Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients

Effective Neuroleptic Medication Removes Prepulse Inhibition Deficits in Schizophrenia Patients Almut I. Weike, Ulrike Bauer, and Alfons O. Hamm Background: The magnitude of the startle eyeblink response is reduced if the startle eliciting stimulus is shortly preceded by another stimulus. There is evidence that schizophrenia patients exhibit impairments in this socalled prepulse inhibition. Our study investigated whether prepulse inhibition is affected by neuroleptic drug treatment as is suggested by animal research. Methods: Prepulse inhibition was tested in five unmedicated and 20 medicated inpatients with schizophrenia, and 12 normal controls. Results: The unmedicated schizophrenia patients showed a strong impairment of sensorimotor gating as indexed by the absence of prepulse inhibition. By contrast, the medicated patients showed a pronounced prepulse inhibition that did not differ from that of the normal controls. There was a substantial covariation between the rated severity of the positive syndrome and the amount of prepulse inhibition—i.e., the patients whose positive symptoms were rated as more severe showed less prepulse inhibition. Conclusions: These data suggest that the impaired sensorimotor gating of schizophrenia patients is not a stable vulnerability indicator, but may rather be related to the positive syndrome and may be improved by treatments with neuroleptic medication. Biol Psychiatry 2000;47: 61–70 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, prepulse inhibition, sensorimotor gating, startle eyeblink, neuroleptic medication, positive syndrome

Introduction

D

ysfunctions in attention and information processing have long been considered a hallmark of schizophrenia. By using a wide range of different experimental techniques to quantify these dysfunctions, it has been demonstrated that schizophrenia patients have difficulties

From the Department of Psychology, University of Greifswald, Greifswald (AIW, AOH) and the Department of Psychiatry, University of Giessen, Giessen (UB), Germany. Address reprint requests to Prof. Dr. Alfons Hamm, Ernst-Moritz-Arndt-Universitaet Greifswald, Institut fu¨r Psychologie, Franz-Mehring-Strasse 47, 17487 Greifswald, Germany. Received March 5, 1999; revised July 28, 1999; accepted August 10, 1999.

© 1999 Society of Biological Psychiatry

in focussing their attention to relevant stimuli. This is indicated by longer reaction times in cross-modal reaction time tasks or impairments in the Continuous Performance Task (for reviews see Braff 1993; Braff et al 1991; Nuechterlein and Dawson 1984). Because schizophrenia patients are unable to screen out irrelevant stimuli, they seem to be vulnerable to stimulus inundation, particularly if external stimuli are presented in rapid succession. In such conditions the response to a second stimulus has to be inhibited or attenuated to protect the processing of the first stimulus. Schizophrenia patients reliably exhibit a deficit in effectively inhibiting the processing of a second disruptive stimulus, as assessed by various tasks. These include visual backward-masking performance (Braff et al 1991; Rund 1993) and the decline in amplitude of the P50 component of the event-related potential to the second of a pair of clicks (Freedman et al 1987). The modulation of the startle response by weak prestimulation has also been used to assess these deficits in information processing in schizophrenia patients. The measurement of startle modulation to study these dysfunctions has a number of advantages. First, the startle reflex is relatively free from voluntary control and requires minimal effort from the subject. Second, startle modulation is particularly amenable to animal modeling because it occurs in infrahuman species as well. Third, the neural circuits mediating evocation and modulation of the acoustic startle response are increasingly well understood (Davis 1997). Finally, startle modulation is influenced by psychoactive drugs and by various manipulations of neurotransmitter systems (see Koch and Schnitzler 1997), which may allow one to tentatively link startle modulation deficits in schizophrenia patients to underlying neurobiological dysfunctions. The magnitude of the startle response—a fast protective reflex to an unexpected intense stimulus with rapid onset—is reduced if weak sensory events (prepulses) are presented at brief intervals (i.e., between 30 and 500 msec) prior to the startle-eliciting stimuli. This phenomenon is called prepulse inhibition (PPI) and has been observed across a wide range of stimulus intensities and modalities in animals (Hoffman 1997; Hoffman and Ison 1980, 1992) and humans (see reviews by Anthony 1985; Filion et al 0006-3223/00/$20.00 PII S0006-3223(99)00229-2

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1998; Graham 1975). Prepulse inhibition is very robust and occurs in 90 –100% of normal subjects who exhibit a normal startle eyeblink response. Prepulse inhibition seems to be a rather automatic and low-level phenomenon, since it can be obtained during sleep (Silverstein et al 1980) and at the very first presentation of the lead stimulus. According to Graham (1975, 1992) and Braff and colleagues (Braff 1985; Braff et al 1991; Geyer and Braff 1987), PPI may reflect the action of a sensorimotor gating system that operates to protect early preattentive processing of a weak stimulus (prepulse) by inhibiting or attenuating the disruptive effects of the intense startleeliciting stimulus. Braff and coworkers were the first to demonstrate that schizophrenia patients have a deficit in this sensorimotor gating mechanism (Braff et al 1978). In that study, a continuous mild tone (71 dB) served as the prepulse and a burst of white noise as the startle stimulus. Inpatients with schizophrenia showed impaired PPI relative to normal controls, especially at the 60- and 120-msec lead intervals. These findings were replicated and extended by two additional studies, showing that reduced PPI in inpatients with schizophrenia can also be obtained with a tactile startle-eliciting stimulus (Braff et al 1992) and with different prepulse intensities, ranging from 75 to 90 dB (Grillon et al 1992). Deficient PPI was also found for inpatients and outpatients diagnosed as having a schizotypal personality disorder (Cadenhead et al 1993) and for college students scoring high on perceptual aberration (Simons and Giardina 1992). Moreover, Swerdlow and coworkers found reduced PPI in individuals who were classified as psychosis-prone based on theoretically and empirically derived Minnesota Multiphasic Personality Inventory (MMPI) criteria (Swerdlow et al 1995a). These data suggest that the deficit in the sensorimotor gating mechanism might be a trait-linked vulnerability for developing thought disorders or cognitive fragmentation, symptoms characteristic of schizophrenia disorders (Braff 1993; Braff et al 1991). The relationship between reduced PPI and psychosis proneness in “normal” volunteers, however, is not a reliable finding. In three studies, no differences in PPI were found for individuals scoring high or low on perceptual aberration (Blumenthal and Creps 1994; Cadenhead et al 1996; Lipp et al 1994). Strikingly, although individuals scoring high on perceptual aberration and magical ideation also scored higher on the MMPI psychoticism subscale and showed more mild psychotic symptoms as assessed by clinical interview, the PPI of these subjects did not differ from that of a control group (Cadenhead et al 1996). Moreover, even when clinically diagnosed but relatively asymptomatic schizophrenia patients were compared with

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normal controls, there was no difference in PPI between the groups, if an insignificant (to be ignored) tone stimulus preceded the startle-eliciting noise burst (Dawson et al 1993). Reduced PPI in schizophrenia patients compared with controls was only observed when individuals were instructed to selectively attend to the prepulse stimulus. These findings were recently replicated by Hazlett and coworkers comparing schizophrenia patients during the period of washout with normal volunteers; again, normal controls exhibited stronger PPI following the to-be-attended tone, compared with the to-be-ignored tone, at the 120-msec lead interval, while schizophrenia patients failed to show such attentional modulation of startle inhibition (Hazlett et al 1998). One reason for the differences between the results of Braff and collaborators and those obtained by Dawson et al might be that the instruction to ignore a prepulse stimulus is not completely comparable to the condition where individuals process the prepulse passively—i.e., without any specific task to allocate their attention either towards or away from that stimulus. In addition to these procedural differences, the severity of psychopathology and medication status of the schizophrenia patient samples varied substantially across studies. Dawson and colleagues studied relatively asymptomatic schizophrenia outpatients who were either off all medication or on a low to moderate dose of neuroleptic medication (Dawson et al 1993). By contrast, Braff and collaborators tested schizophrenia inpatients treated with relatively high doses of antipsychotic medication (chlorpromazine equivalents varied in a range of 1640 to 2245 mg between studies). Evidence from animal experimentation suggests that it is unlikely that neuroleptic medication might induce deficits in PPI. By contrast, PPI deficits induced by apomorphine can be removed by haloperidol, which blocks the dopamine D2 receptors (Koch and Bubser 1994; Mansbach et al 1988). Moreover, PPI deficits induced by the noncompetitive NMDA antagonist phencyclidine are reversed by clozapine (Bakshi et al 1994). These substances are frequently used as typical and atypical antipsychotic drugs in humans. Findings such as these have been incorporated into an animal model for PPI deficits which states that the nucleus accumbens is the core structure in the regulation of PPI in the context of dopaminergic and glutamatergic dysregulations (for reviews see Geyer et al 1990; Koch and Schnitzler 1997; and Swerdlow et al 1992). These animal data suggest that neuroleptic drugs might not induce but on the contrary remove deficits in PPI in schizophrenia patients. To our knowledge, there is no study that has systematically tested the influence of antipsychotic medication on PPI in humans. Thus the purpose of the present experiment was to assess the

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amount of PPI in schizophrenia patients who were either without any medication or were treated with either typical or atypical antipsychotic drugs. In contrast to animal experimentation, where the dose-dependent influence of a single drug can be tested systematically, medication in the clinic is predominantly used to reduce the patients’ psychopathology. Generally, the dose and type of psychoactive medication are adjusted to the severity of the patients’ symptoms. Therefore, the covariations between status of medication, severity of symptoms, and PPI were assessed in an exploratory analysis in our sample of schizophrenia patients.

Methods and Materials Participants Twenty-seven schizophrenia inpatients (10 women) participated in the experiment. The patients were diagnosed as having schizophrenia (in 15 cases a paranoid subtype was diagnosed; for the other patients a disorganized subtype (n ⫽ 2), a residual schizophrenia (n ⫽ 5), and a schizoaffective disorder mainly schizophrenic (n ⫽ 5) was diagnosed) according to criteria from the DSM-III-R (American Psychiatric Association 1987) or from the ICD-10 (World Health Organization 1992), respectively. Seven schizophrenia patients (three women) were tested immediately following their admission to the hospital before receiving any neuroleptic medication. Five of these patients had their first psychotic episode and had not been medicated before. The other two patients were neuroleptic-free for at least 6 months. Patients in a period of washout were explicitly not included in the study. Twenty patients (seven women) were tested after being treated with neuroleptic medication for 11 weeks on average (range: 2– 41). Eleven patients (five women, seven paranoid patients) received typical neuroleptic medication (i.e., haloperidol or fluphenazine), and the remaining nine patients (two women, four paranoid patients) were treated with atypical neuroleptics such as clozapine or zotepine. The mean daily doses were 20.2 (range: 5– 45) mg for typical and 311.1 (range: 175– 400) mg for atypical medication, respectively. Psychopathology was assessed for 12 medicated and five unmedicated schizophrenia patients at the time of testing, using the Positive and Negative Syndrome Scale (PANSS; Kay et al 1987). The unmedicated patients showed a significantly more severe positive syndrome compared with the medicated patients [t(15)⫽ 3.28, p ⬍ .01; d ⫽ 1.38; power ⫽ .67] (Table 1) . Neither the negative syndrome severity nor the scores on the general psychopathology scale differed between the unmedicated and medicated schizophrenia patients. Fourteen age-matched healthy controls (six women) were recruited from the hospital and laboratory staff. Mean ages in years (⫾ SE) were 32.6 (⫾ 2.4), 34.6 (⫾ 2.5), and 37.6 (⫾ 5.1) for healthy controls, medicated, and unmedicated patients, respectively. Gender was counterbalanced across groups (␹2 ⬍ 1). Psychopathology scores were only obtained for schizophrenia patients.

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Table 1. Unmedicated and Medicated Schizophrenia Patients’ Scores on the Positive, Negative, and General Psychopathology Scales of the Positive and Negative Syndrome Scale (Kay et al 1987)

Positive syndrome scale Negative syndrome scale General psychopathology scale

Unmedicated (n ⫽ 12)

Medicated (n ⫽ 5)

23.0 (⫾2.4) 19.4 (⫾2.7) 42.2 (⫾4.0)

13.6 (⫾1.6) 19.8 (⫾2.3) 35.8 (⫾2.7)

Stimulus Materials and Physiological Recording The acoustic startle-eliciting stimulus was a 50-msec burst of 105 dB[A] white noise generated by a Coulbourn Instruments (Allentown, PA) S81-02 and gated through a Coulbourn S82-24 amplifier. Prepulse stimuli were 1000-Hz tones with a duration of 20 msec and an intensity of 85 dB[A], generated by a Belco (New Castle, DE) audio generator. Startle and prepulse stimuli were both presented binaurally through headphones (Steintron, Conrad, Germany). The eyeblink component of the startle reflex was measured by recording the electromyogram (EMG) from the orbicularis oculi muscle beneath the left eye using miniature Ag/AgCl electrodes (Sensor Medics, Yorba Linda, CA) filled with Beckman electrolyte (Marquette, Milwaukee). The raw signal was amplified with a Coulbourn S75-01 bioamplifier, filtered through a bandpass of 90 –1000 Hz, and digitized at 1 kHz for 500 msec, beginning 100 msec before the onset of the startle probes.

Procedure After the participant gave informed consent, the physiological sensors were attached while the participant reclined in a comfortable chair. Each person was instructed that a series of tones and noises heard over the headphones could be ignored. After the presentation of a single noise burst to familiarize the person with the startle-eliciting stimulus, each 25-min test session consisted of 75 trials. In 60 of those trials, the onset of the prepulse stimuli preceded the onset of the startle-eliciting stimulus by 30, 60, 120, or 240 msec. There were 15 presentations of each of these four lead intervals. Fifteen startle probes were presented without prestimulation to determine the control level of responsivity. The intertrial intervals varied between 7 and 21 sec. The different lead intervals and the probe-alone trials were presented in a pseudorandom order.

Data Reduction and Response Definition Startle-response magnitude and latency were scored offline using the rectified and boxcar-filtered EMG (11-msec time window; Cook and Miller 1992). Responses starting 20 –100 msec after probe onset and reaching peak amplitude within 150 msec were identified as startle eyeblinks. Response magnitude was scored as the difference between onset and peak amplitude in microvolts (␮V). Onset latency was scored in msec. No detectable eyeblinks were scored as zero responses. Electromyogram baseline activity was measured for 20 msec after startle-probe onset. Trials with

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clear movement artifacts or excessive baseline activity were rejected. Missing values were replaced by the average of the values of that condition from the preceding and following trials. As in our previous experiments, results of various distribution analyses suggested that startle should be standardized. Therefore, blink amplitudes were standardized to z scores individually for each subject. Following the criteria defined by Graham and Murray (1977), the subjects were excluded from further analyses if 1) rejected trials exceeded 33% of all trials, 2) rejected trials exceeded 50% of the trials in any condition, or 3) less than 50% nonzero responses were elicited in the control trials. According to the third criterion, two unmedicated schizophrenia patients and one control subject had to be excluded from subsequent analyses. One further control subject was excluded due to more than 50% missing values. Thus, five unmedicated and 20 medicated schizophrenia patients and 12 control subjects were included in the statistical analyses. The ratio of discarded trials was overall 5.4% (150 out of 2775 trials) and was larger for the unmedicated schizophrenia patients (16.3%) than for medicated patients (4.5%) and controls (2.4%). The higher rate of rejected trials in the group of unmedicated patients was due to higher EMG baseline level in this group, which deteriorates the signal-to-noise ratio.

Data Analysis To assess the overall responsivity across groups, blink magnitudes were first analyzed for the probe-alone trials using a univariate analysis of variance (ANOVA) with group (unmedicated vs. medicated schizophrenia patients vs. controls) as a between factor. To test the overall effects of prestimulation, average startle-response magnitudes in the control condition were compared with the average blink magnitudes in each of the four prestimulus conditions. To compare the amount of inhibition across the four lead intervals, mean standardized difference scores were computed between the blink magnitudes in the probe-alone control condition and the blink-response magnitudes in each lead interval condition. These difference scores were analyzed within each group using the four lead conditions (30- vs. 60- vs. 120- vs. 240-msec lead intervals) as a repeated measures factor. According to previous research, strongest PPI was expected for the 60- and 120-msec lead intervals (Braff et al 1992; Graham 1975). Therefore, between-group comparisons of the amount of PPI were carried out for these two lead intervals. For all correlational analyses between the amount of PPI and the patients’ symptomatic status, the difference scores were averaged across the 60- and 120-msec lead condition. The unmedicated schizophrenia patients showed a higher EMG baseline level (3.7 ␮V) relative to the medicated patients (2.1 ␮V) and controls (2.0 ␮V). Furthermore, there was a small positive correlation (r ⫽ .20) between the baseline level and response magnitudes. Therefore, additional analyses of covariance (ANCOVA) with the baseline level as the covariate were computed in all between-group analyses. Results of these ANCOVAs are only reported if they differed from the findings in the ANOVAs. Onset latencies of the startle response were analyzed using the same analysis plan as for the magnitude data. Unlike the startle magnitudes, between-group comparisons were carried out for the 30-msec lead condition (see Graham and Murray 1977).

Results Startle Response Magnitude Startle response magnitudes elicited during the control condition did not differ between groups (F ⬍ 1, Eta2 ⫽ 0, power ⫽ .07) (means were 11.8, 14.0, and 12.8 ␮V for the unmedicated schizophrenia patients, medicated schizophrenia patients, and controls, respectively). As expected, the control subjects showed a significant reduction of their blink magnitudes relative to the control condition when prepulse stimuli preceded the startle-eliciting probe [Fs(1,11) ⫽ 10.36, 32.51, 28.94, and 8.62, p ⬍ .01; Eta2 ⫽ .49, .75, .73, and .44; power ⫽ .83, ⬎.99, ⬎.99, and .76 for the 30-, 60-, 120-, and 240-msec lead intervals, respectively]. As predicted, this PPI was strongest for the 60- and the 120-msec lead intervals [quadratic component: F(1,11) ⫽ 11.27, p ⬍ .01; Eta2 ⫽ .51; power ⫽ .86]. Medicated schizophrenia patients showed the same effects [Fs(1,19) ⫽ 10.6, 38.22, 33.65, and 11.04, p ⬍ 01; Eta2 ⫽ .36, .67, .64, and .37; power ⫽ .87, ⬎.99, ⬎.99, and .98 for the four different lead conditions]. Again, PPI was strongest for the 60- and 120-msec lead intervals [quadratic component: F(1,19) ⫽ 23.88, p⬍ .001; Eta2 ⫽ .56; power ⫽ ⬎.99]. By contrast, prestimulation did not affect startle magnitudes in the unmedicated schizophrenia patients for either lead condition (all Fs ⬍ 1, Eta2 ⬍ .13, power ⬍ .12). Between-group comparisons supported the specific deficit in prepulse inhibition in the unmedicated schizophrenia patients. An ANOVA comparing the amount of PPI in the 60and 120-msec lead conditions among all three groups revealed a significant overall group effect [F(2,34) ⫽ 5.44, p ⬍ .01; Eta2 ⫽ .24; power ⫽ .81]. Post hoc group comparisons showed that while the amount of PPI in the medicated patients did not differ from that in the controls (F ⬍ 1, Eta2 ⫽ .02, power ⫽ .16), unmedicated schizophrenia patients showed a significant deficit in prepulse inhibition relative to both controls [Group: F(1,15) ⫽ 11.42, p ⬍ .01; Eta2 ⫽ .43; power ⫽ .88] and medicated patients [Group: F(1,23) ⫽ 8.62, p ⬍ .01; Eta2 ⫽ .75; power ⫽ .80]. These group differences were stable throughout the entire experiment. A 3 (group) ⫻ 5 (blocks of three trials) ANOVA of the mean amount of PPI (mean differences between response magnitudes in the control condition and those in the 60- and 120-msec lead interval conditions) did not reveal any significant Group ⫻ Trialblock interaction (F ⬍ 1, Eta2 ⫽ .04, power ⫽ .33). Figure 1 illustrates the mean startle-response magnitudes for the different lead intervals and the control condition in all three groups.

Startle-Response Latency As for magnitudes, the latencies of blink onset did not differ across groups in the control condition [F(2,34) ⫽ 1.66, ns; Eta2 ⫽ .09; power ⫽ .32] (mean latencies were

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Figure 1. Mean (⫾ SE) blink magnitudes to startle probes presented at 30, 60, 120, or 240 msec after the onset of acoustic prepulses for unmedicated and medicated schizophrenia patients and healthy control subjects. The 0-msec lead interval corresponds to the control condition—i.e., startle probes were presented without prestimulation. Blink magnitudes are expressed as stardardized differences from the control condition with negative values reflecting blink inhibition.

50.0, 53.3, and 49.0 msec for the unmedicated and medicated schizophrenia patients and the control subjects, respectively). Relative to the control condition there was a clear facilitation of blink-onset latency if a prepulse preceded the startle-eliciting stimulus by 30 msec in controls [F(1,11) ⫽ 14.18, p ⬍ .01; Eta2 ⫽ .56; power ⫽ .93] and medicated schizophrenia patients [F(1,19) ⫽ 47.81, p ⬍ .001; Eta2 ⫽ .56; power ⫽ .93]. This latency modulation of the startle by prestimulation was absent in the unmedicated patients (F ⬍ 1, Eta2 ⫽ .02, power ⫽ .06). This pattern of results was again supported by the overall between-group analysis of the blink latencies in the 30-msec lead interval condition [Group: F(2,34) ⫽ 6.59, p ⬍ .01; Eta2 ⫽ .28; power ⫽ .88]. Post hoc analyses revealed that the unmedicated schizophrenia patients showed a lack of response facilitation at the 30-msec lead interval relative to both the controls [F(1,15) ⫽ 5.67, p ⬍ .05; Eta2 ⫽ .27; power ⫽ .60] and the medicated patients [F(1,23) ⫽ 11.86, p ⬍ .01; Eta2 ⫽ .34; power ⫽ .91]. Figure 2 illustrates the mean startle-onset latencies in msec for the three groups and the different lead conditions. The type of neuroleptic medication did not affect the modulation of the startle response magnitudes. The amount of PPI did not differ for the patients receiving either typical or atypical neuroleptic medication. Accordingly, no such differences were observed for response latencies.

Psychopathology and Startle Modulation The unmedicated schizophrenia patients showed a significantly severer positive syndrome compared with the medicated patients as assessed by the PANSS, and they

also exhibited a clear deficit in PPI [Group1: F(1,13) ⫽ 6.35, p ⬍ .05; Eta2 ⫽ .33; power ⫽ .64]. To test whether the lack of startle inhibition was related to the severity of the positive syndrome, ANCOVAs were computed. Using the severity of the positive syndrome as a covariate, the difference in prepulse inhibition between the medicated and unmedicated schizophrenia patients was no longer significant. By contrast, if the severity of the negative syndrome or the general psychopathology was used as a covariate, the group differences remained significant in this comparison [F(1,12) ⫽ 6.91, p ⬍ .05; Eta2 ⫽ .37; power ⫽ .67 for the negative syndrome scale as covariate] [F(1,12) ⫽ 5.81, p ⬍ .05; Eta2 ⫽ .33; power ⫽ .60 for general psychopathology as covariate]. The relationship between severity of the positive syndrome and the deficit in PPI corresponded to a significant Spearman correlation coefficient of rs ⫽ .66 (p ⬍ .01). The patients whose positive symptoms were rated as more severe showed less PPI2 in the 60- and 120-msec lead conditions (see Figure 3). By contrast, no significant correlations were found between the amount of PPI and the severity of the negative syndrome (rs ⫽ .11, p ⫽ .70) or the severity of general psychopathology (rs ⫽ .49, p ⫽ .06). Moreover, PPI was 1

Twelve medicated and three unmedicated patients were included in this comparison (the startle data of two unmedicated schizophrenia patients had to be discarded due to nonresponsiveness). 2 Prepulse inhibition is expressed as the mean standardized difference between the blink magnitudes in the control condition and those in the 60- and 120-msec lead intervals—i.e., less PPI corresponds to numerically higher values. The correlations between the amount of PPI and the psychopathology scores were also significant, if the difference scores for each of the two lead intervals were analyzed (rs ⫽ .67, p ⬍ .01 for the 60-msec and rs ⫽ .62, p ⬍ .02 for the 120-msec lead interval).

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Figure 2. Mean (⫾ SE) blink onset latencies to startle probes presented at 30, 60, 120, or 240 msec after the onset of acoustic prepulses for unmedicated and medicated schizophrenia patients and healthy control subjects. The 0-msec lead interval corresponds to the control condition—i.e., startle probes were presented without prestimulation. Blink-onset latencies are expressed as differences from the control condition in msec with negative values reflecting blink facilitation.

not significantly related to the dose ⫻ duration interaction of neuroleptic medication as assessed by nonlinear regression analyses (R2 ⬍ 0 for typical and atypical medication, respectively).

Discussion Sensorimotor Gating and Schizophrenia The unmedicated schizophrenia patients showed a clear deficit in PPI relative to the control subjects, supported by both between- and within-group comparisons. This reduced inhibition of the startle response after weak prestimulation was not due to general deficits in startle reactivity in these patients, since the normal controls and schizophrenia patients did not differ in startleresponse magnitudes to the probe-alone presentations. These data support the findings of Braff and collaborators (Braff et al 1978, 1992; Grillon et al 1992) indicating that schizophrenia patients might have deficits in automatic sensorimotor gating. On the other hand, for the medicated schizophrenia patients, the blink magnitudes were substantially reduced if a tone preceded the startle-eliciting stimulus at lead intervals of 60 and 120 msec. The amount of PPI for these patients was identical to that obtained in the control group. The findings in this patient group thus confirm the results from Dawson and collaborators (Dawson et al 1993; Hazlett et al 1998) indicating that schizophrenia patients do show the same amount of PPI compared with controls in the so-called “passive attention paradigm”—i.e., when subjects were instructed that the tones that served as prestimuli were task irrelevant and

could therefore be ignored. In these studies, differences between schizophrenia patients and healthy controls were only obtained in the “active attention paradigm.” In this paradigm, healthy controls exhibited a relative enhancement of PPI when they were instructed to selectively attend to the prepulses, whereas schizophrenia patients failed to show this attentional modulation of PPI (for review see Dawson et al 1997). The findings in our experiment suggest that differences in the type of paradigm might not be the main reason for the different findings of Braff et al and Dawson and coworkers. Using the same experimental procedure in our study, the unmedicated schizophrenia patients showed substantial impairment of PPI, while the medicated patients did not differ from the controls. These findings suggest that medication status might be important in modulating the amount of PPI in schizophrenia patients when no explicit instructions are given to either attend to or ignore the prepulse stimuli. On the other hand, Hazlett et al (1998) found no differences between unmedicated schizophrenia patients and normal controls in a passive attention condition. However, 81% of the unmedicated patients had received neuroleptic medication before with a substantial variation of the periods of washout. Moreover, there were also strong differences in the total psychopathology scores within the sample of schizophrenia patients in that study. Thus, besides the medication status, specific patient characteristics might also be important in modulating the amount of PPI. The data from our study suggest that patients’ symptomatic status might be an important factor.

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Figure 3. Correlation between the amount of prepulse inhibition and the positive syndrome severity. Each data point represents one schizophrenia patient. The amount of prepulse inhibition is expressed as the mean standardized difference score of the blink magnitudes at the 60- and 120-msec lead intervals. Positive syndrome severity relates to the individual score in the corresponding subscale (range: 7– 49) of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia (Kay et al 1987). The dashed line reflects the linear regression.

Prepulse Inhibition and Psychopathology The differences in PPI between the medicated and unmedicated schizophrenia patients were no longer significant if the severity of positive symptoms was used as a covariate in the statistical analyses—i.e., the correlation between the amount of PPI and the rated severity of the patients’ positive symptoms was significant. By contrast, the general psychopathology scores and the negative syndrome showed only a moderate relationship to the amount of PPI in the entire group of schizophrenia patients, which, however, was not significant. This was also supported in a recent study by Volz et al (M. Volz et al, unpublished data, 1999), who found no deficits in PPI in a sample of 49 schizophrenia outpatients who exhibited pronounced negative symptoms but showed virtually no florid psychopathology at the time of testing. Moreover, in our study three patients who despite being medicated exhibited the same amount of positive symptoms as unmedicated schizophrenia patients also showed the same deficits in PPI as the unmedicated patients. This finding suggests that in cases wherein the neuroleptic treatment is not effective in reducing the positive symptoms, schizophrenia patients show an impairment of PPI. The data from our experiment suggest that PPI might be a useful prescreening method for testing the clinical potential of neuroleptics. Medication that effectively reduced positive symptoms also removed PPI deficits, whereas drugs that were clinically less effective also failed to restore PPI. These data are in line with animal models of PPI deficits. In rats, a systemic administration of the indirect dopamine agonist amphetamine as well as the noncompetitive NMDA antagonist phencyclidine (PCP)

induced deficits in PPI (Mansbach and Geyer 1989; Mansbach et al 1988). While pretreatment with typical neuroleptics restores amphetamine-induced PPI deficits, these drugs are ineffective in restoring PCP-induced PPI deficits. Phencyclidine-induced deficits in PPI can, however, be antagonized by the atypical antipsychotic clozapine, which has blocking properties to multiple receptors in various neurotransmitter systems (Bakshi et al 1994). These findings suggest that there is not a general effect of neuroleptic medication on PPI; rather, neuroleptic medication is only effective if it acts on the system where the disturbance occurred. In our study the medicated schizophrenia patients showed overall less positive symptoms compared with the unmedicated patients. However, the severity of the positive syndrome varied substantially within the group of medicated patients, indicating that some patients did not show an adequate clinical response to their medication. These patients also exhibited clear deficits in PPI. Although there were substantial differences in the duration of treatment within the group of medicated patients, treatment duration cannot completely explain the differences in the clinical response. For the three medicated patients showing enhanced psychopathology scores and clear PPI deficits, the treatment durations were 2, 7, and 25 weeks. These findings question the hypothesis that simple blockade of the receptors is sufficient to reduce PPI deficits in these patients. Future research should test more explicitly the time course of recovery of PPI with regard to treatment duration, the effects of different neuroleptics, and their doses and interactions with the clinical drug response— i.e., changes in psychopathology. Moreover, future studies

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should also include more chronically ill schizophrenia patients to explore PPI in patients who are less responsive to neuroleptic medication. Supporting the findings from Dawson and his collaborators, symptomatic medicated schizophrenia patients did not differ in their PPI relative to the controls in our study—i.e., when participants were not instructed to selectively attend to or ignore the prepulse stimuli. These results are also concordant with recent findings from Hazlett et al (1998), suggesting that deficits in automatic sensorimotor gating might not be a general trait-linked, stable vulnerability indicator for schizophrenia. The mixed results regarding PPI deficits in psychosis-prone college students support this notion (Cadenhead et al 1996). On the other hand, one has to acknowledge that the lack of a strong correlation between PPI deficits and schizotypy or psychosis proneness scales does not mean that PPI impairment is not a trait marker, since PPI deficits might be associated with one gene and schizotypy or psychosis proneness might reflect another inherited trait, but both markers might be related to schizophrenia. However, before drawing any definite conclusions it would be desirable to test PPI in a clinical group of schizophrenia patients and also to assess PPI in their first-degree relatives. Moreover, it would also be interesting to relate PPI to other psychophysiological variables that have been used to identify vulnerability markers for schizophrenia— e.g., the eye-tracking performance (Iacono 1998). Although no relations were found between PPI and the suppression of the P50 component of the evoked potential in a doubleclick paradigm (Schwarzkopf et al 1993), the performance in negative priming or the Stroop test (Swerdlow et al 1995a) in normal volunteers, a covariation between PPI and behavioral measures of distractibility was observed in a sample of chronic schizophrenia patients (Karper et al 1996).

Caveats and Conclusions One caveat is that the effect of medication and psychopathology was tested in a relatively small sample of schizophrenia patients in a between-subject design. Therefore, it is difficult to determine whether medication effects or patient characteristics were responsible for the PPI deficits or the lack thereof. This point is all the more important considering that PPI was tested in a quasi-experimental ex post facto design, and patients were not assigned randomly to the different conditions due to clinical reasons. On the other hand, PPI deficits correlated significantly with the severity of the patients’ positive symptoms, but not with the negative syndrome and only moderately with the general psychopathology. The present covariations between medication, psychopathology, and PPI, however,

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need to be replicated in a within-subjects design in future research. Preliminary data of a single case yielded promising results. One unmedicated schizophrenia patient who showed no PPI (⌬z ⫽ .15) in a first test session also exhibited severe positive symptoms (the positive syndrome score was 19). When tested again 38 days later after being treated with fluphenazine, the patient’s positive symptom score was reduced to 14 and the same patient showed PPI (⌬z ⫽ ⫺.30) at the second test session. Our data support the notion that deficits in sensorimotor gating might be related to sensory overload, cognitive fragmentation, and thought disorder—i.e., characteristic symptoms of an active episode of the disorder. However, in the current sample of medicated and unmedicated schizophrenia patients, the severity of positive symptoms accounted for only about 39% of the variance of PPI, suggesting that factors other than psychopathology are influencing the amount of PPI as well. It has been demonstrated that gender accounts for differences in the amount of PPI. In three studies, Swerdlow and colleagues found that men exhibited stronger PPI than women (Swerdlow et al 1993a, 1995a, 1997), a finding that was replicated in the present study, but only for the healthy controls. No gender effects occurred in the schizophrenia patients. This finding must be interpreted cautiously because we investigated only a small sample of female subjects and we did not assess the menstrual cycle for these participants. It has been shown that PPI covaries with the menstrual cycle (Swerdlow et al 1997). Reduced PPI has also been reported in other clinical populations as well, including patients with Huntington’s disease (Swerdlow et al 1995b), obsessive– compulsive disorder (Swerdlow et al 1993b), Tourette’s syndrome with attention-deficit/hyperactivity disorder (Castellanos et al 1996), and nocturnal enuresis (Ornitz et al 1992). As revealed by animal research, a complex corticolimbic striatopallidal circuitry modulates the primary PPI pathway via a projection to the pedunculopontine tegmental nucleus, suggesting that a variety of neurophysiological dysregulations may result in deficits in PPI (Koch and Schnitzler 1997; Swerdlow et al 1992). In our study, clear deficits in PPI were obtained for unmedicated schizophrenia patients. Moreover, the amount of PPI covaried with the severity of positive symptoms. Those patients who did not respond very well to the antipsychotic medication also showed a clear deficit in PPI, suggesting that PPI might be used as a method to assess the clinical potential of neuroleptic medication.

This research was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Society) to Alfons Hamm (Ha 1593/6-2; Ha 1593/10-2).

Prepulse Inhibition and Schizophrenia

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