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Study samples key to assessing risk

Vol. 6, No. 1 / January 2007

We agree with Drs. Tandon’s and Constantine’s explanation of the difference between the results of the CATIE trial1 and previous studies—specifically that CATIE showed no differences between 4 SGAs and an intermediate potency FGA on EPS and tardive dyskinesia (TD). As the authors suggest, these results are best explained by the use of high-dose, high-potency haloperidol as the comparator in pre-CATIE studies, which magnified differences between FGAs and SGAs. A recent study has further suggested that in most of these trials the doses of haloperidol were above FDA-approved levels,2 and few, if any, used prophylactic anticholinergics, further biasing the comparisons.

Drs. Tandon and Constantine further assert that the CATIE sample was at less risk of EPS or TD than previous samples because it excluded first-episode patients and those with TD and addressed a population that had used medications for 14 years without a history of adverse effects. CATIE—like any other ethical human investigation—excluded patients if they had well-documented, drug-related, adverse reactions to any of the proposed treatments.

Many, if not most, FDA registration trials (the source of most data on EPS with SGAs) excluded all patients with previous exposure to the new SGA drugs they tested but did not apply this criterion to patients exposed to older drugs. Thus the trials were more likely to include patients who would have responded poorly to FGAs than those who would have responded poorly to SGAs. Others have recognized that this reduces the validity of such FGA-SGA comparisons.3


Study populations of SGA-FGA comparison trials



Age at onset

Duration of illness

CATIE (Lieberman et al, 2005)




Olanzapine (Beasley et al, 1998)




Risperidone (Csernansky et al, 2002)




Amisulpride (Rein and L’Heritier, 1999)




Ziprasidone (Arato et al, 2002)




Risperidone (Marder et al, 1994)




Risperidone (Marder, 2003)




Aripiprazole (Kane et al, 2002)




In the Table we present data comparing population characteristics from CATIE, from a meta-analysis that identified all 4 published controlled trials that have examined TD outcomes in FGA and SGAs,4 and from several other well-known comparable trials. The CATIE sample was similar to patients who participated in the other trials in average age, age of onset, and duration of illness.

Beasley et al5 similarly presented an analysis that excluded patients without TD at baseline, which we believe is the optimal population to use when evaluating medication-related risk for TD. CATIE is the only study that conducted a sound randomization comparing FGAs and SGAs in patients without current TD who are at risk for it, and—more than other studies—used an unbiased and thus more informative comparator.

Unfortunately there have been numerous factual errors in published critiques of CATIE. In one, CATIE was deemed disappointing6 because it had “a large percentage of discontinuations for all causes,” but the data presented for comparison were from a 28-week study7—less than half as long as the 72-week CATIE trial. CATIE, in fact, had better overall follow-up rates than the cited study at 28 weeks and also had better long-term follow-up rates than either the paper by Beasley et al5 or by Csernansky et al8—the most often cited “long-term” studies comparing FGAs and SGAs on TD.

Another commentary, like that of Drs. Tandon and Constantine, described CATIE patients as having more chronic illness that those in other trials, with “24 years since first treatment,”9 a misreading of the average age of first onset (which was 24) as if it was the average duration of illness (which was 16 years).

Many commentators have further asserted that because patients with TD at baseline “were not randomly assigned to conventional drugs” the comparison of either outcomes or TD risk was invalid.6,9 As noted above, comparison of side effect risk is properly tested by trials involving patients without that risk at onset.

CATIE represented a major investment of public dollars to learn more about antipsychotic medications. Erroneous critiques needlessly mislead the professional community about what can be learned from this initiative.

The CATIE investigators
Robert Rosenheck, MD, New Haven, CT
T. Scott Stroup, MD, MPH, Chapel Hill, NC
Richard SE Keefe, PhD, Durham, NC
Joseph McEvoy, MD, Durham, NC
Marvin Swartz, MD, Durham, NC
Jeffrey Lieberman, MD, New York, NY


1. Lieberman JA, Stroup ST, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

2. Hugenholtz GWK, Heerdink ER, Stolker JJ, et al. Haloperidol dose when used as active comparitor in randomized controlled trials with atypical antipsychotics in schizophrenia: Comparison with officially recommended doses. J Clin Psychiatry 2006;67(6):897-903.

3. Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002;159:255-62.

4. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004;161:414-25.

5. Beasley CM, Dellva MA, Tamura RN, et al. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999;174:23-30.

6. Meltzer HY, Bobo WV. Interpreting the efficacy findings in the CATIE study: what clinicians should know. CNS Spectrums 2006;11(suppl 7):14-24.

7. Breier A, Berg PH, Thakore JH, et al. Olanzapine versus ziprasidone: results of a 28-week double blind study in patients with schizophrenia. Am J Psychiatry 2005;162(10):1879-87.

8. Csernansky JG, Mahmoud R, Brenner R. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346:16-22.

9. Kane JM. Commentary on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). J Clin Psychiatry 2006;67(5):831-2.

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