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Persistent psychoses in first episode patients
Schizophrenia Research 80 (2005) 113 – 116 www.elsevier.com/locate/schres
Persistent psychoses in first episode patients Rahul Manchanda a,*, Ross M.G. Norman a, Ashok K. Malla b, Rajendra Harricharan a, Sandra Northcott a a
b
Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, 392 South Street, London, Ontario, Canada N6A 4G5 Department of Psychiatry, Douglas Hospital Research Centre, Frank B. Common Pavilion, 6875 LaSalle Blvd, Verdun, Quebec, Canada H4H 1R3 Received 7 June 2005; received in revised form 11 August 2005; accepted 15 August 2005 Available online 19 September 2005
Abstract This study was carried out to identify characteristics of patients with schizophrenia spectrum disorder who continue to have persistent psychoses (15%) for 2 years after initiation of treatment by comparing them to those who maintained full recovery of positive symptoms (42%) up to 2 years. Compared to those in recovery, significantly more patients with persistent psychoses were single, male, had a higher prevalence of drug abuse and abnormal EEG findings at presentation for treatment. Duration of untreated psychoses or untreated illness did not discriminate between the groups. D 2005 Elsevier B.V. All rights reserved. Keywords: Persistent psychoses; First episode; Outcome; DUP
1. Introduction It has been suggested that inadequate response to treatment for psychoses can be established relatively early (Edwards et al., 1998). Careful follow-up of psychotic patients from their first presentation should help us identify those at high risk for persistent psychoses. The present study was undertaken to identify characteristics of patients with first episode psychoses (FEP) in whom positive symptoms persist for 2 years, * Corresponding author. Tel.: +1 519 667 6866; fax: +1 519 667 6867. E-mail address: [email protected] (R. Manchanda). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.08.005
despite treatment by contrasting their presenting characteristics with those who achieve and maintain full recovery during the same period.
2. Materials and methods The Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario, Canada, provides assessment and treatment to all cases of FEP (predominantly non-affective). The selection criteria, antipsychotic treatment algorithm and psycho-social interventions at PEPP are detailed elsewhere (Malla et al., 2003).
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R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
2.1. Assessments The diagnosis of a psychotic disorder was established on the basis of the Structured Clinical Interview for DSM-IV (SCID-IV) (First et al., 1995). Symptoms were assessed using the Scale for Assessment of Positive Symptoms (SAPS) (Andreason, 1984), Scale for Assessment of Negative Symptoms (SANS) (Andreason, 1983), Calgary Depression Scale (CDS) (Addington et al., 1992) and Hamilton Anxiety Scale (HAS) (Hamilton, 1959). Patients were seen at least once/month and assessed with above scales at entry and at 1 and 2 years of participation in PEPP. Total positive and negative symptom scores were derived by adding all global scores for each subscale of the SAPS and SANS, respectively. The criteria for a personal history of current drug/alcohol abuse at entry into PEPP was based on SCID-IV carried out when patients could cooperate in completing the assessment. Patients also had a standard surface EEG in an awake state at baseline. EEG’s were classified according to the Mayo Clinic Classification of EEG: Normal, Essentially Normal and Dysrhythmia (see Manchanda et al., 2005). 2.2. Operational definitions Full Recovery: rating of 0 on all subscales of SAPS by the end of 1 year in PEPP and maintaining this rating at 2-year follow-up; no period of recurrence of positive symptoms between 1 and 2 years based on consensus rating of independent chart review using a modified version of the Life Chart Schedule (Susser et al., 2000). Persistent Psychoses: rating of 3 or more on any subscale of SAPS at baseline, 1 and 2 years; no period of full recovery of symptoms at any time during the 2year period based on independent chart review as above. Duration of Untreated Psychoses (DUP): period between the time of onset of psychotic symptoms to the initiation of antipsychotics. Duration of Untreated Illness (DUI): period between the onset of any psychiatric symptom to the initiation of antipsychotics. These ratings were based on an adaptation of the IRAOS (Hafner et al., 1992). In order to correct positively skewed distributions of
DUP and DUI, a log transformation of these variables was used for analyses.
3. Results There were 159 consecutive patients in PEPP for whom 2-year follow-up was available. There were 67 (42.1%) patients in full recovery compared to 24 (15.1%) with persistent psychoses based on the SAPS criteria and/or Life Chart Schedule and consensus rating. The remaining 68 patients did not meet the specific criteria for full recovery or persistent psychoses and were excluded from comparison. The socio-demographic characteristics and baseline symptom scores of the two groups are shown in Table 1. In comparison to the full recovery group, those showing persistent psychoses were more likely to be male (91.7% versus 71.6%, chi-square = 3.99, df = 1, p b .05). There were also more single individuals in the persistent psychoses group than in the recovery group (95.8% versus 74.6%, chi-square = 5.0, df = 1, p b .05) and a more frequent personal history of drug abuse (41.6% versus 20.9%, chi-square 3.92, df = 1, p b .05). There were no significant differences in the two groups with regard to the level of education, age of onset, personal history of alcohol abuse, family history of schizophrenia spectrum disorder, DUP, DUI, baseline symptoms scores on SAPS or SANS, CDS or HAS or DSM-IV diagnostic categories. There was a similar distribution in the use of atypicals in the two groups. The distribution for clozapine was similar at 1 year (b 5%), but at 2 years, more patients in the persistent psychoses group (20.8%) were on clozapine compared to 1.5% in the recovery group. This is in keeping with the clinical practice. Patients are advised clozapine when they fail to respond to two antipsychotic drugs. EEG results were available for 54 / 67 patients in the recovery group and 21 / 24 in the persistent psychoses group at entry into treatment. Significantly fewer patients in the persistent psychoses group (23.8%) had a normal EEG in comparison to the recovery group (55.5%) (chi-square = 6.2, df = 2, p b .05). A logistic regression analysis was carried out to predict status of recovery versus persistent psychoses. There were 75 patients for whom complete data were available for each of the variables that had been shown to have a significant binary relationship with outcome: gender, marital status (single versus not single), history of drug abuse and EEG. Only EEG results and drug abuse predicted recovery status independently of the other variables (betas of .968, p b .05 and 1.435, p b .05, respectively). A classification table based on predictions from the logistic equation using EEG status and drug abuse and a cut-off of .50 probability showed that
R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
115
Table 1 Socio-demographic, clinical characteristics and baseline symptom ratings of the sample (N = 91) Persistent psychoses (N = 24)
Male Single High school/higher ed. Mean age of onset Mean age of entry Family history of SSD—in first degree relative Personal history of alcohol abuse Personal history of drug abuse Mean DUP Mean DUI Positive symptoms (SAPS) Negative symptoms (SANS) Calgary depression (CDS) Hamilton anxiety (HAS)
Recovery (N = 67)
N (%)
N (%)
22 (91.7) 23 (95.8) 10 (41.7) 21.8 years 23.3 years 2 / 18 (11.2) 3 (12.5) 10 (41.6) 1.5 (F0.6) years 2.1 (F0.6) years 9.5 (F3.3) 11.3 (F3.1) 2.8 (F3.5) 7.4 (F5.0)
48 (71.6) 50 (74.6) 40 (59.7) 24.6 years 26.1 years 11 / 57 (19.2) 14 (20.9) 14 (20.9) 1.2 (F0.7) years 2.1 (F0.6) years 10.0 (F3.9) 11.4 (F 5.6) 3.3 (F3.9) 8.3 (F7.7)
75% of cases could be correctly classified as showing persistent psychoses versus full recovery. The predictions showed .89 sensitivity and .43 specificity with respect to classification of treatment outcome.
4. Discussion This is the first study to identify persistent psychoses patients in an early intervention program. Significantly more patients with persistent psychoses as compared to those in recovery were single and male. It is, of course, possible that some of these significant relationships occurred by chance, and we recognize the need for replication. Nevertheless, it has long been suggested that schizophrenic patients living in stable marital or other partnership may be a positively selected group with a milder form of the disease (Odegaard, 1946). Evidence that being married (or living with a partner) may act as a risk modifier was obtained from the WHO ten country study after controlling for the effects of gender, premorbid personality traits, family history of psychoses and marital status at age of onset (Jablensky and Cole, 1997). It has been well established that female patients have a better response to treatment with conventional antipsychotic medications although it has been less clear whether this holds true for atypical antipsychotics (Barnes et al., 2003). In our study, all
p value
.04 .02 ns ns ns ns ns .04 ns ns ns ns ns ns
patients were treated with atypical antipsychotics as first line. It has been proposed that the favourable treatment responsivity in female patients may be as a result of oestrogen regulation of the dopaminergic tone (Leung and Chue, 2000). Patients with persistent psychoses had a significantly higher prevalence of drug abuse (mainly cannabis). Patients who abuse illicit drugs or alcohol are more likely to have more prominent symptomatology, more frequent relapses and repeated hospitalizations (Seibyl and Lieberman, 1993). The dynamic between persistent psychotic symptoms, antipsychotic side effects and the potential for substance use as selfmedication remains uncertain. The associated social aspects of substance abuse such as lack of self-care and/or non-compliance with medications may also contribute to failure to improve. The neurochemical basis for such an effect, possibly acting through alteration of dopamine-receptor sensitivity, merits further attention because it may suggest more effective alternative treatment strategies for these patients (Buckley et al., 1994). We also observed that significantly fewer patients in the persistent psychoses group (23.8%) had a normal baseline EEG compared to the recovery group (55.5%). None of our patients suffered from epilepsy. The value of EEG as a predictor of treatment response has been suggested previously (Itil, 1982). This study lends further support to this hypothesis (Manchanda et al., 2005), although the
116
R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
findings are qualitative and lack a healthy comparison group. Identification of those at high risk of a persistent psychoses early in the course of illness leads to the challenge of providing specialized long-term care for these individuals in order to improve functioning and enhance quality of life. This study attempts to identify characteristics of the patients within the limitations of a primarily qualitative data, multiple statistical tests and the exploratory nature of the study in an early intervention program.
Acknowledgement This research was supported by a grant from the Canadian Institute of Health Research.
References Addington, D., Addington, J., Maticka-Tyndale, E., 1992. Reliability and validity of a depression rating scale for schizophrenics. Schizophrenia Research 6, 201 – 208. Andreason, N.C., 1983. Scale for Assessment of Positive Symptoms (SANS). University of Iowa, Iowa City, IA. Andreason, N.C., 1984. Scale for Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City, IA. Barnes, T.R.E., Buckley, P., Schulz, S.C., 2003. Treatment-resistant schizophrenia (ch. 26). In: Hirsch, S.R., Weinberger, D.R. (Eds.), Schizophrenia. Blackwell Publishing, Oxford. Buckley, P.F., Thompson, P., Way, L., et al., 1994. Substance use among patients with treatment resistant schizophrenia: charac-
teristics and implications for clozapine therapy. American Journal of Psychiatry 151, 385 – 389. Edwards, J., Maude, D., McGorry, P.D., et al., 1998. Prolonged recovery in first episode psychoses. British Journal of Psychiatry 172 (suppl. 33), 107 – 116. First, M.B., Spitzer, R.L., Gibbon, M., et al., 1995. SCID Clinician Version Administration Booklet. Biometrics Research Department, N.Y. State Psychiatric Institute, New York. Hafner, H., Reicher-Rossler, A., Hambrecht, M., et al., 1992. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophrenia Research 6, 209 – 223. Hamilton, M., 1959. The assessment of anxiety states by rating. British Journal of Medical Psychology 32, 50 – 55. Itil, T.M., 1982. The use of electroencephalography in the practice of psychiatry. Psychosomatics 23, 799 – 813. Jablensky, A., Cole, S.W., 1997. Is earlier age at onset of schizophrenia in males a confounded finding? Results from a cross-cultural investigation. British Journal of Psychiatry 170, 234 – 240. Leung, A., Chue, P., 2000. Sex differences in schizophrenia: a review of the literature. Acta Psychiatrica Scandinavica 101, 3 – 38. Malla, A.K., Norman, R.M.G., McLean, T.S., et al., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Australian and New Zealand Journal of Psychiatry 37, 407 – 413. Manchanda, R., Norman, R., Malla, A., et al., 2005. EEG abnormalities and two-year outcome in first episode psychoses. Acta Psychiatrica Scandinavica 111, 208 – 213. Odegaard, O., 1946. Marriage and mental disease: a study in social psychopathology. Journal of Mental Science 92, 35 – 39. Seibyl, J.P., Lieberman, J.A., 1993. Substance abuse and schizophrenia. In: Powchichk, P., Schultz, S.C. (Eds.), Psychiatric Clinics of North America. W.B. Sanders, Philadelphia, pp. 123 – 138. Susser, E., Finnerty, M., Mojtabai, R., et al., 2000. Reliability of the life chart schedule for assessment of the long-term course of schizophrenia. Schizophrenia Research 42, 67 – 77.
Persistent psychoses in first episode patients Rahul Manchanda a,*, Ross M.G. Norman a, Ashok K. Malla b, Rajendra Harricharan a, Sandra Northcott a a
b
Prevention and Early Intervention Program for Psychoses (PEPP), London Health Sciences Centre, 392 South Street, London, Ontario, Canada N6A 4G5 Department of Psychiatry, Douglas Hospital Research Centre, Frank B. Common Pavilion, 6875 LaSalle Blvd, Verdun, Quebec, Canada H4H 1R3 Received 7 June 2005; received in revised form 11 August 2005; accepted 15 August 2005 Available online 19 September 2005
Abstract This study was carried out to identify characteristics of patients with schizophrenia spectrum disorder who continue to have persistent psychoses (15%) for 2 years after initiation of treatment by comparing them to those who maintained full recovery of positive symptoms (42%) up to 2 years. Compared to those in recovery, significantly more patients with persistent psychoses were single, male, had a higher prevalence of drug abuse and abnormal EEG findings at presentation for treatment. Duration of untreated psychoses or untreated illness did not discriminate between the groups. D 2005 Elsevier B.V. All rights reserved. Keywords: Persistent psychoses; First episode; Outcome; DUP
1. Introduction It has been suggested that inadequate response to treatment for psychoses can be established relatively early (Edwards et al., 1998). Careful follow-up of psychotic patients from their first presentation should help us identify those at high risk for persistent psychoses. The present study was undertaken to identify characteristics of patients with first episode psychoses (FEP) in whom positive symptoms persist for 2 years, * Corresponding author. Tel.: +1 519 667 6866; fax: +1 519 667 6867. E-mail address: [email protected] (R. Manchanda). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.08.005
despite treatment by contrasting their presenting characteristics with those who achieve and maintain full recovery during the same period.
2. Materials and methods The Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario, Canada, provides assessment and treatment to all cases of FEP (predominantly non-affective). The selection criteria, antipsychotic treatment algorithm and psycho-social interventions at PEPP are detailed elsewhere (Malla et al., 2003).
114
R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
2.1. Assessments The diagnosis of a psychotic disorder was established on the basis of the Structured Clinical Interview for DSM-IV (SCID-IV) (First et al., 1995). Symptoms were assessed using the Scale for Assessment of Positive Symptoms (SAPS) (Andreason, 1984), Scale for Assessment of Negative Symptoms (SANS) (Andreason, 1983), Calgary Depression Scale (CDS) (Addington et al., 1992) and Hamilton Anxiety Scale (HAS) (Hamilton, 1959). Patients were seen at least once/month and assessed with above scales at entry and at 1 and 2 years of participation in PEPP. Total positive and negative symptom scores were derived by adding all global scores for each subscale of the SAPS and SANS, respectively. The criteria for a personal history of current drug/alcohol abuse at entry into PEPP was based on SCID-IV carried out when patients could cooperate in completing the assessment. Patients also had a standard surface EEG in an awake state at baseline. EEG’s were classified according to the Mayo Clinic Classification of EEG: Normal, Essentially Normal and Dysrhythmia (see Manchanda et al., 2005). 2.2. Operational definitions Full Recovery: rating of 0 on all subscales of SAPS by the end of 1 year in PEPP and maintaining this rating at 2-year follow-up; no period of recurrence of positive symptoms between 1 and 2 years based on consensus rating of independent chart review using a modified version of the Life Chart Schedule (Susser et al., 2000). Persistent Psychoses: rating of 3 or more on any subscale of SAPS at baseline, 1 and 2 years; no period of full recovery of symptoms at any time during the 2year period based on independent chart review as above. Duration of Untreated Psychoses (DUP): period between the time of onset of psychotic symptoms to the initiation of antipsychotics. Duration of Untreated Illness (DUI): period between the onset of any psychiatric symptom to the initiation of antipsychotics. These ratings were based on an adaptation of the IRAOS (Hafner et al., 1992). In order to correct positively skewed distributions of
DUP and DUI, a log transformation of these variables was used for analyses.
3. Results There were 159 consecutive patients in PEPP for whom 2-year follow-up was available. There were 67 (42.1%) patients in full recovery compared to 24 (15.1%) with persistent psychoses based on the SAPS criteria and/or Life Chart Schedule and consensus rating. The remaining 68 patients did not meet the specific criteria for full recovery or persistent psychoses and were excluded from comparison. The socio-demographic characteristics and baseline symptom scores of the two groups are shown in Table 1. In comparison to the full recovery group, those showing persistent psychoses were more likely to be male (91.7% versus 71.6%, chi-square = 3.99, df = 1, p b .05). There were also more single individuals in the persistent psychoses group than in the recovery group (95.8% versus 74.6%, chi-square = 5.0, df = 1, p b .05) and a more frequent personal history of drug abuse (41.6% versus 20.9%, chi-square 3.92, df = 1, p b .05). There were no significant differences in the two groups with regard to the level of education, age of onset, personal history of alcohol abuse, family history of schizophrenia spectrum disorder, DUP, DUI, baseline symptoms scores on SAPS or SANS, CDS or HAS or DSM-IV diagnostic categories. There was a similar distribution in the use of atypicals in the two groups. The distribution for clozapine was similar at 1 year (b 5%), but at 2 years, more patients in the persistent psychoses group (20.8%) were on clozapine compared to 1.5% in the recovery group. This is in keeping with the clinical practice. Patients are advised clozapine when they fail to respond to two antipsychotic drugs. EEG results were available for 54 / 67 patients in the recovery group and 21 / 24 in the persistent psychoses group at entry into treatment. Significantly fewer patients in the persistent psychoses group (23.8%) had a normal EEG in comparison to the recovery group (55.5%) (chi-square = 6.2, df = 2, p b .05). A logistic regression analysis was carried out to predict status of recovery versus persistent psychoses. There were 75 patients for whom complete data were available for each of the variables that had been shown to have a significant binary relationship with outcome: gender, marital status (single versus not single), history of drug abuse and EEG. Only EEG results and drug abuse predicted recovery status independently of the other variables (betas of .968, p b .05 and 1.435, p b .05, respectively). A classification table based on predictions from the logistic equation using EEG status and drug abuse and a cut-off of .50 probability showed that
R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
115
Table 1 Socio-demographic, clinical characteristics and baseline symptom ratings of the sample (N = 91) Persistent psychoses (N = 24)
Male Single High school/higher ed. Mean age of onset Mean age of entry Family history of SSD—in first degree relative Personal history of alcohol abuse Personal history of drug abuse Mean DUP Mean DUI Positive symptoms (SAPS) Negative symptoms (SANS) Calgary depression (CDS) Hamilton anxiety (HAS)
Recovery (N = 67)
N (%)
N (%)
22 (91.7) 23 (95.8) 10 (41.7) 21.8 years 23.3 years 2 / 18 (11.2) 3 (12.5) 10 (41.6) 1.5 (F0.6) years 2.1 (F0.6) years 9.5 (F3.3) 11.3 (F3.1) 2.8 (F3.5) 7.4 (F5.0)
48 (71.6) 50 (74.6) 40 (59.7) 24.6 years 26.1 years 11 / 57 (19.2) 14 (20.9) 14 (20.9) 1.2 (F0.7) years 2.1 (F0.6) years 10.0 (F3.9) 11.4 (F 5.6) 3.3 (F3.9) 8.3 (F7.7)
75% of cases could be correctly classified as showing persistent psychoses versus full recovery. The predictions showed .89 sensitivity and .43 specificity with respect to classification of treatment outcome.
4. Discussion This is the first study to identify persistent psychoses patients in an early intervention program. Significantly more patients with persistent psychoses as compared to those in recovery were single and male. It is, of course, possible that some of these significant relationships occurred by chance, and we recognize the need for replication. Nevertheless, it has long been suggested that schizophrenic patients living in stable marital or other partnership may be a positively selected group with a milder form of the disease (Odegaard, 1946). Evidence that being married (or living with a partner) may act as a risk modifier was obtained from the WHO ten country study after controlling for the effects of gender, premorbid personality traits, family history of psychoses and marital status at age of onset (Jablensky and Cole, 1997). It has been well established that female patients have a better response to treatment with conventional antipsychotic medications although it has been less clear whether this holds true for atypical antipsychotics (Barnes et al., 2003). In our study, all
p value
.04 .02 ns ns ns ns ns .04 ns ns ns ns ns ns
patients were treated with atypical antipsychotics as first line. It has been proposed that the favourable treatment responsivity in female patients may be as a result of oestrogen regulation of the dopaminergic tone (Leung and Chue, 2000). Patients with persistent psychoses had a significantly higher prevalence of drug abuse (mainly cannabis). Patients who abuse illicit drugs or alcohol are more likely to have more prominent symptomatology, more frequent relapses and repeated hospitalizations (Seibyl and Lieberman, 1993). The dynamic between persistent psychotic symptoms, antipsychotic side effects and the potential for substance use as selfmedication remains uncertain. The associated social aspects of substance abuse such as lack of self-care and/or non-compliance with medications may also contribute to failure to improve. The neurochemical basis for such an effect, possibly acting through alteration of dopamine-receptor sensitivity, merits further attention because it may suggest more effective alternative treatment strategies for these patients (Buckley et al., 1994). We also observed that significantly fewer patients in the persistent psychoses group (23.8%) had a normal baseline EEG compared to the recovery group (55.5%). None of our patients suffered from epilepsy. The value of EEG as a predictor of treatment response has been suggested previously (Itil, 1982). This study lends further support to this hypothesis (Manchanda et al., 2005), although the
116
R. Manchanda et al. / Schizophrenia Research 80 (2005) 113–116
findings are qualitative and lack a healthy comparison group. Identification of those at high risk of a persistent psychoses early in the course of illness leads to the challenge of providing specialized long-term care for these individuals in order to improve functioning and enhance quality of life. This study attempts to identify characteristics of the patients within the limitations of a primarily qualitative data, multiple statistical tests and the exploratory nature of the study in an early intervention program.
Acknowledgement This research was supported by a grant from the Canadian Institute of Health Research.
References Addington, D., Addington, J., Maticka-Tyndale, E., 1992. Reliability and validity of a depression rating scale for schizophrenics. Schizophrenia Research 6, 201 – 208. Andreason, N.C., 1983. Scale for Assessment of Positive Symptoms (SANS). University of Iowa, Iowa City, IA. Andreason, N.C., 1984. Scale for Assessment of Positive Symptoms (SAPS). University of Iowa, Iowa City, IA. Barnes, T.R.E., Buckley, P., Schulz, S.C., 2003. Treatment-resistant schizophrenia (ch. 26). In: Hirsch, S.R., Weinberger, D.R. (Eds.), Schizophrenia. Blackwell Publishing, Oxford. Buckley, P.F., Thompson, P., Way, L., et al., 1994. Substance use among patients with treatment resistant schizophrenia: charac-
teristics and implications for clozapine therapy. American Journal of Psychiatry 151, 385 – 389. Edwards, J., Maude, D., McGorry, P.D., et al., 1998. Prolonged recovery in first episode psychoses. British Journal of Psychiatry 172 (suppl. 33), 107 – 116. First, M.B., Spitzer, R.L., Gibbon, M., et al., 1995. SCID Clinician Version Administration Booklet. Biometrics Research Department, N.Y. State Psychiatric Institute, New York. Hafner, H., Reicher-Rossler, A., Hambrecht, M., et al., 1992. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophrenia Research 6, 209 – 223. Hamilton, M., 1959. The assessment of anxiety states by rating. British Journal of Medical Psychology 32, 50 – 55. Itil, T.M., 1982. The use of electroencephalography in the practice of psychiatry. Psychosomatics 23, 799 – 813. Jablensky, A., Cole, S.W., 1997. Is earlier age at onset of schizophrenia in males a confounded finding? Results from a cross-cultural investigation. British Journal of Psychiatry 170, 234 – 240. Leung, A., Chue, P., 2000. Sex differences in schizophrenia: a review of the literature. Acta Psychiatrica Scandinavica 101, 3 – 38. Malla, A.K., Norman, R.M.G., McLean, T.S., et al., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Australian and New Zealand Journal of Psychiatry 37, 407 – 413. Manchanda, R., Norman, R., Malla, A., et al., 2005. EEG abnormalities and two-year outcome in first episode psychoses. Acta Psychiatrica Scandinavica 111, 208 – 213. Odegaard, O., 1946. Marriage and mental disease: a study in social psychopathology. Journal of Mental Science 92, 35 – 39. Seibyl, J.P., Lieberman, J.A., 1993. Substance abuse and schizophrenia. In: Powchichk, P., Schultz, S.C. (Eds.), Psychiatric Clinics of North America. W.B. Sanders, Philadelphia, pp. 123 – 138. Susser, E., Finnerty, M., Mojtabai, R., et al., 2000. Reliability of the life chart schedule for assessment of the long-term course of schizophrenia. Schizophrenia Research 42, 67 – 77.