The investigator could choose which arm a patient entered, but many more patients entered 2T than 2E (perhaps because they were reluctant to enter a pathway in which they might receive clozapine). Those in phase 2E who were randomly assigned to clozapine knew they were receiving clozapine and that clozapine was a treatment for patients who did not have successful outcomes with other antipsychotic(s). This design may have influenced whether or not patients remained in the study.
In phase 2E, time until treatment discontinuation for any reason was statistically significantly longer for clozapine (median 10.5 months) than for quetiapine (median 3.3 months) or risperidone (median 2.8 months) but not statistically significantly longer than for olanzapine (median 2.7 months).
How to calculate number needed to treat (NNT)
What is the NNT for an outcome for drug A versus drug B?
fA = frequency of outcome for drug A
fB = frequency of outcome for drug B
Attributable risk (AR) = fA-fB
NNT = 1/AR
(By convention, we round up the NNT to the next higher whole number.)
For example, let’s say drugs A and B are used to treat depression, and they result in 6-week response rates of 55% and 75%, respectively. The NNT to see a difference between drug B and drug A in terms of responders at 6 weeks can be calculated as follows:
- Difference in response rates = 0.75-0.55 = 0.20
- NNT = 1/0.20 = 5
What happens if response rates are reversed?
- Difference in response rates = 0.55–0.75 = -0.20
- NNT = 1/(–0.20) = -5
Here the NNT is –5, meaning a disadvantage for drug B, or a number needed to harm (NNH) of +5
What happens if response rates are identical?
- Difference in response rates = 0.75-0.75 = 0
- NNT = 1/0 = "infinity" (∞)
A NNT of 8 means it would take an infinite number of patients on drug A vs drug B to see a difference (in other words, no difference). This is by definition the "weakest" possible effect size.
What happens if the response rate is 100% for one intervention and zero for the other?
- Difference in response rates = 1.00–0 = 1.00
- NNT = 1/1 = 1
Theoretically, this is the "strongest" possible effect size.
Thus all possible values of NNT range from 1 to ∞, or –1 to –∞ it is not possible for a NNT to be zero.
Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperi-done.4 These statements give us the rank order of the tested medications’ performance and some idea of the size of the differences. We do not know, however, how often these differences will affect day-to-day patient treatment.
The question becomes “how many patients do I need to treat with clozapine instead of [olanzapine, quetiapine, or risperidone] before I see 1 extra success (defined as remaining on the medication)?” Similar questions can be asked about other outcomes, such as adverse events. NNT can convert the study results to a common language: numbers of patients.
Advantages for clozapine. NNTs for outcomes in CATIE phase 2E are shown in the Table. From the conventional analysis,4 we knew that patients randomly assigned to clozapine were more likely to stay on clozapine than patients assigned to other SGAs. The NNT comparing clozapine with quetiapine is 3, which means for every 3 patients treated with clozapine instead of quetiapine, 1 extra patient remained on the drug. A NNT of 3 is a medium to large effect size,7 similar to that seen when antidepressant treatment is compared with placebo in terms of reducing depressive symptoms by at least 50% among patients with major depressive disorder.8
The NNT comparing clozapine with risperidone was 4 and that for olanzapine was 7. The difference in all-cause discontinuation between clozapine and olanzapine was not statistically significant, however, perhaps because of a small sample size. The effectiveness analysis included
only 45 patients assigned to clozapine, 14 to quetiapine, 14 to risperidone, and 17 to olanzapine—far fewer than the 183 to 333 subjects in each arm in the phase-1 effectiveness analyses.9
Disadvantages for clozapine can be seen as “negative” NNT values in the Table. A negative NNT can be interpreted as a number needed to harm (NNH).
Tolerability. Discontinuation because of poor tolerability showed a disadvantage when clozapine was compared with risperidone, with a NNT of –9 (in other words, a NNH of 9). This means that for every 9 patients receiving clozapine instead of risperidone, 1 extra patient would discontinue because of poor tolerability.