TY - JOUR
T1 - Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day
T2 - Comparison with reference dose risperidone, 6mg/day
AU - Meltzer, Herbert Y.
AU - Elkis, Helio
AU - Vanover, Kimberly
AU - Weiner, David M.
AU - van Kammen, Daniel P.
AU - Peters, Perry
AU - Hacksell, Uli
N1 - Funding Information:
H.Y. Meltzer is a stockholder of ACADIA. He has received grant support in the last 3 years from BioLIne Rx, Cephalon, Dainippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, and Sunovion. He is, or has been, a consultant to ACADIA, Alkemes, Astellas, Boehringer Mannheim, Bristol Myers Squibb, Cypress, Janssen, Lundbeck, Ovation, Merck, Novartis, Pfizer, Teva, and Valeant (BioVail). The research effort of HYM is supported, in part, by donations from the Hintz, Peterson and Weisman families.
PY - 2012/11
Y1 - 2012/11
N2 - Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)2A than dopamine (DA) D2 receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT2A inverse agonist, to enhance 5-HT2A receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT2A receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT2A receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.
AB - Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)2A than dopamine (DA) D2 receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT2A inverse agonist, to enhance 5-HT2A receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT2A receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT2A receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.
KW - 5-HT
KW - Antipsychotic
KW - Extrapyramidal
KW - Haloperidol
KW - Pimavanserin
KW - Risperidone
KW - Schizophrenia
KW - Weight gain
UR - http://www.scopus.com/inward/record.url?scp=84866935453&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866935453&partnerID=8YFLogxK
U2 - 10.1016/j.schres.2012.07.029
DO - 10.1016/j.schres.2012.07.029
M3 - Article
C2 - 22954754
AN - SCOPUS:84866935453
VL - 141
SP - 144
EP - 152
JO - Schizophrenia Research
JF - Schizophrenia Research
SN - 0920-9964
IS - 2-3
ER -