Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia

Becker, Jéfferson; Gomes, Irênio; Ghisolfi, Eduardo S.; Schuch, Alice; Ramos, Fernanda L. P.; Ehlers, João Arthur; Nora, Daniel Bocchese; Lara, Diogo R.; Costa, Jaderson Costa da

doi:10.1016/j.clinph.2003.09.018

Cited by 50 publications

(39 citation statements)

References 34 publications

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“…Normal control participants normally exhibit suppression in the range of 50-70% , while it has been demonstrated that patients with schizophrenia display significantly lower P50 suppression (Adler et al, 1982;Boutros et al, 1991;Light et al, 2000;Ward et al, 1996;Yee and White, 2001;Braff et al, 2007), which is interpreted as reflecting a deficit in 'sensory gating' (Adler et al, 1982). Analogous to the PPI findings, there is also some evidence that P50 suppression deficits in schizophrenia may be normalized with the use of atypical antipsychotic drugs (Light et al, 2000;Nagamoto et al, 1996Nagamoto et al, , 1999Adler et al, 2004;Becker et al, 2004).…”

Section: Introductionmentioning

confidence: 80%

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: Introductionmentioning

confidence: 80%

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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“…Thus, dopamine D 2 receptor antagonism alone seems insufficient to normalize P50 gating in schizophrenia patients, in contrast to effects seen in healthy subjects with low P50 suppression levels. Indeed, several earlier studies have shown that schizophrenia patients treated with typical antipsychotic medication exhibited significantly less P50 suppression than did patients receiving atypical antipsychotics Becker et al, 2004;Adler et al, 2004). Specifically, patients receiving clozapine (Tandon and Jibson, 2003;Adler et al, 2004) or olanzapine (Berg and Balaban, 1999) had superior suppression levels relative to those treated with typical antipsychotic medication.…”

Section: P50 Suppressionmentioning

confidence: 98%

“…Schizophrenia patients treated with atypical antipsychotics had superior P50 suppression to those treated with conventional antipsychotic medication Becker et al, 2004;Adler et al, 2004). Especially patients receiving the atypical antipsychotic clozapine exhibited P50 suppression in the range of normal controls (Becker et al, 2004;Adler et al, 2004).…”

Section: Introductionmentioning

confidence: 95%

“…As such, these gating measures provide a unique opportunity to characterize the neurochemical basis of information processing deficits and the impact of antipsychotic treatments . Indeed, it has recently been proposed that atypical antipsychotics might be superior over typical antipsychotics in normalizing PPI and P50 suppression deficits in schizophrenia patients Adler et al, 2004;Becker et al, 2004;Light et al, 2000). Nevertheless, a number of studies showed that PPI and P50 suppression are not associated in either healthy volunteers (Schwarzkopf et al, 1993;Oranje et al, 2006;Brenner et al, 2004;Light and Braff, 2001) or schizophrenia patients (Braff et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Csomor

Stadler

Feldon

et al. 2007

Neuropsychopharmacol

100

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Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D 2 -like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebocontrolled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D 2 -like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.

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“…People with schizophrenia treated with clozapine exhibit normalization of their P50 ratio coincident with improvement in their clinical symptoms [33]. Clozapine, which releases acetylcholine in the hippocampus [34], may thereby indirectly act on the nicotinic cholinergic receptors to normalize the P50 ratio, as people with schizophrenia also decrease the amount of cigarettes they smoke while taking this medication [35,36]. Clozapine also has the property of 5HT3 antagonism, which activates nicotinic cholinergic receptors.…”

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confidence: 99%

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

Olincy

Stevens

2007

Biochemical Pharmacology

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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Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia

Cited by 50 publications

References 34 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

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

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

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