempts to differentiate these drugs on the basis of both efficacy and safety. Clinical results in other areas, including neurological uses, will be presented. Finally, preclinical research is already exploring the next generation of antipsychotic medications. Some thoughts on how these may be developed in the clinic in order to differentiate them from our current medications will be outlined.
Richard C. Meibach. Development of Atypical Neuroleptics. Arch Neurol. 2002;59(2):326–327. doi: