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Original Article |

Effect of Antipsychotic Medication Alone vs Combined With Psychosocial Intervention on Outcomes of Early-Stage Schizophrenia:  A Randomized, 1-Year Study FREE

Xiaofeng Guo, MD; Jinguo Zhai, MD; Zhening Liu, MD; Maosheng Fang, MD; Bo Wang, MD; Chuanyue Wang, MD; Bin Hu, MD; Xueli Sun, MD; Luxian Lv, MD; Zheng Lu, MD; Cui Ma, MD; Xiaolin He, MD; Tiansheng Guo, MD; Shiping Xie, MD; Renrong Wu, MD; Zhimin Xue, MD; Jindong Chen, MD; Elizabeth W. Twamley, PhD; Hua Jin, MD; Jingping Zhao, MD, PhD
[+] Author Affiliations

Author Affiliations: Mental Health Institute, Second Xiangya Hospital (Drs X. Guo, Zhai, Liu, Fang, Wu, Xue, Chen, and Zhao), and State Key Laboratory of Medical Genetics of China (Dr Zhao), Central South University, Changsha, Hunan; Jining Medical College, Jining, Shandong, China (Dr Zhai); Chongqing Mental Health Centre, Chongqing, China (Dr B. Wang); Beijing Anding Hospital Affiliated to Capital Medical University, Beijing, China (Dr C. Wang); Psychiatric Hospital of Jiangxi Province, Nanchang, Jiangxi, China (Dr Hu); Mental Health Center of West China Hospital, Sichuan University, Chengdu, Sichuan (Dr Sun); Mental Hospital of Henan Province, Xinxiang, Henan, China (Dr Lv); Shanghai Mental Health Centre, Shanghai, China (Dr Lu); Guangzhou Brain Hospital, Guangzhou, Guangdong, China (Drs Ma and He); Hunan Brain Hospital, Changsha, Hunan, China (Dr T. Guo); Nanjing Brain Hospital, Nanjing, Jiangsu, China (Dr Xie); and Department of Psychiatry, University of California, San Diego (Drs Twamley and Jin).


Arch Gen Psychiatry. 2010;67(9):895-904. doi:10.1001/archgenpsychiatry.2010.105.
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Published online

Context  Antipsychotic drugs are limited in their ability to improve the overall outcome of schizophrenia. Adding psychosocial treatment may produce greater improvement in functional outcome than does medication treatment alone.

Objective  To evaluate the effectiveness of antipsychotic medication alone vs combined with psychosocial intervention on outcomes of early-stage schizophrenia.

Design  Randomized controlled trial.

Setting  Ten clinical sites in China.

Participants  Clinical sample of 1268 patients with early-stage schizophrenia treated from January 1, 2005, through October 31, 2007.

Intervention  Patients were randomly assigned to receive antipsychotic medication treatment only or antipsychotic medication plus 12 months of psychosocial intervention consisting of psychoeducation, family intervention, skills training, and cognitive behavior therapy administered during 48 group sessions.

Main Outcome Measures  The rate of treatment discontinuation or change due to any cause, relapse or remission, and assessments of insight, treatment adherence, quality of life, and social functioning.

Results  The rates of treatment discontinuation or change due to any cause were 32.8% in the combined treatment group and 46.8% in the medication-alone group. Comparisons with medication treatment alone showed lower risk of any-cause discontinuation with combined treatment (hazard ratio, 0.62; 95% confidence interval, 0.52-0.74; P < .001) and lower risk of relapse with combined treatment (0.57; 0.44-0.74; P < .001). The combined treatment group exhibited greater improvement in insight (P < .001), social functioning (P = .002), activities of daily living (P < .001), and 4 domains of quality of life as measured by the Medical Outcomes Study 36-Item Short Form Health Survey (all P ≤ .02). Furthermore, a significantly higher proportion of patients receiving combined treatment obtained employment or accessed education (P = .001).

Conclusion  Compared with those receiving medication only, patients with early-stage schizophrenia receiving medication and psychosocial intervention have a lower rate of treatment discontinuation or change, a lower risk of relapse, and improved insight, quality of life, and social functioning.

Trial Registration  clinicaltrials.gov Identifier: NCT00654576

Figures in this Article

Antipsychotic drugs have been shown to be effective against psychotic symptoms, and they are now the mainstay of therapy for patients with schizophrenia.1,2 However, long-term therapy with antipsychotics is associated with a range of adverse effects, poor adherence, and high rates of medication discontinuation.24 Most patients, even those with a good response to medication, continue to experience disabling residual symptoms, impaired social and occupational functioning, and a high risk of relapse. Certain psychosocial treatments have been shown to have beneficial effects on clinical and functional outcomes.59 For instance, family intervention reduces relapse rate,5 cognitive behavior therapy reduces positive symptoms,5,8 and social skills training improves social competence.7 The combination of pharmacotherapy and psychosocial intervention has been recommended for treatment of schizophrenia by practice guidelines for psychiatrists.10 Psycho social interventions can be best implemented when acute symptoms have been reduced and the patient can be successfully engaged in treatment. The goals of intervention are to reduce stress on the patient, provide support to minimize the likelihood of relapse, enhance the patient's adaptation to life in the community, and facilitate continued reduction in symptoms and consolidation of remission.10 However, the effectiveness of psychosocial intervention approaches has been considered separately. Each intervention has been directed toward one of the components of the problem: the patient's symptoms, relapse, or social skills. Few comprehensive psychosocial intervention packages have been developed that can address several problems simultaneously in schizophrenia.

Early illness course is an important predictive factor for the long-term outcome; intervention during this critical period is considered important.11 As with the published literature on chronic schizophrenia treatment, studies of first-episode and early schizophrenia samples have shown that they benefit from medication management integrated with a variety of psychosocial treatments. For example, the OPUS trial used an intensive early-intervention approach combining assertive community treatment, family psychoeducation, and social skills training, with positive effects on hospitalization rates, living independence, symptom severity, and family burden.12,13 Integrated treatment with medication, skills training, and cognitive behavior therapy is another approach that has been used, with positive effects on symptom severity.14 Finally, medication has also been integrated with cognitive behavior therapy, family support, and vocational services, with positive effects on hospital readmission, functioning, and medication adherence.15,16

In this article, we report on the Antipsychotic Combination With Psychosocial Intervention on the Outcome of Schizophrenia Study (funded by the Ministry of Science and Technology of China), a 1-year randomized clinical trial that tested the effect of medication combined with a group psychosocial intervention vs medication treatment alone on outcomes of patients with early-stage schizophrenia.17 The outcomes measured included the rate of treatment discontinuation or change due to any cause, relapse or remission, and assessments of insight, treatment adherence, quality of life, and social functioning. We hypothesized that combined medication and comprehensive psychosocial treatment would result in lower rates of treatment discontinuation or relapse than would medication treatment alone, which would reflect variations in efficacy, insight and adherence, quality of life, social outcome, and adverse effects.

PARTICIPANTS

The study was conducted between January 1, 2005, and October 31, 2007, at 10 clinical sites in China (6 university clinics and 4 province mental health agencies). All patients were enrolled from outpatient psychiatric clinics and were under maintenance treatment. Eligible patients were those 16 to 50 years of age who met the following enrollment criteria: (1) DSM-IV diagnosis of schizophrenia or schizophreniform disorder within the past 5 years, as determined by the Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version18 administered by study investigators or trained staff; (2) living with family members who could be involved in the patient's care; (3) Positive and Negative Syndrome Scale (PANSS)19 total score of 60 or less; (4) receiving maintenance treatment with one of the following 7 oral antipsychotics: chlorpromazine hydrochloride, sulpiride, clozapine, risperidone, olanzapine, quetiapine fumarate, or aripiprazole. We selected these 7 antipsychotics because more than 90% of schizophrenic patients in China were prescribed one of these antipsychotics.20 Patients were excluded if they were (1) prescribed 2 or more antipsychotics or long-acting injectable antipsychotics, (2) participating in other therapy programs, (3) pregnant or breastfeeding, or (4) diagnosed as having a serious and unstable medical condition. This study was approved by the institutional review board at each site, and written informed consent was obtained from the patients or their legal guardians.

PROCEDURE

After baseline assessment, participants were randomly assigned to receive combined medication and psychosocial treatment or medication treatment alone and were monitored for up to 12 months or until medication treatment was discontinued for any reason. Group assignment was based on a 1:1 randomization scheme balanced by sites and medication prescribed. All medication visits and interventions took place in the outpatient psychiatric clinics in these participating institutes. Members of both study groups came to medication management visits once a month, and the therapy was given on the same day for the combined treatment group. The family members had to bring the patient to each appointment, regardless of treatment group. All patients and their family members from both study groups came to the clinic once a month and received the same compensation for participating in the study. No transportation, outreach, or other logistic supports were provided by this study. In both groups, patients and family members could ask medication- or treatment-related questions of the treating clinicians during their 30-minute visit as standard of outpatient care for medication management. To better keep the assessors and clinicians blinded, the psychotherapy rooms, clinicians' offices, and assessors' offices were isolated from each other; patients and family members were reminded at enrollment and follow-up visits not to discuss treatment assignment with their clinicians and assessors; and investigators and staff were restricted in the discussion of patients within research teams. Further detail about the study rationale, design, and methods have been described previously.17

INTERVENTIONS
Pharmacotherapy

Because all patients were receiving maintenance treatment, we encouraged clinicians to try to keep patients on the same medication regimen for 3 to 6 months to gauge treatment efficacy and minimize early discontinuation. However, medications could be changed at any time during the course of the study if the change was clinically warranted. If a patient's medication was stopped or switched, patients were classified as discontinued and were terminated from the study. No further assessments were required for these patients. Mood stabilizers, benzodiazepines, antidepressants, and anticholinergic medications were permitted, and daily doses of all medications were recorded throughout the study.

Psychosocial Intervention

Patients assigned to the combined treatment group received medication treatment and were enrolled in a psychosocial intervention program. The psychosocial intervention strictly followed a detailed treatment manual designed by the principal investigators (Drs X. Guo, Liu, and Zhao) and included 4 evidence-based practices: psychoeducation, family intervention, skills training, and cognitive behavior therapy.21 Participants receiving psychosocial intervention were seen 12 times (once per month for 12 months), receiving each of the 4 group treatments on the same day, for a total of 48 one-hour sessions (see Table 1 for topics covered). A lunch break and 2 half-hour breaks were provided to maintain engagement and attention. We designed this comprehensive psychosocial intervention to be delivered on the same day once a month mainly owing to the care structure in China, the potential time and cost burden to patients and their family members, and the feasibility of adoption by other care settings. In China, most patients with schizophrenia live with their family members because of limited social welfare for severely mentally ill patients. Many of these family members also work full time, so it is not convenient for them to take time off every week and bring the patients for therapy. In addition, all our psychosocial interventions were group based, so having many patients and their family members come in once a week at the same time was not feasible or practical. Weekly intervention visits also would have increased the costs of transportation and therapist time, making the overall cost of the psychosocial intervention higher. Finally, psychosocial interventions have become more popular in recent decades in China, but the number of well-trained therapists remains limited in many Chinese psychiatric settings. More frequent therapy sessions could be not only difficult for patients and family members but also hard for many psychiatric settings to adopt.

Table Graphic Jump LocationTable 1. Content of Monthly Psychosocial Treatment Sessions

Psychoeducation included teaching patients and caregivers about the symptoms, treatment, and course of mental illness and afforded patients and family members the opportunity to ask questions about psychiatric disorders and treatment options. This group provided a forum in which to discuss concerns and obtain support from the group to reduce the stigma of mental illness. The purpose of psychoeducation was to increase patients' and caregivers' knowledge and understanding of the illness and treatment.2224

Family intervention included developing collaboration with the family, socializing about non–illness-related topics, monthly updates on each family's situation, enhancing family communication, teaching patients and their families to cope with stressful situations and the illness, and teaching patients and their families to detect signs of relapse and intervene in crises.22,25,26

Skills training included modules on medication management and symptom self-management, dealing with stigma, social problem solving, and independent living skills. The training included teaching complex interpersonal skills by breaking down the targeted behaviors into component steps and systematically using modeling, behavioral rehearsal, positive and corrective feedback, and in vivo practice to shape the acquisition and generalization of skills.7,2729

Cognitive behavior therapy involved treatment of auditory hallucinations, delusions, and associated symptoms and problems (ie, anxiety, depression, and self-esteem); prevention of relapse; and enhancement of medication adherence. Treatment included an assessment and engagement phase, education, and building a therapeutic alliance; functional analysis of key symptoms, leading to formulation of a problem list; development of a normalizing rationale for the patients' psychotic experiences; and exploration and enhancement of coping strategies. Concomitant affective symptoms were addressed by means of relaxation training.30,31

Therapists who had at least 2 years of clinical experience after earning an MD or PhD or at least 5 years of experience after earning a masters degree in clinical psychology delivered the psychosocial intervention. They attended training workshops until they had mastered all treatment procedures. Treatment fidelity was maintained by having the therapists' supervisors assess adherence to the treatment manual after each monthly session by reviewing videotapes.

OUTCOME ASSESSMENTS

All subjects were assessed monthly by the study psychiatrists and every 2 weeks by a research assistant who had instructions to contact the psychiatrist if medication discontinuation, relapse, or other problems were suspected. The psychiatrists assessed patients mainly for medication management purposes, evaluating for clinical response to medications, medication adherence, and major adverse effects. The research assistants assessed patients, patients' caregivers, and other sources every 2 weeks by telephone for any hospitalizations, relapses, or other causes of treatment discontinuation. The research assistants also administered the symptom and functioning rating scales at scheduled intervals. The primary measure was rate of treatment discontinuation or change and time to treatment discontinuation. Once a patient discontinued the study, no further assessments were completed. Our criteria for treatment discontinuation or change were somewhat broader than those of the Clinical Antipsychotic Trials of Intervention Effectiveness study2 and included (1) clinical relapse/hospital admission; (2) loss to follow-up or patient's refusal; (3) nonadherence, defined as taking less than 70% of prescribed medications, detected by either the treating psychiatrist or research assistants during follow-up assessments; (4) changing or stopping of the initial antipsychotic medication by physician or patient request; and (5) intolerability, defined as severe adverse effects that caused the treating psychiatrists to stop the medication.

Clinical relapse was defined by any one of the following32: (1) psychiatric hospitalization; (2) an increase in the level of psychiatric care (eg, from clinic visits to day treatment) and a 25% or more increase in the PANSS total score (or 10 points if the initial score was ≤40); (3) a Clinical Global Impressions Scale score of “much worse” or “very much worse”33(pp218-222); (4) deliberate self-injury; (5) emergence of clinically significant suicidal or homicidal ideation; or (6) violent behavior resulting in significant injury to another person or significant property damage.

Secondary outcomes further assessed treatment effectiveness by measuring symptom severity (PANSS), insight (Insight and Treatment Attitudes Questionnaire [ITAQ]),34 treatment adherence (appointment adherence), quality of life (Medical Outcomes Study 36-Item Short Form Health Survey [SF-36]),35,36 and social functioning on the Global Assessment Scale (GAS)37 and the Activities of Daily Living Scale (ADL).38,39 The SF-36 consists of 8 domains that assess bodily pain, general health, general mental health, physical functioning, role-emotional, role-physical, social functioning, and vitality. The GAS is a single-item rating scale for evaluation of overall patient functioning.37 The 14-item independent ADL assesses a person's ability to perform basic (eg, dressing, walking, and bathing) and instrumental (eg, using a telephone, doing laundry, and handling finances) activities of daily living.38,39 This scale has been widely used and has demonstrated validity in studies of medically ill and dementia populations in China.40,41 The rate of obtained work or education during the 12 months was also used to assess role functioning and community integration. The physical examination and the effect of antipsychotic treatment on weight gain were recorded regularly. The Treatment Emergent Symptom Scale33(pp341-350) was used for monitoring adverse effects.

All interviewers trained and received reassessments of interrater reliability on the basis of videotaped demonstration interviews. Agreement among the raters was high for the PANSS, ITAQ, GAS, and ADL (Pearson correlation coefficient, 0.78-0.86) at baseline and every 6 months.

STATISTICAL ANALYSIS

Analyses were performed according to the intention-to-treat principle. Randomized patients who had at least 1 assessment during treatment made up the intention-to-treat population. The sample sizes were selected to make possible the detection of a 15% difference in discontinuation rates after 1 year with 85% power and a 2-tailed α level of significance of .05.

Baseline characteristics were compared between the 2 groups by analysis of variance, Pearson χ2 test, or Fisher exact test, as appropriate. We used Kaplan-Meier survival curves to estimate the time to discontinuation of treatment in the sample. Factors associated with treatment discontinuation were determined by multivariate analysis using a Cox proportional hazards model with stepwise reduction and a log-rank test with control for site.42 Data were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Time course and treatment differences for change in the PANSS, ITAQ, SF-36 domain scores, GAS, and ADL were analyzed by means of a mixed-effects model for repeated-measures analyses with effects of treatment, time, and treatment × time interaction with unrestricted covariance of baseline scores.43 Time was classified into months (baseline and 3, 6, 9, and 12 months). Other categorical outcomes (including data regarding adverse events) were compared with the use of Pearson χ2 test or Fisher exact test. All statistical tests were 2-tailed.

DISPOSITION AND BASELINE CHARACTERISTICS OF PATIENTS

A total of 1563 potentially eligible subjects were screened. Of these subjects, 1268 patients completed the baseline assessment and underwent randomization; 633 were assigned to receive antipsychotics combined with psychosocial intervention (of whom 29 refused the psychosocial intervention and were excluded from analysis) and 635 to receive antipsychotics alone. Overall, 744 patients (60.0%) completed the 1-year follow-up: 406 (67.2%) in the combined intervention group and 338 (53.2%) in the antipsychotics-alone group (Figure 1).

Place holder to copy figure label and caption

Figure 1. Study flowchart showing the numbers of patients screened for potential inclusion, the reasons for exclusions from randomization, and primary outcome in 1-year follow-up. *These patients were excluded from the final analysis because their follow-up was not carried out.

Graphic Jump Location

There were no significant differences between study groups with respect to baseline demographic and clinical characteristics. The mean age was 26 years; 55.0% of the patients were male and most patients (84.6%) had a diagnosis of schizophrenia (Table 2).

Table Graphic Jump LocationTable 2. Baseline Demographic and Clinical Characteristics of Randomly Assigned Patientsa

Among the 406 combined-treatment participants who completed the study, the mean (SD) number of sessions attended was 44.2 (4.4) (92.1% of the 48 total sessions), whereas among the 198 combined-treatment participants who discontinued or changed treatment, the mean number was 18.1 (4.9) (37.7% of total sessions).

RATES OF TREATMENT DISCONTINUATION

Forty percent of patients in the final analysis (495 of 1239) discontinued their treatment during the 12-month treatment period (32.8% of patients in the combined treatment group and 46.8% of patients in the medication-alone group). The difference between groups in treatment discontinuation for any cause was significant (HR, 0.62; 95% CI, 0.52-0.74; P < .001) (Table 3 and Figure 2).

Place holder to copy figure label and caption

Figure 2. Time to treatment discontinuation because of any cause (A) or relapse (B). A, Kaplan-Meier survival analysis showed a significant difference between the medication treatment group and the combined medication and psychosocial intervention group (log-rank test: χ21 = 28.85; P < .001). B, Kaplan-Meier survival analysis showed a significant difference between the medication treatment group and the combined medication and psychosocial intervention group (log-rank test: χ21 = 18.12; P < .001).

Graphic Jump Location
Table Graphic Jump LocationTable 3. Outcome Measures of Effectiveness in Patients Receiving Combined Treatment or Medication Treatment

Relapses occurred in 14.6% of patients in the combined treatment group and 22.5% of patients in the medication-alone group. The risk of relapse was lower among patients assigned to combined treatment (HR, 0.57; 95% CI, 0.44-0.74; P < .001) (Table 3 and Figure 2). Nonadherence was noted in 2.8% of patients in the combined treatment group and 5.7% of patients in the medication-alone group; rates of these events were lower among patients assigned to combined treatment (HR, 0.45; 95% CI, 0.25-0.79; P = .006). Readmission occurred in 6.5% of patients in the combined treatment group and 11.2% of patients in the medication-alone group. The risk of readmission was substantially lower among patients assigned to combined treatment (HR, 0.50; 95% CI, 0.34-0.74; P = .007).

We also analyzed all causes of discontinuation for poor outcomes only by excluding intolerance and changing medication (because these events do not always indicate poor outcomes). The results showed that 29.1% in the combined treatment group and 42.4% in the medication-alone group discontinued treatment because of poor outcomes; this difference was statistically significant (HR, 0.57; 95% CI, 0.46-0.70; P < .001).

CHANGES IN SCALE SCORES

The results of the mixed-effects model for repeated-measures analyses of change in psychopathologic behavior and daily functioning assessments between the 2 treatment groups are presented in Table 4. Although the analyses used data from the baseline and 3-, 6-, 9-, and 12-month assessments, we present only the baseline and 6- and 12-month mean scores in the table. Analyses showed a significant improvement in total PANSS and ITAQ scores over time in both groups (both F > 89.67; both P < .001); however, the change in total ITAQ scores was greater in the combined treatment group than in the medication-alone group (F = 25.94; P < .001). Improvements in GAS (F = 4.33; P = .002) and ADL (F = 12.70; P < .001) scores were also greater over time for the combined treatment group than for the medication-only group. Compared with those in the medication-alone group, those receiving combined treatment showed significantly greater improvement on 4 domains of the SF-36 (role-physical, general health, vitality, and role-emotional; all F ≥ 3.98; all P ≤ .02).

Table Graphic Jump LocationTable 4. MMRM Analysis on Clinical and Functioning Outcomes in Patients Receiving CT or MTa

In addition, a significantly higher proportion of patients receiving combined treatment obtained employment or accessed education (30.1% in the combined treatment group vs 22.2% in the medication-alone group; χ2 = 10.09; P = .001).

ADVERSE EVENTS

There were no significant differences in the frequency and types of adverse events reported between the 2 groups (all P > .05; Table 5). The treatment group effect at the end of treatment (determined by analysis of variance with the baseline value as a covariate) was not significant for the dose of antipsychotic medication (P = .55). There were no differences between the 2 groups in the rates or types of medications added during the study (all P > .05; Table 5).

Table Graphic Jump LocationTable 5. Safety Outcomes of Patients Receiving Combined Treatment or Medication Treatment in 1-Year Follow-up

Treatment of schizophrenia should focus on improving real-world effectiveness outcomes, including functional capacity and health-related quality of life. This study was designed to provide information on the effect of psychosocial intervention on outcome in early-stage schizophrenia, in particular on functional outcome in real-world practice. We found that combined treatment improved medication adherence, risk of relapse and hospital admission, insight, quality of life, and social/occupational functioning.

Treatment discontinuation in patients with schizophrenia is strikingly common; the Clinical Antipsychotic Trials of Intervention Effectiveness study reported that 74% of patients discontinued their medications during the 18-month study,2 and the European First Episode Schizophrenia Trial reported that an average of 42% had discontinued their medications at 1-year follow-up.44 Discontinuing medication is associated with symptom exacerbation, relapse, increased hospitalization, and poor long-term course of illness.45,46 Our study showed a lower rate of medication discontinuation than the above-mentioned studies. One reason could be that our psychosocial intervention reduced the risk of treatment discontinuation and improved insight and medication adherence; another reason could be that family members are more involved in patients' care in China, similar to other Asian or developing countries. This kind of family involvement and support could further reduce medication discontinuation rates and subsequently improve outcomes. Another potential reason for better outcomes in the combined treatment group is that medication and psychosocial treatments occurred on the same day each month for patients, allowing the psychiatrists and other care providers to reinforce the importance of participation in all components of treatment.

Prevention of relapse is the cornerstone to improving all areas of long-term outcome and achieving long-term improvements in quality of life and level of functioning. The risks of relapse and hospital admission were significantly lower in the combined treatment group than in the medication-alone group in this study.

Improvements in quality of life represent evidence of a good treatment outcome for patients with schizophrenia.47,48 After 12 months of treatment, more improvements in quality of life were seen in patients who received combined treatment. Better quality of life outcomes in the combined treatment group were demonstrated not only in mental health domains but also in physical health domains, suggesting that combined treatment may afford the best combination of effectiveness and improved quality of life.

Social outcomes reflect how patients live, function in society, and perform their various roles (eg, having a job, going to school, or having friends). Our study showed that a significantly higher proportion of patients receiving combined treatment obtained employment or accessed education. Thus, the findings support the results from previous studies that patients with schizophrenia receiving combined treatment had better outcomes.12,13,4952 In particular, integrating a comprehensive therapy with medication treatment in patients with early-stage schizophrenia before the disease becomes chronic and disabling could improve long-term outcomes.

Psychoeducation, family intervention, skills training, and cognitive behavior therapy have proved to be effective in treating people with schizophrenia.5,710,31,52 To our knowledge, this is one of a very few studies to take this integrated intervention approach and address outcome as a whole, with the goal of improving overall outcome in patients with early-stage schizophrenia. Our once-monthly comprehensive psychosocial intervention approach is different from the common therapy model used in the United States and other western countries. Although this study cannot indicate whether this intensive therapy model can be applied in other countries, it did provide evidence that the model was practical and showed better efficacy than medications alone in improving overall outcome for patients with early-stage schizophrenia. This result may be particularly informative to Asian, African, or Latin American countries, where patients with schizophrenia tend to live with their families and family members are often involved in patient care.

This study has several limitations. First, this was a 12-month trial; a longer-term randomized clinical trial would contribute substantially to understanding the longer-term effects of psychosocial intervention on outcomes. Second, although measures were taken to maintain the blinding, it is not known how effective the blinding was. However, several outcome measures were not vulnerable to bias, such as rehospitalization, loss to follow-up, and treatment nonadherence. Third, although the combined psychosocial intervention showed better overall efficacy than medications alone, we do not know whether the effects of the combined intervention were equally attributable to all the modules.

In summary, our study suggests that combined treatment in patients with early-stage schizophrenia reduces the rate of treatment discontinuation and risk of relapse. It also improves insight, adherence to treatment, quality of life, and social functioning. Integrating comprehensive therapy with medication treatment in the early stage of schizophrenia is critically important and should be recommended as the standard of care.

Correspondence: Jingping Zhao, MD, PhD, Mental Health Institute, Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Changsha 410011, Hunan, China (fengcsu@yahoo.com.cn); and Hua Jin, MD, Department of Psychiatry, University of California, San Diego, San Diego VA Healthcare, 3350 La Jolla Village Dr, Mail Code 116A-1, La Jolla, CA 92161 (hjin@ucsd.edu).

Submitted for Publication: May 10, 2009; final revision received January 9, 2010; accepted March 5, 2010.

Author Contributions: Drs X. Guo and Zhai contributed equally to the study. Dr Zhao had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This research was supported by grant 2004BA720A22 from the National Key Technologies R&D Program in the 10th 5-year plan of China, grant 30630062 from the National Natural Science Foundation of China, and grant 2010CB529601 from the National Basic Research Program of China.

Role of the Sponsor: The funding organizations played no role in the design, conduct, analysis, or interpretation of the research or in any aspect of preparation or approval of the manuscript.

Additional Contributions: The following individuals collected data at participating sites: Yan Yu, MD, Zhanchou Zhang, PhD, Mental Health Institute of the Second Xiangya Hospital, Central South University; Jianchu Zhou, MD, Jie Ning, MD, Juhong Qiu, PhD, Chongqing Mental Health Centre; Qi Chen, MD, Ying Wang, MD, Qing Huang, PhD, Beijing Anding Hospital Affiliated to Capital Medical University; Fajin Gong, MD, Fang Yu, MD, Shuiquan Xu, MD, Psychiatric Hospital of Jiangxi Province; Hong Deng, MD, Qinglan Tao, MD, Yun Wan, PhD, Mental Health Center of West China Hospital, Sichuan University; Ruiling Zhang, MD, Yingli Zhang, MD, Chuansheng Wang, MD, Mental Hospital of Henan Province; Na Liu, MD, Jie Zhang, MD, Jun Cai, MD, Shanghai Mental Health Centre; Ting Li, MD, Guiying Mai, MD, Guangzhou Brain Hospital; Xiyan Zhang, PhD, Xuejun Liu, MD, Hunan Brain Hospital; and Xiaofang Shang, MD, Yu Cheng, MD, Min Zhou, PhD, Nanjing Brain Hospital. Statistical support was provided by Zhenqiu Sun, PhD, School of Public Health, Central South University.

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Birchwood  MTodd  PJackson  C Early intervention in psychosis: the critical period hypothesis. Br J Psychiatry Suppl 1998;172 (33) 53- 59
PubMed
Bertelsen  MJeppesen  PPetersen  LThorup  AØhlenschlaeger  Jle Quach  PChristensen  TØKrarup  GJørgensen  PNordentoft  M Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychotic illness: the OPUS trial. Arch Gen Psychiatry 2008;65 (7) 762- 771
PubMed
Jeppesen  PPetersen  LThorup  AAbel  MBOehlenschlaeger  JChristensen  TØKrarup  GHemmingsen  RJørgensen  PNordentoft  M Integrated treatment of first-episode psychosis: effect of treatment on family burden: OPUS trial. Br J Psychiatry Suppl 2005;187 (48) s85- s90
PubMed
Grawe  RWFalloon  IRWiden  JHSkogvoll  E Two years of continued early treatment for recent-onset schizophrenia: a randomised controlled study. Acta Psychiatr Scand 2006;114 (5) 328- 336
PubMed
Craig  TKGarety  PPower  PRahaman  NColbert  SFornells-Ambrojo  MDunn  G The Lambeth Early Onset (LEO) Team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ 2004;329 (7474) 1067
PubMeddoi:10.1136/bmj.38246.594873.7C
Garety  PACraig  TKDunn  GFornells-Ambrojo  MColbert  SRahaman  NRead  JPower  P Specialised care for early psychosis: symptoms, social functioning, and patient satisfaction [published correction appears in Br J Psychiatry. 2006;188:295]. Br J Psychiatry 2006;188 (1) 37- 45
PubMed
Guo  XFZhao  JPLiu  ZNZhai  JGXue  ZMChen  JD Antipsychotic Combination With Psychosocial Intervention on Outcome of Schizophrenia (ACPIOS): rationale and design of the clinical trial. Clin Schizophr Relat Psychoses 2007;1 (2) 185- 192
First  MBSpitzer  RLGibbon  MWilliams  JBWBenjamin  LS Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version (SCID-CV).  Washington, DC: American Psychiatry Press; 1997
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13 (2) 261- 276
PubMed
Si  TMShu  LYu  XMa  CWang  GHBai  PSLiu  XHJi  LPShi  JGChen  XSMei  QYSu  KQZhang  HYMa  H Antipsychotic drug patterns of schizophrenia in China: a cross-sectioned study [in Chinese]. Chin J Psychiatry 2004;37 (3) 152- 155
Lehman  AFKreyenbuhl  JBuchanan  RWDickerson  FBDixon  LBGoldberg  RGreen-Paden  LDTenhula  WNBoerescu  DTek  CSandson  NSteinwachs  DM The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2003. Schizophr Bull 2004;30 (2) 193- 217
PubMed
Gleeson  JJackson  HStavely  HBurnett  P Family interventions in early psychosis.  In: McGorry  PD, Henry  HJ, eds. The Recognition and Management of Early Psychosis: A Preventive Approach. Cambridge, England: Cambridge University Press; 1999:306-406
Zhang  MHe  YGittelman  MWong  ZYan  H Group psychoeducation of relatives of schizophrenic patients: two-year experiences. Psychiatry Clin Neurosci 1998;52(suppl)S344- S347
PubMed
Bäuml  JFroböse  TKraemer  SRentrop  MPitschel-Walz  G Psychoeducation: a basic psychotherapeutic intervention for patients with schizophrenia and their families. Schizophr Bull 2006;32(suppl 1)S1- S9
PubMed
Askey  RGamble  CGray  R Family work in first-onset psychosis: a literature review. J Psychiatr Ment Health Nurs 2007;14 (4) 356- 365
PubMed
Addington  JBurnett  P Working with families in the early stages of psychosis.  In: McGorry  PD, Gleeson  JF, eds. Psychological Interventions in Early Psychosis: A Practical Treatment Handbook. Chichester, England: John Wiley & Sons Ltd; 2004:99-116
Liberman  RPEckman  TAMarder  SR Rehab rounds: Training in social problem solving among persons with schizophrenia. Psychiatr Serv 2001;52 (1) 31- 33
PubMed
Liberman  RPWallace  CJBlackwell  GEckman  TAVaccaro  JVKuehnel  TG Innovations in skills training for the seriously mentally ill: the UCLA Social and Independent Living Skills Modules. Innovations Res 1993;2 (2) 43- 60
Bellack  ASMueser  KTGingerich  SAgresta  J Social Skills Training for Schizophrenia: A Step-by-Step Guide. 2nd ed. New York, NY: Guilford Press; 2004
Fowler  DGarety  PAKuipers  L Cognitive Behaviour Therapy for Psychosis: Theory and Practice.  Chichester, England: John Wiley & Sons Ltd; 1999
Turkington  DSensky  TScott  JBarnes  TRNur  USiddle  RHammond  KSamarasekara  NKingdon  D A randomized controlled trial of cognitive-behavior therapy for persistent symptoms in schizophrenia: a five-year follow-up. Schizophr Res 2008;98 (1-3) 1- 7
PubMed
Csernansky  JGMahmoud  RBrenner  RRisperidone-USA-79 Study Group, A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346 (1) 16- 22
PubMed
Guy  W ECDEU Assessment Manual for Psychopharmacology. Rev ed. Rockville, MD: Dept of Health, Education, and Welfare; 1976
McEvoy  JPApperson  LJAppelbaum  PSOrtlip  PBrecosky  JHammill  KGeller  JLRoth  L Insight in schizophrenia: its relationship to acute psychopathology. J Nerv Ment Dis 1989;177 (1) 43- 47
PubMed
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30 (6) 473- 483
PubMed
Ware  JESnow  KKKosisnki  MGandek  B SF-36 Health Survey Manual and Interpretation Guide.  Boston, MA: Health Institute, New England Medical Center; 1993
Endicott  JSpitzer  RLFleiss  JLCohen  J The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976;33 (6) 766- 771
PubMed
Katz  SFord  ABMoskowitz  RWJackson  BAJaffe  MW Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963;185 (12) 914- 919
PubMed
Lawton  MPBrody  EM Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9 (3) 179- 186
PubMed
Zhang  MY Chinese version of ADL [in Chinese]. Shanghai Arch Psychiatry 1989;1 (2) 68- 71
Zhang  MYKatzman  RSalmon  DJin  HCai  GJWang  ZYQu  GYGrant  IYu  ELevy  PKlauber  MRLiu  WT The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education. Ann Neurol 1990;27 (4) 428- 437
PubMed
Cox  DOakes  D Analysis of Survival Data.  London, England: Chapman & Hall; 1984
Everitt  BS Analysis of longitudinal data: beyond MANOVA. Br J Psychiatry 1998;172 (1) 7- 10
PubMed
Kahn  RSFleischhacker  WWBoter  HDavidson  MVergouwe  YKeet  IPGheorghe  MDRybakowski  JKGalderisi  SLibiger  JHummer  MDollfus  SLópez-Ibor  JJHranov  LGGaebel  WPeuskens  JLindefors  NRiecher-Rössler  AGrobbee  DEEUFEST study group, Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008;371 (9618) 1085- 1097
PubMed
Ascher-Svanum  HFaries  DEZhu  BErnst  FRSwartz  MSSwanson  JW Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry 2006;67 (3) 453- 460
PubMed
Osterberg  LBlaschke  T Adherence to medication. N Engl J Med 2005;353 (5) 487- 497
PubMed
Tunis  SLCroghan  TWHeilman  DKJohnstone  BMObenchain  RL Reliability, validity, and application of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) in schizophrenic patients treated with olanzapine versus haloperidol. Med Care 1999;37 (7) 678- 691
PubMed
Nasrallah  HADuchesne  IMehnert  AJanagap  CEerdekens  M Health-related quality of life in patients with schizophrenia during treatment with long-acting, injectable risperidone. J Clin Psychiatry 2004;65 (4) 531- 536
PubMed
Lewis  STarrier  NHaddock  GBentall  RKinderman  PKingdon  DSiddle  RDrake  REveritt  JLeadley  KBenn  AGrazebrook  KHaley  CAkhtar  SDavies  LPalmer  SFaragher  BDunn  G Randomized controlled trial of cognitive-behavioural therapy in early schizophrenia: acute-phase outcomes. Br J Psychiatry Suppl 2002;181 (43) s91- s97
Petersen  LJeppesen  PThorup  AAbel  MBØhlenschlaeger  JChristensen  TØKrarup  GJørgensen  PNordentoft  M A randomised multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness [published correction appears in BMJ. 2005;331(7524):1065]. BMJ 2005;331 (7517) 602
PubMeddoi:10.1136/bmj.38565.415000.E01
Petersen  LNordentoft  MJeppesen  POhlenschaeger  JThorup  AChristensen  TØKrarup  GDahlstrøm  JHaastrup  BJørgensen  P Improving 1-year outcome in first-episode psychosis: OPUS trial. Br J Psychiatry Suppl 2005;48 (8) s98- s103
PubMed
Tarrier  NLewis  SHaddock  GBentall  RDrake  RKinderman  PKingdon  DSiddle  REveritt  JLeadley  KBenn  AGrazebrook  KHaley  CAkhtar  SDavies  LPalmer  SDunn  G Cognitive-behavioural therapy in first-episode and early schizophrenia: 18-month follow-up of a randomised controlled trial. Br J Psychiatry 2004;184 (3) 231- 239
PubMed

Figures

Place holder to copy figure label and caption

Figure 1. Study flowchart showing the numbers of patients screened for potential inclusion, the reasons for exclusions from randomization, and primary outcome in 1-year follow-up. *These patients were excluded from the final analysis because their follow-up was not carried out.

Graphic Jump Location
Place holder to copy figure label and caption

Figure 2. Time to treatment discontinuation because of any cause (A) or relapse (B). A, Kaplan-Meier survival analysis showed a significant difference between the medication treatment group and the combined medication and psychosocial intervention group (log-rank test: χ21 = 28.85; P < .001). B, Kaplan-Meier survival analysis showed a significant difference between the medication treatment group and the combined medication and psychosocial intervention group (log-rank test: χ21 = 18.12; P < .001).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Content of Monthly Psychosocial Treatment Sessions
Table Graphic Jump LocationTable 2. Baseline Demographic and Clinical Characteristics of Randomly Assigned Patientsa
Table Graphic Jump LocationTable 3. Outcome Measures of Effectiveness in Patients Receiving Combined Treatment or Medication Treatment
Table Graphic Jump LocationTable 4. MMRM Analysis on Clinical and Functioning Outcomes in Patients Receiving CT or MTa
Table Graphic Jump LocationTable 5. Safety Outcomes of Patients Receiving Combined Treatment or Medication Treatment in 1-Year Follow-up

References

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Lieberman  JAStroup  TS McEvoy  JPSwartz  MSRosenheck  RAPerkins  DOKeefe  RSDavis  SMDavis  CELebowitz  BDSevere  JHsiao  JKClinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators, Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353 (12) 1209- 1223
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Mojtabai  RLavelle  JGibson  PJBromet  EJ Atypical antipsychotics in first admission schizophrenia: medication continuation and outcomes. Schizophr Bull 2003;29 (3) 519- 530
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Weiden  PJKozma  CGrogg  ALocklear  J Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv 2004;55 (8) 886- 891
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Penn  DLWaldheter  EJPerkins  DOMueser  KTLieberman  JA Psychosocial treatment for first-episode psychosis: a research update. Am J Psychiatry 2005;162 (12) 2220- 2232
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Rosenbaum  BValbak  KHarder  SKnudsen  PKøster  ALajer  MLindhardt  AWinther  GPetersen  LJørgensen  PNordentoft  MAndreasen  AH The Danish National Schizophrenia Project: prospective, comparative longitudinal treatment study of first-episode psychosis. Br J Psychiatry 2005;186 (9) 394- 399
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Marder  SRWirshing  WCMintz  J McKenzie  JJohnston  KEckman  TALebell  MZimmerman  KLiberman  RP Two-year outcome of social skills training and group psychotherapy for outpatients with schizophrenia. Am J Psychiatry 1996;153 (12) 1585- 1592
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Turkington  DKingdon  DWeiden  PJ Cognitive behavior therapy for schizophrenia. Am J Psychiatry 2006;163 (3) 365- 373
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Granholm  E McQuaid  JR McClure  FSLink  PCPerivoliotis  DGottlieb  JDPatterson  TLJeste  DV Randomized controlled trial of cognitive behavioral social skills training for older people with schizophrenia: 12-month follow-up. J Clin Psychiatry 2007;68 (5) 730- 737
PubMed
Lehman  AFLieberman  JADixon  LB McGlashan  THMiller  ALPerkins  DOKreyenbuhl  JAmerican Psychiatric Association; Steering Committee on Practice Guidelines, Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161(suppl 2)s1- s56
PubMed
Birchwood  MTodd  PJackson  C Early intervention in psychosis: the critical period hypothesis. Br J Psychiatry Suppl 1998;172 (33) 53- 59
PubMed
Bertelsen  MJeppesen  PPetersen  LThorup  AØhlenschlaeger  Jle Quach  PChristensen  TØKrarup  GJørgensen  PNordentoft  M Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychotic illness: the OPUS trial. Arch Gen Psychiatry 2008;65 (7) 762- 771
PubMed
Jeppesen  PPetersen  LThorup  AAbel  MBOehlenschlaeger  JChristensen  TØKrarup  GHemmingsen  RJørgensen  PNordentoft  M Integrated treatment of first-episode psychosis: effect of treatment on family burden: OPUS trial. Br J Psychiatry Suppl 2005;187 (48) s85- s90
PubMed
Grawe  RWFalloon  IRWiden  JHSkogvoll  E Two years of continued early treatment for recent-onset schizophrenia: a randomised controlled study. Acta Psychiatr Scand 2006;114 (5) 328- 336
PubMed
Craig  TKGarety  PPower  PRahaman  NColbert  SFornells-Ambrojo  MDunn  G The Lambeth Early Onset (LEO) Team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ 2004;329 (7474) 1067
PubMeddoi:10.1136/bmj.38246.594873.7C
Garety  PACraig  TKDunn  GFornells-Ambrojo  MColbert  SRahaman  NRead  JPower  P Specialised care for early psychosis: symptoms, social functioning, and patient satisfaction [published correction appears in Br J Psychiatry. 2006;188:295]. Br J Psychiatry 2006;188 (1) 37- 45
PubMed
Guo  XFZhao  JPLiu  ZNZhai  JGXue  ZMChen  JD Antipsychotic Combination With Psychosocial Intervention on Outcome of Schizophrenia (ACPIOS): rationale and design of the clinical trial. Clin Schizophr Relat Psychoses 2007;1 (2) 185- 192
First  MBSpitzer  RLGibbon  MWilliams  JBWBenjamin  LS Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version (SCID-CV).  Washington, DC: American Psychiatry Press; 1997
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13 (2) 261- 276
PubMed
Si  TMShu  LYu  XMa  CWang  GHBai  PSLiu  XHJi  LPShi  JGChen  XSMei  QYSu  KQZhang  HYMa  H Antipsychotic drug patterns of schizophrenia in China: a cross-sectioned study [in Chinese]. Chin J Psychiatry 2004;37 (3) 152- 155
Lehman  AFKreyenbuhl  JBuchanan  RWDickerson  FBDixon  LBGoldberg  RGreen-Paden  LDTenhula  WNBoerescu  DTek  CSandson  NSteinwachs  DM The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2003. Schizophr Bull 2004;30 (2) 193- 217
PubMed
Gleeson  JJackson  HStavely  HBurnett  P Family interventions in early psychosis.  In: McGorry  PD, Henry  HJ, eds. The Recognition and Management of Early Psychosis: A Preventive Approach. Cambridge, England: Cambridge University Press; 1999:306-406
Zhang  MHe  YGittelman  MWong  ZYan  H Group psychoeducation of relatives of schizophrenic patients: two-year experiences. Psychiatry Clin Neurosci 1998;52(suppl)S344- S347
PubMed
Bäuml  JFroböse  TKraemer  SRentrop  MPitschel-Walz  G Psychoeducation: a basic psychotherapeutic intervention for patients with schizophrenia and their families. Schizophr Bull 2006;32(suppl 1)S1- S9
PubMed
Askey  RGamble  CGray  R Family work in first-onset psychosis: a literature review. J Psychiatr Ment Health Nurs 2007;14 (4) 356- 365
PubMed
Addington  JBurnett  P Working with families in the early stages of psychosis.  In: McGorry  PD, Gleeson  JF, eds. Psychological Interventions in Early Psychosis: A Practical Treatment Handbook. Chichester, England: John Wiley & Sons Ltd; 2004:99-116
Liberman  RPEckman  TAMarder  SR Rehab rounds: Training in social problem solving among persons with schizophrenia. Psychiatr Serv 2001;52 (1) 31- 33
PubMed
Liberman  RPWallace  CJBlackwell  GEckman  TAVaccaro  JVKuehnel  TG Innovations in skills training for the seriously mentally ill: the UCLA Social and Independent Living Skills Modules. Innovations Res 1993;2 (2) 43- 60
Bellack  ASMueser  KTGingerich  SAgresta  J Social Skills Training for Schizophrenia: A Step-by-Step Guide. 2nd ed. New York, NY: Guilford Press; 2004
Fowler  DGarety  PAKuipers  L Cognitive Behaviour Therapy for Psychosis: Theory and Practice.  Chichester, England: John Wiley & Sons Ltd; 1999
Turkington  DSensky  TScott  JBarnes  TRNur  USiddle  RHammond  KSamarasekara  NKingdon  D A randomized controlled trial of cognitive-behavior therapy for persistent symptoms in schizophrenia: a five-year follow-up. Schizophr Res 2008;98 (1-3) 1- 7
PubMed
Csernansky  JGMahmoud  RBrenner  RRisperidone-USA-79 Study Group, A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346 (1) 16- 22
PubMed
Guy  W ECDEU Assessment Manual for Psychopharmacology. Rev ed. Rockville, MD: Dept of Health, Education, and Welfare; 1976
McEvoy  JPApperson  LJAppelbaum  PSOrtlip  PBrecosky  JHammill  KGeller  JLRoth  L Insight in schizophrenia: its relationship to acute psychopathology. J Nerv Ment Dis 1989;177 (1) 43- 47
PubMed
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30 (6) 473- 483
PubMed
Ware  JESnow  KKKosisnki  MGandek  B SF-36 Health Survey Manual and Interpretation Guide.  Boston, MA: Health Institute, New England Medical Center; 1993
Endicott  JSpitzer  RLFleiss  JLCohen  J The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976;33 (6) 766- 771
PubMed
Katz  SFord  ABMoskowitz  RWJackson  BAJaffe  MW Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function. JAMA 1963;185 (12) 914- 919
PubMed
Lawton  MPBrody  EM Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9 (3) 179- 186
PubMed
Zhang  MY Chinese version of ADL [in Chinese]. Shanghai Arch Psychiatry 1989;1 (2) 68- 71
Zhang  MYKatzman  RSalmon  DJin  HCai  GJWang  ZYQu  GYGrant  IYu  ELevy  PKlauber  MRLiu  WT The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education. Ann Neurol 1990;27 (4) 428- 437
PubMed
Cox  DOakes  D Analysis of Survival Data.  London, England: Chapman & Hall; 1984
Everitt  BS Analysis of longitudinal data: beyond MANOVA. Br J Psychiatry 1998;172 (1) 7- 10
PubMed
Kahn  RSFleischhacker  WWBoter  HDavidson  MVergouwe  YKeet  IPGheorghe  MDRybakowski  JKGalderisi  SLibiger  JHummer  MDollfus  SLópez-Ibor  JJHranov  LGGaebel  WPeuskens  JLindefors  NRiecher-Rössler  AGrobbee  DEEUFEST study group, Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008;371 (9618) 1085- 1097
PubMed
Ascher-Svanum  HFaries  DEZhu  BErnst  FRSwartz  MSSwanson  JW Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry 2006;67 (3) 453- 460
PubMed
Osterberg  LBlaschke  T Adherence to medication. N Engl J Med 2005;353 (5) 487- 497
PubMed
Tunis  SLCroghan  TWHeilman  DKJohnstone  BMObenchain  RL Reliability, validity, and application of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) in schizophrenic patients treated with olanzapine versus haloperidol. Med Care 1999;37 (7) 678- 691
PubMed
Nasrallah  HADuchesne  IMehnert  AJanagap  CEerdekens  M Health-related quality of life in patients with schizophrenia during treatment with long-acting, injectable risperidone. J Clin Psychiatry 2004;65 (4) 531- 536
PubMed
Lewis  STarrier  NHaddock  GBentall  RKinderman  PKingdon  DSiddle  RDrake  REveritt  JLeadley  KBenn  AGrazebrook  KHaley  CAkhtar  SDavies  LPalmer  SFaragher  BDunn  G Randomized controlled trial of cognitive-behavioural therapy in early schizophrenia: acute-phase outcomes. Br J Psychiatry Suppl 2002;181 (43) s91- s97
Petersen  LJeppesen  PThorup  AAbel  MBØhlenschlaeger  JChristensen  TØKrarup  GJørgensen  PNordentoft  M A randomised multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness [published correction appears in BMJ. 2005;331(7524):1065]. BMJ 2005;331 (7517) 602
PubMeddoi:10.1136/bmj.38565.415000.E01
Petersen  LNordentoft  MJeppesen  POhlenschaeger  JThorup  AChristensen  TØKrarup  GDahlstrøm  JHaastrup  BJørgensen  P Improving 1-year outcome in first-episode psychosis: OPUS trial. Br J Psychiatry Suppl 2005;48 (8) s98- s103
PubMed
Tarrier  NLewis  SHaddock  GBentall  RDrake  RKinderman  PKingdon  DSiddle  REveritt  JLeadley  KBenn  AGrazebrook  KHaley  CAkhtar  SDavies  LPalmer  SDunn  G Cognitive-behavioural therapy in first-episode and early schizophrenia: 18-month follow-up of a randomised controlled trial. Br J Psychiatry 2004;184 (3) 231- 239
PubMed

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