Tropisetron improves deficits in auditory P50 suppression in schizophrenia.
Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.
Koike
Kaori
K
Department of Psychiatry, Chiba University Graduate School of Medicine, Japan.
Hashimoto
Kenji
K
Takai
Nobuyuki
N
Shimizu
Eiji
E
Komatsu
Naoya
N
Watanabe
Hiroyuki
H
Nakazato
Michiko
M
Okamura
Naoe
N
Stevens
Karen E
KE
Freedman
Robert
R
Iyo
Masaomi
M
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects*; D005071:Evoked Potentials / Q000187:drug effects*; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D005260:Female; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009433:Neural Inhibition / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects; D012016:Reference Values; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D000077526:Tropisetron; D064569:alpha7 Nicotinic Acetylcholine Receptor
D014150:Antipsychotic Agents; C579167:Chrna7 protein, human; D007211:Indoles; D011978:Receptors, Nicotinic; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077526:Tropisetron