Pii: s0006-3223(99)00229-2

Effective Neuroleptic Medication Removes PrepulseInhibition Deficits in Schizophrenia Patients Almut I. Weike, Ulrike Bauer, and Alfons O. Hamm Background: The magnitude of the startle eyeblink re-
in focussing their attention to relevant stimuli. This is sponse is reduced if the startle eliciting stimulus is shortly indicated by longer reaction times in cross-modal reaction preceded by another stimulus. There is evidence that time tasks or impairments in the Continuous Performance schizophrenia patients exhibit impairments in this so- Task (for reviews see Braff 1993; Braff et al 1991; called prepulse inhibition. Our study investigated whether Nuechterlein and Dawson 1984). Because schizophrenia prepulse inhibition is affected by neuroleptic drug treat- patients are unable to screen out irrelevant stimuli, they ment as is suggested by animal research. seem to be vulnerable to stimulus inundation, particularly Methods: Prepulse inhibition was tested in five unmedi-
if external stimuli are presented in rapid succession. In cated and 20 medicated inpatients with schizophrenia, and such conditions the response to a second stimulus has to be inhibited or attenuated to protect the processing of the first Results: The unmedicated schizophrenia patients showed
stimulus. Schizophrenia patients reliably exhibit a deficit a strong impairment of sensorimotor gating as indexed by in effectively inhibiting the processing of a second disrup- the absence of prepulse inhibition. By contrast, the med- tive stimulus, as assessed by various tasks. These include icated patients showed a pronounced prepulse inhibitionthat did not differ from that of the normal controls. There visual backward-masking performance (Braff et al 1991; was a substantial covariation between the rated severity of Rund 1993) and the decline in amplitude of the P50 the positive syndrome and the amount of prepulse inhibi- component of the event-related potential to the second of tion—i.e., the patients whose positive symptoms were a pair of clicks (Freedman et al 1987). The modulation of rated as more severe showed less prepulse inhibition. the startle response by weak prestimulation has also been Conclusions: These data suggest that the impaired sen-
used to assess these deficits in information processing in sorimotor gating of schizophrenia patients is not a stable vulnerability indicator, but may rather be related to the The measurement of startle modulation to study these positive syndrome and may be improved by treatments dysfunctions has a number of advantages. First, the startle with neuroleptic medication. Biol Psychiatry 2000;47: reflex is relatively free from voluntary control and requires 61–70 1999 Society of Biological Psychiatry minimal effort from the subject. Second, startle modula-tion is particularly amenable to animal modeling because Key Words: Schizophrenia, prepulse inhibition, sensori-
it occurs in infrahuman species as well. Third, the neural motor gating, startle eyeblink, neuroleptic medication, circuits mediating evocation and modulation of the acous- tic startle response are increasingly well understood(Davis 1997). Finally, startle modulation is influenced bypsychoactive drugs and by various manipulations of neu- Introduction
rotransmitter systems (see Koch and Schnitzler 1997), Dysfunctions in attention and information processing whichmayallowonetotentativelylinkstartlemodulation have long been considered a hallmark of schizophre- deficits in schizophrenia patients to underlying neurobio- nia. By using a wide range of different experimental techniques to quantify these dysfunctions, it has been The magnitude of the startle response—a fast protective demonstrated that schizophrenia patients have difficulties reflex to an unexpected intense stimulus with rapid on-set—is reduced if weak sensory events (prepulses) arepresented at brief intervals (i.e., between 30 and 500 msec) From the Department of Psychology, University of Greifswald, Greifswald (AIW, prior to the startle-eliciting stimuli. This phenomenon is AOH) and the Department of Psychiatry, University of Giessen, Giessen (UB), called prepulse inhibition (PPI) and has been observed Address reprint requests to Prof. Dr. Alfons Hamm, Ernst-Moritz-Arndt-Universi- across a wide range of stimulus intensities and modalities taet Greifswald, Institut fu¨r Psychologie, Franz-Mehring-Strasse 47, 17487 in animals (Hoffman 1997; Hoffman and Ison 1980, 1992) Received March 5, 1999; revised July 28, 1999; accepted August 10, 1999.
and humans (see reviews by Anthony 1985; Filion et al 1998; Graham 1975). Prepulse inhibition is very robust normal controls, there was no difference in PPI between and occurs in 90 –100% of normal subjects who exhibit a the groups, if an insignificant (to be ignored) tone stimulus normal startle eyeblink response. Prepulse inhibition preceded the startle-eliciting noise burst (Dawson et al seems to be a rather automatic and low-level phenomenon, 1993). Reduced PPI in schizophrenia patients compared since it can be obtained during sleep (Silverstein et al with controls was only observed when individuals were 1980) and at the very first presentation of the lead instructed to selectively attend to the prepulse stimulus.
stimulus. According to Graham (1975, 1992) and Braff These findings were recently replicated by Hazlett and and colleagues (Braff 1985; Braff et al 1991; Geyer and coworkers comparing schizophrenia patients during the Braff 1987), PPI may reflect the action of a sensorimotor period of washout with normal volunteers; again, normal gating system that operates to protect early preattentive controls exhibited stronger PPI following the to-be-at- processing of a weak stimulus (prepulse) by inhibiting or tended tone, compared with the to-be-ignored tone, at the attenuating the disruptive effects of the intense startle- 120-msec lead interval, while schizophrenia patients failed to show such attentional modulation of startle inhibition Braff and coworkers were the first to demonstrate that schizophrenia patients have a deficit in this sensorimotor One reason for the differences between the results of gating mechanism (Braff et al 1978). In that study, a Braff and collaborators and those obtained by Dawson et continuous mild tone (71 dB) served as the prepulse and a al might be that the instruction to ignore a prepulse burst of white noise as the startle stimulus. Inpatients with stimulus is not completely comparable to the condition schizophrenia showed impaired PPI relative to normal where individuals process the prepulse passively—i.e., controls, especially at the 60- and 120-msec lead intervals.
without any specific task to allocate their attention either These findings were replicated and extended by two towards or away from that stimulus. In addition to these additional studies, showing that reduced PPI in inpatients procedural differences, the severity of psychopathology with schizophrenia can also be obtained with a tactile and medication status of the schizophrenia patient samples startle-eliciting stimulus (Braff et al 1992) and with varied substantially across studies. Dawson and colleagues different prepulse intensities, ranging from 75 to 90 dB studied relatively asymptomatic schizophrenia outpatients (Grillon et al 1992). Deficient PPI was also found for who were either off all medication or on a low to moderate inpatients and outpatients diagnosed as having a schizo- dose of neuroleptic medication (Dawson et al 1993). By typal personality disorder (Cadenhead et al 1993) and for contrast, Braff and collaborators tested schizophrenia in- college students scoring high on perceptual aberration patients treated with relatively high doses of antipsychotic (Simons and Giardina 1992). Moreover, Swerdlow and medication (chlorpromazine equivalents varied in a range coworkers found reduced PPI in individuals who were of 1640 to 2245 mg between studies).
classified as psychosis-prone based on theoretically and Evidence from animal experimentation suggests that it empirically derived Minnesota Multiphasic Personality is unlikely that neuroleptic medication might induce def- Inventory (MMPI) criteria (Swerdlow et al 1995a). These icits in PPI. By contrast, PPI deficits induced by apomor- data suggest that the deficit in the sensorimotor gating phine can be removed by haloperidol, which blocks the mechanism might be a trait-linked vulnerability for devel- dopamine D2 receptors (Koch and Bubser 1994; Mans- oping thought disorders or cognitive fragmentation, symp- bach et al 1988). Moreover, PPI deficits induced by the toms characteristic of schizophrenia disorders (Braff 1993; noncompetitive NMDA antagonist phencyclidine are re- versed by clozapine (Bakshi et al 1994). These substances The relationship between reduced PPI and psychosis are frequently used as typical and atypical antipsychotic proneness in “normal” volunteers, however, is not a drugs in humans. Findings such as these have been reliable finding. In three studies, no differences in PPI incorporated into an animal model for PPI deficits which were found for individuals scoring high or low on states that the nucleus accumbens is the core structure in perceptual aberration (Blumenthal and Creps 1994; the regulation of PPI in the context of dopaminergic and Cadenhead et al 1996; Lipp et al 1994). Strikingly, glutamatergic dysregulations (for reviews see Geyer et al although individuals scoring high on perceptual aberra- 1990; Koch and Schnitzler 1997; and Swerdlow et al tion and magical ideation also scored higher on the MMPI psychoticism subscale and showed more mild These animal data suggest that neuroleptic drugs might psychotic symptoms as assessed by clinical interview, not induce but on the contrary remove deficits in PPI in the PPI of these subjects did not differ from that of a schizophrenia patients. To our knowledge, there is no control group (Cadenhead et al 1996).
study that has systematically tested the influence of Moreover, even when clinically diagnosed but relatively antipsychotic medication on PPI in humans. Thus the asymptomatic schizophrenia patients were compared with purpose of the present experiment was to assess the amount of PPI in schizophrenia patients who were either Table 1. Unmedicated and Medicated Schizophrenia Patients’ without any medication or were treated with either typical Scores on the Positive, Negative, and GeneralPsychopathology Scales of the Positive and Negative or atypical antipsychotic drugs. In contrast to animal experimentation, where the dose-dependent influence of asingle drug can be tested systematically, medication in the clinic is predominantly used to reduce the patients’ psy- chopathology. Generally, the dose and type of psychoac- tive medication are adjusted to the severity of the patients’ symptoms. Therefore, the covariations between status of medication, severity of symptoms, and PPI were assessedin an exploratory analysis in our sample of schizophreniapatients.
Stimulus Materials and Physiological Recording The acoustic startle-eliciting stimulus was a 50-msec burst of 105dB[A] white noise generated by a Coulbourn Instruments (Allen-town, PA) S81-02 and gated through a Coulbourn S82-24 Methods and Materials
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 Twenty-seven schizophrenia inpatients (10 women) participated were both presented binaurally through headphones (Steintron, in the experiment. The patients were diagnosed as having Conrad, Germany). The eyeblink component of the startle reflex schizophrenia (in 15 cases a paranoid subtype was diagnosed; for was measured by recording the electromyogram (EMG) from the the other patients a disorganized subtype (n ϭ 2), a residual orbicularis oculi muscle beneath the left eye using miniature schizophrenia (n ϭ 5), and a schizoaffective disorder mainly Ag/AgCl electrodes (Sensor Medics, Yorba Linda, CA) filled schizophrenic (n ϭ 5) was diagnosed) according to criteria from with Beckman electrolyte (Marquette, Milwaukee). The raw the DSM-III-R (American Psychiatric Association 1987) or from signal was amplified with a Coulbourn S75-01 bioamplifier, the ICD-10 (World Health Organization 1992), respectively.
filtered through a bandpass of 90 –1000 Hz, and digitized at 1 Seven schizophrenia patients (three women) were tested imme- kHz for 500 msec, beginning 100 msec before the onset of the diately following their admission to the hospital before receiving any neuroleptic medication. Five of these patients had their firstpsychotic episode and had not been medicated before. The othertwo patients were neuroleptic-free for at least 6 months. Patients in a period of washout were explicitly not included in the study.
After the participant gave informed consent, the physiological Twenty patients (seven women) were tested after being treated sensors were attached while the participant reclined in a com- with neuroleptic medication for 11 weeks on average (range: fortable chair. Each person was instructed that a series of tones 2– 41). Eleven patients (five women, seven paranoid patients) and noises heard over the headphones could be ignored. After the received typical neuroleptic medication (i.e., haloperidol or presentation of a single noise burst to familiarize the person with fluphenazine), and the remaining nine patients (two women, four the startle-eliciting stimulus, each 25-min test session consisted paranoid patients) were treated with atypical neuroleptics such as of 75 trials. In 60 of those trials, the onset of the prepulse stimuli clozapine or zotepine. The mean daily doses were 20.2 (range: preceded the onset of the startle-eliciting stimulus by 30, 60, 120, 5– 45) mg for typical and 311.1 (range: 175– 400) mg for atypical or 240 msec. There were 15 presentations of each of these four lead intervals. Fifteen startle probes were presented without Psychopathology was assessed for 12 medicated and five prestimulation to determine the control level of responsivity. The unmedicated schizophrenia patients at the time of testing, using intertrial intervals varied between 7 and 21 sec. The different the Positive and Negative Syndrome Scale (PANSS; Kay et al lead intervals and the probe-alone trials were presented in a 1987). The unmedicated patients showed a significantly more severe positive syndrome compared with the medicated patients[t(15)ϭ 3.28, p Ͻ .01; d ϭ 1.38; power ϭ .67] (Table 1) .
Data Reduction and Response Definition Neither the negative syndrome severity nor the scores on thegeneral psychopathology scale differed between the unmedicated Startle-response magnitude and latency were scored offline using and medicated schizophrenia patients.
the rectified and boxcar-filtered EMG (11-msec time window; Fourteen age-matched healthy controls (six women) were Cook and Miller 1992). Responses starting 20 –100 msec after recruited from the hospital and laboratory staff. Mean ages in probe onset and reaching peak amplitude within 150 msec were years (Ϯ SE) were 32.6 (Ϯ 2.4), 34.6 (Ϯ 2.5), and 37.6 (Ϯ 5.1) identified as startle eyeblinks. Response magnitude was scored as for healthy controls, medicated, and unmedicated patients, re- the difference between onset and peak amplitude in microvolts spectively. Gender was counterbalanced across groups (␹2 Ͻ 1).
(␮V). Onset latency was scored in msec. No detectable eyeblinks Psychopathology scores were only obtained for schizophrenia were scored as zero responses. Electromyogram baseline activity was measured for 20 msec after startle-probe onset. Trials with clear movement artifacts or excessive baseline activity were rejected. Missing values were replaced by the average of thevalues of that condition from the preceding and following trials.
As in our previous experiments, results of various distribution Startle response magnitudes elicited during the control con- analyses suggested that startle should be standardized. Therefore, dition did not differ between groups (F Ͻ 1, Eta2 ϭ 0, power blink amplitudes were standardized to z scores individually for ϭ .07) (means were 11.8, 14.0, and 12.8 ␮V for the unmedicated schizophrenia patients, medicated schizophre- Following the criteria defined by Graham and Murray (1977), the subjects were excluded from further analyses if 1) rejected trials nia patients, and controls, respectively). As expected, the exceeded 33% of all trials, 2) rejected trials exceeded 50% of the control subjects showed a significant reduction of their blink trials in any condition, or 3) less than 50% nonzero responses were magnitudes relative to the control condition when prepulse elicited in the control trials. According to the third criterion, two stimuli preceded the startle-eliciting probe [Fs(1,11) ϭ 10.36, unmedicated schizophrenia patients and one control subject had to 32.51, 28.94, and 8.62, p Ͻ .01; Eta2 ϭ .49, .75, .73, and .44; be excluded from subsequent analyses. One further control subject power ϭ .83, Ͼ.99, Ͼ.99, and .76 for the 30-, 60-, 120-, and was excluded due to more than 50% missing values. Thus, five 240-msec lead intervals, respectively]. As predicted, this PPI unmedicated and 20 medicated schizophrenia patients and 12 was strongest for the 60- and the 120-msec lead intervals control subjects were included in the statistical analyses. The ratio of [quadratic component: F(1,11) ϭ 11.27, p Ͻ .01; Eta2 ϭ .51; discarded trials was overall 5.4% (150 out of 2775 trials) and was power ϭ .86]. Medicated schizophrenia patients showed the larger for the unmedicated schizophrenia patients (16.3%) than formedicated patients (4.5%) and controls (2.4%). The higher rate of same effects [Fs(1,19) ϭ 10.6, 38.22, 33.65, and 11.04, p Ͻ rejected trials in the group of unmedicated patients was due to 01; Eta2 ϭ .36, .67, .64, and .37; power ϭ .87, Ͼ.99, Ͼ.99, higher EMG baseline level in this group, which deteriorates the and .98 for the four different lead conditions]. Again, PPI was strongest for the 60- and 120-msec lead intervals [quadraticcomponent: F(1,19) ϭ 23.88, pϽ .001; Eta2 ϭ .56; power ϭ Ͼ.99]. By contrast, prestimulation did not affect startlemagnitudes in the unmedicated schizophrenia patients for To assess the overall responsivity across groups, blink magnitudes either lead condition (all Fs Ͻ 1, Eta2 Ͻ .13, power Ͻ .12).
were first analyzed for the probe-alone trials using a univariate Between-group comparisons supported the specific deficit in analysis of variance (ANOVA) with group (unmedicated vs. med-icated schizophrenia patients vs. controls) as a between factor. To prepulse inhibition in the unmedicated schizophrenia pa- test the overall effects of prestimulation, average startle-response tients. An ANOVA comparing the amount of PPI in the 60- magnitudes in the control condition were compared with the average and 120-msec lead conditions among all three groups re- blink magnitudes in each of the four prestimulus conditions. To vealed a significant overall group effect [F(2,34) ϭ 5.44, p Ͻ compare the amount of inhibition across the four lead intervals, .01; Eta2 ϭ .24; power ϭ .81]. Post hoc group comparisons mean standardized difference scores were computed between the showed that while the amount of PPI in the medicated blink magnitudes in the probe-alone control condition and the patients did not differ from that in the controls (F Ͻ 1, Eta2 ϭ blink-response magnitudes in each lead interval condition. These .02, power ϭ .16), unmedicated schizophrenia patients difference scores were analyzed within each group using the four showed a significant deficit in prepulse inhibition relative to lead conditions (30- vs. 60- vs. 120- vs. 240-msec lead intervals) asa repeated measures factor. According to previous research, stron- both controls [Group: F(1,15) ϭ 11.42, p Ͻ .01; Eta2 ϭ .43; gest PPI was expected for the 60- and 120-msec lead intervals (Braff power ϭ .88] and medicated patients [Group: F(1,23) ϭ et al 1992; Graham 1975). Therefore, between-group comparisons 8.62, p Ͻ .01; Eta2 ϭ .75; power ϭ .80]. These group of the amount of PPI were carried out for these two lead intervals.
differences were stable throughout the entire experiment. A 3 For all correlational analyses between the amount of PPI and the (group) ϫ 5 (blocks of three trials) ANOVA of the mean patients’ symptomatic status, the difference scores were averaged amount of PPI (mean differences between response magni- across the 60- and 120-msec lead condition.
tudes in the control condition and those in the 60- and The unmedicated schizophrenia patients showed a higher EMG 120-msec lead interval conditions) did not reveal any signif- baseline level (3.7 ␮V) relative to the medicated patients (2.1 ␮V) icant Group ϫ Trialblock interaction (F Ͻ 1, Eta2 ϭ .04, and controls (2.0 ␮V). Furthermore, there was a small positive power ϭ .33). Figure 1 illustrates the mean startle-response correlation (r ϭ .20) between the baseline level and responsemagnitudes. Therefore, additional analyses of covariance (AN- magnitudes for the different lead intervals and the control COVA) with the baseline level as the covariate were computed in all between-group analyses. Results of these ANCOVAs are onlyreported 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 As for magnitudes, the latencies of blink onset did not magnitudes, between-group comparisons were carried out for the differ across groups in the control condition [F(2,34) ϭ 30-msec lead condition (see Graham and Murray 1977).
1.66, ns; Eta2 ϭ .09; power ϭ .32] (mean latencies were Figure 1. Mean (Ϯ SE) blink magnitudes tostartle probes presented at 30, 60, 120, or 240msec after the onset of acoustic prepulses forunmedicated and medicated schizophrenia pa-tients and healthy control subjects. The 0-mseclead interval corresponds to the control condi-tion—i.e., startle probes were presented with-out prestimulation. Blink magnitudes are ex-pressed as stardardized differences from thecontrol condition with negative values reflect-ing blink inhibition.
50.0, 53.3, and 49.0 msec for the unmedicated and also exhibited a clear deficit in PPI [Group1: F(1,13) ϭ medicated schizophrenia patients and the control subjects, 6.35, p Ͻ .05; Eta2 ϭ .33; power ϭ .64]. To test whether respectively). Relative to the control condition there was a the lack of startle inhibition was related to the severity of clear facilitation of blink-onset latency if a prepulse the positive syndrome, ANCOVAs were computed. Using preceded the startle-eliciting stimulus by 30 msec in the severity of the positive syndrome as a covariate, the controls [F(1,11) ϭ 14.18, p Ͻ .01; Eta2 ϭ .56; power ϭ difference in prepulse inhibition between the medicated .93] and medicated schizophrenia patients [F(1,19) ϭ and unmedicated schizophrenia patients was no longer 47.81, p Ͻ .001; Eta2 ϭ .56; power ϭ .93]. This latency significant. By contrast, if the severity of the negative modulation of the startle by prestimulation was absent in syndrome or the general psychopathology was used as a the unmedicated patients (F Ͻ 1, Eta2 ϭ .02, power ϭ covariate, the group differences remained significant in .06). This pattern of results was again supported by the this comparison [F(1,12) ϭ 6.91, p Ͻ .05; Eta2 ϭ .37; overall between-group analysis of the blink latencies in the power ϭ .67 for the negative syndrome scale as covariate] 30-msec lead interval condition [Group: F(2,34) ϭ 6.59, p [F(1,12) ϭ 5.81, p Ͻ .05; Eta2 ϭ .33; power ϭ .60 for Ͻ .01; Eta2 ϭ .28; power ϭ .88]. Post hoc analyses general psychopathology as covariate]. The relationship revealed that the unmedicated schizophrenia patients between severity of the positive syndrome and the deficit showed a lack of response facilitation at the 30-msec lead in PPI corresponded to a significant Spearman correlation interval relative to both the controls [F(1,15) ϭ 5.67, p Ͻ coefficient of r ϭ .66 (p Ͻ .01). The patients whose .05; Eta2 ϭ .27; power ϭ .60] and the medicated patients positive symptoms were rated as more severe showed less [F(1,23) ϭ 11.86, p Ͻ .01; Eta2 ϭ .34; power ϭ .91].
PPI2 in the 60- and 120-msec lead conditions (see Figure Figure 2 illustrates the mean startle-onset latencies in msec 3). By contrast, no significant correlations were found for the three groups and the different lead conditions.
between the amount of PPI and the severity of the negative The type of neuroleptic medication did not affect the syndrome (r ϭ .11, p ϭ .70) or the severity of general modulation of the startle response magnitudes. The amount psychopathology (r ϭ .49, p ϭ .06). Moreover, PPI was of PPI did not differ for the patients receiving either typical oratypical neuroleptic medication. Accordingly, no such differ- ences were observed for response latencies.
Twelve medicated and three unmedicated patients were included in this compar- ison (the startle data of two unmedicated schizophrenia patients had to bediscarded due to nonresponsiveness).
2Prepulse inhibition is expressed as the mean standardized difference between the Psychopathology and Startle Modulation blink magnitudes in the control condition and those in the 60- and 120-mseclead intervals—i.e., less PPI corresponds to numerically higher values. The The unmedicated schizophrenia patients showed a signif- correlations between the amount of PPI and the psychopathology scores were icantly severer positive syndrome compared with the also significant, if the difference scores for each of the two lead intervals wereanalyzed (r ϭ .67, p Ͻ .01 for the 60-msec and r ϭ .62, p Ͻ .02 for the medicated patients as assessed by the PANSS, and they Figure 2. Mean (Ϯ SE) blink onset laten-cies to startle probes presented at 30, 60,120, or 240 msec after the onset of acousticprepulses for unmedicated and medicatedschizophrenia patients and healthy controlsubjects. The 0-msec lead interval corre-sponds to the control condition—i.e., star-tle probes were presented without pre-stimulation.
expressed as differences from the controlcondition in msec with negative valuesreflecting blink facilitation.
not significantly related to the dose ϫ duration interaction could therefore be ignored. In these studies, differences of neuroleptic medication as assessed by nonlinear regres- between schizophrenia patients and healthy controls sion analyses (R2 Ͻ 0 for typical and atypical medication, were only obtained in the “active attention paradigm.” In this paradigm, healthy controls exhibited a relativeenhancement of PPI when they were instructed to Discussion
selectively attend to the prepulses, whereas schizophre-nia patients failed to show this attentional modulation of Sensorimotor Gating and Schizophrenia PPI (for review see Dawson et al 1997).
The unmedicated schizophrenia patients showed a clear The findings in our experiment suggest that differ- deficit in PPI relative to the control subjects, supported ences in the type of paradigm might not be the main by both between- and within-group comparisons. This reason for the different findings of Braff et al and reduced inhibition of the startle response after weak Dawson and coworkers. Using the same experimental prestimulation was not due to general deficits in startle procedure in our study, the unmedicated schizophrenia reactivity in these patients, since the normal controls patients showed substantial impairment of PPI, while and schizophrenia patients did not differ in startle- the medicated patients did not differ from the controls.
response magnitudes to the probe-alone presentations.
These findings suggest that medication status might be These data support the findings of Braff and collabora- important in modulating the amount of PPI in schizo- tors (Braff et al 1978, 1992; Grillon et al 1992) phrenia patients when no explicit instructions are given indicating that schizophrenia patients might have defi- to either attend to or ignore the prepulse stimuli. On the cits in automatic sensorimotor gating. On the other other hand, Hazlett et al (1998) found no differences hand, for the medicated schizophrenia patients, the between unmedicated schizophrenia patients and nor- blink magnitudes were substantially reduced if a tone mal controls in a passive attention condition. However, preceded the startle-eliciting stimulus at lead intervals 81% of the unmedicated patients had received neuro- of 60 and 120 msec. The amount of PPI for these leptic medication before with a substantial variation of patients was identical to that obtained in the control the periods of washout. Moreover, there were also group. The findings in this patient group thus confirm strong differences in the total psychopathology scores the results from Dawson and collaborators (Dawson et within the sample of schizophrenia patients in that al 1993; Hazlett et al 1998) indicating that schizophre- study. Thus, besides the medication status, specific nia patients do show the same amount of PPI compared patient characteristics might also be important in mod- with controls in the so-called “passive attention para- ulating the amount of PPI. The data from our study digm”—i.e., when subjects were instructed that the suggest that patients’ symptomatic status might be an tones that served as prestimuli were task irrelevant and Figure 3. Correlation between the amount of prepulseinhibition and the positive syndrome severity. Eachdata point represents one schizophrenia patient. Theamount of prepulse inhibition is expressed as the meanstandardized difference score of the blink magnitudesat the 60- and 120-msec lead intervals. Positive syn-drome severity relates to the individual score in thecorresponding subscale (range: 7– 49) of the Positiveand Negative Syndrome Scale (PANSS) for schizo-phrenia (Kay et al 1987). The dashed line reflects thelinear regression.
Prepulse Inhibition and Psychopathology induced deficits in PPI (Mansbach and Geyer 1989; The differences in PPI between the medicated and un- Mansbach et al 1988). While pretreatment with typical medicated schizophrenia patients were no longer signifi- neuroleptics restores amphetamine-induced PPI deficits, cant if the severity of positive symptoms was used as a these drugs are ineffective in restoring PCP-induced PPI covariate in the statistical analyses—i.e., the correlation deficits. Phencyclidine-induced deficits in PPI can, how- between the amount of PPI and the rated severity of the ever, be antagonized by the atypical antipsychotic cloza- patients’ positive symptoms was significant. By contrast, pine, which has blocking properties to multiple receptors the general psychopathology scores and the negative in various neurotransmitter systems (Bakshi et al 1994).
syndrome showed only a moderate relationship to the These findings suggest that there is not a general effect of amount of PPI in the entire group of schizophrenia neuroleptic medication on PPI; rather, neuroleptic medi- patients, which, however, was not significant. This was cation is only effective if it acts on the system where the also supported in a recent study by Volz et al (M. Volz et al, unpublished data, 1999), who found no deficits in PPI In our study the medicated schizophrenia patients in a sample of 49 schizophrenia outpatients who exhibited showed overall less positive symptoms compared with the pronounced negative symptoms but showed virtually no unmedicated patients. However, the severity of the posi- florid psychopathology at the time of testing. Moreover, in tive syndrome varied substantially within the group of our study three patients who despite being medicated medicated patients, indicating that some patients did not exhibited the same amount of positive symptoms as show an adequate clinical response to their medication.
unmedicated schizophrenia patients also showed the same These patients also exhibited clear deficits in PPI. Al- deficits in PPI as the unmedicated patients. This finding though there were substantial differences in the duration of suggests that in cases wherein the neuroleptic treatment is treatment within the group of medicated patients, treat- not effective in reducing the positive symptoms, schizo- ment duration cannot completely explain the differences in phrenia patients show an impairment of PPI.
the clinical response. For the three medicated patients The data from our experiment suggest that PPI might be showing enhanced psychopathology scores and clear PPI a useful prescreening method for testing the clinical deficits, the treatment durations were 2, 7, and 25 weeks.
potential of neuroleptics. Medication that effectively re- These findings question the hypothesis that simple block- duced positive symptoms also removed PPI deficits, ade of the receptors is sufficient to reduce PPI deficits in whereas drugs that were clinically less effective also failed these patients. Future research should test more explicitly to restore PPI. These data are in line with animal models the time course of recovery of PPI with regard to treatment of PPI deficits. In rats, a systemic administration of the duration, the effects of different neuroleptics, and their indirect dopamine agonist amphetamine as well as the doses and interactions with the clinical drug response— noncompetitive NMDA antagonist phencyclidine (PCP) i.e., changes in psychopathology. Moreover, future studies should also include more chronically ill schizophrenia need to be replicated in a within-subjects design in future patients to explore PPI in patients who are less responsive research. Preliminary data of a single case yielded prom- ising results. One unmedicated schizophrenia patient who Supporting the findings from Dawson and his collabo- showed no PPI (⌬z ϭ .15) in a first test session also rators, symptomatic medicated schizophrenia patients did exhibited severe positive symptoms (the positive syn- not differ in their PPI relative to the controls in our drome score was 19). When tested again 38 days later after study—i.e., when participants were not instructed to se- being treated with fluphenazine, the patient’s positive lectively attend to or ignore the prepulse stimuli. These symptom score was reduced to 14 and the same patient results are also concordant with recent findings from showed PPI (⌬z ϭ Ϫ.30) at the second test session.
Hazlett et al (1998), suggesting that deficits in automatic Our data support the notion that deficits in sensorimotor sensorimotor gating might not be a general trait-linked, gating might be related to sensory overload, cognitive stable vulnerability indicator for schizophrenia. The mixed fragmentation, and thought disorder—i.e., characteristic results regarding PPI deficits in psychosis-prone college symptoms of an active episode of the disorder. However, students support this notion (Cadenhead et al 1996). On in the current sample of medicated and unmedicated the other hand, one has to acknowledge that the lack of a schizophrenia patients, the severity of positive symptoms strong correlation between PPI deficits and schizotypy or accounted for only about 39% of the variance of PPI, psychosis proneness scales does not mean that PPI impair- suggesting that factors other than psychopathology are ment is not a trait marker, since PPI deficits might be influencing the amount of PPI as well. It has been associated with one gene and schizotypy or psychosis demonstrated that gender accounts for differences in the proneness might reflect another inherited trait, but both amount of PPI. In three studies, Swerdlow and colleagues markers might be related to schizophrenia. However, found that men exhibited stronger PPI than women (Swerd- before drawing any definite conclusions it would be low et al 1993a, 1995a, 1997), a finding that was repli- desirable to test PPI in a clinical group of schizophrenia cated in the present study, but only for the healthy patients and also to assess PPI in their first-degree rela- controls. No gender effects occurred in the schizophrenia tives. Moreover, it would also be interesting to relate PPI patients. This finding must be interpreted cautiously be-cause we investigated only a small sample of female to other psychophysiological variables that have been used subjects and we did not assess the menstrual cycle for to identify vulnerability markers for schizophrenia— e.g., these participants. It has been shown that PPI covaries the eye-tracking performance (Iacono 1998). Although no with the menstrual cycle (Swerdlow et al 1997).
relations were found between PPI and the suppression of Reduced PPI has also been reported in other clinical the P50 component of the evoked potential in a double- populations as well, including patients with Huntington’s click paradigm (Schwarzkopf et al 1993), the performance disease (Swerdlow et al 1995b), obsessive– compulsive in negative priming or the Stroop test (Swerdlow et al disorder (Swerdlow et al 1993b), Tourette’s syndrome 1995a) in normal volunteers, a covariation between PPI with attention-deficit/hyperactivity disorder (Castellanos and behavioral measures of distractibility was observed in et al 1996), and nocturnal enuresis (Ornitz et al 1992). As a sample of chronic schizophrenia patients (Karper et al revealed by animal research, a complex corticolimbic striatopallidal circuitry modulates the primary PPI path-way via a projection to the pedunculopontine tegmental nucleus, suggesting that a variety of neurophysiological One caveat is that the effect of medication and psychopa- dysregulations may result in deficits in PPI (Koch and thology was tested in a relatively small sample of schizo- Schnitzler 1997; Swerdlow et al 1992).
phrenia patients in a between-subject design. Therefore, it In our study, clear deficits in PPI were obtained for is difficult to determine whether medication effects or patient characteristics were responsible for the PPI deficits amount of PPI covaried with the severity of positive or the lack thereof. This point is all the more important symptoms. Those patients who did not respond very well considering that PPI was tested in a quasi-experimental ex to the antipsychotic medication also showed a clear deficit post facto design, and patients were not assigned randomly in PPI, suggesting that PPI might be used as a method to to the different conditions due to clinical reasons. On the assess the clinical potential of neuroleptic medication.
other hand, PPI deficits correlated significantly with theseverity of the patients’ positive symptoms, but not withthe negative syndrome and only moderately with the This research was supported by grants from the Deutsche Forschungs- general psychopathology. The present covariations be- gemeinschaft (German Research Society) to Alfons Hamm (Ha 1593/6-2;Ha 1593/10-2).
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