Evidence-Based Reviews

Antipsychotics equivalent? CUtLASS renews the debate

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Is UK trial the final word, or another piece of the puzzle?


 

References

When treating chronic psychotic disorders, U.S. psychiatrists generally prefer second-generation antipsychotics (SGAs) to first-generation antipsychotics (FGAs) because of widely held views1,2 that SGAs:

  • are more effective for negative and cognitive symptoms
  • produce fewer troublesome side effects
  • help patients realize a better quality of life.

These beliefs have been challenged by two large-scale, government-supported studies: the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) in the United States3-6 and more recently the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) from the United Kingdom.7,8

CATIE and CUtLASS data suggest that the SGA advantage has been exaggerated, if in fact such an advantage exists. Other Current Psychiatry articles for the clinical practitioner have discussed the CATIE findings.9-11 This article addresses the CUtLASS results in the context of the trial’s methodology, using information from the primary publications7,8 and technical report.12

Cutlass study

Design. CUtLASS included 2 “bands” (Table 1):

  • Band 1 compared the clinical usefulness and cost effectiveness of FGAs and SGAs in treating schizophrenia7
  • Band 2 compared the effectiveness of clozapine versus other SGAs in treating refractory schizophrenia.8

CUtLASS Band 1 was not as extensive in scope as CATIE, and its design had some important differences (Table 2). Patients were referred for participation because their psychiatrists were considering a change in antipsychotic medication to address adverse effects or inadequate response. Fewer patients were recruited than expected—40% of the planned sample during 30 months of recruitment—but researchers considered the size sufficient to compare the effectiveness of FGAs and SGAs.

Patients were randomly assigned to treatment with an antipsychotic class, either:

  • an FGA (1 of 11 options—including 5 depot formulations—chosen by the treating clinician)
  • or an SGA (risperidone, olanzapine, quetiapine, or amisulpride, also chosen by the clinician).

Physicians and patients were not blinded to the medications used. They could choose medications within patients’ assigned classes and switch as needed in ways that mimicked clinical practice. Trained assessors, who were blinded to the medications being used, evaluated the patients after 12, 26, and 52 weeks.

Quality of life was the primary outcome measure.13 Secondary measures included symptoms, side effects, patient satisfaction, and cost of care.

Band 1 results. Patients assigned to the SGA or FGA classes showed no significant differences in quality of life measures or schizophrenia symptoms. If anything, the findings slightly favored the FGAs.

Patient satisfaction and overall cost of care were similar, and rates of extrapyramidal symptoms (EPS), tardive dyskinesia, and akathisia did not differ significantly.

Clozapine comparison. In CUtLASS band 2, a different sample of 136 schizophrenia patients who had responded poorly to ≥2 antipsychotics was randomly assigned to clozapine or one of the above four SGAs. During the 1-year comparison trial, clozapine:

  • was found to be significantly more effective (P=0.01) in managing patients’ symptoms, as measured by total Positive and Negative Syndrome Scale (PANSS) score
  • showed a trend (P=0.08) towards providing these treatment-resistant patients with a better quality of life.8

Table 1

Summary of CUtLASS trial design and results

Band 1
  • 1-year study comparing FGAs with SGAs in 14 community psychiatric services in the United Kingdom
  • 227 patients with mean illness duration of 14 years and mean PANSS score of 72 (moderately ill); 99% were receiving antipsychotics at enrollment
  • Found FGAs and SGAs equal in overall effectiveness and quality of life, with no significant difference in side effects
Band 2
  • 1-year study comparing clozapine with other SGAs in 136 patients with treatment-resistant schizophrenia
  • Found clozapine significantly more effective (P<0.02) than other SGAs in reducing symptoms but not in improving quality of life (P=0.08)
CUtLASS: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study
FGA: First-generation antipsychotic
PANSS: Positive and Negative Syndrome Scale
SGA: Second-generation antipsychotic

Table 2

Comparing designs of the CUtLASS and CATIE schizophrenia trials

CUtLASSCATIE
Trial duration12 months18 months
Clinical sites14 (United Kingdom)57 (United States)
Number of Subjects2271,460
Gender and age68% male; mean age 4174% male; mean age 41
Mental illness duration (mean)14 years16 years
Diagnosis75% schizophrenia100% schizophrenia
First-episode patients included?Yes (13% of sample)No
% of patients receiving antipsychotics at enrollment99%74%
Baseline PANSS score (mean)82% FGAs; 40% depot15% FGAs; <5% depot
Baseline PANSS score72.275.7
Baseline EPS scoresLowLow
Antipsychotic options in randomization2 classes (SGA or FGA) (50% of subjects assigned to an FGA)4 SGAs, 1 FGA (20% of subjects assigned to an FGA)
% of subjects given sulpiride49%0%
Administration methodologyMedication blinded to raters but not to patients and physiciansMedication blinded to patients and physicians
Primary outcomeQuality of lifeDiscontinuation of medication
Long-acting antipsychotic option?YesNo
Antipsychotic switchingAll patients switched agents; 49% changed antipsychotic class15% stayed on some agent
CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness
CUtLASS: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study
EPS: Extrapyramidal symptom
FGA: First-generation antipsychotic
PANSS: Positive and Negative Syndrome Scale
SGA: Second-generation antipsychotic

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