Improved P50 Auditory Gating With Ondansetron in Medicated Schizophrenia Patients

Adler, Lawrence E.; Cawthra, Ellen; Donovan, Kara A.; Harris, Josette G.; Nagamoto, Herbert T.; Olincy, Ann; Waldo, Merilyne

doi:10.1176/appi.ajp.162.2.386

Cited by 77 publications

(61 citation statements)

References 8 publications

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“…However, the latter findings should be interpreted with caution, as ayahuasca has multiple pharmacological actions in addition to its 5-HT 2A/2C receptor agonistic properties, and hence the P50 suppression reduction could not be attributed specifically to serotonergic effects. Two other studies in patients with schizophrenia reported increases in P50 suppression with the 5-HT 3 antagonists odansetron and tropisetron (Adler et al, 2005;Koike et al, 2005), providing some evidence for serotonergic regulation of P50 suppression. However, the latter studies were conducted in patients with schizophrenia who were on atypical antipsychotics and these drugs have multiple pharmacological effects, making it difficult to elucidate the exact mechanisms responsible for the P50 increases.…”

Section: Serotonin Depletionmentioning

confidence: 84%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Neuropsychopharmacol

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Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/ phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

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Section: Serotonin Depletionmentioning

confidence: 84%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Neuropsychopharmacol

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“…This 3-pronged strategy can be utilized to successfully complete endophenotyping projects with appropriate rigor. Still, the normalizing role of atypical antipsychotic medications on endophenotypes such as P50 suppression [88][89][90][91] and PPI 92 combined with the difficulty of ascertaining nonmedicated but ill patients is a major obstacle for the endophenotype strategy and all sorts of other schizophrenia research. Because, it is becoming increasingly clear that many neurocognitive and neurophysiological endophenotypes are at least partially normalized by second-generation antipsychotic medications, there currently exists a state of affairs that will offer challenges to endophenotype-based (and other) gene finding approaches in schizophrenia research.…”

Section: Medication Effectsmentioning

confidence: 99%

Deconstructing Schizophrenia: An Overview of the Use of Endophenotypes in Order to Understand a Complex Disorder

Braff¹,

Freedman²,

Schork³

et al. 2008

FOC

116

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The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brainbased deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, traitrelated deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of secondgeneration antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

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“…Ondansetron, an antiemetic, increases acetylcholine levels via 5HT 3 receptors antagonism. Ondansetron enhances P50 auditory suppression in persons with schizophrenia two hours after acute dosing [129]. Tropisetron, also a 5HT 3 antagonist marketed outside the United States as an antinausea drug, also has efficacy as an α7 nicotinic cholinergic receptor agonist [130,131].…”

Section: Other Potential Nicotinic Targetsmentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

Self Cite

125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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Improved P50 Auditory Gating With Ondansetron in Medicated Schizophrenia Patients

Abstract: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.

Cited by 77 publications

References 8 publications

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Deconstructing Schizophrenia: An Overview of the Use of Endophenotypes in Order to Understand a Complex Disorder

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

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