Do high or low doses of anxiolytics and hypnotics affect mismatch negativity in schizophrenic subjects? An EEG and MEG study
Introduction
Since the early clinical description by Bleuler (1911), it has been recognized that attentional deficits are one of the primary dysfunctions in schizophrenic psychopathology. The advent of event-related brain potential (ERP) studies has enabled an electrophysiological assessment of attentional dysfunction in schizophrenia. Earlier investigations focused on the evaluation of conscious, controlled aspects of attention in schizophrenia, and thus abnormalities of P300 (Roth et al., 1981, Kutcher et al., 1987, McCarley et al., 1989), N2b (Brecher et al., 1987), and the processing negativity (Michie et al., 1990) component of ERPs have been repeatedly reported. However, in 1991 Shelley et al. (1991) reported on impaired mismatch negativity (MMN) in response to a duration change of tones, an ERP index of auditory preattentive processing (Näätänen et al., 1978) in schizophrenia. Subsequent studies have replicated a reduction in MMN amplitude in response to a duration (Catts et al., 1995, Kasai et al., 1999c, Javitt et al., 2000b, Michie et al., 2000, Todd et al., 2000) and frequency (Javitt et al., 1993, Javitt et al., 1995, Javitt et al., 1998, Javitt et al., 2000a, Javitt et al., 2000b, Shutara et al., 1996, Alain et al., 1998, Hirayasu et al., 1998, Umbricht et al., 1998, Shelley et al., 1999) changes of tones in schizophrenia, although others did not find a significant reduction in the MMN in response to a frequency change of tones (O'Donnell et al., 1994, Kathmann et al., 1995, Oades et al., 1996, Kirino and Inoue, 1999). Recently, magnetoencephalography (MEG) (Kreitschmann-Andermahr et al., 1999) and functional magnetic resonance imaging (Wible et al., 2001) investigations have also demonstrated abnormalities of auditory mismatch detection in response to frequency changes of tones in schizophrenia.
Regarding the effects of psychotropic drugs on the MMN in schizophrenia, several reports have described no significant correlation between reported MMN amplitudes and the dose of neuroleptics administered to patients with chronic schizophrenia (Shelley et al., 1991, Shutara et al., 1996, Kasai et al., 1999c, Michie et al., 2000, Todd et al., 2000). Catts et al. (1995) and Javitt et al. (1995) independently found no significant difference in MMN amplitude between medicated and neuroleptic-free patients. Umbricht et al., 1998, Umbricht et al., 1999 showed that MMN reduction was not ameliorated by either typical (haloperidol) or atypical (clozapine or risperidone) medication. These reports provide a consensus that neuroleptics have no effect on MMN amplitude in schizophrenia. On the other hand, there is evidence from primate and human studies indicating that the interplay between excitatory glutamatergic and inhibitory GABAergic neurons regulates MMN generation (Javitt et al., 1996, Umbricht et al., 2000). Supporting this hypothesis, Nakagome et al. (1998) reported MMN amplitude reduction in the morning following administration of triazolam in normal subjects. Furthermore, Smolnik et al. (1998) observed a tendency towards an increase in MMN amplitude after the administration of the benzodiazepine antagonist, flumazenil, in normal subjects although the effect was not statistically significant. Considering that a substantial proportion of patients with schizophrenia receive anxiolytics and hypnotics to reduce the comorbid symptoms of anxiety and sleep disturbances, respectively (Carpenter et al., 1999, Hardy et al., 1999, Ito et al., 1999, Voirol et al., 1999), and that these drugs have affinity to GABAA receptors (Schroder et al., 1997, Fujita et al., 1999), we need to assess the possibility that anxiolytics/hypnotics might have some effect on MMN amplitude in schizophrenic patients. However, to our knowledge, only one preliminary study from our group (Murakami et al., 2001) has evaluated the possible effects of anxiolytics/hypnotics on the MMN in schizophrenic patients. Using a 16-channel montage, Murakami et al. compared the MMN and N2b in response to pure-tone stimuli between two subgroups of schizophrenic patients, one comprised of patients who did not receive benzodiazepines (benzodiazepine-off group; n=7) and the other of those who were administered benzodiazepines during daytime (benzodiazepine-on group; n=7). They found no significant differences in MMN and N2b amplitudes between the two subgroups, whereas the N2b latency was significantly prolonged in the benzodiazepine-on group relative to the benzodiazepine-off group. These results suggested that benzodiazepine had no marked effects on the MMN amplitude/latency in schizophrenia. The present study is an extension of our preliminary study; here, we determine whether the dose of anxiolytics/hypnotics affects MMN (or its magnetic counterpart, MMNm) amplitude (or MMNm power)/latency/topography (or laterality) in response to pure-tone and speech sounds in two new groups of patients with schizophrenia, using ERP and MEG recordings, respectively.
Section snippets
Subjects
Twenty-three right-handed (determined using the Edinburgh Inventory (Oldfield, 1971); we used a laterality index ≥0.8 as the cutoff for right-handedness), medicated outpatients with schizophrenia participated in this part of the study. Sixteen were male and 7 were female. This study is a post hoc analysis of our previous study comparing MMN between these 23 schizophrenic patients and 28 healthy subjects (Kasai et al., 2001a). Diagnosis was determined according to DSM-IV criteria (American
Results of ERP recording
The repeated measures ANOVA of MMN amplitude showed no significant main effects of group or interactions between group and any other factors: the main effect of group, F(1,21)=0.953, not significant (n.s.); group-by-condition interaction, F(2,42)=1.17, n.s.; group-by-hemisphere interaction, F(1,21)=0.042, n.s.; group-by-channel interaction, F(21,441)=0.577, n.s.; group-by-condition-by-hemisphere interaction, F(2,42)=0.342, n.s.; group-by-condition-by-channel interaction, F(42,882)=1.10, n.s.;
Discussion
The results of this study can be summarized as follows. (1) There were no differences in MMN amplitude (MMNm power), latency, effect of type of stimuli (nonverbal, verbal), or topography (laterality) between schizophrenic patients who received high and low doses of anxiolytics/hypnotics. (2) There were no significant correlations between MMN amplitude (MMNm power) or latency and dose of anxiolytics/hypnotics. Our results support our preliminary finding that there is no effect of benzodiazepines
Acknowledgements
This study was supported in part by a grant-in-aid for Scientific Research (No. 11680836) from the Japan Society for the Promotion of Science and a grant-in-aid for Scientific Research (C12670928) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by grants from the Welfide Medicinal Research Foundation, Japan and from the Uehara Memorial Foundation, Japan. The authors also gratefully acknowledge the technical support of Dr. S.F. Huang, and the administrative
References (65)
- et al.
Processing of auditory stimuli during visual attention in patients with schizophrenia
Biol Psychiatry
(1998) - et al.
Processing of novel sounds and frequency changes in the human auditory cortex: magnetoencephalographic recordings
Psychophysiology
(1998) DSM-IV: Diagnostic and statistical manual of mental disorders
(1994)- et al.
Differential changes in frontal and sub-temporal components of mismatch negativity
Int J Psychophysiol
(1999) Dementia praecox or the group of schizophrenias
(1911)- et al.
The N2 component of the event-related potential in schizophrenic patients
Electroenceph clin Neurophysiol
(1987) - et al.
Diazepam treatment of early signs of exacerbation in schizophrenia
Am J Psychiatry
(1999) - et al.
Brain potential evidence for an auditory sensory memory deficit in schizophrenia
Am J Psychiatry
(1995) - et al.
Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans
Eur J Pharmacol
(1999) - et al.
Brain generators implicated in the processing of auditory stimulus deviance: a topographic event-related potential study
Psychophysiology
(1990)
Magnetoencephalography: theory, instrumentation, and applications to noninvasive studies of the working human brain
Rev Mod Phys
Anxiolytic and hypnotic use in 376 psychiatric inpatients. GERMED Neuropsychotropics Group
Eur Psychiatry
Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage
Am J Psychiatry
Dose equivalence of neuroleptics
Dose equivalence of neuroleptics
Dose equivalence of anxiolytic drugs, sedatives and hypnotics
A prospective survey on drug choice for prescriptions for admitted patients with schizophrenia
Psychiatry Clin Neurosci
Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study
Biol Psychiatry
Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia
Arch Gen Psychiatry
Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia
Proc Natl Acad Sci USA
Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval
Electroenceph clin Neurophysiol
Associated deficits in mismatch negativity generation and tone matching in schizophrenia
Clin Neurophysiol
Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern
Arch Gen Psychiatry
Multiple generators in the auditory automatic discrimination process in humans
Neuroreport
Electrophysiological evidence for sequential activation of multiple brain regions during the auditory selective attention process in humans
Neuroreport
Mismatch negativity and N2b attenuation as an indicator for dysfunction of the preattentive and controlled processing for deviance detection in schizophrenia: a topographic event-related potential study
Schizophr Res
Impaired cortical network for preattentive change detection of speech sounds in schizophrenia
Am J Psychiatry
Brain lateralization for mismatch response to across- and within-category change of vowels
Neuroreport
Neuromagnetic correlates of impaired automatic categorical perception of speech sounds in schizophrenia
Schizophr Res
Delayed peak latency of the mismatch negativity in schizophrenics and alcoholics
Biol Psychiatry
The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia
Schizophr Bull
Relationship of mismatch negativity to background EEG and morphological findings in schizophrenia
Neuropsychobiology
Cited by (55)
Mismatch negativity in bipolar disorder: A neurophysiological biomarker of intermediate effect?
2018, Schizophrenia ResearchCitation Excerpt :In terms of serotonergic modulation, while there is purportedly no change in MMN after 5HT depletion (Leung et al., 2010) or psilocybin (Umbricht et al., 2002), however, the administration of high-dose escitalopram (Wienberg et al., 2010) and tryptophan depletion (Kahkonen et al., 2005) has been shown to increase MMN amplitudes. Studies also have found that MMN does not change with the mood stabilizers, lamotrigine (Vayisoglu et al., 2013) and lithium (Jahshan et al., 2012), nor with anxiolytics and hypnotics (Kasai et al., 2002), benzodiazepines (Murakami et al., 2002), and methylphenidate (Korostenskaja et al., 2008). However, as these findings have not been reproduced, they should be treated with caution.
Mismatch negativity (MMN) deficiency: A break-through biomarker in predicting psychosis onset
2015, International Journal of PsychophysiologyRisky alcohol use predicts temporal mismatch negativity impairments in young people with bipolar disorder
2014, Biological PsychologyCitation Excerpt :Jahshan et al. (2012) has evaluated lithium in BD and found no effect on MMN. Previous studies have found no effect of benzodiazepines on MMN in schizophrenia (Kasai, Yamada, et al., 2002; Murakami et al., 2002), but this has not been investigated in BD. Antidepressants have been shown to have inconsistent effects, with research suggesting a broad range of serotonergic activity affects MMN (Wienberg, Glenthoj, Jensen, & Oranje, 2010), but this has not been specifically investigated in relation to BD.
A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder
2013, European NeuropsychopharmacologyCitation Excerpt :Jahshan et al. (2012) also looked at lithium in bipolar disorder and found no effect on MMN. Previous studies have found no effect of benzodiazepines on MMN in schizophrenia (Kasai et al., 2002; Murakami et al., 2002), but this has not been investigated in bipolar disorder. Antidepressants also seem to have mixed effects on MMN, with research investigating citalopram suggesting a broad range of serotonergic activity affects MMN (Wienberg et al., 2010), but again this has not been specifically looked at in bipolar disorder.