Between September 2003 and July 2006, we assessed consecutive patients already enrolled in the early psychosis programme for eligibility to participate in the relapse prevention study. We screened 1606 patients for eligibility (fig 1). Schizophrenia was the most common diagnosis in enrolled patients (table 4). Before randomisation, patients had received antipsychotic drugs for a median of 21 months (618 (interquartile range 472-784) days) (table 2). The total symptom severity scores were low, and the median global severity of illness rating was 1, or “not mentally ill.” The level of functioning as assessed by the rating scales and proportion employed was moderately high. Baseline variables in the group randomised to quetiapine did not differ from those randomised to placebo (all P>0.05). Including patients who completed the study, relapsed, or were withdrawn, the median duration of follow-up was 145 (41-351) days for the quetiapine group and 106 (57-243) days for the placebo group.
Fig 1Enrolment and outcomes. ITT=intention to treat
Table 4 Baseline characteristics of patients. Values are numbers (percentages) unless stated otherwise
Primary outcome: relapse
Twenty-seven of 89 patients relapsed in the quetiapine group, and 56 of 89 patients relapsed in the placebo group. The Kaplan-Meier estimate of the proportion relapsed at 12 months was 41% (95% confidence interval 29% to 53%) in the quetiapine group and 79% (68% to 90%) in the placebo group (χ2=15.65, df=1; P<0.001 by log-rank) (fig 2). In the post-transition subgroup analysis excluding the 23 patients who relapsed within 60 days, fewer patients in the quetiapine group relapsed (22% (17/79); 12 month Kaplan-Meier estimate 32%, 19% to 45%) than in the placebo group (57% (43/76); 75%, 62% to 89%) (χ2=19.17, df=1; P<0.001 by log-rank).
Fig 2Kaplan-Meier analysis in remitted first episode psychosis patients with and without antipsychotic maintenance treatment. Median duration of follow-up was 145 (interquartile range 41-351) days for quetiapine group and 106 (57-243) days for (more ...)
In relapses, specific symptoms that scored at or above the threshold included delusions (72%; 58/81), hallucinations (54%; 44/81), suspiciousness (38%; 31/81), conceptual disorganisation (30%; 24/81), and unusual thought content (23%; 19/81); 68% (55/81) of patients had two or more types of psychotic symptom. The most common co-occurring psychotic symptoms were delusions and hallucinations (37%; 30/81) and delusions and suspiciousness (31%; 25/81). The magnitude of the highest score of the five key symptoms defining relapse did not differ between relapsing patients in the two treatment groups (mean (SD) 4.30 (0.91) in quetiapine group (n=27) v 4.50 (0.82) in placebo group (n=54); t=−1.02, df=79; P=0.31). Nor did we find a difference in the magnitude of the change in score from baseline for these symptoms (mean (SD) 3.22 (1.01) in quetiapine group v 3.46 (0.82) in placebo group; t=−1.15, df=79; P=0.25). We found no significant correlation between severity of symptoms at relapse and the time to receiving treatment (r=−0.37, P=0.06 for quetiapine group; r=0.07, P=0.61 for placebo group).
We did two sensitivity analyses defining relapse with more stringent criteria: two or more psychotic symptoms above the threshold, and requiring a score of 5 (moderately severe) to define relapse. We censored patients with less severe psychotic symptoms. When we used the first criterion, the quetiapine group showed a significantly lower relapse rate (30%, 95% confidence interval 18% to 42%) than did the placebo group (68%, 56% to 80%) (χ2=14.67, df=1; P<0.001 by log-rank). When we used the second criterion, the quetiapine group also showed a significantly lower relapse rate (27%, 15% to 39%) than did the placebo group (63%, 46% to 79%) (χ2=11.81, df=1; P=0.001 by log-rank).
In the post hoc sensitivity analysis of the worst case scenario, we treated all discontinuations/dropouts as having relapsed at point of discontinuation. The Kaplan-Meier estimate of the proportion of relapse at 12 months was 62% (51% to 72%) in the quetiapine group and 85% (76% to 93%) in the placebo group (χ2=5.59, df=1; P=0.018 by log-rank). We did another post hoc sensitivity analysis with information from case notes about relapses for the post-discontinuation period. This provides a pragmatic estimate by including all clinically significant relapses in the post-discontinuation period. The Kaplan-Meier estimate of the proportion of relapse at 12 months was 41% (30% to 51%) in the quetiapine group and 69% (59% to 79%) in the placebo group (χ2=14.25, df=1; P<0.001 by log-rank).
Secondary outcome measures
Readmission to hospital was more common in the placebo group (16% (14/89); 12 relapse, 2 serious adverse events) than in the quetiapine group (6% (5/89); 4 relapse, 1 serious adverse event) (Fisher’s exact test (two tailed) P<0.05). The groups did not differ in baseline occupational status—open employment: quetiapine group 70% (62/89); placebo group 73% (65/89). Some participants lost open employment status in the study period—quetiapine group 27% (17/62); placebo group 32% (21/65). Changes in occupational status (from employed to unemployed, from unemployed to employed, employed with no change, or unemployed with no change) during the study did not differ statistically between the two treatment groups (χ2=1.52, df=3; P=0.68).
Predictors of relapse
We studied predetermined potential predictors of relapse initially with a univariate Cox regression model. We then entered variables with P values of 0.1 or below into a multivariate Cox regression. We found the assumption of proportionality to be valid. Significant independent predictors of relapse were maintenance treatment, pre-morbid schizoid and schizotypal traits, functioning, and diagnosis of schizophrenia (table 3).
Side effects, adverse events, and discontinuations
Patients taking quetiapine reported more side effects (sleepiness or sedation, reduced salivation, and constipation) than did those taking placebo (table 5). Only 11% (20/178; 9 in quetiapine group and 11 in placebo group) of patients had a Simpson Angus scale score above zero at baseline. Those previously treated with typical antipsychotics had higher mean scores (P=0.02). Most (145/168; 76 in quetiapine group and 69 in placebo group) had no change in these scores during the study. Five had a higher score (four in placebo group, one in quetiapine group), and 18 had lower scores (nine in each group). We found no difference in the change in scores between the two groups. Only two participants had positive abnormal involuntary movement scale scores at baseline (one in quetiapine group, one in placebo group); both scores decreased during the study. Two other patients in the placebo group (one previously treated with a typical antipsychotic and one with an atypical antipsychotic) had an increase in this score during the study. Four patients had positive scores for akathisia at baseline (all in placebo group), and six had positive scores at follow-up (four in quetiapine group, two in placebo group). Six patients had an increased score (four in quetiapine group, two in placebo group), and four had a reduced score at follow-up (all in placebo group).
Table 5 Side effects reported at baseline and during study period. Values are numbers (percentages) of patients (n=178)
Table 6 shows changes in body weight and body mass index; it also shows some summary statistics by subsets. We found an overall trend for weight reduction, which was greater in the placebo group (mean (SD) −3.08 (8.22) kg) than in the quetiapine group (−0.75 (4.65) kg) (P=0.02). Baseline weight had a significant effect on the change in weight for the placebo group; heavier patients at baseline had more weight reduction (unstandardised regression coefficient −0.19, 95% confidence interval −0.28 to −0.10; P<0.001). The baseline effect was not significant for the quetiapine group (regression coefficient −0.08, −0.17 to 0.2; P=0.11). Previous drug type had a minor effect on weight change (typical antipsychotic 1.72 (−0.15 to 3.59) kg more than atypical antipsychotic; P=0.07). Weight change over time did not differ between the groups after adjustment for weight at baseline (placebo group 5.39 (−3.22 to 14.0) kg more than quetiapine group; P=0.22). The body mass index at baseline had a significant effect on the change in body mass index for the placebo group (regression coefficient −0.25, −0.35 to −0.15; P<0.001) but not for the quetiapine group (regression coefficient −0.06, −0.16 to 0.40; P=0.26). Previous drug type had no significant effect on body mass index (typical antipsychotic 0.57 (−0.12 to 1.26) kg more than atypical; P=0.11), but the mean change in body mass index differed somewhat between the groups (placebo group 3.74 (0.17 to 7.31) kg more than quetiapine group; P=0.04) after adjustment for body mass index at baseline. No diabetes or ketoacidosis emerged during the study period.
Table 6 Weight and body mass index (BMI) at baseline and changes during study period*
Figure 1 gives reasons for discontinuation. Adverse events that occurred in more than one case were fatigue, sedation, or tiredness (n=9; 7 in quetiapine group, 2 in placebo group), dizziness (n=7; all in quetiapine group), nausea (n=2; both in quetiapine group), limb weakness (n=2; both in quetiapine group), and insomnia (n=2; 1 in quetiapine group, 1 in placebo group). Three serious adverse events occurred. One patient taking quetiapine was admitted to hospital after impulsive self-laceration following an argument with a partner, and one assigned to placebo was admitted after a non-fatal overdose of hypnotics during an adjustment reaction to financial difficulties. Both were discontinued. A third patient in the placebo group had transient repetitive imagery for three days and was briefly admitted for observation, but continued. The rate of discontinuation for both adverse events and serious adverse events was higher for the quetiapine group (18%; 16/89) than the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; χ2=3.20, df=1; P=0.07).
Other reasons for discontinuation included need for a mood stabiliser (n=3; 2 in quetiapine group, 1 in placebo group), inability to tolerate the transition protocol (n=7; 4 in quetiapine group, 3 in placebo group), and unwillingness to attend the study assessments (n=1; in placebo group). Discontinuation for all causes did not differ significantly between the quetiapine group (31%; 28/89) and the placebo group (20%; 18/89) (relative risk 1.32, 0.98 to 1.77; χ2=2.38, df=1; P=0.12).