Effects of clozapine on auditory event-related potentials in schizophrenia

Effects of Clozapine on Auditory Event-Related Potentials in Schizophrenia Daniel Umbricht, Daniel Javitt, Gerald Novak, John Bates, Simcha Pollack, Jeffrey Lieberman, and John Kane Background: Schizophrenia is associated with cognitive deficits that are an intrinsic component of the disorder. Clozapine is an atypical antipsychotic that is superior to typical agents in the treatment of positive symptoms. The degree to which clozapine ameliorates cognitive deficits, however, is still controversial. Mismatch negativity (MMN), N200 (N2), and P300 (P3) are cognitive eventrelated potentials (ERPs) that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits associated with schizophrenia. In schizophrenic patients deficient generation of MMN, N2, and P3 has been observed, suggesting impairments of discrete stages of information processing. Methods: This study investigates the effects of clozapine treatment on MMN, N2, and P3 generation. Patients were recruited from a haloperidol-controlled, double-blind treatment study of clozapine in chronic schizophrenia. ERPs were obtained at the beginning of the study and after 9 weeks (4 patients) and 16 weeks (13 patients) of treatment. Results: Clozapine treatment was associated with a significant increase of P3 amplitude, which was not observed in the haloperidol group; however, clozapine treatment did not affect deficits in MMN and N2. Conclusions: These findings suggest that clozapine—in contrast to conventional antipsychotics—improves electrophysiological measures of attention-dependent information processing, but does not ameliorate preattentive deficits. Biol Psychiatry 1998;44:716 –725 © 1998 Society of Biological Psychiatry Key Words: Event-related potentials, mismatch negativity, clozapine, atypical antipsychotics, schizophrenia, treatment resistance From the Research Department, Psychiatric University Hospital, Zurich, Switzerland (DU); Research Department, Hillside Hospital, Glen Oaks, New York (DU, DJ, GN, JB, SP, JK); Nathan Kline Institute for Psychiatric Research, Orangeburg, New York (DJ); St. John’s University, Jamaica, New York (SP); and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (JL). Address reprint requests to Daniel Umbricht, MD, Research Department, Psychiatric University Hospital, PO Box 68, Lenggstr.31, 8029 Zurich, Switzerland. Received January 21, 1997; revised September 18, 1997; revised November 5, 1997; accepted November 12, 1997. © 1998 Society of Biological Psychiatry Introduction C ognitive deficits are a major cause of disability in schizophrenia and an important hurdle in the rehabilitation of schizophrenic patients (Gold and Harvey 1993; Green 1996). There are no proven treatments available for this important aspect of schizophrenia. Clozapine, an atypical antipsychotic, has been shown to be superior to conventional agents in the treatment of positive symptoms (Kane et al 1988, 1996; Breier et al 1994), yet it has not been proven to have clinically significant effects on cognitive deficits (Goldberg et al 1993; Hagger et al 1993; Williams et al 1993; Buchanan et al 1994; Zahn et al 1994; Lee et al 1994; Goldman et al 1996; Hoff et al 1996). This study investigates the effects of clozapine on cognitive deficits by utilizing the technique of auditory event-related potentials (ERPs). ERPs provide an objective index of cognitive dysfunction, and a reliable method for assessing effects of medication on underlying brain activity. Most ERP studies in schizophrenia have focused on abnormalities in the generation of the P300 (P3) amplitude—a positive potential that occurs with an approximate latency of 300 ms after the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli (McCarley et al 1991, 1993; Pritchard 1986). Its amplitude depends, among other factors, on overall probability of the deviant stimulus and is believed to reflect allocation of attention and activation of immediate memory (Johnson 1986; Polich and Kok 1995). In recent years several studies have also demonstrated abnormalities in the generation of several potentials preceding P3 that index discrete stages of information processing. They include mismatch negativity (MMN) (Shelley et al 1991; Oades et al 1993; Catts et al 1995; Javitt et al 1993, 1995) and N200 (N2) (O’Donnell et al 1993; Egan et al 1994). MMN is an early cognitive potential, occurring with an approximate latency of 100 –200 ms after the presentation of a stimulus that deviates in any physical dimension (pitch, duration, location) from preceding stimuli. MMN is assumed to be the manifestation of a comparison process that operates independently of the specific task and the subject’s attention 0006-3223/98/$19.00 PII S0006-3223(97)00524-6 Clozapine and ERPs in Schizophrenia and motivation, but requires the presence of a sensory memory trace of the standard stimulus with which the deviant stimulus is compared (Näätänen 1990; Novak et al 1990; Ritter et al 1992). In contrast, N2, occurring frontocentrally with an approximate latency of 200 ms, is—like P3—an attention-dependent potential that is thought to reflect stimulus categorization (Ritter et al 1979, 1983; Sams et al 1985). MMN, N2, and P3 thus provide a sequence of potentials that index different stages—preattentive and attention-dependent—in the processing of behaviorally relevant target stimuli (Novak et al 1990). Studies in schizophrenic patients have provided some evidence that abnormalities in the early stages of auditory information processing as evidenced in abnormal MMN contribute to subsequent neurophysiological dysfunction, manifested in deficient N2 and P3 generation (Javitt et al 1995). Treatment with typical antipsychotics followed by symptomatic remission is not associated with a normalization of deficient auditory ERPs in schizophrenic patients (Blackwood et al 1987; Duncan et al 1987; Eikmeier et al 1992; Ford et al 1994a). Despite the fact that clozapine has been in use for over two decades, its effects on ERP abnormalities in schizophrenia have not been investigated under controlled conditions. The goal of this study was to determine whether clozapine would differ from conventional antipsychotics, i.e., haloperidol, and ameliorate deficits in preattentive and attention-dependent information processing as evidenced in abnormalities of MMN, N2, and P3 in schizophrenia. This question was investigated in the context of a double-blind treatment study, in which patients were switched from treatment with conventional antipsychotics to treatment with either clozapine or haloperidol and, additionally, with patients whose treatment was changed to clozapine by their clinicians. Methods and Materials Study Design ERPs were recorded in a group of normal controls (n 5 13), in patients who had consented to participate in a double-blind treatment study comparing clozapine to haloperidol (n 5 14), and in patients who were assigned to open clozapine treatment by their clinician (n 5 3). In patients ERPs were recorded on two occasions: at baseline, and after 16 weeks (13 patients) and 9 weeks (4 patients), respectively. At baseline patients were treated with conventional antipsychotics and other psychotropics (see below) prescribed by patients’ clinicians. After the baseline assessments all psychotropics (with the exception of lorazepam on p.r.n. basis) were tapered off, and study medication or open-label clozapine was started. Thus, the design of the study assessed the effects of switching form treatment with conventional antipsychotics to treatment with clozapine or haloperidol. BIOL PSYCHIATRY 1998;44:716 –725 717 In the normal control group, ERPs were obtained once. To be eligible for the double-blind treatment study and for open-label clozapine treatment, patients had to be partially treatment refractory to treatment with conventional antipsychotics as evidenced in a rating of 4 (5 moderate) on any of the four positive symptom items (conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought content) of the Brief Psychiatric Rating Scale (BPRS, anchored version; Woerner et al 1988). Patients had to meet the diagnostic criteria of schizophrenia or schizoaffective disorder according to DSMIII-R established by a structured clinical interview (SCID; Spitzer et al 1990) (n 5 15) or by a clinical interview and chart review (n 5 2) performed by the first author (D.U.). All patients provided written informed consent to participate in the ERP study. Patients A total of 17 patients were studied. Nine patients were diagnosed with chronic schizophrenia, undifferentiated type, 6 patients with chronic schizophrenia, paranoid type, and 2 patients with chronic schizophrenia, disorganized type. Patient characteristics are described in Table 1. At baseline patients received the following medications in addition to neuroleptic treatment (in parentheses are the numbers of patients who went on to receive clozapine or haloperidol plus 4 mg of benztropine): anticholinergic medication 10 (6/4), chlomipramine 3 (1/2), lithium carbonate 3 (3/0), and benzodiazepines 5 (4/1). The clozapine group comprised 11 patients; 6 patients were assigned to haloperidol. At follow-up the mean doses of clozapine and haloperidol were 540 6 217 mg and 20 6 8 mg, respectively. Patients in the two treatment groups did not differ with regard to age, duration of illness, prior months on neuroleptics, mean neuroleptic dose in chlorpromazine (CPZ) equivalents, or total scores of BPRS, and SANS (Schedule for the Assessment of Negative Symptoms; Andreasen 1982), and CGI (Clinical Global Impression; Guy 1976) ratings at baseline (Table 1). Controls Thirteen normal controls were recruited from staff at the Long Island Jewish Medical Center (Table 1). Absence of any past or present psychopathology was ensured by a clinical interview. Normal controls were younger than the patients, but this difference did not reach statistical significance (t 5 2.02, df 5 28, p . .5). Clinical Ratings and Assessments Symptomatology was assessed with the help of the BPRS, SANS, and CGI. Behavioral ratings were performed within 5 days of the ERP recording session. The measures of psychopathology used for analysis were the BPRS total score, the BPRS psychosis factor score, the SANS total score, and the CGI severity of illness rating. Information regarding past history was obtained through patient interview and chart review. Writing preference was used to assess handedness. 718 D. Umbricht et al BIOL PSYCHIATRY 1998;44:716 –725 Table 1. Characteristics of Normal Controls and Patients N (m/f) Age (y) Handedness (r/l) Duration of Illness (y) Age at first psychotic hospitalization Number of previous hospitalizations Neuroleptic Dose at Baseline (in mg CPZ equivalents) BPRS Total Score BPRS Psychosis Factor Score SANS Total Score CGI Patients Normal Controls Total Sample Clozapine Group Haloperidol Group 13 (8/5) 31.2 6 8.9 13/0 — — 17 (15/2) 37.2 6 7.4 16/1 17.4 6 8.9 23.7 6 7.5 11 (11/0) 36.8 6 8.6 10/1 16.7 6 8.2 24.2 6 7.3 6 (4/2) 38.0 6 7.6 6/0 18.7 6 10.8 22.8 6 8.6 — 6.7 6 6.1 6.12 6 3.8 7.5 6 8.7 — 1026 6 761 855 6 638 1342 6 924 — — 41.1 6 10.8 14.2 6 4.1 41.9 6 12.6 14.1 6 4.7 39.7 6 7.1 14.3 6 2.9 — — 31.9 6 7.8 4.6 6 0.9 31.3 6 7.1 4.6 6 1.1 33.0 6 9.5 4.7 6 0.5 ERP Recording and Analysis ERPs were recorded during an active and a “no response” auditory “oddball” paradigm. Standard stimuli were 1000-Hz tones, deviants were tones of 1200 Hz. Both standard and deviant stimuli were of 50-ms duration with 5-ms rise/fall time, delivered binaurally via headphones. Intensity of all stimuli was 85 dB SPL. Interstimulus interval varied randomly between 700 and 800 ms. Deviants were randomly presented with an overall probability of .14, with the exception that deviants were always followed by one or more standards. In the active paradigm subjects were asked to press a button after the presentation of a deviant tone. Two blocks with 80 deviants each were presented. In the “no response” paradigm subjects were watching a silent movie and were told to ignore the tones. Four blocks with 110 deviants each were presented. The active paradigm always preceded the “no response” condition. ERPs were recorded using a 16-electrode montage [F3, Fz, F4, left mastoid (LM), T3, C3, Cz, C4, T4, right mastoid (RM), T5, P3, Pz, P4, T6, and one electrode attached above the left outer canthus for monitoring of blinks and eye movements] referenced to a nose electrode. Electroencephalograms (EEGs) were recorded with a Nihon Koden EEG amplifier (band-pass 0.1–70 Hz). EEGs were digitized with a sampling rate of 256 Hz and saved with markers indexing the various stimuli. All data processing was performed off-line using NEUROSCAN software. Averages of 1024 ms with a 100-msec prestimulus baseline were constructed after automatic rejection of sweeps with potentials exceeding 6100 mV in any of the channels. Average waves were obtained separately for standard and deviant stimuli. In the active paradigm only sweeps associated with correctly detected deviant stimuli were included in the averaging. A button press within 200 –1000 ms poststimulus was considered a correct response. Average waves were baseline corrected and digitally filtered with a low-pass filter of 30 Hz (6 dB down). Since N1 and MMN are known to invert between Fz and mastoid leads, MMN and N1 averages were rereferenced to a mathematically computed average mastoid derivation for the purpose of peak measurements. For the determination of MMN and N2, difference waves (ERPs to deviants minus ERPs to standards) were used. N1 was determined from waveforms to standard stimuli in the “no response” paradigm and defined as peak negativity at Fz within the 50 –150-ms latency range. MMN was defined as the peak negativity at Fz within the 100 –225-ms latency range in the “no response” condition difference wave. N2 was defined as peak negativity at Cz within the 150 –300-ms latency range in the active condition difference wave. P3 was defined as the peak positivity at Pz within a latency range of 225–550 ms in the ERPs to deviant tones. For the measurement of MMN, the required minimum of sweeps surviving artifact rejection was set at 100; and for the measurement of N2 and P3, the required minimum of sweeps surviving artifact rejection was set at 25. Automatic latency and peak measurements were done by the NEUROSCAN software. The number of sweeps surviving artifact rejection in the “attend” paradigm and usable for analyses of N2 and P3 waves was too low in 2 patients at baseline and 2 patients at follow-up. ERPs for the “attend” paradigm were therefore available for analyses in 13 patients (9 in clozapine group; 4 in haloperidol group). In the control group ERPs in the attend paradigm were available in 10 subjects. Statistical Test The main analyses concerned baseline comparisons between the patients and the normal controls and the effects of the two treatments on ERP parameters and psychopathology. Baseline comparisons between the patients and the normal controls and between the two treatment groups, respectively, were performed with the help of t tests for the four defined ERP components (N1, MMN, N2, P3) and for the behavioral measures. Topographical analyses were performed for MMN, N2, and P3 with the help of repeated-measures analysis of variance (ANOVA) with group as between-subject factor and electrode site as repeated measure (within-subject factor). Drug effects on peak amplitude and Clozapine and ERPs in Schizophrenia BIOL PSYCHIATRY 1998;44:716 –725 719 Table 2. Amplitudes and Latencies of Mismatch Negativity (MMN), N2 and P3 of the Normal Controls and Patients at Baseline and Follow-up Patients Normal Controls N1 (Fz) MMN (Fz) N2 (Cz) P3* Fz Cz Pz Amplitude Latency Amplitude Latency Amplitude Latency Amplitude Amplitude Amplitude Latency 21.9 6 1.7 90 6 21 24.1 6 1.6 150 6 22 25.3 6 4.4 211 6 64 6.4 6 4.0 7.9 6 4.6 10.0 6 4.0 394 6 62 Total Sample (n 5 17) 21.1 6 1.7 88 6 27 22.9 6 1.4 148 6 30 22.9 6 3.0 179 6 60 2.8 6 3.4 5.5 6 4.7 8.4 6 5.8 395 6 93 Clozapine Group (n 5 11) Haloperidol Group (n 5 6) Baseline Follow-up Baseline Follow-up 21.5 6 1.9 85 6 31 22.7 6 1.2 141 6 33 23.5 6 3.2 189 6 59 1.9 6 3.1 4.2 6 4.3 7.4 6 6.1 400 6 93 20.9 6 1.5 102 6 21 22.4 6 1.6 159 6 38 24.1 6 4.8 200 6 83 4.1 6 3.3 7.6 6 4.5 9.4 6 4.8 464 6 65 20.4 6 1.0 94 6 22 23.1 6 1.8 161 6 18 21.6 6 2.5 158 6 63 4.7 6 3.6 8.3 6 4.7 10.6 6 5.3 383 6 105 20.6 6 1.5 97 6 22 22.7 6 1.3 148 6 23 24.8 6 7.1 155 6 40 4.3 6 2.8 7.4 6 4.2 7.8 6 5.34 445 6 78 Amplitudes in mVolts, latencies in ms; * 5 Normal Controls N 5 10, Clozapine Group N 5 9, Haloperidol Group N 5 4. latency of the four defined ERP variables (MMN, N1, N2, P3) and on behavioral measures were evaluated using repeatedmeasures ANOVAs with drug treatment as between-subject factor and session as repeated measure. Because of the limited number of patients relative to electrode positions, multivariate analysis of treatment effects on ERP topography could not be employed. Instead, univariate repeated-measures ANOVA with Greenhouse–Geisser correction with the treatment group as between-subject factor and session and electrode site as withinsubject factors was used. Alpha values of .05 were considered significant. Values in text are mean 6 standard deviation. Results Schizophrenics versus Controls TASK PERFORMANCE. Behaviorally, reaction time, hit rate, and false alarm rate differed significantly between patients and controls, with normal controls showing shorter reaction times, higher hit rates, and lower false alarm rates (reaction time: 512 6 87 ms versus 430 6 90 ms; t 5 2.2, df 5 21, p , .05; hit rate: 80.4 6 21.3% versus 95.7 6 4.4%; t 5 22.5, df 5 13.36, p , .05; false alarm rate: 1.2 6 1.4% versus 0.07 6 0.2%, t 5 2.9, df 5 12.4, p , .05). N1 AND MMN. At baseline patients showed smaller peak amplitudes of N1, but this difference was not statistically significant (t 5 1.31, df 5 28, p 5 ns; Table 2). MMN amplitude at baseline was largest at Fz and inverted between Fz and the mastoids in both the patient and the normal control group (Figure 1). In the patient group MMN amplitude at Fz was significantly smaller in the patient group than in the normal control group (t 5 2.37, df 5 28, p , .05; Table 2, Figures 1 and 2). Topographical comparison using a repeated-measures ANOVA confirmed a significant effect of group [F(1,28) 5 5.97, p , .05], with patients showing smaller MMN, but no group 3 electrode interaction [F(14,16) 5 1.82, p 5 ns]. Peak latencies of N1 and MMN were not significantly different between patients and normal controls (see Table 2). N2. For all subject groups, N2 was the largest at Cz. The mean amplitude of N2 at Cz was smaller in the patients than the normal controls, but this difference did not reach statistical significance (t 5 1.57, df 5 21, p 5 ns; Table 2). Topographical analyses did not show significant group effects or group 3 electrode interactions [main effect: F(1,21) 5 0.99, p 5 ns; group 3 electrode interaction F(3,49) 5 1.89, p 5 ns]. Peak latencies of N2 were not significantly different between patients and normal controls (see Table 2). P3. The mean amplitude of P3 at Pz was smaller in the patients than the normal controls, but these differences did not reach statistical significance (t 5 20.74, df 5 21, p 5 ns; Table 2). Topographical analyses did not show significant group effects or group 3 electrode interactions [main effect: F(1,21) 5 1.38, p 5 ns; group 3 electrode interaction: F(14,8) 5 0.97, p 5 ns]. Peak latencies P3 were not significantly different between patients and normal controls (see Table 2). Effects of Treatment on Symptomatology and ERP Parameters SYMPTOMATOLOGY AND TASK PERFORMANCE. In the clozapine group the BPRS total score decreased by 6.3 6 9.5 points and the BPRS psychosis factor score by 3.9 6 3.8 points, whereas in the haloperidol group the mean BPRS total score increased by 5.2 6 7.7 points and the BPRS psychosis factor score by 0.5 6 3.9 points. These differences were statistically significant [BPRS total score: repeated-measures ANOVA, treatment 720 BIOL PSYCHIATRY 1998;44:716 –725 D. Umbricht et al rate was not significantly affected by clozapine or haloperidol treatment [Hit rate: repeated-measures ANOVA treatment group 3 session interaction: F(1,13) 5 0.24, p 5 ns; False alarm rate: repeated-measures ANOVA treatment group 3 session interaction: F(1,13) 5 0.51, p 5 ns]. N1 AND MMN. Peak amplitudes and latencies of N1 and MMN did not differ between the two treatment groups at baseline (Table 2 and Figures 1 and 3). Repeatedmeasures (session) ANOVAs did not reveal any significant differences in the effects of treatment with clozapine or haloperidol on peak amplitude and latency of N1 at Fz [amplitude: treatment 3 session interaction: F(1,15) 5 2.36, p 5 ns; latency: treatment group 3 session interaction: F(1,15) 5 1.10, p 5 ns] and MMN at Fz [amplitude: treatment group 3 session interaction: F(1,15) 5 0.08, p 5 ns; latency: treatment group 3 session interaction: F(1,15) 5 2.80, p 5 ns]. Topographical analysis of the drug effects of MMN amplitudes did not show any significant treatment group 3 session [F(1,15) 5 1.51, p 5 ns] and treatment group 3 session 3 electrode interactions [F(14,2) 5 1.77, p 5 ns]. Figure 1. Mean MMN amplitudes at baseline and follow-up of clozapine group, haloperidol group, and normal controls. Open squares, clozapine group at baseline; filled squares, clozapine group at follow-up; open circles, haloperidol group at baseline; filled circles, haloperidol group at follow-up; triangles, normal controls. group 3 session interaction: F(1,15) 5 6.43, p 5 .02; BPRS psychosis factor score: repeated-measures ANOVA, treatment group 3 session interaction: F(1,15) 5 5.14, p , .05]. In the clozapine group mean BPRS total and mean BPRS psychosis factor scores were significantly lower at follow-up than at baseline (BPRS total score: paired t test: t 5 2.2, df 5 10, p 5 .05; BPRS psychosis factor score: paired t test: t 5 3.4, df 5 10, p , .01). Clinical Global Impression Change scores were significantly greater for the clozapine than the haloperidol group at follow-up (3.1 6 0.8 vs. 4.0 6 0.9; t 5 22.1, df 5 15, p 5 .05). No significant changes in SANS total scores were observed in any treatment group. Task performance as measured by hit and false alarm N2. Peak amplitudes and latencies of N2 did not differ between the two treatment groups at baseline (Table 2 and Figures 1 and 3). Repeated-measures (session) ANOVA did not reveal any significant differences in the effects of treatment with clozapine or haloperidol on peak amplitude and latency of N2 at Cz [amplitude: treatment group 3 session interaction: F(1,11) 5 0.44, p 5 ns; latency: treatment group 3 session interaction: F(1,11) 5 0.54, p 5 ns; Table 2 and Figures 1 and 3]. Topographical analyses of the drug effects on N2 amplitudes did not show any significant treatment group 3 session [F(1,11) 5 0.25, p 5 ns] and treatment group 3 session 3 electrode interactions [F(2.13) 5 0.50, p 5 ns]. P3. Peak amplitudes and latencies of P3 did not differ significantly between the two treatment groups at baseline (Table 2 and Figures 1 and 3). Clozapine treatment was associated with a significant increase of P3 amplitude at Pz compared to the haloperidol group [repeated-measures (session) ANOVA drug 3 session interaction: F(1,11) 5 4.3, p 5 .03]. The topographical analysis of P3 revealed a significant treatment group 3 session interaction [F(1,11) 5 11.31, p , .01], but no treatment group 3 session 3 electrode interaction [F(2.72) 5 0.82, p 5 ns], confirming an overall enhancing effect of clozapine on P3 amplitude. Neither clozapine nor haloperidol treatment was associated with an effect on P3 latency at Pz [repeated-measures Clozapine and ERPs in Schizophrenia BIOL PSYCHIATRY 1998;44:716 –725 721 Figure 2. Grand averages of MMN (difference wave) at baseline and follow-up of clozapine group, haloperidol group, and normal controls at midline electrodes. Solid lines, clozapine group; dashed lines, haloperidol group. (session) ANOVA drug 3 session interaction: F(1,11) 5 0.47, p 5 ns]. The increase of P3 amplitude at Pz in the clozapine group was not significantly correlated with change of BPRS psychosis score (Figure 4). Discussion Despite its clinical use for over 30 years, the effects of clozapine on brain function as measured by ERPs have not been studied under controlled conditions. This study is the first to attempt this, investigating the effects of clozapine on ERP measures of neurocognitive deficits in a doubleblind, haloperidol-controlled study in partially treatmentrefractory schizophrenic subjects. In the present study clozapine significantly improved electrophysiological measures of attention-dependent information processing (P3), but failed to alter deficits in preattentive information processing as indexed by MMN. Clozapine treatment led to an increase in P3 amplitudes, but did not reverse the deficient MMN generation in schizophrenic patients. In addition, clozapine treatment was associated with a significant reduction of positive symptoms and clearly showed its superiority over haloperidol even in this small patient sample. The observed effect of clozapine on auditory P3 generation differs from those of typical antipsychotics, since it has been well documented that treatment with standard antipsychotics does not normalize P3 deficits in schizophrenic patients (Blackwood et al 1987; Eikmeier et al 1992; Ford et al 1994a). The results of this study are in agreement with a brief report by Schall et al (1995) on a study comparing the effects of clozapine on auditory ERPs to those of haloperidol in an uncontrolled, open study. Schall et al also observed a significant increase of P3 amplitude in clozapine-treated patients, but failed to find an effect of clozapine on MMN. Taken together, the results of this study and those reported by Schall et al (1995) support the concept that clozapine has actions in schizophrenia that are qualitatively different from those of typical antipsychotics. There are different possible explanations for the observed effect of clozapine on P3 generation. P3 depends, among other factors, on attentional functions. First, the increase of P3 by clozapine might thus be the “top-down” effect of clozapine-induced improvements in attention. In agreement with such a view are the reports of a small, but significant positive effect of long-term treatment clozapine on the performance of the Digit Symbol Test—a measure of attention (Hagger et al 1993; Lee et al 1994); however, other studies using this 722 BIOL PSYCHIATRY 1998;44:716 –725 D. Umbricht et al Figure 3. P3 amplitudes (grand averages) at baseline and follow-up of clozapine group, haloperidol group, and normal controls at midline electrodes. Solid lines, clozapine group; dashed lines, haloperidol group. specific test did not detect a significant improvement during clozapine treatment (Goldberg et al 1993). Second, since P3 also reflects the processing of relevant stimuli in specific brain areas, the observed increase of P3 amplitude might be the direct manifestation of an improved functioning of these brain areas, secondarily resulting in the improvement of certain cognitive functions. A third possibility is given by results of a study by Ford et al (1994b), who conducted a single-trial analysis of P3 generation in schizophrenic patients and found that schizophrenic patients showed P3 waves to fewer trials to which they had correctly responded and smaller P3 amplitude on each trial. The authors suggested that patients show intermittent waning of attentional engagement, which might result in a disengagement of P3 generation from the motor response process. It is possible that the observed effect of clozapine could be the result of patients remaining more engaged during the task, thus simply generating more P3 waves without any changes of P3 amplitude. Future studies will have to answer these questions. The observation that clozapine treatment not only led to a significant reduction of positive symptoms, but also improved auditory P3 as a measure of attention-dependent information processing is only partly consistent with the results seen in studies that investigated the effect of clozapine on a wide range of neuropsychological deficits (Goldberg et al 1993; Hagger et al 1993; Williams et al 1993; Buchanan et al 1994; Zahn et al 1994; Lee et al 1994; Goldman et al 1996; Hoff et al 1996). Goldberg et al (1993), investigating the effects of clozapine in an open-label treatment study, did not find an ameliorative effect of clozapine on deficits in attention, memory, and higher-level problem solving in 13 patients on long-term clozapine treatment. Zahn et al (1994) also failed to show any beneficial effects of clozapine—in comparison with fluphenazine treatment and placebo— on measures of sustained and selective attention in a reaction time paradigm. In both studies, however, patients showed significant reductions of positive symptoms despite the absence of neuropsychological improvement. In other studies (Haggre et al 1993; Lee et al 1994; Buchanan et al 1994; Hoff et al 1996) clozapine was found to improve performance on tests of retrieval from reference memory, measures of attention, verbal and category fluency and perceptual discrimination, whereas on other tests such as the Wisconsin Card Sorting Test no improvement was seen; however, the observed improvements were modest and much smaller than the effects of clozapine on positive symptoms. In the context of the findings in this study, it is of interest that some of the studies—as mentioned Clozapine and ERPs in Schizophrenia Figure 4. Mean P3 amplitudes at baseline and follow-up of clozapine group, haloperidol group, and normal controls. Open squares, clozapine group at baseline; filled squares, clozapine group at follow-up; open circles, haloperidol group at baseline; filled circles, haloperidol group at follow-up; triangles, normal controls. above—found improvement on measures of attention (Hagger et al 1993; Lee et al 1994) and on tests of the ability to concentrate (Hoff et al 1996). In summary, these studies of the effects of clozapine on neurocognition have not yielded consistent results. The results of this study thus suggest that normalization of certain brain activity may occur during clozapine therapy, but be poorly detected by routine neuropsychological test batteries and difficult to define with traditional instruments. It is of interest that in this study symptomatic improvement did not correlate with ERP measures of attention. This is in agreement with the results of all neuropsychological studies, even those that reported significant effects on some aspects of cognition. None of them found a correlation of changes of neuropsychological test performance with symptomatic BIOL PSYCHIATRY 1998;44:716 –725 723 improvement. The finding of this study thus supports the notion that neuropsychological deficits and positive symptomatology are independent areas of schizophrenic pathology. In contrast to its effect on P3, clozapine treatment did not alter deficient MMN generation, indicating that it does not affect deficits at more basic levels of information processing in schizophrenic patients. The question to what extent the failure of clozapine to affect these abnormalities relates to its lacking effect on deficit symptoms (Breier et al 1994; Kane et al 1996), and to the negative findings in the neuropsychological studies cited above, remains open and an issue for further research. This study is limited by several factors. The number of subjects studied was small, reducing the power to detect small differences and changes. In addition, at baseline patients could not be studied in a medication-free condition. Thus, the observed increase of P3 amplitude in the clozapine group could be the result of the taper of conventional antipsychotics; however, Ford et al (1994a) observed a slight decrease of P3 amplitudes after a 1 week washout of conventional antipsychotics, suggesting that P3 deficits, if anything, become more pronounced in a medication-free condition. A third limitation is the lack of follow-up data in the normal control group, which would have allowed the evaluation of effects of retesting on ERPs in the analyses. In conclusion, the results of our study indicate that clozapine, in contrast to conventional antipsychotics, may improve certain deficits in attention-dependent functions as manifested in reduced P3 amplitude, but lacks a distinct and unique effect on ERP indices of preattentive information processing in schizophrenia. 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