Elsevier

Biological Psychiatry

Volume 47, Issue 1, 1 January 2000, Pages 61-70
Biological Psychiatry

Original Articles
Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients

https://doi.org/10.1016/S0006-3223(99)00229-2Get rights and content

Abstract

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 so-called 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.

Introduction

Dysfunctions 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 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, Hoffman and Ison 1992 and humans (see reviews by Anthony 1985, Filion et al 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, Graham 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 startle-eliciting 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 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 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.

Section snippets

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 (APA American Psychiatric Association 1987) or from the ICD-10 (World Health Organization 1992), respectively.

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 μV 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<

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 startle-response magnitudes to the probe-alone presentations. These data support the findings of Braff and collaborators

Acknowledgements

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

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