Increased rate of P300 latency prolongation with age in drug-naive and first episode schizophrenia

Clinical Neurophysiology 114 (2003) 2029–2035 www.elsevier.com/locate/clinph

Increased rate of P300 latency prolongation with age in drug-naive and first episode schizophrenia Jijun Wanga,*, Yoshio Hirayasua,b, Ken-Ichi Hiramatsua, Hiroto Hokamaa, Hiroshi Miyazatoa, Chikara Oguraa a

Department of Neuropsychiatry, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan b Department of Neuropsychiatry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan Accepted 4 June 2003

Abstract Objective: Previous studies have found an increased rate of P300 latency prolongation with age in medicated chronic patients with schizophrenia, suggesting a pathological neurodegenerative process. In this study, we investigated whether this abnormality was identified in drug-naive and first episode patients with schizophrenia. Methods: P300 from auditory stimuli was recorded from 20 drug naive and first episode male patients with schizophrenia and compared with 23 age and handedness matched healthy male controls. The relationship of P300 latency and P300 amplitude to age in each group was evaluated using polynomial regression analyses. Results: Reduction of P300 amplitude was significant in drug-naive and first episode schizophrenia patients. P300 amplitude negatively correlated with age in schizophrenia patients but not in controls. Although the prolongation of P300 latency with age was observed in both groups, the regression slope for P300 latency with age was significantly steeper in patients with schizophrenia than in normal controls. Significant overall curvilinear correlations with age were also found for P300 latency and amplitude in patients with schizophrenia, and for P300 latency in normal controls. Conclusions: The greater increase in P300 latency and reduction in P300 amplitude with age may be a primary neuropathological effect of schizophrenia. Significance: This study suggests that neurodegenerative processes are involved in the etiology of schizophrenia. q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Event-related potentials (ERPs); Schizophrenia; First episode; Neurodegeneration

1. Introduction The P300 component of event-related potentials (ERPs) has been clinically applied to evaluate the cognitive process in schizophrenia. Increased P300 latency was found systematically in dementing illness as cognitive function deteriorates (Goodin et al., 1978b; Polich et al., 1986; Ball et al., 1989). It is also sensitive to neural changes in developmental and aging processes. From childhood to adolescence, P300 latency is inversely correlated with age, perhaps reflecting processes such as myelination and cognitive development (Goodin et al., 1978a; Polich et al., 1990). P300 latency increases with age at a rate of 1 –2 ms * Corresponding author. Tel.: þ 81-98-895-1157; fax: þ81-98-895-1419. E-mail addresses: [email protected], [email protected] (J. Wang).

every year from adolescence or early adulthood (Goodin et al., 1978a; Polich, 1996, etc.). The positive slope for P300 latency on age was also reported steeper in older subjects than in younger subjects (Brown et al., 1983; Emmerson et al., 1989; Coyle et al., 1991). The prolongation of P300 latency with aging during adulthood is a physiological phenomenon that might reflect a slow neurodegenerative process. Several studies have suggested an increased rate of P300 latency prolongation with age in patients with schizophrenia (O’Donnell et al., 1995; Frangou et al., 1997; Mathalon et al., 2000b). However, it remains unclear whether this abnormality is a primary pathophysiological effect of schizophrenia or whether it is a secondary effect associated with chronicity or neuroleptic treatment since previous studies included chronic and medicated patients.

1388-2457/03/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00207-4

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In this study, we attempted to replicate the P300-age relationship in both drug-naive and first episode patients with schizophrenia so as to avoid the effects of neuroleptics and illness duration. The P300-age relationship in schizophrenia was investigated with reference to previous studies (O’Donnell et al., 1995; Mathalon et al., 2000b) and only male subjects were tested, since gender differences in the P300-aging relationship have been reported in normal controls (Hirayasu et al., 2000). To determine whether the P300-aging relationship differs among the subtypes of schizophrenia, separate exploratory analyses were performed in which the patient group was subdivided into the non-paranoid and paranoid groups.

2. Methods 2.1. Subjects This study was approved by the Ethics Committee of the Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. Informed consent was obtained from each subject before the ERP test. Twenty drug-naive male schizophrenia patients were tested. The patients were recruited from the Outpatient clinics or Inpatient units of psychiatry departments in the Affiliated Hospital of University of the Ryukyus, Okinawa, Japan. All patients were in their first episode with illness duration of less than 1 year. All patients met the DSM-IV (the Diagnostic and Statistical Manual of Mental Disorder, 4th eds.) criteria for schizophrenia based on their final diagnosis. Clinical symptoms were evaluated using the 18-item Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1962). The control subjects were 23 healthy males, none of whom had a history of psychiatric illnesses. All the subjects, including the patients, were free of neurological disease, mental retardation, alcohol and drug abuse, and physical illness that might affect cognitive function or produce hearing loss. Group characteristics are shown in Table 1. All

Table 1 Demographic and clinical characteristics of schizophrenia patients and controls (means ^ SD)

Cases Gender Age (years) Age range (years) Onset age (years) Illness duration (months) Total BPRS Subtypes Non-paranoid Paranoid

Patient group

Control group

20 Male, 20 26.4 ^ 6.8 16 –42 26.1 ^ 7.0 6.7 ^ 4.0 38.9 ^ 6.4

23 Male, 23 27.3 ^ 7.1 18– 40

11 (age: 24.3 ^ 5.3 years) 9 (age: 29.1 ^ 7.8 years)

subjects were right-handed (Edinburgh Handedness Inventory, Oldfield, 1971). 2.2. ERP recording Auditory ERPs were obtained using an oddball paradigm. Infrequent (P ¼ 0:20) target tones (2000 Hz, 75 dB sound pressure level) were presented among frequent (P ¼ 0:80) standard tones (1000 Hz, 75 dB sound pressure level). The tone duration was 90 ms with a rise and fall time of 10 ms. The interstimulus interval was 1.7 ^ 0.1 seconds. The ERP recordings were terminated when 40 artifact-free responses to target stimuli were collected. The subjects were instructed to count silently the number of the target tones, and to report their counts after each run; if the counting accuracy was less than 90%, the subject was excluded from the experiment. When listening to the tones, the subjects stared at a central fixation point to reduce eye movements. The subjects were evaluated in a session either after breakfast (10:00– 11:00 AM) or after lunch (13:30– 14:30 PM). The ERPs were recorded from 16 Ag-AgCl disc electrodes placed at Fp1, Fp2, F7, F3, Fz, F4, F8, C3, C4, T5, P3, Pz, P4, T6, O1 and O2, according to the International 10/20 system. All electrodes were referred to linked earlobes. Electrode impedance was maintained at less than 5 kO. The electrooculogram (EOG) was recorded from electrodes placed above and below the right eye. Amplifiers had a bandpass of 0.16 – 30 Hz. The EEGs and EOG were sampled at a rate of 1 ms per point with a laboratory computer (DP 1200, Japan). ERPs were online averaged separately for target and standard tones. Trials were automatically rejected if at any point during the averaging epoch the voltages exceed ^ 100 mV in the EOG lead. The averaged potentials were baselined to the mean potential of the 200 ms period before stimulus onset. 2.3. Data analysis Both P300 amplitude and latency were measured at all 16 recording sites as the most positive voltage sampled in the latency range of 260– 400 ms after the stimulus onset. N100 was measured as the most negative peak between 50 and 150 ms at Fz. The group and topographical differences in P300 amplitude and latency were evaluated using repeated measures analysis of variance (ANOVA) with diagnosis group as the between-subject factor and electrode as the within-subject factor. Initial analyses including all 16 electrodes as level in one factor had not permitted dissection of the location of group differences, therefore electrodebased regions of interest (ROIs) were defined for comparing patients and controls. Defined ROIs are frontal (F3, Fz, F4), parietal (P3, Pz, P4), left (F3, C3, P3) and right (F4, C4, P4). ANOVAs were performed separately for each ROI, first with two groups (schizophrenia and controls), then with 3 groups (non-paranoid, paranoid and controls). Post hoc

J. Wang et al. / Clinical Neurophysiology 114 (2003) 2029–2035

assessment of multiple comparisons employed Tukey’s test. When the Mauchly’s sphericity assumption about the repeated measure factor was violated, Greenhouse-Geisser correction of degrees of freedom was applied, with only the corrected probability values reported. P300 amplitude and latency measured at Pz were used to evaluate the age effect. The age effect was assessed separately within each group using Pearson correlation analysis and polynomial regression. Polynomial regression first tests for linear effects and then adds the second order polynomial to determine if the amount of variance accounted for is significantly greater for a curvilinear model. Results of variables-added-in-order tests were summarized in Table 3. Differences in the linear regression slopes between group pairs were assessed by t test for comparison of the regression coefficients (Kleinbaum et al., 1987). Correlation analyses of P300 with age were also performed for non-paranoid and paranoid patients.

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3. Results 3.1. P300 amplitude and P300 latency The grand averaged ERP waveforms to target stimuli are shown in Fig. 1. Means of P300 amplitude and latency at electrodes of ROIs are presented in Table 2. P300 amplitude was smaller for patients with schizophrenia than unaffected controls for all ROIs (frontal: F1;41 ¼ 8:91, P ¼ 0:005; parietal: F1;41 ¼ 7:86, P ¼ 0:008; left: F1;41 ¼ 6:99, P ¼ 0:012; right: F1;41 ¼ 9:86, P ¼ 0:003). An interaction of group with electrode was detected for frontal and parietal ROIs (frontal: F2;82 ¼ 3:20, P ¼ 0:050; parietal: F2;82 ¼ 5:48, P ¼ 0:009). Multiple comparison by Tukey’s test revealed that P300 amplitude decreased in schizophrenia patients particularly at Fz (ts ¼ 5:16, df ¼ 6/ 123, P , 0:01) and at Pz (ts ¼ 4:94, df ¼ 6/123, P , 0:01). Exploratory analyses performed with 3 groups

Fig. 1. Grand average ERP waveforms elicited by target stimuli at 16 recording sites.

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Table 2 Means (^SD) of P300 amplitude and P300 latency at electrodes of ROIs P300 amplitude (mV)

F3 Fz F4 C3 C4 P3 Pz P4

P300 latency (ms)

Controls

Non-paranoid

Paranoid

Controls

Non-paranoid

Paranoid

8.8 ^ 5.6 11.5 ^ 5.9 9.2 ^ 4.5 12.8 ^ 7.3 12.3 ^ 5.7 13.3 ^ 5.4 15.0 ^ 6.5 13.2 ^ 5.3

4.2 ^ 4.1 4.1 ^ 5.0 4.8 ^ 4.5 6.1 ^ 5.0 6.0 ^ 4.9 9.0 ^ 5.9 8.1 ^ 5.6 8.8 ^ 5.2

5.9 ^ 5.2 7.5 ^ 6.2 6.1 ^ 5.4 9.0 ^ 7.3 7.2 ^ 5.0 9.3 ^ 7.0 9.4 ^ 7.4 9.3 ^ 5.9

329.2 ^ 23.7 326.0 ^ 18.5 326.5 ^ 20.4 332.1 ^ 19.1 331.3 ^ 18.6 336.3 ^ 18.1 331.6 ^ 17.9 337.4 ^ 22.0

325.3 ^ 30.7 310.8 ^ 14.9 318.9 ^ 28.9 314.6 ^ 19.9 313.3 ^ 28.0 327.2 ^ 34.5 318.0 ^ 34.7 314.5 ^ 27.7

357.7 ^ 36.2 350.1 ^ 31.4 350.4 ^ 29.5 355.3 ^ 34.2 353.8 ^ 29.4 349.0 ^ 26.4 351.2 ^ 27.2 350.8 ^ 20.6

(non-paranoid, paranoid and controls) detected similar group differences of P300 amplitude as the initial ANOVAs. Post hoc tests further revealed a significant P300 amplitude reduction in non-paranoid patients compared to controls for frontal ROI (ts ¼ 3:86, df ¼ 3/40, P , 0:05) and for right ROI (ts ¼ 3:64, df ¼ 3/40, P , 0:05), but not for parietal and left ROIs (parietal: ts ¼ 3:15, df ¼ 3/40, P . 0:05; left: ts ¼ 3:27, df ¼ 3/40, P . 0:05). No significant group difference of P300 amplitude had been detected between paranoid patients and controls for any ROI. P300 latency had not shown the significant group difference between patients with schizophrenia and control subjects for any ROI. Although exploratory ANOVAs performed with 3 groups had detected a significant group difference for all ROIs (frontal: F2;40 ¼ 6:21, P ¼ 0:004; parietal: F2;40 ¼ 4:58, P ¼ 0:016; left: F2;40 ¼ 5:51, P ¼ 0:008; right: F2;40 ¼ 6:83, P ¼ 0:003), post hoc assessments revealed that this group difference was mainly derived from a longer P300 latency in paranoid patients than in non-paranoid patients (frontal: ts ¼ 5:33, df ¼ 3/40, P , 0:01; parietal: ts ¼ 4:74, df ¼ 3/40, P , 0:01; left:

ts ¼ 5:12, df ¼ 3/40, P , 0:01; right: ts ¼ 5:81, df ¼ 3/40, P , 0:01). In addition, as compared with controls, the paranoid patients showed P300 latency prolongation for frontal ROI (ts ¼ 3:95, df ¼ 3/40, P , 0:05) and for left ROI (ts ¼ 3:48, df ¼ 3/40, P , 0:05), but not for parietal and right ROIs (parietal: ts ¼ 2:38, df ¼ 3/40, P . 0:05; right: ts ¼ 3:20, df ¼ 3/40, P . 0:05). No group difference of P300 latency had been found between non-paranoid patients and controls. 3.2. Age effect on P300 amplitude and P300 latency Age effect was evaluated from ERP data obtained at Pz. ANOVA results of polynomial regression tests for each pair of variables had been summarized in Table 3. Pearson correlation analysis revealed that P300 amplitude negatively correlated with age in the patients with schizophrenia (r ¼ 20:650, P ¼ 0:002) while P300 amplitude had no correlation with the age in the normal controls (r ¼ 20:078, P ¼ 0:722). A negative correlation of P300 amplitude with age was also detected in the non-paranoid patients (r ¼ 20:752, P ¼ 0:008) and

Table 3 ANOVA results of polynomial regression analyses Subjects P300 amplitude (Y)/age (X) Controls

Patients

P300 latency (Y)/age (X) Controls

Patients

Sources

df

X X2/X Residual X X2/X Residual

1 1 20 1 1 17

5.7 108.0 40.4 324.1 81.0 21.3

X X2/X Residual X X2/X Residual

1 1 20 1 1 17

3376.0 449.8 161.7 11731 150.7 678.4

MS, mean square; and **, P , 0.01.

MS

Partial F

Regression equation

Overall F

Y ¼ 16.91 2 0.07X Y ¼ 220.56 þ 2.71X 2 0.05X2

1.41

13.16** 3.80

Y ¼ 24.70 2 0.60X Y ¼ 55.77 2 2.91X þ 0.04X2

9.51**

19.24** 2.78

Y ¼ 283.96 þ 1.75X Y ¼ 360.44 2 3.94X þ 0.10X2

11.83**

18.07** 0.22

Y ¼ 236.77 þ 3.64X Y ¼ 194.40 þ 6.78X 2 0.05X2

8.76**

0.13 2.67

J. Wang et al. / Clinical Neurophysiology 114 (2003) 2029–2035

the paranoid patients (r ¼ 20:736, P ¼ 0:024) with schizophrenia. The linear regression slope of P300 amplitude on age was 2 0.07 mV/year (P ¼ 0:722) for the control subjects, and 2 0.60 mV/year (P ¼ 0:002) for the patients. The difference between these two slopes approached significance (t ¼ 2:00, df ¼ 39, P ¼ 0:052), suggesting a possible difference in the aging process between the two subject groups within the observed age range. A significant overall regression of the curvilinear model was observed for the patients (P ¼ 0:002), but not for the controls (P ¼ 0:268). An accelerated change in P300 amplitude with age possibly existed among those patients under about 30 years, as indicated by the secondorder polynomial model regression test (F1;17 ¼ 3:80, P ¼ 0:07). Pearson correlation analysis revealed a significant positive correlation between P300 latency at Pz and age

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within each subject group (normal controls, r ¼ 0:691, P , 0:001; patients, r ¼ 0:708, P , 0:001). However, within the patient group, the correlation was only detected in the paranoid patients (r ¼ 0:823, P ¼ 0:006), and not in the non-paranoid patients (r ¼ 0:560, P ¼ 0:073). The linear regression slope of P300 latency with age was 1.75 ms/year for normal males (P , 0:001) and 3.64 ms/year for males with schizophrenia (P , 0:001). The slope was steeper in the patient group than in the control group (t ¼ 2:11, df ¼ 39, P ¼ 0:041) (Fig. 2). Polynomial regression analyses also revealed a significant overall curvilinear regression of P300 latency with age for both the patients (P ¼ 0:002) and controls (P , 0:001). Accelerated prolongation of P300 latency with age was visually detectable in older control subjects (Fig. 2), although this curvilinear effect was under a significant level (F1;20 ¼ 2:78, P ¼ 0:111).

Fig. 2. Polynomial regression analyses of P300 amplitude and latency at Pz with age for two subject groups. Solid line: linear regression; dotted line: curvilinear regression. Both linear and curvilinear regression models were significant in providing predictive power for describing P300 amplitude/age relationship of patients, P300 latency/age relationships of controls and patients. The tendency for P300 amplitude reduction with age was more conspicuous in the younger patients. The slope for P300 latency with age was significantly steeper in the patient group than in the control group.

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3.3. Onset age, BPRS and N100 In the patients with schizophrenia, the onset age had the same correlations with P300 amplitude (r ¼ 20:657, P ¼ 0:002) and P300 latency (r ¼ 0:698, P ¼ 0:001) as the current age, mainly because the illness durations were less than 1 year. Neither P300 amplitude nor P300 latency showed a significant correlation with the patient’s BPRS scores. N100 measurements were analyzed only at Fz where the amplitude was most prominent. The N100 amplitude was smaller in the patient group than in the control group, but the difference was not significant (F1;41 ¼ 3:10, P ¼ 0:086). No group difference in N100 latency was detected (F1;41 ¼ 2:06, P ¼ 0:159). No significant correlation between N100 and age was detected in either the patients or the controls. N100 also showed no association with disease onset age or BPRS score.

4. Discussion The results of the present study suggest a reduction of P300 amplitude and an increased rate of P300 latency prolongation with age in male patients with schizophrenia who were drug-naive and in their first episode. A negative correlation between P300 amplitude and age was observed in the patients but not in the control subjects, suggesting that P300 amplitude was sensitive to the aging process in schizophrenia patients. This sensitivity to age may be associated with the inverse correlation of P300 amplitude with illness duration in chronic schizophrenia patients (Olichney et al., 1998; Mathalon et al., 2000b; MartinLoeches et al., 2001; Frodl et al., 2002). P300 latency did not show a significant group difference in the present study, a finding consistent with most, but not all previous studies of P300 latency in schizophrenia. However, P300 latency correlated with age in each subject group, demonstrating its sensitivity to aging processes. The linear slope of P300 latency with age in the normal controls was consistent with previous reports of a change of 1 –2 ms/year. In the present study, the slope of P300 latency-age relationship was significantly steeper in the patient group than in the control group. Although the same result was previously reported in chronic and medicated patients (O’Donnell et al., 1995; Frangou et al., 1997; Mathalon et al., 2000b), this is the first report in first-episode patients with schizophrenia. In addition, a significant overall curvilinear correlation was found for P300 latency with age in normal controls. The curvilinear correlation also suggested the possibility that P300 latency was accelerated with age in older normal male subjects. This finding was consistent with our previous report on normal male subjects (Hirayasu et al., 2000). The reduction in P300 amplitude and the increased rate of P300 latency prolongation with age is very likely independent on medication effect and illness duration,

since the patients in our study were drug-naive and their illness duration was under 1 year. These P300 abnormalities might have resulted from neurodegenerative processes in schizophrenia at the early stage of the illness, perhaps interacting with normal aging processes. Such an interaction could help to explain the relatively worse prognosis for the early onset patients (Olichney et al., 1998; Mathalon et al., 2000b), since they would suffer from neurodegeneration, aging and the interaction of these two factors. In the present study, younger patients showed a tendency of accelerated change in P300 amplitude with age. These findings were consistent with the clinical impression that patients with schizophrenia usually manifest progressive deterioration within the first 5 – 10 years (Buchanan and Carpenter, 2000). Recent MRI volumetric studies suggest that anatomical abnormalities are present during the early stage of illness in patients with first episode schizophrenia. The affected brain structures include the frontal lobe, temporal lobe and hippocampus, which are also involved with the generation of P300 (Hirayasu et al., 1998b, 2001). More recently, Kasai et al. (2003) found a progressive volume reduction in gray matter of the superior temporal gyrus during follow up MRI analysis of patients with first episode schizophrenia. Longitudinal MRI studies of first episode schizophrenia have generally uncovered poorly treated patients and patients with a worse course of illness. Such patients are more likely to show progressive changes in brain morphology, with ventricular enlargement being the most consistently reported feature (DeLisi et al., 1995, 1997; Gur et al., 1998; Lieberman et al., 2001). P300 amplitude reduction reported in early stage patients has been postulated as a trait marker of schizophrenia (Hirayasu et al., 1998a; Salisbury et al., 1998; Mathalon et al., 2000a; Demiralp et al., 2002). However, it remains uncertain whether the first episode patients had the same P300 topographic abnormalities as those of the chronic patients. Salisbury et al. (1998) replicated the left-to-right asymmetry in P300 reduction in their medicated firstepisode patients. Demiralp et al. (2002) reported that, in contrast to a widespread decrease in chronic patients, P300 amplitude reduction occurred most prominently over the frontal areas in first episode patients. The present study confirmed the finding by Demiralp et al. (2002) only in the non-paranoid patients, suggesting that the anterior-posterior asymmetry in P300 amplitude reduction might differ according to subtype of schizophrenia. While schizophrenia is accurately conceptualized as a disease process, it seems more likely that more than one disease entity exists within the clinical syndrome of schizophrenia, with each having a distinguishable etiology and pathophysiology (Buchanan and Carpenter, 2000). The present study demonstrated topographic difference in P300 amplitude between paranoid and non-paranoid patients, and P300 latency prolongation in paranoid patients but not in non-paranoid patients. These findings further attest to the heterogeneous nature of schizophrenia. Further studies will

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be necessary in order to clarify the processes involved in the etiology of different schizophrenia subtypes.

Acknowledgements We gratefully acknowledge Dr Maxine Randall for her editorial comments.

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