did the catie trial find the newer antipsychotics no more effective than the older drug?
“Are the new drugs more efficacious than the old drug? No.”
a guest, a historian of psychiatry (Andrew Scull) said on Lex Fridman Podcast, 2026-09-20, at 19:24. hear it in context → the speaker cited: the CATIE study, New England Journal of Medicine.
first, the part that holds
the core of this is right. in the CATIE trial, published in the New England Journal of Medicine in 2005, the older drug perphenazine did about as well as three of the four newer drugs tested (quetiapine, risperidone and ziprasidone), and the trial's funder, NIMH, summarized it as the newer drugs having "no substantial advantage" over the older one.
what we found when we went and looked
we read the CATIE abstract, NIMH's own summary of the phase 1 results, a 2007 review that walks through the trial's design, and the largest meta-analysis comparing newer and older antipsychotics. CATIE randomized 1,493 people with chronic schizophrenia to one of five drugs. 74 percent stopped their assigned drug before 18 months: 64 percent on olanzapine, 75 percent on perphenazine, 74 percent on risperidone, 79 percent on ziprasidone and 82 percent on quetiapine. the authors concluded that perphenazine's efficacy "appeared similar to that of quetiapine, risperidone, and ziprasidone", so the claim holds for three of the four newer drugs. the blanket "no" leaves out olanzapine. the authors called it "the most effective in terms of the rates of discontinuation", and NIMH reports that people on it were less likely to be hospitalized for a psychotic relapse, though its edge over perphenazine on the main outcome was not statistically significant (P=0.021).
assertion by assertion
| assertion | verdict | what the record says |
|---|---|---|
| the source is the CATIE study, published in the New England Journal of Medicine | confirmed | the paper is 'Effectiveness of antipsychotic drugs in patients with chronic schizophrenia', N Engl J Med 2005, doi 10.1056/NEJMoa051688. it compared olanzapine, perphenazine, quetiapine, risperidone and ziprasidone in 1,493 patients for up to 18 months. [1][3] |
| in CATIE, the older drug perphenazine worked about as well as the newer drugs quetiapine, risperidone and ziprasidone | confirmed | the abstract concludes that the efficacy of perphenazine 'appeared similar to that of quetiapine, risperidone, and ziprasidone.' NIMH calls perphenazine 'equally as effective as the other three newer medications.' one caveat: CATIE's main outcome was stopping the drug for any reason, a combined measure of efficacy and tolerability, not symptom change on its own. [1][3] |
| none of the newer drugs in CATIE was more efficacious than the older drug | overstated | olanzapine stood out. 64 percent of people on it stopped before 18 months, against 75 percent on perphenazine, and the authors called it 'the most effective in terms of the rates of discontinuation.' NIMH says people started on olanzapine were less likely to be hospitalized for a psychotic relapse and stayed on their drug longer. a 2007 review says olanzapine 'had advantages in terms of all-cause discontinuation and efficacy, particularly in Phase 1.' still, on time to stopping for any reason, olanzapine's lead over perphenazine (P=0.021) did not reach the paper's threshold for significance. so the gap over the older drug is real but modest and not firmly established. it came with more weight gain and metabolic changes. [1][3][4] |
| a common framing: newer antipsychotics as a class are no more efficacious than older ones, across the evidence and not just in CATIE | misattributed | a 2009 Lancet meta-analysis of 150 trials with 21,533 participants found four of nine newer drugs more efficacious overall than first-generation drugs. the effect sizes were clozapine -0.52, amisulpride -0.31, olanzapine -0.28 and risperidone -0.13. 'the other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms.' the authors say the newer drugs 'are not a homogeneous class.' the effects are modest, but treating them as one class hides real differences between drugs. [2] |
both directions
for the speaker: CATIE's own conclusion puts perphenazine level with quetiapine, risperidone and ziprasidone. NIMH's public summary says outright that the newer drugs had "no substantial advantage" over the older drug in the study. perphenazine's dropout rate (75 percent) was about the same as risperidone's (74 percent) and lower than ziprasidone's (79 percent) and quetiapine's (82 percent). olanzapine's lead over perphenazine on the main outcome was not statistically significant (P=0.021). NIMH also notes that movement side effects were not seen more often with perphenazine than with the newer drugs, which undercuts the usual reason given for the newer class. so as a summary of CATIE's headline finding, the speaker's "no" is close.
against: "the new drugs" lumps olanzapine in with the others, and CATIE did not. the authors named olanzapine the most effective drug by discontinuation rate. NIMH reports fewer psychotic-relapse hospitalizations with it, and a 2007 review credits it with advantages in efficacy as well as all-cause discontinuation. the trial design favored perphenazine somewhat: by design, people with existing tardive dyskinesia could not be randomized to it, so the older drug was tested in a group less prone to movement problems. outside CATIE, the largest meta-analysis found clozapine, amisulpride, olanzapine and risperidone more efficacious than first-generation drugs (clozapine and amisulpride were not tested in CATIE). the effects were modest but real. a flat "no" for the whole class goes further than the record.
what this cannot say
CATIE tested one older drug, perphenazine, at moderate doses. it says nothing direct about haloperidol or other first-generation drugs. its main outcome, stopping the drug for any reason, mixes efficacy, side effects and patient choice, so "efficacious" does not map cleanly onto it. three-quarters of patients stopped their assigned drug, which limits what the later comparisons can show. we read abstracts, NIMH's summary and a secondary review, not the full NEJM text, which returned an access error. so we did not check the per-drug symptom-score tables or the exact significance threshold the authors used. we also did not hear the full conversation, so we can't say whether the speaker qualified the point about olanzapine elsewhere. none of this is advice about any individual's medication.
sources, each one fetched and read
- CATIE investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005. doi:10.1056/NEJMoa051688. PMID 16172203 (PubMed abstract) What we read there: 74 percent discontinued before 18 months (1061 of 1432): 64% olanzapine, 75% perphenazine, 82% quetiapine, 74% risperidone, 79% ziprasidone. time to discontinuation was longer with olanzapine than quetiapine (P<0.001) or risperidone (P=0.002), 'but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group.' conclusion: 'Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone.' Fetched 2026-10-13 (HTTP 203). https://pubmed.ncbi.nlm.nih.gov/16172203/
- Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009. doi:10.1016/S0140-6736(08)61764-X. PMID 19058842 (PubMed abstract) What we read there: 150 trials, 21,533 participants. overall efficacy versus first-generation drugs: clozapine -0.52 (-0.75 to -0.29), amisulpride -0.31 (-0.44 to -0.19), olanzapine -0.28 (-0.38 to -0.18), risperidone -0.13 (-0.22 to -0.05). 'The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms.' Fetched 2026-10-13 (HTTP 203). https://pubmed.ncbi.nlm.nih.gov/19058842/
- National Institute of Mental Health. Questions and answers about the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness study (CATIE), phase 1 results What we read there: perphenazine was 'equally as effective as the other three newer medications (risperidone, quetiapine, and ziprasidone)'; 'the newer medications have no substantial advantage over the older medication used in this study'; patients started on olanzapine 'were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer.' Fetched 2026-10-13 (HTTP 200). https://www.nimh.nih.gov/funding/clinical-research/practical/catie/phase1results
- Interpreting and applying the CATIE results: with CATIE, context is key, when sorting out phases 1, 1A, 1B, 2E, and 2T. Psychiatry (Edgmont). 2007. PMC2860523 What we read there: 'Olanzapine had advantages in terms of all-cause discontinuation and efficacy, particularly in Phase 1.' 'By design, patients with pre-existing tardive dyskinesia could not be randomized to perphenazine, a first-generation antipsychotic.' Fetched 2026-10-13 (HTTP 200). https://pmc.ncbi.nlm.nih.gov/articles/PMC2860523/
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