Antipsychotics equivalent? CUtLASS renews the debate

What was compared?

Classes vs individual drugs. The decision in CUtLASS-1 to compare antipsychotic classes rather than individual agents makes it difficult to interpret its findings. Antipsychotics are not homogeneous; clear differences exist within both the SGA and FGA classes in terms of individual agents’ efficacy and tolerability, and each SGA has a reasonably well-established and different side-effect profile.²³

Sulpiride was the most commonly used FGA in CUtLASS-1 (by 49% of FGA patients). Sulpiride has some unusual attributes—such as lower EPS liability—and is not available in the United States. Thus, including this agent might have affected how applicable CUtLASS findings are to clinical practice in the United States.

Oral vs depot delivery. Individuals assigned to an FGA could receive either oral or long-acting depot medication, whereas those assigned to an SGA could receive only oral medication. At baseline, 84 of 227 CUtLASS-1 participants were receiving a depot antipsychotic, which was discontinued during randomization in 72 patients. During the 1-year study, the number of patients receiving a depot antipsychotic tripled from 12 to 35, suggesting the usefulness of long-acting agents in this population.¹⁹

Cross-class switching. Although participating physicians and their patients were urged to stay within assigned antipsychotic classes at least for the first 12 weeks and ideally for 1 year, a high rate of cross-class switching occurred (Figure). At the 52-week assessment, 51 of 118 patients (43%) in the intent-to-treat FGA group were receiving SGAs instead.

The CUtLASS authors’ assert that the trial refutes the hypothesis that using SGAs is superior to using FGAs in improving quality of life. This conclusion is difficult to justify when so many patients assigned to the FGA class actually were receiving SGAs. The conclusion is further weakened if differential switching rates put SGAs at a disadvantage in the first 12 weeks of the trial.

A more accurate conclusion of the intent-to-treat comparison appears in the technical report: “There was no statistically significant difference in terms of quality of life or symptoms over 1 year in commencing [italics added] conventional antipsychotic drugs rather than new atypical drugs.”¹²

Figure CUtLASS-1: Did switching rate affect trial outcome?

The high rate of cross-class medication switching in CUtLASS-1 may have weakened the study’s conclusion that virtually no difference in effectiveness exists between first- and second-generation antipsychotics. At the 52-week assessment, 51 of 118 patients (43%) in the intent-to-treat FGA group were receiving SGAs instead. Not shown in the figure is that 4 of the total 55 patients who switched from FGAs to SGAs had switched back to FGAs by the 52-week assessment.

CUtLASS: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study

FGA: First-generation antipsychotic

SGA: Second-generation antipsychotic

Source: Adapted from reference 7, Figure 1

Clinical implications

Notwithstanding these cautionary notes, CUtLASS-1 findings add to the questions raised by CATIE about the relative effectiveness of SGAs and FGAs. At a minimum, the data indicate that the SGA advantage has been overstated or oversimplified and that FGAs may be suitable options for meeting the needs of some patients with psychosis (particularly those at low risk for EPS).

Depot antipsychotics. CUtLASS also suggests a wider role for long-acting antipsychotics in chronic psychotic disorders, beyond treating patients with severe nonadherence.^19,23 The number of patients receiving long-acting agents tripled over the 1-year study.¹²

Clozapine. Both CATIE and CUtLASS-2 confirmed clozapine’s superior efficacy for patients with treatment-resistant psychotic illness (Table 4). CUtLASS-2 also reaffirmed the challenges of clozapine’s metabolic and other side effects, such as sedation, hypotension, and hypersalivation.

All-cause discontinuation was significantly higher (P<0.05) in patients taking clozapine (73%) than in those taking other SGAs (52%). Even so, clozapine-group patients achieved significantly greater symptom reduction and tended toward a higher quality of life than other SGA-group patients.

Table 4

Clinical ‘pearls’ from the CUtLASS trial data

Overview. In conclusion, one can reasonably conclude from analyzing the CATIE and CUtLASS data that:

• FGA-SGA differences are not as great as previously thought.
• Substantial differences exist among agents within both antipsychotic classes, particularly in side effect profiles.
• Neither study disproves the following presumed benefit of SGAs: that compared with FGAs, SGAs provide an equivalent antipsychotic effect and pose a lower risk of problems related to unmitigated dopamine blockade—such as EPS, dysphoria, bradyphrenia, neuroleptic-induced deficit syndrome, and tardive dyskinesia.¹¹
• To use antipsychotics effectively and optimize individual treatment, consider the CATIE and CUtLASS trials in the contexts of their designs and the results of other studies of patients with chronic schizophrenia.