Effectiveness of Second-generation Antipsychotics: A Naturalistic, Randomized Comparison of Olanzapine, Quetiapine, Risperidone, and Ziprasidone

Erik Johnsen; Rune A Kroken; Tore Wentzel-Larsen; Hugo A Jørgensen

Disclosures

BMC Psychiatry. 2010;10:26 

In This Article

Results

The patient enrolment is displayed in Figure 1. A total of 213 patients were allocated to randomized sequences of the first-line SGAs listed from 1 to 4. The SGAs listed as 1 defined the randomization groups (RGs). A total of 173 (81.2%) patients received the SGA listed as 1, whereas 39 (18.3%) chose another SGA on the list. The choice of SGA was unknown for one patient. There were no differences among RGs in the fractions of patients that did not choose the SGA listed as 1.

Figure 1.

Flow of patients through the study. Not meeting inclusion criteria = Score below 4 on all the items Delusions, Hallucinatory behaviour, Grandiosity, Suspiciousness/persecution, or Unusual thought content in the Positive and Negative Syndrome Scale (PANSS); Uncoop. = the patient was not able or willing to cooperate with testing and assessments; Organic braindis. = Organic brain disorder, principally dementia; Randomization not acceptable = patient or treating clinician not willing to change existing antipsychotic medication; Administrative causes = principally patient discharged before assessments could be made. 1 Enrolment started March 2003 until 2008, week 26. Full details on enrolment were only registered from 2006, week 31 until 2008, week 26. Consequently only percentages are displayed for patients assessed for eligibility and excluded patients. 2 Before discharge/6 weeks. 3 One patient in the risperidone and olanzapine groups missed the first follow-up visit, but was retested on later visits.

Primary Outcomes - ITT Analyses Based on RGs

Baseline demographic and clinical characteristics are presented in Additional file 1. There were no substantial differences between the randomization groups regarding proportions with life-time antipsychotic drug exposure, or proportions that had used antipsychotic drugs in the 12 months prior to admittance or in the antipsychotic agents used in that period. There were generally no substantial differences on baseline clinical or demographic characteristics between those who were lost to follow-up before retesting and those who were retested, with the exception of a slightly higher PANSS negative subscore for those lost to follow up (20.9 vs. 18.1 points (independent samples T-Test: p = 0.007; mean difference 2.75 points; 95% confidence interval (CI) 0.74–4.75)).

Global Outcomes Times until discontinuation of the first offered antipsychotic drug, until discharge from index admission, and from discharge from index admission until readmission, were not different among RGs (Figures 2, 3, and 4).

Figure 2.

Survival functions. Time to discontinuation = Time (days) until discontinuation of first antipsychotic drug since index admission.

Figure 3.

Survival functions. Time to discharge from index admission = Time (days) until hospital discharge after index hospital admission.

Figure 4.

Survival functions. Time to rehospitalisation = Time (days) until rehospitalisation after discharge from index admission.

Symptom Outcomes Outcomes related to symptom reduction and increased functioning are shown in Additional file 2 and Figures 5 and 6. There were significant differences among SGAs as quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the CGI-S; and in increasing the GAF-F score. Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. Curves for each individual regarding the PANSS total score revealed a steeper decline initially as compared to later in the follow-up period (curves not shown). Curves for each individual on the other outcomes followed the same general pattern, with the slope being steepest initially (curves not shown). The sensitivity analyses in separate follow-up periods were performed from baseline to 90 days, corresponding to the steep part of the course, and after 90 days, corresponding to the flatter part of the course. The analyses revealed trends for the RGs that were essentially similar to the findings for the whole 2-year follow-up (data not shown). Before 90 days quetiapine and ziprasidone were superior to risperidone in increasing the GAF-F score (LME: p < 0.05, unadjusted for multiple comparisons), and quetiapine was superior to risperidone in reducing the CGI-S score (LME: p < 0.05, unadjusted for multiple comparisons). The differences were no longer statistically significant after adjusting for multiple comparisons.

Figure 5.

Reduction of PANSS total score. Linear mixed effects model curves. Linear slopes for the randomization groups generated based on linear mixed effects models PANSS total score output as displayed in Additional file 2 for risperidone, olanzapine, quetiapine, and ziprasidone, respectively. The curves are confined to the first 300 days because the major bulk of data is obtained before 300 days.

Figure 6.

Change of PANSS subscores, CDSS, GAF-F, and CGI-S scores. The curves are generated based on drug-specific linear mixed effects slopes as displayed in Additional file 2 for risperidone, olanzapine, quetiapine, and ziprasidone, respectively. PANSS = the Positive and Negative Syndrome Scale; CDSS = the Calgary Depression Scale for Schizophrenia; GAF-F = the Global Assessment of Functioning scale - Split Version, Functions scale; CGI-S = the Clinical Global Impression - Severity of Illness Scale. The curves are confined to the first 300 days because the major bulk of data is obtained before 300 days.

Sensitivity analyses that adjusted for numerically higher proportions of antipsychotic naïve patients in the quetiapine and ziprasidone RGs, revealed essentially identical results with regards to symptom reduction and increased functioning. Sensitivity analyses that excluded patients with drug-induced psychoses revealed essentially identical results with regards to symptom reduction and increased functioning.

Tolerability Outcomes There were differences among the drugs for only a limited number of tolerability outcomes (Additional file 3).

Secondary Outcomes - Analyses Based on FCGs

There were generally no substantial differences among FCGs on baseline demographic and clinical characteristics with the exception of a slightly higher PANSS positive subscore for olanzapine (21.3 points) compared with risperidone (18.5 points) (one-way ANOVA: p = 0.007; mean difference 2.8 points; 95% CI -5.0- -0.5). The mean doses in milligrams per day with standard deviations (SD) were 3.3 (1.2) for risperidone, 14.5 (5.2) for olanzapine, 357.0 (187.2) for quetiapine, and 101.3 (44.7) for ziprasidone treated groups. The mean serum levels in nanomoles per liter with SD were 82.4 (56.9) for risperidone, 102.4 (75.1) for olanzapine, 419.7 (544.9) for quetiapine, and 173.8 (81.4) for ziprasidone. The reference ranges were 30–120, 30–200, 100–800, and 30–200 for risperidone, olanzapine, quetiapine, and ziprasidone, respectively. A total of 24 (24.7%) patients changed their first-chosen SGA during follow-up. There were no differences among the FCGs in the rates of change or choice of new antipsychotic drug. One or more doses of low-potency first-generation antipsychotics were given to 15 patients (15.8%). There were no differences among the FCGs in the number of patients receiving additional antipsychotics or the mean daily additional antipsychotic dose in chlorpromazine equivalents. Seventy-one (74.7%), 23 (24.2%), and 7 (7.4%) patients received additional benzodiazepines, antidepressants, and mood stabilizers, respectively. In 30 (39.5%) of these patients 2 or more of the additional psychotropics were used in combinations. There were no differences among FCGs in the use of these additional psychotropics. Anticholinergics were prescribed for 6 (27.3%) of risperidone treated FCGs. The corresponding figures were 1 (3.8%) for olanzapine, 0 for quetiapine, and 3 (13.0%) for ziprasidone-treated FCGs (exact χ2 test: p = 0.010). There were no differences among FCGs in the rates of users of antipsychotics the year prior to index hospitalization.

Global Outcomes The time until discontinuation of the initially chosen SGA was significantly different among FCGs (log rank test: p = 0.028). In subanalyses, patients with olanzapine showed a longer time until discontinuation compared with those treated with ziprasidone (log rank test: p = 0.007), but not compared with the quetiapine and risperidone groups. Times until discharge from index admission and until readmission were not different among FCGs.

Symptom Outcomes Symptom reduction outcomes were not substantially different from those of the primary analyses (Additional file 2). The exception was for the ziprasidone comparisons with risperidone not being significantly different for the change of the PANSS positive subscore, the GAF-F score, and the CGI-S score. Sensitivity analyses before 90 days in the FCGs revealed trends similar to the ones from the ITT-analyses for the PANSS total and subscores, with the quetiapine group having the steepest slope, though not statistically significant. Olanzapine and quetiapine were superior to risperidone and ziprasidone in increasing the GAF-F score before 90 days (LME: p < 0.05 adjusted for multiple comparisons). Olanzapine was superior to risperidone and ziprasidone in reducing the CGI-S score (LME: p < 0.05 adjusted for multiple comparisons). In the analyses in the period after 90 days the other groups were superior to risperidone regarding increase of the GAF-F score (LME: p < 0.05 adjusted for multiple comparisons).

Tolerability Outcomes Baseline registrations of laboratory measures were not different in FCGs with the exception of a higher baseline prolactin level for risperidone (Mean 746.8 IU/L) compared with quetiapine (one-way ANOVA: p = 0.001; mean diffence 401.4 IU/L; 95% CI 128.1–674.6) and ziprasidone (one-way ANOVA: p = 0.017; mean difference IU/L 293.3; 95% CI 35.9–550.6). With regards to UKU-SERS-Pat outcomes the only statistically significant difference between FCGs was less decrease of sexual desire in the ziprasidone group compared to the olanzapine group (LME: p = 0.026). Regarding physical and laboratory measures the following comparisons revealed statistically significant differences (LME: p < 0.05): The ziprasidone group had the largest increase of triglycerides per day compared to the other groups. The risperidone group had larger increase of body weight per day than the olanzapine and quetiapine groups; as well as larger increase per day of BMI compared to the olanzapine group.

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