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Untitled documentNormalization of Information Processing Deficits
in Schizophrenia With Clozapine
Veena Kumari, Ph.D.,
William Soni, M.B., B.S., M.Sc., and Tonmoy Sharma, M.Sc., M.R.C.Psych.
Objective: The authors tested the hypothesis that the use of an atypical drug, clozapine,
for patients with schizophrenia is related to less impairment in information processing def-
icits (assessed by prepulse inhibition of the startle response) than is the use of typical anti-
psychotics. Method: Two groups of schizophrenic patients—receiving either clozapine or a
range of typical antipsychotics—were tested for prepulse inhibition (a reduction in re-
sponse to a startling stimulus, if preceded briefly by a weak, nonstartling stimulus; mea-
sured at prepulse-to-pulse intervals of 30 msec, 60 msec, and 120 msec) of the acoustic
startle response and compared with a group of healthy volunteers. Results: Patients re-
ceiving typical antipsychotics showed less prepulse inhibition with 30-msec and 60-msec
prepulse trials than did comparison subjects. Clozapine-treated patients showed normal
levels of prepulse inhibition. Conclusions: Clozapine is superior to typical antipsychotics
in normalizing prepulse inhibition, presumably because of its pharmacological effects on
prefrontal regions of the brain or its effects on a broader range of neuroreceptors.
(Am J Psychiatry 1999; 156:1046–1051)
Schizophrenia has long been associated with abnor- Pharmacological agents that disrupt and enhance malities in information processing and attention mech- prepulse inhibition in experimental animals have psy- anisms (1, 2). Prepulse inhibition of the startle reflex, a chotic and antipsychotic properties, respectively, in hu- cross-species phenomenon, provides a valuable oppor- man beings. In the rat, prepulse inhibition is disrupted tunity to study such abnormalities (3). Prepulse inhibi- by dopamine agonists (10–12), an observation consis- tion refers to a reduction in response to a strong star- tent with the dopamine hypothesis of schizophrenia tling stimulus, “pulse,” if this is preceded shortly by a (13). Serotonin (5-HT) agonists and N-methyl-D-as- prestimulus, “prepulse,” too weak to elicit a measur- partate (NMDA) antagonists also disrupt prepulse in- able startle response itself (4, 5). The paradigms most hibition (10–12); this finding is in line with the sug- often employed to demonstrate this effect use a strong gested involvement of these systems in the etiology and noise burst as the pulse and a weak noise as the treatment of schizophrenia (14). In addition, environ- prepulse. The inhibitory mechanisms activated by the mental manipulations, such as rearing in isolation, prepulse are thought to reduce the impact of the pulse, with possible relevance to neurodevelopmental models a powerful sensory stimulus, until the processing of the of schizophrenia (15), are found to disrupt prepulse in- prepulse is complete and thus serve to prevent the or- hibition (10–12). The disruption of prepulse inhibition ganism from overload of information. In line with pos- by dopamine agonists and social isolation is reversed tulated deficiencies in early stages of information pro- by typical and atypical antipsychotics. However, atyp- cessing, reduced prepulse inhibition has repeatedly ical, but not typical, antipsychotics are able to reversethe disruption of prepulse inhibition by 5-HT agonists been demonstrated in people with schizophrenia as compared to healthy people (6–12).
Although preclinical evidence points, as noted ear- lier in this article, to the differential effects of typical Received Oct. 6, 1998; revision received Jan. 8, 1999; accepted and atypical antipsychotics on prepulse inhibition, Jan. 15, 1999. From the Section of Cognitive Psychopharmacol-ogy, Department of Psychological Medicine, Institute of Psychiatry.
with a possible superiority of atypical drugs over typ- Address reprint requests to Dr. Sharma, Section of Cognitive Psy- ical ones, no published studies are available on the ef- chopharmacology, Department of Psychological Medicine, Insti- fects of typical and atypical antipsychotic drugs on tute of Psychiatry, De Crespigny Park, London SE5 8AF, U.K.; prepulse inhibition in schizophrenic patients. A re- Supported by a donation from Grosvenor Group Estates and cent study (16) reported that oral administration of the dopamine D2 receptor agonist bromocriptine TABLE 1. Demographic and Clinical Characteristics of Schizophrenic Patients Receiving Treatment With Typical Antipsychotics
Positive and Negative Syndrome Scale score a First appearance of psychotic symptoms.
b Current age minus age at onset of illness.
(1.25 mg) suppresses prepulse inhibition in normal sion, a history of mental illness, anorexia, violent or rapid mood male subjects, compared to placebo, and that halo- changes, drug abuse (ascertained by urine toxicology screen) and al- peridol (3 mg) antagonizes the suppression by bro- cohol abuse, regular medical prescriptions, and presence of psycho-sis in their first-degree relatives before they were accepted as sub- mocriptine but reduces prepulse inhibition when ad- jects. All subjects were screened for intact auditory abilities through ministered on its own. We (17) also observed that oral use of an audiometer at 40 dB [A] (1000 Hz).
haloperidol (5 mg) disrupted prepulse inhibition in A commercial human startle response monitoring system (San Di- normal male smokers. These findings suggest that ego Instruments) was used to generate and deliver the startle stimuliand to record and score the electromyographic (EMG) activity for both hypo- and hyperdopaminergic states may reduce 250 msec starting from the onset of the acoustic startle stimulus. Au- prepulse inhibition in normal human beings. However, ditory stimuli were presented to subjects binaurally through head- the cognitive effects of antipsychotics are known to phones. EMG recordings were taken while subjects were sitting differ in schizophrenic patients and normal volunteers comfortably in a moderately lit, soundproof laboratory.
(18). Given that prepulse inhibition deficits were noted The eye-blink component of the startle response was indexed by recording EMG activity of the orbicularis oculi muscle directly be- in clinically stable, medicated (presumably with typical neath the right eye, by positioning two miniature silver/silver chlo- antipsychotics) schizophrenic patients in a number of ride electrodes filled with electrolyte paste, following standard pro- previous studies (6–9), it seems likely that typical med- cedures (17, 20–22). The startle system recorded EMG activity for ication leads to, at best, a partial rather than a full res- 250 msec (sample interval=1 msec) from the onset of the startle stim-ulus. Recorded EMG activity was band-pass filtered, as recom- toration of underlying deficits in postulated prepulse mended by San Diego Instruments. A 50-Hz filter was used to elim- inhibition circuitry with inputs from dopaminergic as inate the 50-Hz interference. EMG data were scored off-line, by the well as from nondopaminergic systems (11).
analytic program of this system, for response amplitude (in arbitrary We therefore measured prepulse inhibition of the analog-to-digit units) and latencies to response onset and peak (inmilliseconds). Scoring criteria were identical to those reported in our acoustic startle response in two groups of schizo- phrenic patients—those receiving clozapine and those The session began with a 5-minute acclimatization period consist- receiving a range of typical antipsychotics—and com- ing of 70-dB [A] continuous white noise. The pulse-alone (non- pared them with a group of healthy subjects. Given prepulse) stimulus was a 40-msec presentation of 115-dB [A] whitenoise, and the prepulse stimulus was a 20-msec presentation of 85- the superiority of clozapine over typical antipsychot- dB [A] white noise, both over 70-dB [A] continuous background ics in reversing prepulse inhibition deficits in the rat, noise. The pulse-alone stimulus was presented 30, 60, and 120 msec we predicted greater prepulse inhibition with clozap- after the onset of the prepulse stimulus. Each lead interval was pre- ine-treated patients than with those receiving typical sented 12 times; probe without prepulse was also presented 12 times (excluding the first initial trial). There were 61 startle stimuli in all,with a mean intertrial interval of 15 seconds (range=9–23 seconds).
The session lasted approximately 20 minutes.
All subjects gave written informed consent after the aim and the procedure of the study were explained to them. They were told thatthe purpose of the experiment was to measure their reactivity to loudnoises and were told, “You are going to hear a number of auditory Twenty-two male patients (age range=20–65 years) with a DSM- clicks, some of which may make you blink. Please keep your eyes IV diagnosis of schizophrenia or schizoaffective disorder were re- open during this experiment, which will last about 20 minutes.” cruited through the inpatient and outpatient services at the Mauds- All analyses were performed by SPSS (Windows, Version 6.0).
ley Hospital, London. Of these, 11 patients were receiving typical Prepulse inhibition was computed as the percentage reduction of antipsychotics and 11, clozapine for a minimum of 6 weeks. Because the amplitude over pulse-alone (non-prepulse) trials, i.e., prepulse of unusable eye-blink data, two patients receiving typical antipsy- inhibition=(a–b)/a × 100, where a=amplitude over pulse-alone tri- chotics were excluded from the final analysis, thus reducing the size als and b=amplitude over prepulse trials. Such a procedure is re- of this group to nine subjects. Symptoms were rated with the Positive quired to correct for the influence of individual differences in star- and Negative Syndrome Scale (19). Table 1 presents demographic tle amplitude (23). First, the two patient groups were compared and clinical characteristics of the patients. Eleven normal volunteers through use of between-subjects t tests for the clinical and demo- (all men, age range=20–50 years; mean age=28.36, SD=6.72) were graphic variables reported in table 1. Next, the effects of diagnosis recruited through advertisement in the local newspaper and were (patients versus comparison subjects) and medication type (clozap- screened for thyroid dysfunction, heart disease, hypo- and hyperten- ine versus typical antipsychotics) on prepulse inhibition of the startle TABLE 2. Prepulse Inhibition of Startle Response by Prepulse
rable to that of comparison subjects at the 120-msec Trials With 30-, 60-, and 120-msec Prepulse-to-Pulse Intervals
lead interval. The finding of normal prepulse inhibi- for Schizophrenic Patients Treated With Typical Antipsychot-
tion in patients receiving typical antipsychotics with ics and Clozapine and for Normal Comparison Subjects
120-msec prepulse trials lends support to numerous previous findings showing positive effects of typical neuroleptic medication on controlled attention (25).
Prepulse inhibition, at least in part, is thought to re- flect automatic (preattentive, mainly in prepulse inhi- bition with prepulses delivered at 60 msec or shorter prepulse-to-pulse intervals) processing, but it can be modulated to some degree by voluntary attention (in-volving conscious awareness) in human beings (26).
Active attention to the prepulses, especially at long response were examined by a three- (group: patients receiving cloza- lead intervals (>100 msec), produces an increase in pine, patients receiving typical antipsychotics, comparison subjects)by-three (trial type: prepulse trials with prepulse-to-pulse intervals of prepulse inhibition (26, 27). We used a neutral task 30-msec, 60-msec, and 120-msec) multivariate analysis of variance (subjects were not instructed to pay attention to or ig- (MANOVA; Wilks’s F) with repeated measures on trial type. Further nore the prepulses) in order to facilitate the compari- MANOVAs on prepulse inhibition scores were conducted to com- son of resulting data with those obtained from animal pare the two patient groups (separately) with comparison subjects.
pharmacological studies; however, prepulses with a120-msec prepulse-to-pulse interval are likely to haveinvolved conscious awareness and active processing of the prepulse (although not intention, which would berequired if subjects were to ignore some and pay atten- There was no difference (p>0.05) between patients tion to other prepulses) and thus differed from the receiving clozapine and typical antipsychotics in symp- prepulses with shorter prepulse-to-pulse intervals.
toms, age at onset of illness, or duration of illness, but Clozapine-treated patients showed normal levels of clozapine-treated patients were relatively younger.
prepulse inhibition at all prepulse intervals. This find- Age, however, has no influence on human prepulse in- ing suggests that in schizophrenic patients, clozapine hibition (24). Medication, calculated as chlorprom- normalizes information processing functions, as as- azine equivalents, and current symptoms had no rela- sessed by prepulse inhibition of the startle response.
These findings have significance for clinical and func- The MANOVA (three by three) revealed a significant tional outcome of schizophrenia given that 1) poor group-by-trial type interaction (F=2.73, df=4, 56, p= cognitive functioning is related to poor functional out- 0.04), although the main effect of group failed to reach come in schizophrenia (28), and 2) impaired prepulse a conventional level of significance (F=2.75, df=2, 28, inhibition is positively associated with various cogni- p=0.08). Further analysis of the data (two-by-three tive deficits. Impaired prepulse inhibition in schizo- MANOVA; patients receiving typical antipsychotics phrenia predicts poor responses on the Ego Impairment versus comparison subjects) revealed less prepulse in- Index human experience variable, a measure of thought hibition in patients receiving typical antipsychotics (F= disorder (29), and correlates positively with poor per- 7.55, df=1, 18, p=0.01). However, this effect was true formance on Wisconsin Card Sort Test (30, 31) and for 30-msec and 60-msec prepulse trials but not for with distractibility on the Continuous Performance 120-msec prepulse trials (group-by-trial type interac- Test (32). Impaired inhibitory processes underlying di- tion: F=7.19, df=2, 17, p=0.005). Patients receiving minished prepulse inhibition in schizophrenia (6, 11) typical antipsychotics showed less prepulse inhibition are conceptualized to reflect an overload of sensory in- than comparison subjects with 30-msec (t=1.83, df= formation, which in turn leads to cognitive fragmenta- 18, p=0.08) and 60-msec (t=3.13, df=18, p=0.006) tion frequently seen in schizophrenia (33). An improve- prepulse trials, but they showed prepulse inhibition ment in cognitive functions with clozapine treatment comparable to that of comparison subjects with 120- would thus be expected to result in better functional msec prepulse trials (t=1.19, df=18, p=0.25). Prepulse outcome in schizophrenia. In line with our findings, a inhibition in clozapine-treated patients was not signif- positive effect of clozapine has also been noted in a icantly less than that in comparison subjects (F=0.49, number of cognitive domains (25), especially attention and verbal fluency in both treatment-resistant and non-treatment-resistant schizophrenia (34).
The exact mechanism responsible for the superiority DISCUSSION
of clozapine over typical antipsychotics, particularly atshort prepulse intervals, cannot be specified at present.
We found less prepulse inhibition in patients receiv- This effect may be due to clozapine’s effects on pre- ing typical antipsychotics than in comparison subjects frontal regions of the brain, especially (but not exclu- at 30-msec and 60-msec prepulse-to-pulse lead inter- sively) 5-HT2 antagonism or its limbic selectivity, or vals; however, they showed prepulse inhibition compa- due to its actions on a range of neuroreceptors that is broader than the range affected by typical antipsychot- across these disorders. Prepulse inhibition deficits have ics (35, 36); the last possibility seems more likely given most thoroughly been investigated in schizophrenia, the involvement of multiple receptors in the regulation and disruptions have been found across a range of of prepulse inhibition in the rat (11, 12). Clozapine prepulse intensities and intervals in this disease. Given also reduces ad lib smoking in schizophrenic patients that schizophrenic patients are known to have abnor- (37), and smoking itself is known to enhance prepulse malities at various levels of prepulse inhibition cir- inhibition of the acoustic startle response in normal cuitry, these findings do not appear surprising. Patients smokers (22). However, the mechanism responsible for with Huntington’s disease show profound disruption the positive actions of nicotine on prepulse inhibition of acoustic prepulse inhibition across 30-msec, 60- in the rat (38) and in human beings (20, 21) is not yet msec, and 120-msec prepulse-to-pulse intervals (42).
understood. It is possible that clozapine’s effect on The pattern of disruption in these patients is remark- prepulse inhibition is mediated by the same mechanism ably different from that in schizophrenic patients. Al- that underlies its effect on smoking.
though schizophrenic patients show less prepulse inhi- Although much remains to be learned about the pro- bition than control subjects, they show an increase in cesses underlying, and the pharmacology of, prepulse prepulse inhibition with 30-msec to 120-msec inhibition in human beings, our findings suggest that prepulse-to-pulse intervals, with the appearance of sig- antipsychotic drugs with different pharmacological nificant prepulse inhibition at the 120-msec prepulse- profiles would produce differential effects on auto- to-pulse interval. Consistent with the possibility of dif- matic and controlled components of information pro- ferent, but overlapping, pharmacological and neural cessing, as assessed by prepulse inhibition of the startle correlates of prepulse inhibition with different prepulse- response. It is possible that impairments in prepulse in- to-pulse intervals, our recent neuroimaging study (47) hibition at short and long intervals reflect dysfunctions revealed different patterns of brain activation during at different stages or processes of information process- production of prepulse inhibition with 60-msec and ing and at different levels of the neurophysiological 120-msec prepulse trials in normal human volunteers, startle gating (prepulse inhibition) circuitry (26). There with significant greater prefrontal activation during 60- are indications of such effects in both experimental an- msec prepulse condition, as compared to the 120-msec prepulse condition. The 120-msec prepulse condition Prepulse inhibition in rats is thought to be controlled elicited significantly greater activation than the 60- by the limbic and mesolimbic-cortico-pallido-thalamic msec prepulse condition in the striatum (caudate nu- circuitry (12). The drugs primarily acting at different cleus), an observation that may help to explain the pre- neural structures in this circuitry are found to produce vious finding of a profound loss of prepulse inhibition different patterns of prepulse inhibition disruption (or with the 120-msec prepulse-to-pulse interval in pa- enhancement) in the rat (39–41). For example, apomor- tients with Huntington’s disease, since they are known phine, at doses that have no effect on control animals, to have substantial damage to the corpus striatum disrupts prepulse inhibition in rats with supersensitive (42). Taken together, these observations suggest that nucleus accumbens dopamine receptors following intra- parametric manipulations may be critical in determin- accumbal infusion of 6-hydroxydopamine. This effect ing, with the prepulse inhibition model, the effects of is particularly strong for prepulse inhibition at 60- pharmacological agents on information processing msec prepulse-to-pulse intervals, although it is also observed with prepulses delivered at 120-msec and In conclusion, our findings suggest that clozapine is 480-msec intervals (40). Apomorphine’s disruptive ef- superior to typical antipsychotics in normalizing cog- fect on prepulse inhibition is seen in rats with 6-hydrox- nitive deficits in schizophrenia, at least as assessed by ydopamine lesions in the substantia nigra, but most evi- prepulse inhibition of the acoustic startle response.
dent in this case, at prepulses delivered at 120-msec The findings also suggest that for several investigations interval, with no effect at the 60-msec interval (34). The of schizophrenic patients treated with atypical antipsy- NMDA antagonist ketamine not only disrupts prepulse chotics, the findings of normal or minimally impaired inhibition at 60–500-msec prepulse-to-pulse intervals attentional and information processing functions may but also produces significant prepulse facilitation at the be attributable to the cognitive enhancing characteris- 30-msec prepulse-to-pulse interval; prepulses with a 30- tics of atypical antipsychotics. The present findings msec prepulse-to-pulse interval have no effect in no- support the view that prepulse inhibition is a useful an- imal model for future investigations of novel potential In addition to schizophrenia, deficient prepulse in- antipsychotic agents for the treatment of schizophrenia hibition is observed in a number of psychiatric disor- (11) but also indicate that antipsychotics with different ders that are characterized by abnormalities in limbic pharmacological profiles may produce differential and mesolimbic-cortico-striato-pallido-thalamic cir- cuitry and exhibit deficient gating of cognitive, sen- There are some limitations to this study. First, this sory, or motor information, such as Huntington’s dis- study, as a first step, used a between-subjects design.
ease (42), obsessive-compulsive disorder (43), attention However, this should not be considered a serious limi- deficit disorder (44), and Tourette’s syndrome (45, 46).
tation because all subjects were of the same sex and However, the pattern of disruption is not uniform had been free of substance abuse for at least 6 weeks before their participation in the study, and the two pa- 7. Braff DL, Geyer MA: Sensorimotor gating and schizophrenia.
tient groups did not differ significantly in symptoms or duration of illness. Furthermore, no relationships were 8. Braff DL, Grillon C, Geyer MA: Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry found between these variables and prepulse inhibition levels in general, although the small study group did 9. Grillon C, Ameli R, Charney DS, Krystal JH, Braff DL: Startle not allow a meaningful evaluation of effects of symp- gating deficit occurs across prepulse intensities in schizo- toms. Clozapine-treated patients were younger than phrenic patients. Biol Psychiatry 1992; 32:929–943 10. Swerdlow NR, Braff DL, Taaid N, Geyer MA: Assessing the patients receiving typical antipsychotics, but age of validity of an animal model of deficient sensorimotor gating in subjects is known to have no relationship to prepulse schizophrenic patients. Arch Gen Psychiatry 1994; 51:139– inhibition (24). The finding of normal prepulse inhibi- tion in clozapine-treated patients is thus best explained 11. Swerdlow NR, Geyer MA: Using an animal model of deficient in terms of pharmacological effects of clozapine. An- sensorimotor gating to study the pathophysiology and newtreatments of schizophrenia. Schizophr Bull 1998; 24:285– other limitation of the present study is the lack of data for drug-free patients, which makes it difficult to sus- 12. Swerdlow NR, Caine SB, Braff DL, Geyer MA: The neural tain the conclusion that clozapine normalized rather substrates of sensorimotor gating of the startle reflex: a re- than reversed deficits caused by typical antipsychotics.
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