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Predicting outcome in psychotic disorders is of considerable interest to mental health professionals. Despite all the efforts to establish predictors, the results in this field are at best equivocal. In particular, psychopathological predictors described in classic long-term studies have limited value (1). With regard to biological tests, CT findings suggesting cortical atrophy predicted poor outcome in a large series of recent-onset psychosis patients (2). The EEGs of schizophrenia patients have no clearly discernable or specific abnormalities, although EEG has been examined as a predictor of response to treatment: a review of early studies of resting EEG and subsequent quantitative EEG investigations supported the hypothesis that poorer prognosis in schizophrenia is associated with an abnormal EEG (3). However, contrasting results have been reported with the finding that, in general, patients with normal EEG recordings had a more severe and prolonged course of illness, and those with distinct focal or paroxysmal EEG abnormalities had a better prognosis (4). All the studies were carried out in patients with a history of prolonged exposure to neuroleptics. The only EEG study of first-episode, drug-naive psychosis patients used quantitative EEG in relatively small numbers and had a short follow-up (5). Interest in the early identification and treatment of patients with psychotic disorders has recently increased, many of these patients have not had prolonged exposure to antipsychotic drug treatment. This report is based on the incidental observation that, in a group of first-episode psychosis patients, a normal, routine EEG was related to symptomatic improvement at the end of 1 year following neuroleptic treatment. MethodThe Prevention and Early Intervention Program for Psychoses (PEPP) at London Health Sciences Centre (LHSC), London, Ontario, was established to serve a predominantly urban population of approximately 390 000 in southwestern Ontario. The program provides comprehensive assessment and treatment for individuals aged 16 to 50 years who have experienced for more than 1 week the first onset of symptoms of a nonaffective psychosis and who have not previously received more than 1 month of antipsychotic treatment for their first episode of psychosis . As part of a comprehensive assessment protocol for the study of early identification and intervention for psychosis, all patients undergo several rating scale assessments and laboratory investigations, including standard surface EEG in an awake state (for which written informed consent is obtained). All procedures for assessment and investigations, including EEG, are explained to the patients. (For details, please see our Web site at: www.pepp.ca). Twenty- one electrodes are placed in accordance with the International 10–20 Electrode Placement System. EEGs are classified as follows, according to a modified version of the Mayo Clinic classification of EEG abnormalities (6): normal = normal limits for age and state of alertness; essentially normal = probably normal but contains one or more elements of questionable normality; and dysrhythmia Grade I to V = 5 categories of varying intensity and frequency of theta–delta or rhythmic activity, including spikes or recorded seizures. Only the highest dysrhythmia grade is given; if significant abnormalities in lower grades exist, they are included within the higher grade. When EEG abnormalities are not epileptiform, they are termed “nonspecific” and localized in the usual manner (that is, localized to a lobe or lobes, hemispheric, or generalized). A neurologist specializing in EEG and epilepsy, who had no knowledge of the patients’ psychiatric conditions, interpreted all EEGs. The patients had EEGs at baseline only. For diagnostic assessment at baseline, all patients admitted to the PEPP undergo the Structured Clinical Interview for DSM-IV (SCID-IV) (7). For this study, we assessed positive symptoms of psychosis using the Scale for Assessment of Positive Symptoms (SAPS) (8); we assessed negative symptoms using the Scale for Assessment of Negative Symptoms (SANS) (9). We assessed symptoms both at baseline and after 1 year of participation in the PEPP. All clinical ratings were completed by experienced clinicians who had achieved acceptable levels of interrater reliability (at least 80% agreement to within 1 point for all SAPS and SANS items). On entry into the PEPP, symptom ratings were conducted with reference to the 1-month period prior to the assessment date. For negative symptom ratings, we also incorporated information available from the patients’ families and case managers. We arrived at total positive and negative symptoms scores by adding all composite scores on each subscale of the SAPS and SANS, respectively. Symptomatic improvement is indicated by remission of positive symptoms and change in negative symptoms. Remission generally refers to the loss or reduction of positive symptoms. For this study, we defined remission as a score of 2 or less on all global items of the SAPS for a period of at least 1 month prior to assessment. The global items assess symptoms of hallucinations, delusions, bizarre behaviour, and formal thought disorder. As there are no agreed-upon criteria for remission of negative symptoms, we report the improvement of negative symptoms as a percent change at 1 year, compared with baseline (that is, reductions of less than 30%, 30% to 50%, or more than 50%). We used these criteria for outcome in our previous study (10). ResultsOf 109 patients who met criteria for a first episode of nonaffective psychosis and were admitted to the PEPP during a 30-month period, 82 had an EEG at baseline. The baseline and 1-year data on SAPS ratings were available to determine the psychosis remission rates for 61 patients. The baseline and 1-year data on SANS were available for a total of 54 patients. This reduced sample size (n = 61 and n = 54, respectively) reflects the clinical reality: patients were either uncooperative or unwilling to have an EEG or comply with rating scales assessments within the time frame, or they were lost to follow- up. To ascertain the comparability of the 61 and 54 patients for whom complete SAPS and SANS data, respectively, were available at 1 year with those patients (48 and 55, respectively) remaining from the total originally admitted to the program during this period (n = 109), we carried out a contrast on baseline measurements between these groups. There were no significant differences in sex, age, age at onset of psychosis, level of education, or marital status, or in the baseline SAPS and SANS scores. Most patients in the subgroup of 61 patients were men (75.9%) and single (72.2%), with a mean age of 24.8 (SD 8.9) years and a mean age at onset of psychosis of 23.3 (SD 9.4 years). Although every effort was made to include subjects with a nonaffective psychosis at baseline, the diagnostic breakup at 1-year follow-up was as follows: schizophrenia 53 (87%), bipolar disorder 3 (4.9%), psychosis not otherwise specified 2 (3.3%), substance-induced psychosis 2 (3.3%), and delusional disorder 1 (1.6%). With regard to the use of medications, 27 (44.3%) patients were not taking any neuroleptics at baseline. Patients taking neuroleptics (n = 34) had a lifetime exposure of less than 1 month at the time of the EEG, with the distribution as follows: atypicals 23 (37.7%) and typicals 6 (9.8%), with equivocal information on 5 (8.2%). The prevalence of EEG abnormalities did not differ between the drug-naVve patients and those treated with neuroleptics for less than 1 month. Of the 82 patients who had an EEG at baseline, 30 (36.6%) had a normal recording, 36 (43.9%) had an essentially normal recording, and 16 (19.5%) showed “dysrhythmia.” Of the 61 patients for whom baseline and 1-year SAP scores were available, 21 (34.4%) had a normal baseline EEG , 28 (45.9%) had an essentially normal EEG, and 12 (19.7%) showed “dysrhythmia.” Of the 54 patients for whom baseline and 1-year scores on SANS were available, 18 (33.3%) had a normal baseline EEG, 28 (51.8%) had an essentially normal EEG, and 8 (14.8%). showed “dysrhythmia.” There was no statistically significant difference in baseline SAPS and SANS scores between subjects in the 3 EEG categories. Further, there was no significant difference in baseline studies between those who were and those who were not available for follow-up using SAPS and SANS at 1 year. Of the 21/61 (34.4%) patients with a normal EEG for whom the data for EEG and remission rate were available, 19 (90.5%) had a remission of their psychosis at the end of 1 year, compared with 18/28 (64.3%) of those with an essentially normal EEG and only 7/12 (58.3%) of those with dysrhythmia on EEG (see Table 1). These findings are statistically significant (c2 = 5.51, df = 2, P = 0.045). Of the 54 patients for whom data for EEG and negative symptoms were available at baseline and at the end of 1 year, 11/18 (61.1%) patients with normal EEG at baseline showed more than a 50% reduction of negative symptoms, compared with 10/28 (35.7%) who had an essentially normal EEG. None of the 8 patients with dysrhythmia showed more than a 50% reduction in negative symptoms (see Table 1). These findings were highly significant (c2 = 13.7, df = 4, P = 0.004).
DiscussionPredicting symptomatic response to treatment in patients with schizophrenia has important clinical and research implications. Studies using samples of patients with first-episode psychosis from a well-defined catchment area and with limited exposure to previous neuroleptic treatment are rare. The current clinical setting of the PEPP and the larger research study on early identification, treatment, and outcome provided an excellent opportunity to examine all first-episode psychosis patients. In this study, patients had a baseline EEG. The rating-scale assessments were carried out at baseline and repeated after 1 year. We found that significantly more patients with normal EEG showed remission of positive symptoms and a greater than 50% reduction in negative symptoms at 1 year, compared with those with an abnormal EEG. If the presence of EEG abnormality in first-episode psychosis at baseline predicts a lack of improvement in both positive and negative symptoms, this has significant clinical implications, because EEG is a relatively simple and inexpensive investigative tool. The only EEG study of first-episode, drug-naïve, acute psychosis patients had relatively small numbers (n = 13) (5). However, it did have a control group of healthy volunteers. In it, the resting EEG (19 leads) was subjected to spectral analysis. The symptom ratings were divided into 2 groups: early responders, who showed reduction in scores of more than 30% after 7 days of treatment; and late responders, who showed this improvement after 28 days of treatment. This study showed that the early-response group did not show significant differences, compared with control subjects, whereas the late-response group had higher values in the alpha 2 and beta 2 bands. Our study did not use computerized spectral analysis of EEG. Further, the duration of follow-up in our study is 1 year, compared with the above-mentioned study, where it is less than 1 month. Our results are particularly interesting in view of some of the recent studies suggesting that schizophrenia patients with EEG abnormalities respond well to clozapine (11–13). Perhaps treatment refractoriness and EEG abnormalities coexist in this group of patients and the presence of EEG abnormalities may be an epiphenomenon. It is also possible that EEG abnormalities, subtle as they are, may reflect additional support for the hypothesis of an underlying biological basis and (or) contribute to some other factors that determine poor outcome. This is relevant, because consensus that the structure of the brain is abnormal in major psychotic disorders is increasing. However, whether these abnormalities predate illness onset and are relatively fixed over its course, or whether they are progressive, remains controversial (14). A recent longitudinal magnetic resonance imaging study shows that some of the grey matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression (15). This is an uncontrolled, prospective cohort study, and thus, no strong inferences can be made. However, it is the first report of the relation of abnormal EEG to poorer symptomatic (both positive and negative) improvement at 1-year follow-up. This incidental and preliminary finding has been observed in a group of first-episode psychosis patients, most of whom met criteria for a schizophrenia spectrum psychosis at 1 year and had either no exposure (44.3%) or less than 1 month’s exposure (55.7%) to neuroleptics at baseline. Given the nature of the service of early identification and treatment, it is not possible or ethical to withhold treatment until an EEG is carried out, especially since EEG has been of low priority and considered of little value in psychiatric patients. Although neuroleptics are known to affect EEG, it is interesting that these findings are significant in the group of patients with relatively poorer symptomatic outcome at 1 year. We propose to examine how robust these findings are by studying a larger cohort over a longer follow-up period. It would also be of interest to see how these findings relate to other clinical variables influencing outcome in first-episode psychosis. AcknowledgementsOur thanks to Dr GB Young, Epileptologist, London Health Sciences Centre, for his reports on the EEG. Funding and SupportThe research reported here is part of a study on early intervention supported by an operating grant from the Canadian Institutes of Health Research. References1. Moller HJ, Von Zerssen D. Course and outcome of schizophrenia. In: Hirsch SR, Weinberger DR, editors. Schizophrenia. Oxford: Blackwell Science Ltd; 1995. p 106–27. 2. Van Os J, Fahy A, Jones P, Harvey I, Sham P, Lewis S. Psychopathological syndromes in the functional psychosis: associations with course and outcome. Psychol Med 1996;26:203–8. 3. Czobor P, Volavka J. Pretreatment EEG predicts short-term response to haloperidol treatment. Biol Psychiatry 1991;30:927–42. 4. Small JG, Small IF. Re-evaluation of clinical EEG findings in schizophrenia. Dis Nervous System 1965;6:345–49. 5. Merlo MCG, Kleinlogel H, Koukkou M. Differences in the EEG profiles of early and late responders to antipsychotic treatment in first episode drug-naive psychotic patients. Schizophr Res 1998;30:221–8. 6. Mayo Clinic. Clinical examinations in neurology. Ch. 15. Rochester (MN): Mayo Clinic and Mayo Foundation for Medical Education and Research; 1991. 7. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV Axis I disorders. Washington (DC): American Psychiatric Press; 1978. 8. Andreasen NC. Scale for assessment of positive symptoms (SAPS). Iowa City: University of Iowa College of Medicine; 1984. 9. Andreasen NC. Scale for assessment of negative symptoms (SANS). Iowa City: University of Iowa College of Medicine; 1983. 10. Malla AK, Norman RMG, Manchanda R, Ahmed R, Scholten D, Harricharan R, and others. One year outcome in first episode psychosis: influence of DUP and other predictors. Schizophr Res 2002;54:231–42. 11. Treves IA, Neufeld MY. EEG abnormalities in clozapine-treated schizophrenic patients. Eur Neuropsychopharmacol 1996;6:8:93–4. 12. Pillay SS, Stoll AL, Weiss MK, Tohen M, Zarate CA, Banov MD, and others. EEG abnormalities before clozapine therapy predict a good clinical response to clozapine. Ann Clin Psychiatry 1996;8:1–5. 13. Knott V, Labelle A, Jones B, Mahoney C. EEG hemispheric asymmetry as a predictor and correlate of short-term response to clozapine treatment in schizophrenia. Clin Electroencephalogr 2000;31:3:145–52. 14. Weinberger DR, McClure RK. Neurotoxicity, neuroplasticity and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 2002;49:553–8. 15. Pantelis C, Velakoulls D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, and others. Neuroanatomical abnormalities before and after onset of psychosis: a cross sectional and longitudinal MRI comparison. Lancet 2003;361:281–7. AuthorsManuscript received January 2003, revised, and accepted April 2003. 1. Associate Professor of Psychiatry, University of Western Ontario, London, Ontario. 2. Professor of Psychiatry, McGill University; Director, Clinical Research, Douglas Hospital Research Centre, Montreal, Quebec. 3. Assistant Professor of Psychiatry, University of Western Ontario, London, Ontario Address for correspondence: Dr R Manchanda, London Health Sciences Centre South Street Campus, University of Western Ontario, Dept of Psychiatry, WMC Building, 1st Floor, 392 South Street, London, ON N6A 4G5
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