The effects of benzodiazepines on event-related potential indices of automatic and controlled processing in schizophrenia

Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 651 – 661

Article

The effects of benzodiazepines on event-related potential indices of automatic and controlled processing in schizophrenia A preliminary report Tadashi Murakamia, Kazuyuki Nakagomeb,*, Satoru Kamioc, Kiyoto Kasaic,d,e, Akira Iwanamic, Ken-Ichi Hiramatsua, Masato Fukudaf, Akinobu Hatac, Makoto Hondag, Akira Watanabec, Nobumasa Katoc a

Department of Neuropsychiatry, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan b Department of Psychiatry, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8566, Japan c Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan d Laboratory of Neuroscience, Department of Psychiatry, Clinical Neuroscience Division, Boston VA Healthcare System—Brockton Division, 116A, Brockton, MA, USA e Harvard Medical School, Boston, MA, USA f Department of Neuropsychiatry, School of Medicine, Gunma University, Gunma, Japan g Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan

Abstract The effects of benzodiazepines on cognitive function in schizophrenic patients were investigated using event-related potential (ERP) measurement during an auditory selective attention task. In this study, the authors compared the mismatch negativity (MMN) and N2b components between two subgroups of schizophrenic patients: one is comprised of patients who received no benzodiazepines (NT group, n = 7) and the other is comprised of those administered benzodiazepines in the daytime (T group, n = 7). There were no significant differences in MMN and N2b amplitudes between the two subgroups, whereas the N2b latency was significantly prolonged in the T group relative to the NT group. This suggested that benzodiazepines induce delayed stimulus classification processing in schizophrenic patients. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Benzodiazepines; ERP; N2b; Schizophrenia; Selective attention task

1. Introduction Antipsychotic drugs play a central role in the treatment of schizophrenic patients. However, clinical studies indicate that schizophrenic patients may also benefit from benzodiazepine treatment. Benzodiazepines may be effective through their action of alleviating stress, which is one mediator of relapse in schizophrenia. In addition, inhibition of dopamine transmission through g-aminobutyric acid (GABA)-enhan-

Abbreviations: BPRS, Brief Psychiatric Rating Scale; ERP, eventrelated potential; MMN, mismatch negativity; SPL, sound pressure level; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartate * Corresponding author. Tel.: +81-3-3784-8703; fax: +81-3-37848703. E-mail address: [email protected] (K. Nakagome).

cing activity may provide a direct antipsychotic effect (Wasseff et al., 1999; Wolkowitz and Pickar, 1991; Wolkowitz et al., 1992). On the other hand, it is widely accepted that the adverse effects of benzodiazepines include sedation, cognitive impairment, behavioral disinhibition, and the potential for dependence, withdrawal, and abuse. Lingjærde (1991), in his review article, summarized reports regarding the effects of benzodiazepines in schizophrenic patients as follows. Benzodiazepines used as an adjunct to neuroleptics, in conventional doses, can enhance the antipsychotic effect of neuroleptics in schizophrenic patients who have not responded satisfactorily to typical neuroleptics, whereas schizophrenic patients who are well stabilized on neuroleptic medication may be destabilized by adding benzodiazepines. The beneficial effect includes improvement of anxiety, but also of psychotic symptoms such as hallucina-

0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 3 0 2 - 5

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tions, delusions, and thought disturbance, although some patients may exhibit loss of social and sexual disinhibition. More recent research indicates that the effect of diazepam in treating prodromal and early warning signs of symptom exacerbation in schizophrenia was comparable to that of fluphenazine, and much superior to that of a placebo (Carpenter et al., 1999). However, as Lingjærde (1991) noted, since the conclusions of previous reports vary from worse than the placebo to better than neuroleptics, and moreover, since the predictors of benzodiazepine responsivity are not yet clear, the issue regarding the efficacy of benzodiazepines remains a matter of debate. Further evidence that the benzodiazepine receptor system may be involved in the pathophysiology of schizophrenia comes from post-mortem and in vivo studies investigating benzodiazepine receptor distribution and density. While some of these studies indicate reductions in GABA receptor bindings or GABA uptake in several brain regions, including the frontal and temporal cortices (Squires et al., 1993), hippocampus (Reynolds et al., 1990; Simpson et al., 1989; Squires et al., 1993) and globus pallidus (Squires et al., 1993), other studies found an increase in the anterior cingulate cortex (Benes et al., 1992), prefrontal cortex, and caudate nucleus (Hanada et al., 1987). Schro¨der et al. (1997) suggested that these discrepancies, in addition to their finding an association between GABAA/benzodiazepine receptor abnormalities in the medial frontal cortex and the severity/chronicity of the disease, lead to the view that changes in the GABAA receptor system may be related to certain clinical characteristics rather than to schizophrenia in general. The role of GABA in information processing and cognitive deficits in schizophrenia has hardly been studied. Impaired cognitive function in schizophrenic patients has been widely documented, and various models have been generated. Hemsley (1987) proposed a hypothesis that attentional abnormalities and positive symptoms in schizophrenia may be interpreted as a ‘‘weakening of the influences of stored memories of regularities of previous input on current perception.’’ Gray et al. (1991) related this to the disrupted interaction between a glutamatergic excitatory input from the subiculum and a dopaminergic inhibitory input from A10 onto GABA-ergic efferents originating in nucleus accumbens, which interferes with the comparatory function of the hippocampus. Moreover, Ball et al. (1998) demonstrated a relationship between reduced GABAA/benzodiazepine receptor binding and poorer cognitive function, involving memory and visual attention processes in schizophrenic patients using a battery of neuropsychological tests. Event-related potential (ERP) studies have implicated various models regarding cognitive deficits in schizophrenia. Earlier studies focused on amplitude reduction and latency prolongation of the P3 component in schizophrenic patients (Blackwood et al., 1987; Muir et al., 1991; McCarley et al., 1991; Prichard, 1986; Roth, 1977), which repre-

sents high-level controlled processing functions, such as ‘‘context updating’’ and ‘‘cognitive resource allocation.’’ Other studies, although not as consistent as P3, indicated amplitude reduction in the negative difference wave (Nd) (Michie et al., 1990), which represents selective attention function, and N2b (Kasai et al., 1999, O’Donnell et al., 1993; Ogura et al., 1991; Salibury et al., 1994), an index of stimulus classification, all of which are involved in controlled processing. However, recent studies reported amplitude reduction in mismatch negativity (MMN) in schizophrenic patients (Catts et al., 1995; Javitt et al., 1996; Kasai et al., 1999; Oades et al., 1997; Shelley et al., 1991; Shutara et al., 1996), which reflects the automatic stimulus discrimination process related to sensory memory function (Na¨a¨ta¨nen, 1992; Na¨a¨ta¨nen et al., 1982). This finding leads to the important implication that schizophrenic patients may exhibit a deficiency in information processing from the early automatic processing stage. Javitt et al. (1996) demonstrated that MMN generation depends on the interaction between excitatory and inhibitory processes within the cortex mediated by N-methyl-D-aspartate (NMDA) and GABAA receptors in monkeys. Furthermore, Umbricht et al. (2000) showed that the NMDA receptor antagonist ketamine significantly reduced the amplitude of MMN, as well as inducing performance deficits in the AX-CPT (continuous performance test), which were in accordance with the findings obtained in schizophrenic patients. From this point of view, the effect of GABA-ergic drugs such as benzodiazepines on MMN in medicated schizophrenic patients is an important issue to be clarified, although there are several reports suggesting MMN attenuation even in unmedicated patients (Catts et al., 1995; Javitt et al., 1995). Our previous findings suggested MMN and N2b attenuation in medicated schizophrenic patients relative to normal controls in an auditory selective attention task (Kasai et al., 1999). MMN and N2b amplitudes in schizophrenic patients showed no significant correlation with daily dosage of antipsychotic drugs, but the effect of benzodiazepine medication on these components was not considered in the paper. With the aim of addressing the issue, data obtained from 14 of 21 schizophrenic patients, who were either not treated with benzodiazepines or receiving benzodiazepines in the daytime, were reanalyzed in this study. Seven patients were excluded, because they were either administered benzodiazepines only before sleep, or GABA-ergic drugs such as sodium valproate and/or barbiturates, to eliminate possible confounding effects.

2. Subjects and methods 2.1. Subjects Fourteen DSM-IV (American Psychiatric Association, 1994) patients with schizophrenia were selected for this study. The patients were either not treated with benzodia-

T. Murakami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 651–661

zepine drugs (not treated group: NT group) or treated with benzodiazepine drugs in the daytime as adjunctive agents to conventional antipsychotic drugs (treated group: T group). Those to whom benzodiazepines were administered before sleep were not included in the study, because it was not clear whether residual effects of the drug were present at the time of the experimental session (14:00 h). Moreover, those who were administered other GABA-ergic drugs, such as sodium valproate and/or phenobarbital, were excluded from the study to eliminate confounding effects. All the subjects were right-handed with normal hearing acuity and had no history of drug or alcohol abuse. The demographic and clinical features of the subjects are shown in Table 1. The NT group comprised more male subjects than the T group, but the between-group difference in sexual proportion did not reach statistical significance (Fisher’s Exact Test, P = .11). Moreover, the subjects in the NT group showed an older mean age, lower Brief Psychiatric Rating Scale (BPRS) (Kolakowska, 1976) mean score and lower daily dosage of antipsychotic drugs, whereas neither of these indices was significantly different between the two groups in the Student’s t test. This study was approved by the Ethical Committee of the University of Tokyo. All the subjects participated in the study after giving written informed consent. 2.2. Task procedures The subjects performed a selective attention task, during which tone pips of 1-kHz, 70-dB sound pressure level (SPL, rise/fall time 10 ms) were presented dichotically to the subjects’ ears via headphones. The whole task involved six blocks of tone pips. Each block consisted of 50 deviant stimuli (probability 25%) and 150 standard stimuli (75%),

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varying in duration, presented to each ear in random order. The duration of the deviant stimuli was 50 ms and that of the standard stimuli was 100 ms. The interstimulus interval was fixed at 600 ms. The subjects were required to focus on one ear and silently count the deviant stimuli while ignoring all the stimuli delivered to the opposite ear. Ear designation was counterbalanced across the blocks. In addition, the order of ear designation through the sequential blocks was counterbalanced across subjects. Therefore, the total number of trials in each stimulated ear and each attentional condition was 150 for the deviant stimuli and 450 for the standard stimuli. 2.3. ERP recording While performing the task, the subjects sat comfortably in a dimly lit, sound-proof, electrically shielded room with their eyes closed. EEGs were recorded via 16 Ag –AgCl electrodes placed according to the international 10 – 20 system at Fp1, Fp2, F3, Fz, F4, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, and Oz. The tip of the nose was used as a reference for all the electrodes. Two electrodes were placed at the outer canthus and above the left eye to monitor eye movements. The sampling rate was 500 Hz/channel, and the analog filter bandpass was 0.16 –60 Hz. The analysis period was 512 ms, including a 64-ms prestimulus baseline. Averaging and artifact rejection were conducted on-line with a DP-1100 (NEC, Japan). The baseline was corrected separately for each channel according to the mean amplitude of the EEG over 64 ms prior to stimulus onset. The EEG epochs that contained peak-to-peak amplitudes exceeding 150 mV at any electrode were automatically excluded from averaging. The average waveforms elicited by deviant and standard stimuli were obtained separately in the attended

Table 1 Demographic and clinical features of each subject in the NT and T groups Group

ID number

Sex

Age (years)

Duration of illness (years)

NT group

3 6 7 19 22 26 35 Mean (S.D.) 10 13 15 16 23 30 34 Mean (S.D.)

female female male male male male male

35 34 29 25 23 25 34 29.3 (5.1) 24 29 26 23 28 26 17 24.7 (4.0)

10 8 9 6 8 4 1 6.6 (3.2) 7 9 5 5 8 6 5 6.4 (1.6)

T group

female male female female female male female

Subtype disorganized undifferentiated catatonic undifferentiated paranoid residual paranoid residual undifferentiated undifferentiated paranoid paranoid undifferentiated disorganized

Total BPRS score (Kolakowska, 1976)

Antipsychotic drugs (CPa equivalent)

18 5 19 11 13 5 19 12.9 (6.2) 14 23 7 16 37 29 16 20.3 (10.1)

150 38 125 350 975 112.5 0 250.1 (338.5) 300 200 551 202.5 800 162.5 1350 509.4 (437.2)

Benzodiazepines none none none none none none none bromazepam, 3
5 mg bromazepam, 2
2 mg bromazepam, 3
4 mg diazepam, 1
2 mg diazepam, 3
5 mg bromazepam, 2
2 mg bromazepam, 3
2 mg

The between-group difference did not reach significance for sex, age, duration of illness, total BPRS score, or daily dosage of antipsychotic drugs. a CP = chlorpromazine.

Fig. 1. Superimposed grand average waveforms obtained by subtracting the ERPs to the standard stimuli from those to the deviant stimuli in the unattended condition. The upper figures show those elicited by the left stimulated ear, whereas the lower ones show those elicited by the right stimulated ear. Note that a negative deflection, although small in amplitude, is shown at frontal sites in the latency range of 100 – 180 ms. Negative is up.

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and unattended condition for each ear, and digitally filtered with a cut off frequency of 30 Hz.

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3. Results 3.1. Between-group comparison of the performance level

2.4. ERP and behavioral performance measurement The mean error rates in reporting the number of deviants in the NT and T groups were 12.5% (S.D. = 5.4) and 13.9% (S.D. = 8.3) for the left ear stimuli, 15.9% (S.D. = 12.1) and 18.0% (S.D. = 9.9) for the right ear stimuli. Repeated measures ANOVA revealed that the discrimination performance was not significantly different between the groups [ F(1,12) = 0.17, P = .69].

The time windows for measuring the MMN amplitude and N2b amplitude and latency were estimated from the grand average difference waveforms obtained for each group by subtracting the ERPs elicited by the standard stimuli from those elicited by the deviant stimuli in the unattended (MMN) and attended (N2b) conditions. Thus, MMN amplitude was calculated as the mean amplitude between 100 and 180 ms at F3, Fz, and F4, as MMN showed frontal predominance. Since negative peaks were not clear in several cases, we did not adopt MMN latencies in the present study. The N2b latency was determined as the peak latency of the negative deflection present within the latency range of 200 –400 ms at C3, Cz, and C4, as N2b showed predominance at these electrode sites. Since visual inspection of the waveform suggested a between-group difference in N2b latencies, N2b amplitude was calculated separately for each group at C3, Cz, and C4, as the mean amplitudes between 200 and 320 ms in the NT group, and between 240 and 360 ms in the T group. Counting performance was assessed by calculating the average rate of deviation of counts from the current number of targets for each stimulated ear.

3.2. Between-group comparison of the ERP indices As shown in Fig. 1, although extremely small, a negative deflection was visible at frontal sites in the latency range of 100 – 180 ms in the NT group for the left stimulated ear and in the T group for the right stimulated ear (Table 2). Moreover, a polarity inversion was observed between the frontal and temporal electrode sites within the same latency range. In addition, as shown in Fig. 2, a negative deflection appeared in the same latency range in the attended condition, which also supports the validity of representing the mean amplitude between 100 and 180 ms as the MMN amplitude. Repeated measures ANOVA using MMN amplitudes obtained from F3, Fz, and F4 revealed no significant difference between the groups [ F(1,12) = 0.03, P = .86]. Moreover, no significant interactions between group and other factors were obtained. As shown in Fig. 2, a prominent N2b appeared predominantly at C3, Cz, and C4 in the difference waveforms of the attended condition for both groups, although the latencies seemed to differ between the groups. Accordingly, the time windows for calculating the mean amplitude of N2b were determined from a visual inspection of the waveforms, as noted above. From the visual inspection of the waveforms, the N2b amplitude appeared to be attenuated and latency prolonged in the T group relative to the NT group. One subject was excluded from the analysis for N2b latency, because no negative deflection was observed within the latency range of 200 – 400 ms to the left stimulated ear. Repeated measures ANOVA using N2b amplitude and

2.5. Data analysis Counting performance was compared between the NT and T groups using repeated measures ANOVA, with each group (‘‘group’’) representing the interindividual factor and stimulated ear (‘‘stimulus’’) as the intraindividual factor. ERP indices were compared between the two groups using repeated measures ANOVA, with ‘‘group’’ representing the interindividual factor and ‘‘stimulus’’ and ‘‘electrode sites’’ as the intraindividual factors. In order to minimize Type 1 errors possibly due to violations of the sphericity assumption, reduced degrees of freedom (Greenhouse – Geisser correction) were applied when appropriate. Relationships between ERP indices and other demographic and clinical features were tested by calculating Spearman’s rho.

Table 2 Mean (S.D.) levels of MMN amplitudes, N2b amplitudes, and latencies for group, stimulus, and electrode sites MMN amplitude (mV) Group

Stimulus F3

NT group left right T group left right

 0.31  0.08 0.59  0.65

Fz

N2b amplitude (mV) F4

(0.87)  0.53 (1.02)  0.45 (0.98) 0.32 (1.42) 0.56 (1.03) 0.44 (0.76) 0.51 (1.41)  0.28 (1.97)  0.18

C3

Cz

N2b latency (ms)** C4

(0.83)  1.37 (1.84)  1.18 (2.19)  1.10 (1.67)  0.96 (1.81)  0.88 (1.48)  0.72 (1.08) 0.00 (1.59) 0.41 (1.91)  0.16 (1.70)  0.51 (1.33) 0.22 (1.48)  0.49

C3 (2.13) (1.66) (2.23) (1.82)

Note that only N2b latencies showed a significant between-group difference in repeated measures ANOVA. ** Significant main effect of group, P < .01.

282.57 257.75 331.71 333.43

Cz (22.47) (48.31) (22.85) (39.68)

283.43 257.50 337.43 315.14

C4 (24.43) (45.10) (26.83) (42.58)

276.57 260.50 336.86 334.86

(33.56) (43.64) (21.10) (31.43)

Fig. 2. Superimposed grand average waveforms obtained by subtracting the ERPs to the standard stimuli from those to the deviant stimuli in the attended condition. The upper waveforms show those elicited by the left stimulated ear, whereas the lower ones show those elicited by the right stimulated ear. A relatively prominent negative deflection appeared at C3, Cz, and C4 for both groups, but its latency appeared to be delayed in the T group relative to the NT group. Negative is up.

T. Murakami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 651–661 Table 3 Spearman’s rho obtained among N2b latencies and demographic and clinical features Stimulus Left

Right

Electrode site C3 Cz C4 C3 Cz C4

Age

 .63*  .60*

Duration of illness

Total BPRS score

Antipsychotic drugs .57* .64* .64* .72** .67* .66*

Only those that reached significance ( P = .05) are shown in the table. * P < .05. * * P < .01.

latency obtained from C3, Cz, and C4 revealed a significant between-group difference for N2b latency [ F(1,11) = 19.34, P = .001], but not for N2b amplitude [ F(1,12) = 1.43, P = .25]. Moreover, no significant interactions between group and other factors were obtained for either N2b amplitude or latency. 3.3. Relationship between N2b latency and other clinical factors To elucidate whether the between-group difference obtained for N2b latency was due to confounding effect of the difference in other demographic and clinical features between the groups, Spearman’s rho were calculated between N2b latency and age, duration of illness, daily dosage of antipsychotic drugs, and total BPRS scores. Between-group differences of these variables did not reach a significant level, but at least some of these differences appeared to be substantial enough to be investigated. As shown in Table 3, significant correlations were suggested between N2b latency and age to the right stimulated ear at C3 and Cz, and daily dosage of antipsychotic drugs to either stimulated ear and electrode site, although neither of these correlations reached a significant level after applying Bonferroni’s correction ( P = .002). In order to eliminate these possible effects on the between-group difference of N2b latency, repeated measures ANCOVA was performed, including age and daily dosage of antipsychotic drugs as covariances. Statistical analysis using ANCOVA revealed that the main effect of group remained significant [ F(1,9) = 6.81, P = .028]. Therefore, it seemed that the between-group difference in N2b latency could not be solely explained by the difference in these variables.

4. Discussion The findings of this study suggest that benzodiazepines cause a prolongation effect on the N2b component of the ERP in schizophrenic patients. On the other hand, it appeared that MMN and N2b amplitudes were relatively unaffected by benzodiazepines.

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4.1. Previous findings regarding the effect of benzodiazepines on ERP indices An increasing number of studies have reported the effects of benzodiazepines on ERPs (Table 4) (Berchou et al., 1986; Heinze et al., 1994; Krull et al., 1994; Mu¨nte et al., 1993, 1996; Nakagome et al., 1998; Nichols and Martin, 1996; Noldy et al., 1990; Pang and Fowler, 1994; Reinsel et al., 1991; Rockstroh et al., 1991; Semlitsch et al., 1995; Urata et al., 1996; van Leeuwen et al., 1995). However, to the best of our knowledge, there have been no studies investigating the effects of benzodiazepines on ERPs in schizophrenic patients. Moreover, most of the previous studies were designed to investigate the acute effects of benzodiazepines, in contrast to this study, in which the subjects presumably well tolerated benzodiazepines after long-term medication. In spite of these discrepancies between this study and previous reports, there are some interesting consistencies in the findings. Prolongation of P3 latency was reported in four studies, while one study suggested a prolongation of N2 latency. Berchou et al. (1986) demonstrated that reduced N2 amplitude and prolonged N2 latency were observed even 3 h after medication with lorazepam, whereas P3 amplitude, but not P3 latency, was affected only 1.5 h after medication, suggesting that N2 is a more significant index for the study of cognitive function than P3. However, studies that reported prolongation of P3 latency did not take into account N2 latency. Semlitsch et al. (1995) noted that N2 latency was not measurable in several subjects. In this study, the N2b peak was not detected within the latency range of 200– 400 ms in only one subject, to the left stimulated ear. The inconsistency is presumably due to the methodological differences in how the component was measured. We measured the N2b component from a difference waveform obtained by subtracting the ERPs to standard tones from those to deviant tones, whereas in previous reports, the N2 component was measured from the ERPs to deviant tones. O’Donnell et al. (1993) noted that the former method is the preferred measure, because the N2b measured from the difference waveform is less contaminated by other ERP components, such as P2, which is presumably removed by the subtraction. 4.2. Prolongation of N2b latency P3 latency is thought to reflect the stimulus evaluation time, which is relatively independent of response selection and execution (Kutas et al., 1977; Magliero et al., 1984; McCarthy and Donchin, 1981). N2b, on the other hand, indexes the categorization process of deviant stimuli. Therefore, its latency is thought to reflect the stimulus classification time (Ritter et al., 1979). The ERP epoch adopted in our study (64-ms prestimulus to 448 ms-poststimulus) was not long enough to measure the P3 latency, however, the finding regarding N2b latency in our study suggested that

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Table 4 Previous studies on the effects of benzodiazepines on ERP components Study

Medication

ERP task

Effect on ERP components

Conclusion

15 healthy subjects

lorazepam

2 mg

auditory oddball

affects the neural processing of cognitive functions N2 is more sensitive than P3

Noldy et al. (1990) Reinsel et al. (1991)

4 healthy subjects 10 healthy subjects

diazepam midazolam

passive auditory auditory oddball

Rockstroh et al. (1991)

36 healthy male subjects

clonazepam

20 mg 0.07 mg/kg, intravenous infusion 50 min before the experiment gradually raised by 0.5 mg/day, beginning with 1.0 mg/day on Day 1 and ending with 4.5 mg on Days 8 and 9 15 mg on the day before testing, 75 mg on the morning of the experiment 0.07 mg/kg, 0.14 mg/kg 0.25 mg (1 h before the experiment) 15 mg on the day before testing, 75 mg on the morning of the experiment 20 mg, 40 mg (1 h before the experiment) 1 mg (3 h before the experiment)

N2 lat ", N2 amp # 3 h after medication, P3 amp # 1.5 h after medication N1 – P2 amp # P3 amp #, slow negative component lat " P1 amp #

Mu¨nte et al. (1993)

Subjects

12 healthy male subjects

oxazepam

108 healthy male subjects 12 healthy subjects (7 males) 12 healthy male subjects

diazepam triazolam oxazepam

van Leeuwen et al. (1995)

18 healthy male subjects

oxazepam

Semlitsch et al. (1995)

15 healthy subjects (5 males)

alprazolam

Mu¨nte et al. (1996)

12 healthy male subjects

alprazolam

Krull et al. (1994) Pang and Fowler (1994) Heinze et al. (1994)

13 heavy social drinkers, 13 light social drinkers 10 healthy male subjects

lorazepam

alprazolam: 2
1 mg (3 days) plus 1 mg on the morning of the experiment bromazepam: 2
6 mg (3 days) plus 6 mg on the morning of the experiment 2 mg

triazolam

0.125 mg

8 healthy male subjects

triazolam

0.25 mg (the night before the experiment)

bromazepam

Nichols and Martin (1996) Urata et al. (1996)

Nakagome et al. (1998)

visual pattern reversal auditory S1 – S2 paradigm visual word recognition

N1, P3, CNV amp #, N2 amp " N4 amp #

decrease in CNS excitability causes deficiency in memory updating

attentional processes, information intake and processing, response preparation processes are modified build up of an insufficient or rudimentary code for the words

visual pattern reversal visual oddball

P1 amp # P3 lat "

impaired sensory – perceptual processes delayed perceptual processing stage

visual search

parietal N1, frontal and contralateral posterior N2, occipital P3 amp # P1, N1, P2N2, P3 amp #, dose-dependently N1, P2, P3 amp #, P3 lat "

deficits in automatic feature registration, allocation of attention, the available processing capacity N1, P3 amp reduction induced by the lowered arousal level, but not P1/P2N2 inhibitory influence on stimulus-induced cortical arousal, reduced cognitive information processing capacity, prolonged stimulus evaluation time impairment in selective attention and of automatic feature registration

visual vigilance auditory oddball

visual search

visual word recognition continuous recognition auditory oddball

auditory oddball (attend and ignore condition)

With the exception of Reinsel et al. (1991), benzodiazepines were orally administered. Min = minutes; h = hours; amp = amplitude; lat = latency, " = augmentation or prolongation; # = attenuation or shortening.

posterior N1, contralateral posterior N2 amp # for both drugs N400 amp # for both drugs P3 lat ", P3 amp " in light social drinkers P3 lat ", P3 amp #, lasting for 4 h after administration MMN amp #

deficits in integration process

indicates a tolerance in heavy social drinkers to the effects of lorazepam a direct effect on the cognitive function, not a secondary effect of general sedation overnight residual effect of triazolam on the preattentive process

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Drugs

Berchou et al. (1986)

T. Murakami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 651–661

benzodiazepines induce delayed stimulus classification processing in schizophrenic patients. The relationship between prolonged N2b latency and GABA-ergic mechanisms related to benzodiazepines is not at all clear. In addition, slowed controlled processing, as reflected in N2b and P3 latency prolongation (Brecher et al., 1987; Blackwood et al., 1987; Muir et al., 1991), is one of the major cognitive deficits demonstrated in schizophrenia. However, the contribution of GABA functioning disturbances to the deficit is not yet clear. As noted earlier, Ball et al. (1998) reported that various cognitive deficits in schizophrenia were related to reduced GABA functioning, whereas benzodiazepines potentiate it. Although speculative, the inhibitory effect of GABA on human association cortex cortico-cortical connections (Kisvarday et al., 1990) may have contributed to the prolonged N2b latency, as well as controlled processing. 4.3. MMN and N2b amplitudes There are inconsistencies regarding the findings obtained for MMN and N2b amplitudes between this study and previous ones. The mean level of MMN amplitudes appeared to be extremely small with relatively large interindividual variances and possibly a poor S/N ratio, which may have obscured the drug effect. It is possible that the relatively high presentation rate of deviant stimuli (25%) contributed to the general MMN attenuation. However, taking into account of all the stimuli presented to the other ear, which also differed from the deviant stimuli in terms of location, the probability of deviant stimuli may be counted as 12.5%. The above view is partly supported by Deacon et al. (1998), who demonstrated that MMN elicited by three different deviants with a probability of 10% each (overall probability of 30%) presented within a block was the same when three blocks were run separately for each deviant with a probability of 10%. Up to now, the effect of the stimuli presented to the opposite ear on MMN formation is not well understood, and further studies are needed to clarify this point. Moreover, previous studies suggest that MMN is larger when the deviant involved is a duration increment relative to a decrement (Shelley et al., 1991; Catts et al., 1995). However, to avoid the effect of the duration increment on exogenous components, such as N1 or the sustained potential that lasts through the duration of the stimulus showing a fronto-central predominance, and possibly overlap the genuine MMN, we adopted shorter duration deviants (Picton et al., 1978a,b; Scherg et al., 1989). It is possible that the sustained potential in longer standards led to the attenuation of MMN, even showing a positive deflection in some cases. Most previous studies that suggested the N2 amplitude reduction effect of benzodiazepines were performed using a visual task, whereas only one study using an auditory oddball task indicated this effect. Owing to the methodological difference in measuring the N2 component, the

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findings obtained for N2 amplitudes in this study cannot be directly related to those in previous studies. In this study, N2b amplitude appeared to be smaller in the T group than in the NT group, but between-group difference failed to reach statistical significance, possibly due to the lack of statistical power because of the small sample size in this study. The negative findings regarding the effect of benzodiazepines on MMN and N2b amplitudes suggest that the significant attenuation of these components found in our previous study (Kasai et al., 1999) cannot be solely attributed to the effect of benzodiazepine drugs, which were administered in the daytime to some patients. 4.4. Limitations of this study The findings obtained in this study should be carefully considered due to the small sample size, and the study design that was not randomized for the patient groups; therefore, this study is best seen as preliminary and any detailed analysis is speculative only. However, to the best of our knowledge, this is the first study that investigated the effect of benzodiazepine administration on cognitive function in schizophrenic patients using ERP methods. Considering the inconsistent views regarding the beneficial and adverse effects of benzodiazepines in the pharmacological treatment of schizophrenia, further research related to this study is necessary, using a randomized study design with a larger sample size.

5. Conclusion The effects of benzodiazepines on cognitive function in schizophrenic patients were investigated using ERP components, such as MMN and N2b, elicited during an auditory selective attention task. MMN and N2b amplitudes, which are assumed to reflect automatic and controlled stimulus discrimination processes, appeared to be relatively unaffected by the benzodiazepines, whereas a prolongation effect on N2b latency was suggested. This indicates that benzodiazepine drugs may induce delayed stimulus classification processing in schizophrenic patients.

Acknowledgments This research was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, and Culture, Japan.

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