Improved P50 Auditory Gating With Ondansetron in Medicated Schizophrenia Patients
Abstract
OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the α-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.
Most schizophrenia patients have a deficit in auditory sensory gating (1–3). This deficit in P50 auditory gating, which appears to be mediated by the α-7 nicotinic receptor, is not improved by conventional antipsychotic treatment (2). Nicotine briefly improves P50 auditory gating in schizophrenia patients, probably because the α-7 nicotinic receptor desensitizes rapidly (4). Another way to enhance cholinergic transmission in this pathway is to use ondansetron, an antagonist of the serotonin type 3 (5-HT3) receptor. The 5-HT3 receptor tonically inhibits the release of acetylcholine (5). In rats, 5-HT3 antagonists cause release of acetylcholine, which acts at the α-7 nicotinic receptor and improves P50 auditory gating in the hippocampus (6). The 5-HT3 receptors also inhibit GABAB inhibitory interneurons. Therefore, 5-HT3 blockade would be expected to potentiate the action of GABAB interneurons.
Ondansetron also facilitates release of a variety of neurotransmitters—not only acetylcholine but also norepinephrine and dopamine. Excessive catecholaminergic release exacerbates psychoses and disrupts P50 sensory gating (3). Ancillary catecholaminergic blockade may be required to permit ondansetron’s positive effects on acetylcholine release to be therapeutically useful. Its effects on P50 sensory gating have not been studied previously. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential.
Method
Eight stable schizophrenia patients (four men and four women, mean age=41.5 years, SD=5.9) were studied on two occasions, 1 week apart. Six were taking conventional antipsychotic medications; one was also taking a low dose of olanzapine, and one subject was taking only olanzapine. All had impaired baseline P50 auditory gating. All gave informed consent before participation in the study.
Subjects were given a single dose of ondansetron (16 mg) or placebo in a double-blind, placebo-controlled, randomized and balanced crossover design. Serial measurements of the P50 evoked potential were done at baseline and 1 hour, 2 hours, and 3 hours after receipt of placebo or ondansetron. Subjects were assessed with the Positive and Negative Syndrome Scale (7) and the Brief Psychiatric Rating Scale (BPRS) (8).
Details of the paired-click recording paradigm have been described previously (9). The P50 potential was identified and measured by using a previously described computer algorithm (9). The amplitude of the P50 test wave was divided by the amplitude of the P50 conditioning wave, expressed as a percentage: the P50 ratio. Subjects were given no special instructions concerning the clicks they were hearing.
Both parametric and nonparametric methods were used to evaluate the data. An a priori comparison was made for the P50 ratio at 2 hours posttreatment, which corresponds to peak plasma ondansetron levels for oral ondansetron in most subjects (per the United States Pharmacopeia Drug Information [USP DI], 2001) by Student’s t test (two-tailed). Other t tests were Bonferroni corrected.
Results
Ondansetron significantly enhanced P50 auditory gating compared with placebo (mixed effects, type III, analysis of variance [ANOVA]: F=14.54, df=1, 55, p=0.0003) (Figure 1). A planned separate variance Student’s t test at 2 hours was significant (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3% [t=–2.43, df=10.7, p<0.04]). The effect of ondansetron tended to persist beyond the 2-hour time point to 3 hours (ondansetron: mean=51.9%, SD=43.1%; placebo: mean=87.3%, SD=14.8% [separate variance t test: t=–2.2, df=8.6, p<0.06]).
Test amplitude decreased with ondansetron treatment (mixed effects ANOVA: F=5.97, df=1, 56, p=0.02). There was no effect on either conditioning amplitude or latency, consistent with prior normalization with antipsychotic treatment (2).
Although all subjects but one had a definite decrease in P50 ratio with ondansetron (Figure 1), they did not all experience the greatest effect at 2 hours posttreatment. This is consistent with a range of peak plasma concentration and clinical effect of 1–3 hours posttreatment (USP DI, 2001). The single nonresponder was the individual treated solely with olanzapine.
There were no significant effects on BPRS total score, positive or negative symptoms, or anxiety.
Discussion
P50 auditory gating was significantly improved by ondansetron, as evidenced by the decreased P50 ratios of the schizophrenia patients. These results did not occur with placebo. The decrease (improvement) in P50 ratio and significant decrease of the test amplitude, without associated changes in the conditioning amplitude, parallel results seen in longer-term clozapine studies (10) and more briefly in nicotine studies in schizophrenia patients (4).
Sirota et al. (11) found that combining ondansetron with a conventional antipsychotic reduced psychotic symptoms. The Sirota et al. study and ours may both have demonstrated positive effects with ondansetron because the patients were not required to be antipsychotic free, and adequate associated catecholaminergic blockade was therefore maintained. All but one of the patients in this study were taking typical antipsychotics. The subject who was only taking olanzapine was also the only subject who did not demonstrate transient improvement on sensory gating with ondansetron.
The results of this experiment would seem to support a greater role for the usefulness of 5-HT3 receptor blockade combined with catecholaminergic blockade in restoring P50 auditory gating. However, this experiment, by limiting the study to a single 5-HT3 receptor antagonist, does not lend itself to broad generalizations about other possible effective combinations of receptor antagonism.
A similar limitation is that this study only followed a small group of stable outpatients. The results cannot be applied to other populations without further study. Furthermore, the possibility of a dose response has not been addressed. However, to our knowledge, ours is the only study to date to use a double-blind, placebo-controlled design and demonstrate that selective 5-HT3 blockade added to an antipsychotic regimen significantly enhanced P50 auditory gating in schizophrenia patients.
Received May 1, 2003; revisions received July 10, 2003, and March 17, 2004; accepted May 25, 2004. From the Denver VA Medical Center; the Mental Illness Research Education and Clinical Center, VA Rocky Mountain Network (VISN 19), Glendale, Colo.; and the University of Colorado Health Sciences Center, Denver. Address correspondence and reprint requests to Dr. Adler, Chief, Mental Health Service, Denver VA Medical Center, 1055 Clermont St., Denver, CO 80220; [email protected] (e-mail). Supported by the Department of Veterans Affairs, NIMH grants 5R01 MH-50787 and 2K02 MH-01121, and a previous grant from the National Alliance for Research in Schizophrenia and Affective Disorders.
Figure 1. Change in P50 Sensory Gating Following Receipt of Ondansetron Versus Placebo in Medicated Schizophrenia Patientsa
aThe largest improvement in P50 gating from baseline is shown for each subject. Seven of the subjects were clinically stable on typical antipsychotic medication regimens. Subject 5 was also being treated with olanzapine. Subject 6, the only subject who did not show improvement in sensory gating following ondansetron, was being treated only with olanzapine.
1. Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R: Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 1982; 17:639–654Medline, Google Scholar
2. Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD: Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry 1983; 18:537–551Medline, Google Scholar
3. Adler LE, Gerhardt GA, Franks R, Baker N, Nagamoto H, Drebing C, Freedman R: Sensory physiology and catecholamines in schizophrenia and mania. Psychiatry Res 1990; 31:297–309Crossref, Medline, Google Scholar
4. Adler LE, Hoffer LD, Wiser A, Freedman R: Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993; 150:1856–1861Link, Google Scholar
5. Ramirez MJ, Cenarruzabeitia E, Lasheras B, Del Rio J: Involvement of GABA systems in acetylcholine release induced by 5HT3 receptor blockade in slices from rat entorhinal cortex. Brain Res 1996; 712:274–280Crossref, Medline, Google Scholar
6. Stevens K, Wear K: Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 1997; 57:869–874Crossref, Medline, Google Scholar
7. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276Crossref, Medline, Google Scholar
8. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertaining and scaling. Psychopharmacol Bull 1988; 24:97–99Google Scholar
9. Adler LE, Olincy A, Cawthra EM, McRae KA, Harris JG, Nagamoto HT, Waldo MC, Hall M-H, Bowles A, Woodward L, Ross RG, Freedman R: Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients. Am J Psychiatry 2004; 161:1822–1828Link, Google Scholar
10. Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R: Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry 1996; 40:181–188Crossref, Medline, Google Scholar
11. Sirota P, Mosheva T, Shabtai H, Giladi N, Korczyn AD: Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. Am J Psychiatry 2000; 157:287–289Link, Google Scholar
