A randomised multicentre trial of integrated versus standard treatment
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《英国医生杂志》
1 Bispebjerg Hospital, Department of Psychiatry, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark; and Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen ?, Denmark, 2 Bispebjerg Hospital, Department of Psychiatry, Copenhagen NV, Denmark, 3 Sct Hans Hospital, DK-4000 Roskilde, Denmark, 4 Psychiatric Hospital Risskov, Skovagervej 2, DK-8240 Risskov, Denmark
Correspondence to: M Nordentoft merete.nordentoft@dadlnet.dk
Objectives To evaluate the effects of integrated treatment for patients with a first episode of psychotic illness.
Table 2 Clinical outcomes and user satisfaction of patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are means (SD) unless stated otherwise
Design Randomised clinical trial.
Setting Copenhagen Hospital Corporation and Psychiatric Hospital Aarhus, Denmark.
Participants 547 patients with first episode of schizophrenia spectrum disorder.
Interventions Integrated treatment and standard treatment. The integrated treatment lasted for two years and consisted of assertive community treatment with programmes for family involvement and social skills training. Standard treatment offered contact with a community mental health centre.
Main outcome measures Psychotic and negative symptoms (each scored from 0 to a maximum of 5) at one and two years' follow-up.
Results At one year's follow-up, psychotic symptoms changed favourably to a mean of 1.09 (standard deviation 1.27) with an estimated mean difference between groups of –0.31 (95% confidence interval –0.55 to –0.07, P = 0.02) in favour of integrated treatment. Negative symptoms changed favourably with an estimated difference between groups of –0.36 (–0.54 to –0.17, P < 0.001) in favour of integrated treatment. At two years' follow-up the estimated mean difference between groups in psychotic symptoms was –0.32 (–0.58 to –0.06, P = 0.02) and in negative symptoms was –0.45 (–0.67 to –0.22, P < 0.001), both in favour of integrated treatment. Patients who received integrated treatment had significantly less comorbid substance misuse, better adherence to treatment, and more satisfaction with treatment.
Conclusion Integrated treatment improved clinical outcome and adherence to treatment. The improvement in clinical outcome was consistent at one year and two year follow-ups.
Certain psychosocial treatments have been shown to have beneficial effects on clinical and social outcomes for patients with schizophrenia: for example, assertive community treatment improved independent living, affiliation into the labour market, satisfaction with treatment, and use of bed days for patients with severe mental illness,1 and family intervention reduced rates of relapse.2 It has also been suggested that early treatment after the onset of psychotic illness provides the best chance of preventing relapse.3 4
Our study (the OPUS trial) is the first large randomised clinical trial of integrated treatment versus standard treatment for patients who had experienced a first episode of psychosis.5 The null hypothesis investigated was that there would be no differences between integrated treatment and standard treatment with regard to psychotic and negative symptoms, treatment adherence, admissions, use of bed days, substance abuse, accommodation status, labour market affiliation, and user satisfaction.
Participants and methods
Patients
Patients were included from all inpatient and outpatient mental health services in Copenhagen (Copenhagen Hospital Corporation) and Aarhus County. From January 1998 until December 2000, 547 patients aged 18-45 years with a diagnosis in the schizophrenia spectrum ((ICD-10 codes in the F2 category) and who had not been given antipsychotic drugs for more than 12 weeks of continuous treatment were included in the trial.
Randomisation
The included patients were centrally randomised to integrated treatment or standard treatment. In Copenhagen, randomisation was carried out through centralised telephone randomisation at the Copenhagen Trial Unit. The allocation sequence was computer generated, 1:1, in blocks of six, and stratified for each of five centres. In Aarhus, the researchers contacted a secretary by telephone when they had finished the entry assessment of each patient. The secretary then drew one lot from among five red and five white lots out of a black box. When the block of 10 was used, the lots were redrawn. Block sizes were unknown to the investigators.
Interventions
The trial was pragmatic, comparing integrated treatment defined by a set of protocols with treatment as usual.6
Integrated treatment
This was as assertive community treatment7 enhanced by better specific content via family involvement and social skills training. Two multidisciplinary teams in Copenhagen and one in Aarhus were established and trained to provide integrated treatment. Caseload reached a level of about 10. Each patient was offered integrated treatment for a period of two years. A primary team member was designated for each patient and was then responsible for maintaining contact and coordinating treatment within the team and across different treatment and support facilities. Patients were visited in their homes or other places in their community or at their primary team member's office according to their preference. During hospitalisation, treatment responsibility was transferred to the hospital, but a team member visited the patient once a week. The office hours were Monday to Friday, 8 am to 5 pm. All team members had a mobile phone with an answering function. Outside office hours, patients could leave a message and be sure that the team would respond the next morning. A crisis plan was developed for each patient. If the patient was reluctant about treatment, the team stayed in contact with the patient and tried to motivate the patient to continue treatment.
The fidelity of the programme, measured with the index of fidelity of assertive community treatment,8 was 70% in both Copenhagen and Aarhus. The factors responsible for the reduced fidelity were time limited treatment, 24 hour coverage in other settings, and about two contacts weekly with each patient, patient's family, and collaborating partners.
Psychoeducational family treatment was offered, and team members always tried to make contact with at least one family member and motivate patients and families to participate in a psychoeducational group. Family treatment followed McFarlane's manual for psychoeducational treatment for multiple family groups9 and included 18 months of treatment, 1.5 hours twice weekly, in a multiple family group with two therapists and four to six patients with their families. The multiple family group focused on problem solving and development of skills to cope with the illness.
Patients' social skills were assessed using the World Health Organization's psychiatric disability assessment.10 Patients with impaired social skills were offered social skills training focusing on medication, coping with symptoms, conversation, and problem solving skills in a group of maximum six patients and two therapists.11
Standard treatment
Standard treatment usually offered the patient treatment at a community mental health centre. Each patient was usually in contact with a physician, a community mental health nurse, and in some cases also a social worker. Home visit was possible, but office visits were the general rule. A staff member's caseload in the community mental health centres varied between 1:20 and 1:30. Outside office hours, patients could refer themselves to the psychiatric emergency room.
Antipsychotic drugs
Patients in both treatment groups were offered antipsychotic drugs according to guidelines from the Danish Psychiatric Society, which recommend a low dose strategy for patients with a first episode of psychotic illness and use of second generation antipsychotic drugs as first choice.
Assessments
Only independent investigators (PiJ, MA, PK, RM, LP, AT, TC, J?) were involved in follow-up interviews. For practical reasons, they could not be kept blind to treatment allocation. At study entry and at the one and two year follow-ups, the following information was collected:
Main diagnosis and comorbidity based on the schedule for clinical assessment in neuropsychiatry (SCAN 2.0 in 1998, SCAN 2.1 since 1999)12
Scale for assessment of positive symptoms (SAPS) and scale for assessment of negative symptoms (SANS).13 The scales are summed up in three dimensions (psychotic, negative, and disorganised) with values ranging from 0 to 514
Sociodemographic factors
Global assessment of functioning, function and symptoms (GAF)
Social network schedule15
Client satisfaction questionnaire. This is a ranking scale based on eight questions with four answering categories added together for a total score16
Suicide attempts and suicidal ideation based on self reporting17
Duration of untreated psychosis, assessed with the interview for retrospective assessment of onset of schizophrenia18
We used algorithms to investigate whether patients fulfilled the general criteria for depression in ICD-10. The algorithms were based on selected items in the section in SCAN that covered depressed mood and ideation, thinking, concentration, energy, interests, and bodily functions, and for which patient data were available.
Other data sources
Information about use of bed days was available from official registers for all patients (except those who died or emigrated). We used patients' full medical records as data source for service use (besides bed days), use of antipsychotic drugs, and treatment adherence.
Inter-rater reliability
All investigators were trained in the SCAN interview at the WHO collaborating centre and trained once every second month in SAPS (for assessing positive symptoms) with live interviews. At the end of the trial LP, JO, GK, TC, and AT did 14 reliability interviews for SANS (for assessing negative symptoms) and 12 for SAPS. Intra-class correlation coefficient was 0.54 for the negative dimension (moderate agreement) and 0.88 for the psychotic dimension (very good agreement).19
Statistical methods
Attrition to the two year follow-up interview was skewed: 75% of the patients randomised to integrated treatment attended the interview compared with only 60% of control patients (see figure). In order to assess the influence of missing data on the one and two year outcome measures, we subjected the data on SAPS, SANS, and GAF (global assessment of functioning) to further analysis in a repeated measurements model with unstructured variance matrix. This approach assumed that the distribution of missing data could be estimated from the information from previous interviews. The condition for using this method is the assumption that data were missing at random when taking into consideration the information extracted from the baseline and one year follow-up interviews. Covariates entered in the repeated measurements model were treatment, sex, substance misuse, and treatment site. Accounting for the baseline value was automatic since it is included in the model, and no treatment effect was allowed for at baseline. An alternative approach to manage the skewed attrition is sensitivity analyses, which we also carried out.
We calculated odds ratios for treatment effect with logistic regression analyses, with treatment site (Copenhagen and Aarhus) included as covariates. When possible, we also included the baseline value of the variable as covariate.
We assessed differences in continuous variables (client satisfaction questionnaire) using analysis of variance, with treatment sites included as covariates. We used Mann-Whitney's U test to test differences in continuous data with skewed distribution. All statistical analyses were done with SPSS 11.0 (Statistical Package, 2000).
Power calculation
When the trial was planned, we considered relapse to be the primary outcome measure, and we intended to assess each patient every third month for positive symptoms with SAPS interviews. However, since participation in these interviews was only about 60%, we decided in September 1999 to use psychotic and negative symptoms at one and two year follow-up as the primary outcome measures. We analysed these outcome measures on the basis of intention to treat. We expected that the mean reduction of psychotic symptoms measured by SAPS would be one point for the patients allocated standard treatment with standard deviation of 1.3. As a minimum, we wanted to be able to detect a 50% greater reduction in psychotic symptoms in the experimental group at the 0.05 level of significance and with power of 0.9. Using Pocock's formula,20 we calculated that we required 142 patients for each study group and that, to compensate for 20% attrition during follow-up, 178 patients should be included in each group.
Results
Baseline characteristics
Table 1 summarises the results of the baseline interview. The two treatment groups had no significant differences in their baseline characteristics.
Table 1 Sociodemographic and clinical characteristics of 547 patients with a first episode of psychotic illness at entry into trial of integrated treatment versus standard treatment. Values are numbers (percentages) unless stated otherwise
Attrition from study
The figure shows the patient flow through the study, and the attrition from it. We found no significant difference in baseline measures between those patients who participated in the follow-up interviews and those who did not, except that patients from Aarhus and patients with a relative attending the baseline interview in both treatment groups were more likely to attend the follow-up interview. In the control group, patients who had not completed high school and those with substance misuse diagnosed at baseline interview were less likely to participate in the follow-up interviews.
Main outcomes
Table 2 shows the clinical outcomes and user satisfaction in the two treatment groups. Integrated treatment was significantly better than standard treatment with regard to both psychotic symptoms and negative symptoms. There were no differential treatment effects between the two sites. The estimated effect of integrated treatment versus standard treatment on the psychotic symptoms was equal to every third patient in the integrated treatment group gaining one point (from "severe" to "marked" or from "moderate" to "mild") when measured with the SAPS scale. The effect on negative symptoms is equal to every second patient in integrated treatment gaining one point compared with standard treatment. This is of clinical importance.
Integrated treatment also resulted in significantly greater patient satisfaction, and this difference between treatment groups was larger at two year follow-up than at one year. Cohen's d standardised effect size for client satisfaction was 0.69, which is fairly large.
Sensitivity analyses of psychotic and negative symptoms
Because of the skewed attrition (figure), we tested two different assumptions about the patients who did not participate in the two year follow-up interview. The less favourable prognostic factors among non-participants compared with participants suggest that non-participants as a group fared worse. Thus, we carried forward the non-participants' baseline values and one year values (if available) for the psychotic and negative dimensions to the two year follow-up. This resulted in integrated treatment having an even greater positive effect on both psychotic and negative symptoms (data not shown).
The other (less likely) assumption was that non-participants had experienced a total remission of psychotic and negative symptoms. On this basis, we set their psychotic and negative dimensions at two years to zero, and the positive effect of integrated treatment on the psychotic and negative dimensions became non-significant.
Comorbidity and social outcomes
Integrated treatment significantly reduced substance misuse both at one year and two year follow-up, but it had no significant effect on depression or suicidal behaviour and ideation (table 3).
Table 3 Comorbidity and social outcomes of patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are percentages of patients unless stated otherwise
A significantly smaller proportion of patients given integrated treatment did not live independently at one year follow-up compared with patients given standard treatment (10% v 17%), but not at two year follow-up (13% v 14%) (table 3). At one year follow-up significantly more of the patients given integrated treatment than those given standard treatment were attending a rehabilitation programme (14% v 7%), but at two years the difference was not significant (17% v 12%).
Non-adherence to treatment
During the first year, patients were significantly less likely to discontinue integrated treatment for at least a month than standard treatment (8% v 22%) (table 4). Integrated treatment was also clearly superior to standard treatment when non-adherence was measured in terms of treatment discontinued in spite of need (3% v 15%) or in terms of not making any outpatient visits (3% v 15% in first year, 7% v 31% in second year) (table 4).
Table 4 Non-adherence to treatment, health service use, and antipsychotic drug use for patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are percentages of patients unless stated otherwise
Patient flow through study
Use of health services and antipsychotic drugs
From official registers, we found that patients given integrated treatment spent significantly fewer days in hospital in the first year than did patients given standard treatment (mean 62 days v 79 days) (table 4). For the total intervention period, patients given integrated treatment used 22% fewer bed days than those given standard treatment (mean 89 days v 114 days; difference –25.0, 95% confidence interval –51.0 to 1.1, P = 0.06).
The proportion of patients receiving first or second generation antipsychotic drugs was not significantly different in the two treatment groups (table 4). To establish whether differences in antipsychotic medication in the two groups were responsible for the differences in psychotic and negative dimension, we analysed drug use by treatment allocation, treatment site, baseline value of scale, and use of second generation antipsychotics (or first and second generation, or first generation only). All analyses showed a significant positive effect of integrated treatment on psychotic and negative symptoms. Patients given integrated treatment received significantly lower doses of second generation antipsychotics (table 4).
Discussion
Marshall M, Lockwood A. Assertive community treatment for people with severe mental disorders. Cochrane Database Syst Rev 2000;(2): CD001089.
Pharoah FM, Mari JJ, Streiner D. Family intervention for schizophrenia. Cochrane Database Syst Rev 2000;(2): CD000088.
Nordentoft M, Laursen TM, Agerbo E, Qin P, Hoyer EH, Mortensen PB. Change in suicide rates for patients with schizophrenia in Denmark, 1981-97: nested case-control study. BMJ 2004;329: 261.
Birchwood M, Todd P, Jackson C. Early intervention in psychosis. The critical period hypothesis. Br J Psychiatry Suppl 1998;172: 53-9.
Jorgensen P, Nordentoft M, Abel MB, Gouliaev G, Jeppesen P, Kassow P. Early detection and assertive community treatment of young psychotics: the opus study rationale and design of the trial. Soc Psychiatry Psychiatr Epidemiol 2000;35: 283-7.
Roland M, Torgerson DJ. What are pragmatic trials? BMJ 1998;316: 285.
Stein LI, Test MA. Alternative to mental hospital treatment. I. Conceptual model, treatment program, and clinical evaluation. Arch Gen Psychiatry 1980;37: 392-7.
McGrew JH, Bond GR, Dietzen L, Salyers M. Measuring the fidelity of implementation of a mental health program model. J Consult Clin Psychol 1994;62: 670-8.
McFarlane WR, Lukens E, Link B, Dushay R, Deakins SA, Newmark M, et al. Multiple-family groups and psychoeducation in the treatment of schizophrenia. Arch Gen Psychiatry 1995;52: 679-87.
World Health Organization. WHO Psychiatric Disability Assessment Schedule (WHO/DAS). Geneva: WHO, 1998.
Liberman RP, Mueser KT, Wallace CJ, Jacobs HE, Eckman T, Massel HK. Training skills in the psychiatrically disabled: learning coping and competence. Schizophr Bull 1986;12: 631-47.
World Health Organization Division of Mental Health. Schedule for clinical assessment in neuropsychiatry, version 2.1. Present state examination. Geneva: WHO, 1998.
Andreasen NC, Olsen S. Negative v positive schizophrenia. Arch Gen Psychiatry 1982;39: 789-94.
Andreasen NC, Arndt S, Alliger R, Miller D, Flaum M. Symptoms of schizophrenia. Methods, meanings, and mechanisms. Arch Gen Psychiatry 1995;52: 341-51.
Dunn M, O'Driscoll C, Dayson D, Wills W, Leff J. The TAPS project 4: an observational study of the social life of long-stay patients. Br J Psychiatry 1990;157: 842-8, 852.
Larsen DH, Attkison CC, Hargreaves WA, Nguyen TD. Assessment of client/patient satisfaction: development of a general scale. Eval Progress Planning 1979;2: 197-207.
Nordentoft M, Jeppesen P, Abel M, Kassow P, Petersen L, Thorup A, et al. OPUS study: suicidal behaviour, suicidal ideation and hopelessness among patients with first-episode psychosis. One-year follow-up of a randomised controlled trial. Br J Psychiatry Suppl 2002;43: s98-106.
Hafner H, Riecher-Rossler A, Hambrecht M, Maurer K, Meissner S, Schmidtke A, et al. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr Res 1992;6: 209-23.
Bartko JJ, Carpenter WT Jr. On the methods and theory of reliability. J Nerv Ment Dis 1976;163: 307-17.
Pocock SJ. Clinical trials. A practical approach. Chichester: John Wiley, 1996.
McGorry PD, Edwards J, Mihalopoulos C, Harringan SM, Jackson HJ. EPPIC: an evolving system of early detection and optimal management. Schizophr Bull 1996;22: 305-26.
Carbone S, Harrigan S, McGorry PD, Curry C, Elkins K. Duration of untreated psychosis and 12-month outcome in first-episode psychosis: the impact of treatment approach. Acta Psychiatr Scand 1999;100: 96-104.
Malla AK, Norman RM, Manchanda R, McLean TS, Harricharan R, Cortese L, et al. Status of patients with first-episode psychosis after one year of phase-specific community-oriented treatment. Psychiatr Serv 2002;53: 458-63.
Craig TK, Garety P, Power P, Rahaman N, Colbert S, Fornells-Ambrojo M, et al. The Lambeth Early Onset (LEO) Team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ 2004;329: 1067.
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001;135: 982-9.(Lone Petersen, research fellow1, Pia Jep)
Correspondence to: M Nordentoft merete.nordentoft@dadlnet.dk
Objectives To evaluate the effects of integrated treatment for patients with a first episode of psychotic illness.
Table 2 Clinical outcomes and user satisfaction of patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are means (SD) unless stated otherwise
Design Randomised clinical trial.
Setting Copenhagen Hospital Corporation and Psychiatric Hospital Aarhus, Denmark.
Participants 547 patients with first episode of schizophrenia spectrum disorder.
Interventions Integrated treatment and standard treatment. The integrated treatment lasted for two years and consisted of assertive community treatment with programmes for family involvement and social skills training. Standard treatment offered contact with a community mental health centre.
Main outcome measures Psychotic and negative symptoms (each scored from 0 to a maximum of 5) at one and two years' follow-up.
Results At one year's follow-up, psychotic symptoms changed favourably to a mean of 1.09 (standard deviation 1.27) with an estimated mean difference between groups of –0.31 (95% confidence interval –0.55 to –0.07, P = 0.02) in favour of integrated treatment. Negative symptoms changed favourably with an estimated difference between groups of –0.36 (–0.54 to –0.17, P < 0.001) in favour of integrated treatment. At two years' follow-up the estimated mean difference between groups in psychotic symptoms was –0.32 (–0.58 to –0.06, P = 0.02) and in negative symptoms was –0.45 (–0.67 to –0.22, P < 0.001), both in favour of integrated treatment. Patients who received integrated treatment had significantly less comorbid substance misuse, better adherence to treatment, and more satisfaction with treatment.
Conclusion Integrated treatment improved clinical outcome and adherence to treatment. The improvement in clinical outcome was consistent at one year and two year follow-ups.
Certain psychosocial treatments have been shown to have beneficial effects on clinical and social outcomes for patients with schizophrenia: for example, assertive community treatment improved independent living, affiliation into the labour market, satisfaction with treatment, and use of bed days for patients with severe mental illness,1 and family intervention reduced rates of relapse.2 It has also been suggested that early treatment after the onset of psychotic illness provides the best chance of preventing relapse.3 4
Our study (the OPUS trial) is the first large randomised clinical trial of integrated treatment versus standard treatment for patients who had experienced a first episode of psychosis.5 The null hypothesis investigated was that there would be no differences between integrated treatment and standard treatment with regard to psychotic and negative symptoms, treatment adherence, admissions, use of bed days, substance abuse, accommodation status, labour market affiliation, and user satisfaction.
Participants and methods
Patients
Patients were included from all inpatient and outpatient mental health services in Copenhagen (Copenhagen Hospital Corporation) and Aarhus County. From January 1998 until December 2000, 547 patients aged 18-45 years with a diagnosis in the schizophrenia spectrum ((ICD-10 codes in the F2 category) and who had not been given antipsychotic drugs for more than 12 weeks of continuous treatment were included in the trial.
Randomisation
The included patients were centrally randomised to integrated treatment or standard treatment. In Copenhagen, randomisation was carried out through centralised telephone randomisation at the Copenhagen Trial Unit. The allocation sequence was computer generated, 1:1, in blocks of six, and stratified for each of five centres. In Aarhus, the researchers contacted a secretary by telephone when they had finished the entry assessment of each patient. The secretary then drew one lot from among five red and five white lots out of a black box. When the block of 10 was used, the lots were redrawn. Block sizes were unknown to the investigators.
Interventions
The trial was pragmatic, comparing integrated treatment defined by a set of protocols with treatment as usual.6
Integrated treatment
This was as assertive community treatment7 enhanced by better specific content via family involvement and social skills training. Two multidisciplinary teams in Copenhagen and one in Aarhus were established and trained to provide integrated treatment. Caseload reached a level of about 10. Each patient was offered integrated treatment for a period of two years. A primary team member was designated for each patient and was then responsible for maintaining contact and coordinating treatment within the team and across different treatment and support facilities. Patients were visited in their homes or other places in their community or at their primary team member's office according to their preference. During hospitalisation, treatment responsibility was transferred to the hospital, but a team member visited the patient once a week. The office hours were Monday to Friday, 8 am to 5 pm. All team members had a mobile phone with an answering function. Outside office hours, patients could leave a message and be sure that the team would respond the next morning. A crisis plan was developed for each patient. If the patient was reluctant about treatment, the team stayed in contact with the patient and tried to motivate the patient to continue treatment.
The fidelity of the programme, measured with the index of fidelity of assertive community treatment,8 was 70% in both Copenhagen and Aarhus. The factors responsible for the reduced fidelity were time limited treatment, 24 hour coverage in other settings, and about two contacts weekly with each patient, patient's family, and collaborating partners.
Psychoeducational family treatment was offered, and team members always tried to make contact with at least one family member and motivate patients and families to participate in a psychoeducational group. Family treatment followed McFarlane's manual for psychoeducational treatment for multiple family groups9 and included 18 months of treatment, 1.5 hours twice weekly, in a multiple family group with two therapists and four to six patients with their families. The multiple family group focused on problem solving and development of skills to cope with the illness.
Patients' social skills were assessed using the World Health Organization's psychiatric disability assessment.10 Patients with impaired social skills were offered social skills training focusing on medication, coping with symptoms, conversation, and problem solving skills in a group of maximum six patients and two therapists.11
Standard treatment
Standard treatment usually offered the patient treatment at a community mental health centre. Each patient was usually in contact with a physician, a community mental health nurse, and in some cases also a social worker. Home visit was possible, but office visits were the general rule. A staff member's caseload in the community mental health centres varied between 1:20 and 1:30. Outside office hours, patients could refer themselves to the psychiatric emergency room.
Antipsychotic drugs
Patients in both treatment groups were offered antipsychotic drugs according to guidelines from the Danish Psychiatric Society, which recommend a low dose strategy for patients with a first episode of psychotic illness and use of second generation antipsychotic drugs as first choice.
Assessments
Only independent investigators (PiJ, MA, PK, RM, LP, AT, TC, J?) were involved in follow-up interviews. For practical reasons, they could not be kept blind to treatment allocation. At study entry and at the one and two year follow-ups, the following information was collected:
Main diagnosis and comorbidity based on the schedule for clinical assessment in neuropsychiatry (SCAN 2.0 in 1998, SCAN 2.1 since 1999)12
Scale for assessment of positive symptoms (SAPS) and scale for assessment of negative symptoms (SANS).13 The scales are summed up in three dimensions (psychotic, negative, and disorganised) with values ranging from 0 to 514
Sociodemographic factors
Global assessment of functioning, function and symptoms (GAF)
Social network schedule15
Client satisfaction questionnaire. This is a ranking scale based on eight questions with four answering categories added together for a total score16
Suicide attempts and suicidal ideation based on self reporting17
Duration of untreated psychosis, assessed with the interview for retrospective assessment of onset of schizophrenia18
We used algorithms to investigate whether patients fulfilled the general criteria for depression in ICD-10. The algorithms were based on selected items in the section in SCAN that covered depressed mood and ideation, thinking, concentration, energy, interests, and bodily functions, and for which patient data were available.
Other data sources
Information about use of bed days was available from official registers for all patients (except those who died or emigrated). We used patients' full medical records as data source for service use (besides bed days), use of antipsychotic drugs, and treatment adherence.
Inter-rater reliability
All investigators were trained in the SCAN interview at the WHO collaborating centre and trained once every second month in SAPS (for assessing positive symptoms) with live interviews. At the end of the trial LP, JO, GK, TC, and AT did 14 reliability interviews for SANS (for assessing negative symptoms) and 12 for SAPS. Intra-class correlation coefficient was 0.54 for the negative dimension (moderate agreement) and 0.88 for the psychotic dimension (very good agreement).19
Statistical methods
Attrition to the two year follow-up interview was skewed: 75% of the patients randomised to integrated treatment attended the interview compared with only 60% of control patients (see figure). In order to assess the influence of missing data on the one and two year outcome measures, we subjected the data on SAPS, SANS, and GAF (global assessment of functioning) to further analysis in a repeated measurements model with unstructured variance matrix. This approach assumed that the distribution of missing data could be estimated from the information from previous interviews. The condition for using this method is the assumption that data were missing at random when taking into consideration the information extracted from the baseline and one year follow-up interviews. Covariates entered in the repeated measurements model were treatment, sex, substance misuse, and treatment site. Accounting for the baseline value was automatic since it is included in the model, and no treatment effect was allowed for at baseline. An alternative approach to manage the skewed attrition is sensitivity analyses, which we also carried out.
We calculated odds ratios for treatment effect with logistic regression analyses, with treatment site (Copenhagen and Aarhus) included as covariates. When possible, we also included the baseline value of the variable as covariate.
We assessed differences in continuous variables (client satisfaction questionnaire) using analysis of variance, with treatment sites included as covariates. We used Mann-Whitney's U test to test differences in continuous data with skewed distribution. All statistical analyses were done with SPSS 11.0 (Statistical Package, 2000).
Power calculation
When the trial was planned, we considered relapse to be the primary outcome measure, and we intended to assess each patient every third month for positive symptoms with SAPS interviews. However, since participation in these interviews was only about 60%, we decided in September 1999 to use psychotic and negative symptoms at one and two year follow-up as the primary outcome measures. We analysed these outcome measures on the basis of intention to treat. We expected that the mean reduction of psychotic symptoms measured by SAPS would be one point for the patients allocated standard treatment with standard deviation of 1.3. As a minimum, we wanted to be able to detect a 50% greater reduction in psychotic symptoms in the experimental group at the 0.05 level of significance and with power of 0.9. Using Pocock's formula,20 we calculated that we required 142 patients for each study group and that, to compensate for 20% attrition during follow-up, 178 patients should be included in each group.
Results
Baseline characteristics
Table 1 summarises the results of the baseline interview. The two treatment groups had no significant differences in their baseline characteristics.
Table 1 Sociodemographic and clinical characteristics of 547 patients with a first episode of psychotic illness at entry into trial of integrated treatment versus standard treatment. Values are numbers (percentages) unless stated otherwise
Attrition from study
The figure shows the patient flow through the study, and the attrition from it. We found no significant difference in baseline measures between those patients who participated in the follow-up interviews and those who did not, except that patients from Aarhus and patients with a relative attending the baseline interview in both treatment groups were more likely to attend the follow-up interview. In the control group, patients who had not completed high school and those with substance misuse diagnosed at baseline interview were less likely to participate in the follow-up interviews.
Main outcomes
Table 2 shows the clinical outcomes and user satisfaction in the two treatment groups. Integrated treatment was significantly better than standard treatment with regard to both psychotic symptoms and negative symptoms. There were no differential treatment effects between the two sites. The estimated effect of integrated treatment versus standard treatment on the psychotic symptoms was equal to every third patient in the integrated treatment group gaining one point (from "severe" to "marked" or from "moderate" to "mild") when measured with the SAPS scale. The effect on negative symptoms is equal to every second patient in integrated treatment gaining one point compared with standard treatment. This is of clinical importance.
Integrated treatment also resulted in significantly greater patient satisfaction, and this difference between treatment groups was larger at two year follow-up than at one year. Cohen's d standardised effect size for client satisfaction was 0.69, which is fairly large.
Sensitivity analyses of psychotic and negative symptoms
Because of the skewed attrition (figure), we tested two different assumptions about the patients who did not participate in the two year follow-up interview. The less favourable prognostic factors among non-participants compared with participants suggest that non-participants as a group fared worse. Thus, we carried forward the non-participants' baseline values and one year values (if available) for the psychotic and negative dimensions to the two year follow-up. This resulted in integrated treatment having an even greater positive effect on both psychotic and negative symptoms (data not shown).
The other (less likely) assumption was that non-participants had experienced a total remission of psychotic and negative symptoms. On this basis, we set their psychotic and negative dimensions at two years to zero, and the positive effect of integrated treatment on the psychotic and negative dimensions became non-significant.
Comorbidity and social outcomes
Integrated treatment significantly reduced substance misuse both at one year and two year follow-up, but it had no significant effect on depression or suicidal behaviour and ideation (table 3).
Table 3 Comorbidity and social outcomes of patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are percentages of patients unless stated otherwise
A significantly smaller proportion of patients given integrated treatment did not live independently at one year follow-up compared with patients given standard treatment (10% v 17%), but not at two year follow-up (13% v 14%) (table 3). At one year follow-up significantly more of the patients given integrated treatment than those given standard treatment were attending a rehabilitation programme (14% v 7%), but at two years the difference was not significant (17% v 12%).
Non-adherence to treatment
During the first year, patients were significantly less likely to discontinue integrated treatment for at least a month than standard treatment (8% v 22%) (table 4). Integrated treatment was also clearly superior to standard treatment when non-adherence was measured in terms of treatment discontinued in spite of need (3% v 15%) or in terms of not making any outpatient visits (3% v 15% in first year, 7% v 31% in second year) (table 4).
Table 4 Non-adherence to treatment, health service use, and antipsychotic drug use for patients with a first episode of psychotic illness who received integrated treatment or standard treatment. Values are percentages of patients unless stated otherwise
Patient flow through study
Use of health services and antipsychotic drugs
From official registers, we found that patients given integrated treatment spent significantly fewer days in hospital in the first year than did patients given standard treatment (mean 62 days v 79 days) (table 4). For the total intervention period, patients given integrated treatment used 22% fewer bed days than those given standard treatment (mean 89 days v 114 days; difference –25.0, 95% confidence interval –51.0 to 1.1, P = 0.06).
The proportion of patients receiving first or second generation antipsychotic drugs was not significantly different in the two treatment groups (table 4). To establish whether differences in antipsychotic medication in the two groups were responsible for the differences in psychotic and negative dimension, we analysed drug use by treatment allocation, treatment site, baseline value of scale, and use of second generation antipsychotics (or first and second generation, or first generation only). All analyses showed a significant positive effect of integrated treatment on psychotic and negative symptoms. Patients given integrated treatment received significantly lower doses of second generation antipsychotics (table 4).
Discussion
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