Evidence-Based Reviews

Antipsychotics equivalent? CUtLASS renews the debate

Current Psychiatry. 2007 February;6(2):58-78

References

1. Kane JM, Leucht S, Carpenter D, et al. Expert consensus guideline series: optimizing pharmacologic treatment of psychotic disorders. J Clin Psychiatry 2003;64(suppl 12):1-100.

2. Tandon R, Fleischhacker WW. Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 2005;79:145-55.

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

4. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior antipsychotic treatment. Am J Psychiatry 2006;163:600-10.

5. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006;163:611-22.

6. Rosenheck RA, Leslie DL, Sindelar J, et al. Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006;163:2080-9.

7. Jones PB, Barnes T, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS). Arch Gen Psychiatry 2006;63:1079-87.

8. Lewis SW, Barnes TRE, Davies L, et al. Randomised controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006;32:715-23.

9. Nasrallah HA. CATIE’s surprises: in antipsychotics’ square-off, were there winners or losers? Current Psychiatry 2006;5(2):49-65.

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12. Lewis SW, Davies L, Jones PB, et al. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment. Health Technology Assessment 2006;10(#17):1-182.Available at http://www.hta.ac.uk/project/1078.asp. Accessed January 3, 2007.

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Comparing catie, cutlass data

The CUtLASS findings are not identical to those of CATIE phase 1¹⁴ but are remarkably similar: no differences in effectiveness were seen between FGAs and SGA when treating patients with chronic schizophrenia.^15,16

CUtLASS investigators concluded that “in people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs.”⁷

By confirming CATIE’s results, is CUtLASS the final word on antipsychotic treatment of chronic schizophrenia? Or is it just another piece of the puzzle? CATIE and CUtLASS add much to our knowledge, but methodologic “flies in the ointment” plague all clinical trials. We must consider potential biases and confounding factors to properly interpret and apply their findings.

Although the CUtLASS trial was well-constructed and executed, its conclusions—like those of CATIE—merit careful scrutiny. Its patient recruitment methods and study design involved choices and compromises that are appropriate to evaluate^17,18 as we weigh CUtLASS’ contribution to the SGA/FGA debate (Table 3).

Table 3

‘Flies in the ointment’ of the CUtLASS trial design

Who was studied	Recruited patients were at low risk for EPS A greater number of treatment-refractory patients was assigned to the SGA arm, compared with the FGA arm
What was compared	SGA class vs FGA class (including sulpiride) Oral SGAs vs oral or depot FGAs
Other Issues	Greater initial switching of medication class in the SGA group in relatively stable, moderately ill patients; adverse effects of such switching were seen early (at the 12-week assessment) Substantial contamination (43% of patients in the FGA class were receiving SGAs at 52 weeks, but results were calculated [intent-to-treat analysis] as if the patients were receiving FGAs)
CUtLASS: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study
EPS: Extrapyramidal symptom
FGA: First-generation antipsychotic
SGA: Second-generation antipsychotic

Who was studied?

Selection questions. CUtLASS researchers had problems recruiting patients for their study, in part because clinicians were reluctant to expose their patients to a 50% probability of being assigned to an FGA. Only 40% of the targeted sample was recruited, and participating clinicians referred only 20% to 37% of their eligible patients to the study.¹² Thus, one could ask:

Were enrolled subjects truly representative of the population from which they were drawn?
Or did selection bias result in a disproportionate inclusion of individuals with certain characteristics?

Is it possible, for example, that clinicians preferentially referred medication-noncompliant patients to CUtLASS because they believed the benefits of depot FGAs—such as more assured adherence—would compensate for the potential benefits of SGAs—better efficacy/tolerability?¹⁹

Treatment resistance. Although patients were randomly assigned to FGAs or SGAs, a significantly greater proportion of those whose antipsychotics were being changed because of treatment resistance were assigned to receive SGAs. Treatment resistance was one reason that 88% of subjects in the SGA arm were referred to the trial, compared with 70% of subjects in the FGA arm (P<0.01).¹² The extent to which this differential assignment may have biased results against SGAs is unclear.

EPS risk. CUtLASS-1 patients had been ill a mean of 14 years and had low baseline EPS rates despite receiving long-term antipsychotics (primarily FGAs). Even so, FGAs and SGAs showed similar rates of akathisia and other EPS. Thus—as with the CATIE results—the extent to which CUtLASS-1 findings may apply beyond chronic schizophrenia patients at relatively low risk for EPS is unclear.^11,17

Impact of switching. Although patients were referred to CUtLASS because of adverse effects or inadequate response to one or more antipsychotics, they were only moderately ill (mean PANSS total score 72)²⁰ and probably were deriving some benefit from their baseline antipsychotics. Before randomization, 82% of patients were receiving an FGA and 19% an SGA. Consequently, a far larger percentage of patients in the SGA group had to switch to a different medication class as the trial began.

As observed in CATIE, switching antipsychotics often has short-term negative consequences for patients,²¹ although switching classes (as in CUtLASS) may have had a different impact than switching individual antipsychotics (as in CATIE). If unequal antipsychotic switching rates in the two arms differentially affected patients’ quality of life, we would expect to see this effect emerge at the 12-week assessment, which is precisely where the greatest difference in Quality of Life Scale (QLS)¹³ scores appeared.

The mean QLS score for patients in the SGA arm was 2.6 points lower than in the FGA group at 12 weeks. This difference disappeared and, in fact, reversed at 26 weeks, but this 12-week effect had a strong impact on results of the 52-week intent-to-treat analysis. CUtLASS—like CATIE—might exemplify the risks of switching patients from treatment with partially effective antipsychotics.²²