Third, excluding enrollees with TD from perphenazine may have increased perphenazine’s effectiveness, whereas including them in the atypicals groups may have reduced the atypicals’ effectiveness. TD patients are at increased risk to develop EPS; they had more-severe illness and a higher substance abuse rate among CATIE patients.11 Even so, investigators did control for TD in the data analysis and found no significant difference between typical and atypical antipsychotics.
No ‘Winners’ or ‘Losers’
Effectiveness, tolerability, and safety findings for each antipsychotic are compared in Tables 4A and 4B. Careful review shows no clear “winners” or “losers;” each agent has weaknesses but also strengths that may benefit individual patients.
Efficacy. Olanzapine showed a relatively higher efficacy and lower discontinuation rate but also had the highest risk of adverse metabolic effects. Some have attributed its greater efficacy to its higher dosing compared with the other antipsychotics. Some also have argued that the antipsychotics that showed lower efficacy, such as quetiapine and ziprasidone, were underdosed in this chronic schizophrenia population with a mean duration of illness of 14 years. Perphenazine, too, was dosed at the lower end of its range (mean modal dose 20.8 mg/d) compared with the old community standard of 36 to 64 mg/d.
Generally, a mean modal dosage of 20.1 mg/d for olanzapine is considered equivalent to ziprasidone, 160 mg; quetiapine, 800 mg; and risperidone, 6 mg. In CATIE phase 1, mean modal dosages were:
- ziprasidone, 112.8 mg/d (30% below 160 mg)
- quetiapine, 543.4 mg/d (32% below 800)
- risperidone, 3.9 mg/d (35% below 6 mg).
Olanzapine’s starting dosage of 7.5 mg/d was relatively higher than those of the other atypicals, which may have produced more-rapid onset of efficacy.
Switching. Another potential “advantage” for olanzapine was that 22% of subjects were taking it when they enrolled. By random assignment, 23% of patients who were taking olanzapine stayed on olanzapine and did not switch. By comparison:
- No patients assigned to ziprasidone were taking it before entering the trial.
- Only 5% of those taking quetiapine stayed on that drug after randomization.
- Few were receiving perphenazine before enrollment.
Switching antipsychotics may increase side effect risk or efficacy problems. For example, a patient switched from olanzapine or quetiapine to ziprasidone or perphenazine may experience insomnia during the transition, which may lead to tolerability complaints.
Metabolic side effects seen in this trial support past observations and reports that olanzapine is associated with higher risk for weight gain, hyperglycemia, and hyperlipidemia than other antipsychotics.15 Data on metabolic changes in CATIE patients taking olanzapine are being analyzed.
Hyperprolactinemia was most common with risperidone and practically nonexistent with other antipsychotics—even perphenazine. On the other hand, risperidone had the most favorable tolerability profile. This implies that elevated prolactin does not necessarily lead to antipsychotic discontinuation because of tolerability among patients with schizophrenia.
QTC interval and cataract data were benign across all antipsychotics. These findings appear to exonerate ziprasidone and quetiapine, respectively, which have been perceived as associated with these side effects.
COMING NEXT
When data become available, the next article in this series will discuss CATIE phase 2 findings. This phase includes patients who did not improve with the phase 1 regimens because of efficacy or tolerability problems and were switched to other antipsychotic therapies.
Related resources
- Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia
- Schizophrenia Research Forum. NARSAD, The Mental Health Research Association.www.schizophreniaforum.org
Drug brand names
- Aripiprazole • Abilify
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosures
Dr Nasrallah receives grants/research support from AstraZeneca, Janssen Pharmaceutica, Eli Lilly & Co., and Pfizer. He is a consultant, advisory board member, and speaker for Abbott Laboratories, AstraZeneca, Janssen Pharmaceutica, Pfizer, and Shire Pharmaceuticals Group.