Early Predictors of Ten-Year Course in First-Episode Psychosis

This study is part of the Scandinavian Early Treatment and Intervention in First-Episode Psychosis (TIPS) study (13,14). From 1997 through 2000, patients were recruited from Rogaland County, Norway; from Ullevål health sector, Oslo, Norway; and from Roskilde midsector, Denmark. The combined population of the three areas is approximately 665,000. All patients were provided a two-year standard treatment protocol, including antipsychotic medication, supportive psychotherapy, and multifamily psychoeducation (13,14).

Patients met the following criteria: residence in one of the study areas; age 18–65 years (age 15–65 in Rogaland County); met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder (that is, core schizophrenia spectrum disorder), brief psychotic episode, delusional disorder, affective psychosis with mood-incongruent psychotic features, or psychotic disorder not otherwise specified; actively psychotic as measured by a score of 4 (moderate) or higher for at least seven days on any of five items on the Positive and Negative Syndrome Scale (PANSS) (15) (P1, delusions; P3, hallucinatory behavior; P5, grandiosity; P6, suspiciousness; and G9, unusual thought content); and willingness to provide informed consent. Exclusion criteria were neurological or endocrine disorders related to the psychosis, contraindications to antipsychotic medication, inability to understand or speak a Scandinavian language, IQ score <70, or inability to provide informed consent. Patients had not had any previous psychotic episode and had not received previous adequate treatment for psychosis (defined as antipsychotic medication of >3.5 haloperidol equivalents for >12 weeks or until remission of psychotic symptoms). In fact, 86% of the patients (N=260) proved to be drug naïve. A small group (N=16, 5%) had been taking antipsychotic medication in therapeutic doses before entry but for only a median of two weeks.

Of 397 eligible participants, 23% (N=93) refused to give informed consent. Those who refused had a longer DUP (median of 32 versus 10 weeks; Mann Whitney U test, p<.001) and were slightly older (30.4 versus 28.1 years; t=1.97, df=395, p=.05) (16). Three patients (1%) withdrew their consent shortly after inclusion. A sample of 301 patients thus entered the study. At ten-year follow-up, 186 patients remained. Of the 115 patients lost to ten-year follow-up, 30 were dead, 49 refused follow-up, 23 did not attend their appointment, and 13 could not be traced. As a group, the 115 patients had a longer DUP than those who were available for follow-up at ten years (median of 17 versus six weeks; Mann Whitney U test, p=.016) (17). For these patients, we used all available data until dropout. Nine of the 301 patients who entered the study were permanently lost before one-year follow-up, and they were excluded because of missing values for the dependent variable. This left a total of 292 patients for analysis in this study.

Assessments were carried out by specialized mental health personnel (clinical psychologist, psychiatrist, or psychiatric resident) at baseline, three months, and one, two, five, and ten years (mean±SD years to ten-year follow-up=10.4±.9). During the first two years, patients were also evaluated at least biweekly by their clinicians, who were in close contact with the research team. Data for years 3–5 were collected retrospectively at the five-year follow-up; for years 6–10, data were collected retrospectively at the ten-year follow-up. Data collections at five and ten years were based on patient information and all available clinical information.

When patients entered the study, the assessors estimated DUP by using all available information—from the patient interview, patient files, and family. DUP was defined as the time, in weeks, from psychosis onset to the start of the first adequate treatment of psychosis. Onset of psychosis was equated with the first appearance of being actively psychotic. Adequate treatment was defined as the start of structured treatment with antipsychotic medications or the start of hospitalization in highly staffed psychiatric wards organized to manage disturbing psychotic symptoms. All available information sources, including semistructured personal interviews with patients and relatives, were used to ascertain the length of this period. In the rare case of previous short, self-remitting psychotic episodes, the lengths of these episodes were added to estimate the DUP.

Premorbid functioning was measured by the Premorbid Adjustment Scale (PAS) (18), which subdivides the premorbid period into childhood (ages 11 and younger), early adolescence (ages 12 to 15), late adolescence (ages 16 to 18), and adulthood (ages 19 and older). The final year before psychosis onset was not taken into account in the PAS evaluation to avoid including functional loss in the prodromal phase. As shown previously (19), the scale measures two functional dimensions—social and academic. PAS scores were missing for six of the 292 patients. Among the remaining 286 patients, 111 (39%) had deterioration in premorbid social functioning.

The Structured Clinical Interview for DSM-IV was used for diagnostic purposes (20). For analyses, diagnoses were dichotomized into core schizophrenia spectrum disorders and other psychotic disorders. Symptom levels were measured by five domains of the PANSS: positive, negative, cognitive, depressive, and excitative symptoms (15,21). Level of functioning was assessed with the Global Assessment of Functioning (GAF) (22). GAF scores were split into symptom and function scores (23). Alcohol and drug use for the six months before the start of treatment was assessed with the Clinician Alcohol/Drug Use Rating Scale (24), which measures abuse on a scale from 1 to 5 (1, no use; 2, use without impairment; 3, abuse; 4, dependence; and 5, dependence with need for institutionalization). In this study, we dichotomized the scores, defining abuse as a score of ≥3.

Longitudinal measures were operationalized in the following ways. Remission was defined as at least one week with no score of ≥4 on any of the five PANSS items (P1, P3, P5, P6, or G9). Relapse was defined as at least one week with a score of ≥4 on any of the same items. Duration of psychosis was the number of weeks per year with a score of ≥4 on any of the five PANSS items. Psychotherapy was measured as the number of weeks per year of at least one session of supportive psychotherapy per week or every second week after remission. Medication was the number of weeks per year of treatment with antipsychotic medication. Hospitalization was the number of weeks in the hospital per year. We also calculated the percentage of the entire ten-year follow-up period that a patient was psychotic, was hospitalized, was on antipsychotic medication, and was in psychotherapy. For those who dropped out before the ten-year follow-up, we used the percentage of their shorter follow-up period. Reliability assessments were conducted and found to be satisfactory (17,25).

The project was approved by the Regional Committee for Medical Research Ethics Health Region II, the Regional Committee for Medical Research Ethics Health Region East, the Norwegian Data Inspectorate, the Norwegian Directory of Health, and the Regional Committee for Science Ethics Region Sjaelland in Denmark.

Background characteristics used as predictor variables were male, age <23, single (never married, or with a partner for less than one year), education <13 years, and deterioration in premorbid social functioning as measured by the PAS. Predictor variables related to pathology at baseline were DUP ≥26 weeks, core schizophrenia spectrum disorder, and drug abuse. Rate of improvement—no remission within three months—was also included as a predictor variable. All variables were dichotomized to give optimal discrimination of time in psychosis during follow-up.

The statistical analyses were conducted with PASW Statistics, version 18.0 (26). We used t tests to evaluate whether having a potential risk factor was associated with longer aggregated time in psychosis during follow-up. Factors associated with statistically significantly longer time in psychosis were kept for further analyses. To compensate for multiple comparisons, we set the cutoff for statistical significance at p<.01.

Longitudinal analyses were performed to assess whether the selected variables predicted time in psychosis over the entire follow-up period. To account for missing data and confounding variables, we used a linear mixed model, which has been recommended for repeated measures (27). Model selection was based on restricted maximum likelihood, and nonsignificant covariates were excluded. The following equation describes the model:

Y_ij=(β₁+b_1i)+(β₂+b_2i)*time+β₃*predictor+β₄*predictor*time+e_ij

Y_ij is the time psychotic for patient i=1, . . ., 292 at year j=1 . . ., 10, j=1, . . . 10; e_ij is the error term; β₁ . . . β₄ are the fixed effects (population averages); and b_1i and b_2i are the individual specific random intercept and slopes. The interaction term between the predictor variable and time describes whether the group with a risk factor changes differently over time than those without the factor. We first ran the model with each predictor separately and then with several predictors to test their specific contributions. Residual analysis was carried out to assess the adequacy of the final model.