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In ’ square-off, were there winners or losers?

nvestigators faced a dilemma while designing the Clinical Trials of Inter- I vention Effectiveness (CATIE). More than 200 enrollees with chronic had pre-exist- Henry A. Nasrallah, MD ing (TD). Would it be ethical to Professor of psychiatry, neurology, and neuroscience give them the antipsychotic most likely to worsen Department of psychiatry their TD? Would exempting them from taking that University of Cincinnati College of Medicine Member, CATIE Study Investigators Group drug influence the trial’s outcome? This issue and others had to be resolved before the largest controlled study of “real world” schizo- phrenia could begin. Now that data are unfolding, was as effective groups with diverse agendas are debating CATIE’s as the atypical antipsychotics, methods and surprising results. This article des- but could the study’s design cribes how the trial’s design and findings could have swayed the outcome? transform public policy and clinical practice. EFFICACY VS EFFECTIVENESS The National Institute of funded the prospective CATIE schizophrenia study to compare the effectiveness of atypical antipsy-

ispot chotics versus each other and versus a first-gener- the ation (typical) antipsychotic. c/o

Yeo All approved atypicals have shown similar effi-

Brad cacy compared with placebo in short-term trials ©

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Table 1 medications, or show evidence of Criteria for enrolling patients TD. Their schizophrenia ranged in the CATIE schizophrenia trial from minimal to severe.2,3 The 1,493 patients who complet- Inclusion criteria Ages 18 to 65 yrs ed the study (Table 2) were enrolled DSM-IV diagnosis of schizophrenia at 57 outpatient treatment settings. One site’s 33 patients were eliminat- Able to take oral medication ed from analysis because of doubts Able to give informed consent about the integrity of the data, leav- 4 Exclusion criteria Diagnosis of schizoaffective ing a total of 1,460 subjects. disorder, mental retardation, Medications. Before randomization, or other cognitive disorders 28% of enrollees were not receiving History of serious adverse reactions antipsychotics. The remainder were to one of the study medications receiving: • (22%) Had only one schizophrenic episode • (19%) History of treatment resistance, • (7%) defined as persistence of severe • (0%; approved symptoms despite adequate trials after the trial began) of one of the study antipsychotics • any combination of olanzap- or prior treatment with ine, risperidone, and quetia- Pregnant or breast feeding pine (7%) Serious and unstable medical • typical antipsychotics (16%). conditions Metabolic profile. These outpatients had a high rate of metabolic disor- ders: 42%—twice the rate in the gen- eral population—met criteria for (usually 6 weeks).1 The CATIE trial’s rationale is metabolic syndrome,5 putting them at high risk to that short-term efficacy studies required for FDA die of cardiovascular causes within 10 years.6 approval may not necessarily reflect the drugs’ effectiveness in long-term schizophrenia manage- ment. Effectiveness measures take into account efficacy as well as safety, tolerability, and unpre- What do you think? dictable patient behaviors in the real world. Go to the Instant Poll www.currentpsychiatry.com CATIE'S 'REAL WORLD' PATIENTS CATIE investigators enrolled a community sample Will the CATIE findings of chronic schizophrenia patients similar to those change the way you treat many psychiatrists see. Very liberal inclusion and patients with schizophrenia? exclusion criteria (Table 1) allowed enrollees to have a history of substance abuse, comorbid psy- chiatric or medical disorders, be receiving other continued on page 53

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continued from page 50 They had relatively poor physical Table 2 health self-ratings and increased CATIE’s 1,460 ‘real world’ somatic preoccupation.7 Most worri- schizophrenia patients at trial entry some, many were receiving no med- Mean age 40.6 ± 11.1 yrs ications for their metabolic disor- ders, including 45% of those with Mean age of first treatment 24.0 ± 8.9 yrs diabetes, 89% with hyperlipidemia, Mean duration of treatment 14.4 ± 10.7 yrs and 62% with hypertension.8 Substance abuse. At enrollment, 40% Gender 74% male of patients were abstinent from sub- Race 60% white, 35% black, 5% other stance use, 22% were using sub- Mean education 12.1 ± 2.3 years stances without abuse or depen- dence, and 37% had substance abuse Marital status 59% never married, or dependence. Compared with 29% previously married, nonusers, substance abusers tended 11% married to be male with more childhood Employment status 85% unemployed problems, higher positive symptoms Mean PANSS total score 75.7 ± 17.6 on the Positive and Negative Syndrome Scale (PANSS), and Mean CGI 4.0 ± 0.9 more likely to have had a recent ill- Psychiatric comorbidities 29% drug dependence/abuse ness exacerbation.9 28% depression Tardive dyskinesia. The 231 subjects 25% dependence/abuse who met criteria for probable TD10 14% were older than the overall sample 5% obsessive-compulsive with more years of antipsychotic disorder treatment, especially with conven- Illness severity 4% severe, 20% marked, tional neuroleptics and anticholin- 47% moderate, 23% mild, ergics. Substance abuse was associ- 6% minimal ated with TD, as were severity of PANSS: Positive and Negative Syndrome Scale CGI: Clinician-rated Clinical Global Impressions severity score psychopathology, extrapyramidal Source: Reference 5. symptoms (EPS), and .11 Violent behavior. A history of serious violent behavior was reported in: • 5.4% of patients with high positive and low found to affect decision-making capacity, but negative PANSS symptom scores negative symptoms and diminished working • 1.7% of patients with low positive and high memory did.12 negative PANSS symptom scores. Consent. Patients’ capacity to give consent to par- CATIE’S UNIQUE DESIGN ticipate in the study was assessed with the Defining effectiveness. CATIE was designed in MacArthur Competence Assessment Tool for three phases (Figure, page 54). Phase 1—dis- Clinical Research (MacCAT-CR). cussed here—was a blinded, controlled compari- severity (PANSS positive symptom scale) was not son of four atypical antipsychotics and per-

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Figure CATIE schizophrenia trial design

Phase 1* Phase 2 Phase 3 Double-blind random Participants who discontinue Participants who discontinue treatment assignments phase 1 choose either the phase 2 choose one of the clozapine or ziprasidone following open-label randomization pathways treatments

▼ Olanzapine

Clozapine • 1,460 patients ▼ (open-label) • Clozapine with

▼ Quetiapine schizophrenia R Olazapine, • decanoate (could have ▼ quetiapine, • Olanzapine psychiatric R or risperidone

▼ Risperidone or medical • Perphenazine

comorbidities and be taking ▼ Ziprasidone • Quetiapine

▼ Ziprasidone other R Olazapine, • Risperidone medications) ▼ quetiapine, • Ziprasidone or risperidone

▼ Perphenazine • 2 of the antipsychotics No one assigned to same above drug as in phase 1 R = randomization

* Phase 1A: participants with tardive dyskinesia (N=231) do not get randomized to perphenazine; phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before eligibility for phase 2. Source: Reference 2.

phenazine. Results of phases 2 and 3 have yet to 18-month trial in December 2004, and data analy- be published. The primary effectiveness endpoint, sis began in January 2005. Ziprasidone was added “all-cause discontinuation,” was defined as: to phase 1 after 40% of the sample had been • lack of efficacy (patient was switched to enrolled, and aripiprazole was included as an another drug assigned at random) option in the unblinded phase 3. • lack of tolerability (patient requested a Perphenazine was chosen to represent typical drug change) antipsychotics because it has medium • safety problem (investigator initiated a and less risk of EPS than high-potency drugs such switch) as and is associated with less weight • patient’s decision for any reason (often gain than low-potency drugs such as . dropping out of the study). Dosing. Pharmaceutical manufacturers donated The longer subjects stayed on the first anti- the antipsychotics and were invited to recommend psychotic they received, the more effective that their respective drugs’ starting dosages, dose incre- drug was considered to be. ments, and maximum dosages. Olanzapine’s Medications. Three atypicals—risperidone, olanza- maker requested a higher starting dosage (7.5 pine, and quetiapine—were approved for schizo- mg/d instead of 5.0 mg/d) and a maximum dosage phrenia when the trial began in 1999. Recruitment 50% higher than the FDA-approved range (30 ended in June 2003, the last subject completed the mg/d instead of 20 mg/d). The others recom-

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mended the FDA-approved Table 3 dosage ranges or less: All-cause discontinuation rates in the CATIE trial • quetiapine, 200 to 800 mg/d Percent Duration on Dosage Antipsychotic discontinued antipsychotic (months)* (mg/d)* • risperidone, 1.5 to 6 mg/d Olanzapine 64% 9.2 20.1 • ziprasidone, 40 to 160 mg/d Perphenazine 75% 4.6 20.8 • perphenazine, 8 to Quetiapine 82% 4.8 543.4 32 mg/d. The study team accepted Risperidone 74% 5.6 3.9 their recommendations. The medications were Ziprasidone 79% 3.5 112.8 packaged in identical cap- Overall 74% Median 6.0; mean 8.3 sules. Quetiapine and zi- prasidone were given twice Notes *Mean modal daily because of product la- Olanzapine’s discontinuation rate was significantly lower than those of perphenazine, quetiapine, beling; risperidone, olanza- and risperidone but not of ziprasidone. Olanzapine’s maximum dosage was 30 mg/d (50% higher than FDA-approved 20 mg/d); other pine, and perphenazine agents were dosed within approved ranges. Patients reached maximum daily antipsychotic dosages at these rates: 40% with olanzapine, 40% were given once daily to with perphenazine, 44% with quetiapine, 40% with risperidone, and 48% with ziprasidone. one-half the patients as- signed to them and twice daily to the others to prevent raters from guessing which drug a patient was CATIE trial found a similarly high rate of all- receiving. cause discontinuation (70%) in patients with first- Tardive dyskinesia. For ethical reasons, the 231 episode psychosis.14 Thus, patient-initiated drug patients with TD at enrollment were randomly discontinuation appears to be a core illness behav- assigned in phase 1 to atypicals but not to per- ior from schizophrenia onset to chronic illness. phenazine because of the well-established link The high discontinuation rate shows that we between typical antipsychotics and TD. This need to modify our approach to schizophrenia, exception could have contributed to the closer- emphasizing full adherence to antipsychotic ther- than-expected differences in EPS and perhaps in apy from the onset of the illness. efficacy, given reports that TD patients have more Effectiveness—measured as all-cause discontinu- negative symptoms and cognitive dysfunction.13 ation or switching—was the primary outcome of However, a statistical analysis took that into phase 1. The unexpected finding that perphen- account. azine and the atypicals had similar effectiveness could influence clinical practice. Insurers, for CATIE’S KEY FINDINGS example, might consider promoting cheaper typ- Discontinuation. A disappointingly high discontin- ical antipsychotics for first-line use. CATIE’s uation rate (74% overall) within a few months was cost-effectiveness arm (Rosenheck et al, submit- the most important finding (Table 3). A recent ted for publication) will provide additional data effectiveness study with a design similar to the on this issue. continued

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Table 4A Rankings of effectiveness of antipsychotics in the CATIE trial, phase I

Effectiveness

Highest ▼ Lowest

Overall discontinuation O < R < P < Z < Q rate* 64% 74% 75% 79% 82%

Median duration on the O > P > R > Q > Z antipsychotic (months)* 9.2 5.6 4.8 4.6 3.5

Discontinuation O < Z < P < R < Q for efficacy reasons* 15% 24% 25% 27% 28%

Discontinuation R < Q = P < O < Z for tolerability reasons 10% 15% 15% 18% 28%

Discontinuation P < R < Z < Q < O due to weight gain* 1% 2% 3% 4% 9%

Discontinuation O < Q = R < Z < P due to EPS* 2% 3% 3% 4% 8%

Discontinuation O < R = P < Q < Z due to patient decision* 24% 30% 30% 33% 34%

Duration of successful O > Q = R = P = Z treatment (months) 31111

Hospitalization* O

* Statistically significant difference O: olanzapine; R: risperidone; P: perphenazine; Z: ziprasidone; Q: quetiapine EPS:

Before rushing to use older antipsychotics as ical practice. Since atypical antipsychotics were first-line treatments for schizophrenia, however, approved, clinicians see far fewer psychiatric policymakers should consider three factors in the patients with pill-rolling , rigid posture, or a study design that could have enhanced per- shuffling gait, compared with 10 to 15 years ago phenazine’s efficacy and safety profiles. when typical antipsychotics were widely used. First, perphenazine was given at lower Second, perphenazine was associated with dosages (up to 32 mg/d) than “real world” clini- the highest EPS rate (17%), though its mean cians used a decade ago (up to 64 mg/d). Thus, modal dosage (20.8 mg/d) is considered moder- lower rates of serious side effects, especially TD, ate. Discontinuation because of EPS was highest might have occurred in the study than in past clin- with perphenazine and lowest with quetiapine. continued on page 61

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Table 4B Safety, tolerability rankings among antipsychotics in the CATIE trial, phase 1

Side effect rates

Lowest ▼ Highest

Insomnia* O

Urinary hesitancy, Z < P < O < R < Q dry mouth, constipation* 20% 22% 24% 25% 31%

EPS and TD Q < O = Z < R < P 13% 14% 14% 16% 17%

Use of Q < O = Z < R < P medication 3% 8% 8% 9% 10%

Weight gain (mean P < Z < R < Q < O in lbs), phase 1* –2.0 –1.6 0.8 1.1 9.4

Proportion of subjects Z < P < R < Q < O with >7% body weight gain* 7% 12% 14% 16% 30%

Weight gain per month Z < P < R < Q < O of treatment (mean in lbs)* –0.3 –0.2 0.4 0.5 2.0

Blood glucose rise Z < P < R < Q < O (mean mg/dL) 2.3 5.2 6.7 6.8 15.0

Hg A1C % change*¶ Q

Cholesterol change*¶ Z

Triglycerides change*¶ Z

Prolactin changes*¶ Q

Corrected QTC (mean R < O < Z < P < Q msec from baseline) 0.2 1.2 1.3 1.4 5.9

New cataracts Z < Q < P < R < O (# of cases per sample) 0/142 1/258 1/210 2/260 3/272

Anxiolytic added* O

O: olanzapine; R: risperidone; P: perphenazine; Z: ziprasidone; Q: quetiapine EPS: extrapyramidal symptoms; TD: tardive dyskinesia; Hg A1C%: glycosylated hemoglobin—% * Statistically significant difference ¶ Exposure adjusted mean mg/dL

continued

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Third, excluding enrollees with TD from per- population with a mean duration of illness of 14 phenazine may have increased perphenazine’s years. Perphenazine, too, was dosed at the lower effectiveness, whereas including them in the atyp- end of its range (mean modal dose 20.8 mg/d) icals groups may have reduced the atypicals’ effec- compared with the old community standard of tiveness. TD patients are at increased risk to devel- 36 to 64 mg/d. op EPS; they had more-severe illness and a higher Generally, a mean modal dosage of 20.1 mg/d substance abuse rate among CATIE patients.11 for olanzapine is considered equivalent to Even so, investigators did control for TD in the ziprasidone, 160 mg; quetiapine, 800 mg; and ris- data analysis and found no significant difference peridone, 6 mg. In CATIE phase 1, mean modal between typical and atypical antipsychotics. dosages were: • ziprasidone, 112.8 mg/d (30% below 160 mg) NO 'WINNERS' OR 'LOSERS' • quetiapine, 543.4 mg/d (32% below 800) Effectiveness, tolerability, and safety findings for • risperidone, 3.9 mg/d (35% below 6 mg). each antipsychotic are compared in Tables Olanzapine’s starting dosage 4A and 4B. Careful review shows of 7.5 mg/d was relatively higher no clear “winners” or “losers;” than those of the other atypicals, each agent has weaknesses but Each antipsychotic which may have produced more-rapid also strengths that may benefit has weaknesses onset of efficacy. individual patients. but also strengths Switching. Another potential “advantage” Efficacy. Olanzapine showed a that may benefit for olanzapine was that 22% of subjects were relatively higher efficacy and individual patients taking it when they enrolled. By random lower discontinuation rate but assignment, 23% of patients who were tak- also had the highest risk of adverse ing olanzapine stayed on olanzapine and metabolic effects. Some have attributed its did not switch. By comparison: greater efficacy to its higher dosing compared • No patients assigned to ziprasidone were with the other antipsychotics. Some also have taking it before entering the trial. argued that the antipsychotics that showed lower • Only 5% of those taking quetiapine stayed efficacy, such as quetiapine and ziprasidone, on that drug after randomization. were underdosed in this chronic schizophrenia • Few were receiving perphenazine before enrollment. Switching antipsychotics may increase side effect risk or efficacy problems. For example, a Phase 1 of the CATIE schizophrenia patient switched from olanzapine or quetiapine trial found four atypical and one typical to ziprasidone or perphenazine may experience antipsychotic similarly effective for ‘real during the transition, which may lead world’ patients. Drug dosage decisions to tolerability complaints. and selective randomization of patients Metabolic side effects seen in this trial support past with tardive dyskinesia may explain observations and reports that olanzapine is associ- these results. Discontinuation rates ated with higher risk for weight gain, hyper- averaged 74%, and side effects varied. glycemia, and hyperlipidemia than other antipsy- chotics.15 Data on metabolic changes in CATIE patients taking olanzapine are being analyzed.

Bottom Line continued on page 65

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Hyperprolactinemia was most common with Related resources risperidone and practically nonexistent with  Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) other antipsychotics—even perphenazine. On schizophrenia study. www.catie.unc.edu/schizophrenia the other hand, risperidone had the most favor-  Schizophrenia Research Forum. NARSAD, The Mental Health able tolerability profile. This implies that elevat- Research Association. ed does not necessarily lead to antipsy- www.schizophreniaforum.org chotic discontinuation because of tolerability DRUG BRAND NAMES Aripiprazole • Abilify Quetiapine • Seroquel among patients with schizophrenia. Olanzapine • Zyprexa Risperidone • Risperdal QTC interval and cataract data were benign across Perphenazine • Trilafon Ziprasidone • Geodon all antipsychotics. These findings appear to exon- DISCLOSURE erate ziprasidone and quetiapine, respectively, Dr Nasrallah receives grants/research support from AstraZeneca, Janssen Pharmaceutica, Eli Lilly & Company., and Pfizer Inc. He is a consultant, which have been perceived as associated with advisory board member, and speaker for Abbott Laboratories, AstraZeneca, these side effects. Janssen Pharmaceutica, Pfizer Inc., and Shire Pharmaceuticals Group.

COMING NEXT 6. Goff D, Sullivan LM, McEvoy JP, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE When data become available, the next article in study and matched controls. Schizophr Res 2005;80:45-53. this series will discuss CATIE phase 2 findings. 7 Meyer JM, Nasrallah HA, McEvoy JP, et al. The Clinical This phase includes patients who did not Antipsychotic Trial of Intervention Effectiveness (CATIE) schizophrenia trial: clinical comparison of subgroups with and improve with the phase 1 regimens because of without the metabolic syndrome. Schizophr Res 2005;80:9-18. efficacy or tolerability problems and were 8. Nasrallah HA, McEvoy JP, Meyer JM, et al. Low rates of treatment for metabolic disorders in the CATIE schizophrenia trial. switched to other antipsychotic therapies. Neuropsychopharmacol 2005;(suppl 1):204. 9. Swartz MS, et al (unpublished data). References 10. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia. 1. Tandon R, Jibson MD. Efficacy of newer generation antipsychotics Arch Gen Psychiatry 1982;39:486-7. in the treatment of schizophrenia. Psychoneuroendocrinol 2003; 11. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of 28(suppl 1):9-26. tardive dyskinesia in schizophrenia: baseline data from the CATIE 2. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of schizophrenia trial. Schizophr Res 2005;80:33-43. Mental Health Clinical Antipsychotic Trial of Intervention 12. Stroup TS, Applebaum P, Swartz M, et al. Decision-making Effectiveness (CATIE). Project: schizophrenia trial design and capacity for research participation among individuals in the CATIE protocol development. Schizophr Bull 2003;29:15-31. schizophrenia trial. Schizophr Res 2005;80:1-8. 3. Swartz MS, Perkins DO, Stroup TS, et al. Assessing clinical and 13. Waddington JL, Youssef HA, Dolphin C, et al. Cognitive function, functional outcomes in the Clinical Antipsychotic Trials of negative symptoms and tardive dyskinesia in schizophrenia. Their Intervention Effectiveness (CATIE) schizophrenia trial. Schizophr association in relation to topography of involuntary movements and Bull 2003;29:33-43. criterion of their abnormality. Arch Gen Psychiatry 1987;44:907-12. 4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of 14. Keefe R. The CAFÉ effectiveness study. Amsterdam: European antipsychotic drugs in patients with chronic schizophrenia. N Engl College of Neuropsychopharmacology annual meeting, 2005; J Med 2005;353:1209-23. 15. American Diabetes Association, American Psychiatric Association, 5. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic American Association of Clinical Endocrinologists, and North syndrome in patients with schizophrenia: baseline results from the American Association for the Study of Obesity. Consensus CATIE schizophrenia trial and comparison with national estimates development conference on antipsychotic drugs, obesity, and from NHANES III. Schizophr Res 2005;80:19-32. diabetes. Diabetes Care 2004;27:596-601.

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