Graylands Hospital DRUG BULLETIN Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] Fax (08) 9384 4586 CATIE and Typical Antipsychotics Graylands Hospital Drug Bulletin 2006 Vol. 14 No. 4 December ISSN 1323-1251 Introduction the United States market at the time of the study Atypical antipsychotics have largely replaced typical and clozapine was investigated in phase II of CATIE. antipsychotics in clinical practice due to their perceived superiority in efficacy and lower risk of Significance of CATIE neurological adverse effects, which is believed to CATIE was the largest, longest and most result in improved compliance. In fact, many comprehensive independent trial ever conducted treatment algorithms recommend the use of atypical examining the treatment options for schizophrenia. antipsychotics as the only first-line medication Before CATIE, the relative effectiveness of typical treatment option1,2,3. However, the Clinical and atypical antipsychotics had been incompletely Antipsychotic Trials of Intervention Effectiveness addressed, with the exception of clozapine6,7. Most (CATIE) has cast doubts over the superiority of previous studies of atypical antipsychotics were of atypical antipsychotics over the older, less expensive short duration (4 to 8 weeks), focused on narrow typical antipsychotics4. More recently, an outcomes, had strict inclusion/exclusion criteria and independent British study of similar design has also usually only had one comparator drug. had similar findings to that of CATIE5. This bulletin will review the results of CATIE and revisit the use of What CATIE Found oral typical antipsychotics in clinical practice. The primary endpoint of the CATIE study for determining overall effectiveness was treatment CATIE Background discontinuation for any cause. This measure was CATIE was a landmark study funded by the National selected because it combined efficacy, safety, and Institute of Mental Health in the United States of tolerability and incorporated doctor and patient America and was published in the September 22, assessments4. Overall, 74% of patients in the study 2005, New England Journal of Medicine. One of the discontinued their medication before receiving the aims of CATIE phase 1 was to determine the long- full 18 months of therapy, suggesting substantial term effectiveness and cost-effectiveness of the limitations in the long-term clinical effectiveness of newer atypical antipsychotics, relative to typical currently available antipsychotic drugs; the antipsychotics across the spectrum of schizophrenic discontinuation rates in ascending order were: illness4. The other aim was to compare the atypical olanzapine (64%), risperidone (74%), perphenazine antipsychotics against each other4, however due to (75%), ziprasidone (79%) and quetiapine (82%)4. limitations of this bulletin, this will not be Contrary to expectations, perphenazine was as addressed. CATIE aimed to test the effectiveness of equally efficacious as the atypical antipsychotics different antipsychotics under conditions that more except for olanzapine and was just as well accurately reflect actual clinical practice4. Phase 1 tolerated4. In addition, there were no significant of CATIE randomised and double-blinded 1460 differences across the groups in the incidence of patients to receive oral olanzapine, risperidone, extrapyramidal side effects (EPSE), although quetiapine, ziprasidone (an atypical antipsychotic not significantly more perphenazine patients marketed in Australia) or perphenazine (a typical discontinued treatment due to extrapyramidal antipsychotic not marketed in Australia) over an 18- adverse effects (8 percent vs 2 to 4 percent, month period. Aripiprazole and amisulpride were not P=0.002)4. The advantage of olanzapine over included in the study, as they were not available on perphenazine was moderate and needs to be weighed Graylands Hospital Drug Bulletin 2006 Vol 14 No.4 - 1 - against the burden of greater increases in weight and had a diagnosis of schizophrenia with an average gain and indices of lipid and glucose metabolism that length of illness of 14.4 years. Patients that were were evident in the olanzapine group. excluded included those who were in a first episode of psychosis, those with treatment-resistant In the analysis of costs and quality-of-life factors schizophrenia, and those with serious and unstable associated with each of the five medications used in medical conditions. Patients with other co Phase 1 of the CATIE trial, researchers found that morbidities, receiving concomitant medication or total monthly health costs, a figure that includes who had substance abuse were not excluded from the both average medication costs and inpatient and study. outpatient costs, were up to 30 percent lower for those taking the perphenazine than for those taking Although first-episode patients were excluded, the atypical antipsychotics8. In addition, the comparative studies have found little support for researchers found no statistically significant substantial differences in efficacy of atypical difference in overall effectiveness between antipsychotics relative to typical antipsychotics in perphenazine and the atypical antipsychotics with this group11. Even so, it is important to consider regard to symptom relief and side effect burden8. that these patients may have a different susceptibility to developing EPSE compared to the Applicability of Results and chronic patients that were studied in CATIE12. Limitations The results of CATIE may not be applicable to elderly The finding that perphenazine was as effective and patients, especially considering that these patients well tolerated as most atypical antipsychotics has led may be more susceptible to developing EPSE to calls for typical antipsychotics to be used as a including tardive dyskinesia as well as being more first-line treatment option, especially considering sensitive to other adverse effects13. that perphenazine was also shown to be more cost- 9 effective . However, there are limitations to the The findings of CATIE phase 1 are not applicable to CATIE trial that preclude this conclusion from being treatment resistant patients; treatment resistant reached; these are discussed below. The results of patients were studied in CATIE phase 2, however, CATIE actually suggest that it is necessary that typical antipsychotics were not included in this several drugs are available, from which the phase. appropriate treatment can be selected for the individual10. Long-term Adverse Effects Tardive dyskinesia (TD), a later-onset EPSE Perphenazine as a Representative characterised by involuntary choreoathetoid of Typical Antipsychotics movements that are often irreversible, has been Most drug company sponsored trials of atypical mostly associated with typical antipsychotics. antipsychotics have used haloperidol as a comparator Patients with a history of TD were excluded from drug. Haloperidol is well known for causing amongst being randomised to perphenazine due to ethical 4 the highest rates of EPSE of the typical reasons . Although this may have affected the antipsychotics, making it a difficult drug to tolerate. results, as patients with TD may be more sensitive to Utilizing haloperidol may bias results by making a developing EPSE, it is important to note that comparator drug appear relatively tolerable, comparisons between the atypical antipsychotics and 4 particularly when concomitant anticholinergic perphenazine excluded subjects with TD at baseline . medication is disallowed10. Perphenazine was While there were no significant differences in TD selected as the drug representative of the typical incidence between the treatment groups, the trial antipsychotics due to its intermediate risk of causing may not have been long enough to measure TD and EPSE compared with other typical antipsychotics4. the majority of patients in the trial did not remain on 14 Although all typical antipsychotics are believed to be study medication long enough for TD to occur . The equally effective at therapeutic doses, they differ CATIE trial may not accurately portray the real and markedly in their adverse effect profiles. Hence, it relative risks of developing TD with these is difficult to extrapolate the perphenazine results in medications. Aside from TD, CATIE may not CATIE to other typical antipsychotics. Table 1 adequately address differences in other long-term compares the adverse effects of perphenazine to the adverse effects that can develop years after oral typical antipsychotics that are marketed in treatment such as diabetes, weight gain or Australia. cardiovascular disease. Patient Applicability Dosing Issues CATIE was intended to be representative of ‘real- Since the publication of CATIE, there has been 23,24 world’ patients, however results may not be criticism regarding the doses used . Olanzapine generalisable to the groups of patients that were was dosed comparatively higher (average dose excluded. Enrolees were aged between 18-64 years, 20.1mg), which may partially explain its improved 24 recruited from a variety of mental health settings, effectiveness over the other antipsychotics . Graylands Hospital Drug Bulletin 2006 Vol 14 No.4 - 2 - Table 1 Typical Antipsychotics- Comparative Information10,15,16 ) f ic ure o k Adult dose range (b) s Comments ri ve l i thmia (g) t (j) a potension* (e) l lative seiz sfunction* (k xua ndrome* (h) y e Anticholinerg effects*(c) Sedation* (d) H EPSE* (f) Re arrhy