Sustained favorable long-term outcome in the treatment of schizophrenia: a 3-year prospective observational study

The data source for this study was the United States (US) Schizophrenia Care and Assessment Program (SCAP), a 3-year prospective, observational study (N = 2327). Participants were adults 18 years and older and treated for schizophrenia, schizoaffective, or schizophreniform disorders, based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. The study was conducted between July 1997 and September 2003, and the sample was geographically and ethnically diverse, representing treatment in large systems of care. Patients were recruited from community mental health centers, university healthcare systems, community and state hospitals, and the Department of Veterans Affairs Health Services [16]. The overall objective of US-SCAP was to better understand the treatment of patients with schizophrenia in usual care settings. Patients were excluded if they were unable to provide informed consent or had participated in a clinical drug trial within 30 days prior to enrollment. Enrollment was not contingent upon being treated with a specific antipsychotic or with any medication. Patients could continue with medications they received prior to enrollment for as long as necessary, and decisions about medication changes, if any, reflected those made by physicians and their patients, as they naturally occur in usual practice. Almost all study participants were outpatients at the time of enrollment (93.5%). Of 2327 participants, most completed 1 year of follow-up (78.1%), with fewer completing 2 years (69.6%) and 3 years (65.2%). At enrollment, almost all patients (94.7%) were treated with at least one antipsychotic medication, including oral typical (36.7%), oral atypical (58.1%), and depot typical antipsychotics (19.6%). Treatment throughout the study was based on physicians' decisions, which could include medication augmentation, switching, or discontinuation, reflecting the dynamic antipsychotic treatment observed in naturalistic care settings. Institutional Review Board (IRB) approval was obtained at each regional site prior to initiation of the study, and the study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with good clinical practices and applicable laws and regulations. Informed consent was received from all participants.

This study used a number of clinician-rated and patient-reported measures in addition to patients' medical records. Patients' medical records provided information about healthcare utilization, such as psychiatric hospitalizations and medications (i.e., antipsychotics, antidepressants, mood stabilizers, antiparkinsonian agents, and mood stabilizers). This information was systematically collected using the Medical Records Abstraction Form (MRAF). Information about functional and quality-of-life outcomes was derived from the SCAP Health Questionnaire (SCAP-HQ) [17]. This 102-item structured interview was developed for the US-SCAP study and was administered to patients at enrollment and at 6-month intervals thereafter. Items for the SCAP-HQ were drawn from existing measures, such as the Lehman Quality of Life Interview [18], the Arkansas Schizophrenia Outcomes Module [19, 20], the Medical Outcome Study Short Form-12 (SF-12) [21], and the CAGE, a screening tool for assessment of alcohol-related problems [22]. The psychometric properties of the SCAP-HQ were found to be acceptable for application to large-scale studies in routine care based on a study of its internal consistency, convergent validity, test-retest reliability, and responsiveness to change.

Patient symptoms of schizophrenia and depressive symptoms were assessed annually by a clinician using the Positive and Negative Syndrome Scale (PANSS) [23] and the Montgomery-Åsberg Depression Rating Scale (MADRS) [24], respectively. Clinicians also annually assessed medication-emergent adverse events, including extrapyramidal side effects using the Simpson-Angus Scale [25] and tardive dyskinesia using the Abnormal Involuntary Movement Scale (AIMS) [26]. In addition to using the SCAP-HQ to evaluate both patient-reported level of functioning and quality of life, clinicians also used the Global Assessment of Functioning (GAF) [27] to evaluate level of functioning and the Quality of Life Scales (QLS) [28] to evaluate quality of life.

Socio-demographic information data were collected at enrollment and included age, gender, race, marital status, education, employment, and insurance status. In addition, DSM-IV diagnosis of schizophrenia (i.e., schizophrenia, schizoaffective, or schizophreniform) and age of illness onset were included. The remaining measures investigated in this analysis are described in Table 1.

The objectives of this study were: 1) to identify patients with schizophrenia who experience sustained favorable long-term outcome when the outcome incorporates severity of symptoms, level of functioning, and use of acute care services and 2) to identify the baseline measures that predict sustained favorable long-term outcome.

The first step in this retrospective analysis was to define each patient's health state at baseline using symptom severity, level of functioning, and utilization of acute care services in a cluster analysis. Symptom severity was based on PANSS factor subscale scores [29]: PANSS positive, PANSS negative, PANSS hostility, PANSS disorganized thinking, and PANSS anxiety/depression. The level of functioning reflected patient-reported productivity (SCAP-HQ; composite measure of reported working for pay, volunteering, attending school, and keeping house or taking care of children) and clinician-rated occupational role functioning (QLS item 9) and level of accomplishment (QLS item 10). Acute care services included self-reported psychiatric hospitalization (in the previous 4 weeks) or use of emergency services (emergency room use in the previous 6 months from the medical record or self-reported emergency visit with a psychiatrist in the previous 4 weeks).

Once the health states had been defined by the cluster analysis, the next step included identifying those with sustained favorable long-term outcome, which was the main outcome of interest. A patient was classified as having sustained favorable long-term outcome if they were in the "best" cluster (i.e., experienced the lowest symptom severity and the highest level of functioning) over a 2-year period postbaseline assessment (from year 1 to year 2 and from year 2 to year 3, as assessments were conducted annually postbaseline). Change over time was ascertained by shifts in clusters from baseline to each postbaseline visit (end of year 1, 2, and 3). The last step in the retrospective analysis was to identify baseline measures that were associated with sustained favorable long-term outcome.

As mentioned above, the first step was to define each patient's health state at baseline. This was determined by a hierarchical cluster analysis, using the Ward's minimum variance method [30], of patients' schizophrenia health states to categorize patients into distinct groups at baseline. Postbaseline clusters were defined by first performing a principal component analysis on the 10 health state measures for data at baseline and each postbaseline visit. The "center" for each of the baseline clusters was defined by computing a mean score for each of the resulting 10 principal components at baseline by cluster. Then Euclidean distances were calculated from the "center" of each of the baseline clusters to each patient's 10 principal components at postbaseline. Finally, each patient's postbaseline cluster assignment was determined based on their closest Euclidean distance to each of the clusters at baseline. Patients were required to have nonmissing data for all health state measures (i.e., PANSS subscale scores, QLS items 9 and 10, psychiatric hospitalizations, and emergency services) to be included in the cluster analysis at each time point.

In addition to characterizing patients by sustained favorable long-term outcome in the second step of the analysis, cluster shifts were explored during the three-year period. Improvement of outcome was based on changes to a better cluster from baseline to 1-year postbaseline and maintaining the same improved cluster or moving to an even better cluster the following 2 years. Worsening of outcome was based on changes to a worse cluster from baseline to 1-year postbaseline and staying in that cluster or shifting to an even worse cluster the following 2 years. Patients who did not experience improvement or worsening of outcome were classified as having "no sustained shift in outcome."

Comparisons of baseline characteristics between patients with and without sustained favorable long-term outcome were performed using Fisher's exact tests (categorical) and analysis of variance (continuous). Stepwise logistic regression, following 5 multiple imputations of missing values, was used to determine baseline factors associated with sustained favorable long-term outcome. A total of 62 variables, including the patient-reported variables, clinician-rated variables, and medical record-based resource utilization, were explored. The interdependent variables (variance inflation factor > 10) were removed. A 2-tailed significance level of 0.05 was used to determine whether a baseline measure was included in or excluded from the model.