Weight gain. Patients taking olanzapine gained more weight (average +1.3 lb/mo) than did those taking the other drugs. Patients taking ziprasidone lost weight (average –1.7 lb/mo). Among 61 patients who gained weight during phase 1, 42% of those switched to ziprasidone lost weight in phase 2, as did:
- 20% of those switched to risperidone
- 7% of those switched to quetiapine.
Among those switched to olanzapine in phase 2, no one lost weight and 2% gained weight.
Metabolic effects. Some parameters changed, depending on drug assignment:
- prolactin increased in patients switched to risperidone
- cholesterol and triglycerides increased in patients switched to olanzapine or quetiapine but decreased in those switched to risperidone or ziprasidone
- QTc interval measurements showed no difference across all drugs.
Methodologic caveats
When considering how CATIE’s phase 2 findings might apply to clinical practice, keep in mind four caveats about the study’s design.
Clozapine was given open-label, yet quetiapine, olanzapine, and risperidone were given double-blind in the efficacy pathway. This pathway’s findings are consistent with what we know about clozapine and other SGAs in treatment-refractory schizophrenia, but how the open-label design affected clozapine therapy outcomes is unclear.
Were patients who knew they were taking clozapine more willing to “stay the course” than were patients in the pathway’s double-blind arm?
Discontinuation rates remained high. The 74% “overall discontinuation rate” in phase 1 surprised many psychiatrists because of the perceived high rate at which patients did not adhere to the first medications they received. To some extent, the word “discontinuation” is imprecise, however, because this group includes patients who did not drop out of treatment altogether but chose to move on to phase 2.
It is important to note, however, that nearly one-half of phase 1 patients who were eligible to enter phase 2 (509 of 1,052) did not. This group represents the true drop-out rate, which is substantial. The high rates of discontinuation seen in phase 1 also occurred in both phase 2 pathways (Table 3).
Few patients entered the efficacy pathway. In an approach designed to reflect routine clinical practice, the researchers recommended the efficacy pathway to patients who discontinued phase 1 because of lack of efficacy and the tolerability pathway to those who discontinued phase 1 because of intolerability. Many patients did not follow the recommendations, however, and seemed to choose their pathways based on whether they wanted a chance to receive clozapine or ziprasidone in phase 2.
Thus, among the 543 phase 1 patients who enrolled in phase 2, 99 (18%) entered the efficacy pathway, and 444 (82%) entered the tolerability pathway. The efficacy pathway included 85 patients who discontinued phase 1 for lack of efficacy and 5 for lack of tolerability. The tolerability pathway included 184 patients who discontinued phase 1 for lack of efficacy and 168 for lack of tolerability.
Dosages may not have been equivalent. SGAs’ dosing equivalency is unknown,5,6 which impedes our ability to interpret comparative studies such as CATIE. The study’s designers developed the its dosing ranges by careful consideration, including recommendations from each SGA’s manufacturer. As Nasrallah described,4 the trial’s dosages were not universally consistent with FDA-approved ranges or usual clinical practice (Table 4). In phase 2, for example, ziprasidone dosages were less than psychiatrists usually use, and quetiapine dosages were greater than usual.
Fortunately, studies are underway to determine each SGA’s optimum dosing. This work will help us understand what we can expect when we increase an antipsychotic’s dosage—a key step towards understanding dosing equivalency.
Table 4
Mean modal antipsychotic dosages (mg/d) in CATIE phase 2 pathways*
| Clozapine | Ziprasidone | Olanzapine | Risperidone | Quetiapine | |
|---|---|---|---|---|---|
| Efficacy pathway | 332 | — | 23.4 | 4.8 | 642.9 |
| Tolerability pathway | — | 115.9 | 20.5 | 4.15 | 65.2 |
| * 800 mg/d of quetiapine and 160 mg/d of ziprasidone are generally regarded as therapeutically equivalent to 20 mg/d of olanzapine. | |||||
What clinicians can expect
A recent analysis helps put CATIE’s findings in perspective. Citrome and Stroup7 quantified the results of phase 1 and 2 with respect to:
- number needed to treat (NNT)—how many patients a clinician needs to treat with drug A to see one additional benefit, compared with drug B
- number needed to harm (NNH)—how many patients a clinician needs to treat with drug A to see a given adverse effect, compared with drug B.
In this analysis, the NNT for olanzapine (5.5 to 10) was lowest among the drugs compared in phase 1, and the NNT for clozapine (3) was lowest among those compared in phase 2. A lower number means that, overall, clinicians can expect a more robust treatment response.
On the other hand, the NNH for olanzapine in weight gain and metabolic disturbances (12.4 to 17.7) was the lowest in phase 1, indicating that clinicians can expect more weight gain and metabolic effects with olanzapine than with other SGAs. Ziprasidone had the highest NNH (106 to 208) among the agents in phase 2 for avoiding discontinuation because of weight gain or metabolic disturbances. In other words, ziprasidone appears less likely than other SGAs to cause metabolic problems.