British Study: Older Antipsychotics Just as Good

A new study comparing the benefits of second-generation antipsychotics (SGAs) with their older counterparts in patients with schizophrenia has yielded a surprising result. The study, funded by the UK National Health Service, found that the overall differences between first- and second-generation antipsychotics "did not reach statistical significance."

Appearing in the October 2006 issue of Archives of General Psychiatry, the findings from the project called the Cost Utility of the Latest Antipsychotics in Schizophrenia Study (CUtLASS) surprised the research team that reported them.

"If the investigators themselves had any bias or previous expectations, it was in favor of SGAs; we were surprised to refute that hypothesis," they wrote. "The results of this pragmatic randomized trial refute the hypothesis that the use of SGAs is superior to the use of FGAs [first-generation antipsychotics] in terms of quality of life at 1 year," they wrote, adding, "The confidence intervals for this effect in the opposite direction were wide, including the possibility of a small benefit for SGAs, but much smaller than we had hypothesized."

"What this study and the CATIE [Clinical Antipsychotic Trials of Intervention Effectiveness] study suggest is that FGAs, which are much cheaper than the SGAs, are a reasonable choice," said Anthony F. Lehman, MD, chair of the department of psychiatry at the University of Maryland School of Medicine. "In the recent era, one felt like he was giving inferior care if he prescribed an older drug."

But Lehman noted that treatment for schizophrenia is not a one-size-fits-all proposition. "Taking it from the data to actual practice, what we have to remember is that no one is average. All of these studies tell us about average effects. On average, the agents yield about the same results. That doesn't really predict for an individual patient what's going to happen.

"In clinical practice, you select a drug based on a variety of factors for the needs of the patients: the history of side effects, the prior response to a particular agent, the preference the patient has. You can even add cost into this. You make an informed choice for the patient [of] the best drug to at least start with. What these studies show is that the advantages of one or the other drug may be less than we might have thought they were."

In recent years, second-generation or atypical antipsychotics have attracted a following based in part on concerns that patients receiving the older, or first-generation, drugs "have had a suboptimal outcome, with symptomatic relapses and disabling adverse effects, particularly sedation and extrapyramidal symptoms [EPS]," according to the CUtLASS researchers.

Peter B. Jones, MD, PhD, of the department of psychiatry at the University of Cambridge, the lead researcher on the study, summarized the attitude of clinicians as "beguiled" by the appeal of atypicals.

The UK study involved 227 persons aged 18 to 64 with DSM-IV schizophrenia and related disorders whose psychiatrists had elected to change their treatment because of inadequate clinical response or intolerance of their current medication. They were randomized into 2 groups, one receiving an older antipsychotic and the other an SGA. The patients' own psychiatrists selected one of the agents designated for the appropriate treatment group.

FGAs in the study were chlorpromazine hydrochloride (Thorazine), flupenthixol (Fluanxol), haloperidol (Haldol), loxapine (Loxitane), methotrimeprazine (Nozinan), sulpiride (Dolmatil, Sulpitil), trifluoperazine hydrochloride (Stelazine), zuclopenthixol (Clopixol), and the depot preparations of fluphenazine (Prolixin, others), flupentixol (Depixol), haloperidol, pipotiazine (Piportil), and zuclopenthixol. Two other drugs, thioridazine hydrochloride and droperidol, had been included in the trial protocol but were dropped because they were withdrawn from licensed use.

SGAs used in the trial were risperidone (Risperdol), olanzapine (Zyprexa), amisulpride (Solian), zotepine (Zoleptil), and quetiapine (Seroquel). Another atypical, ziprasidone, was not included because it has not been licensed in England. Not all of the drugs used in the trial are available in the United States.

The patients were evaluated using the Quality of Life Scale (QLS) at baseline and again at 12, 26, and 52 weeks. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS); Calgary Depression Scale; the Drug Attitude Inventory and a 7-point drug adherence scale; Global Assessment of Functioning Scale; and several adverse effects scales to monitor for negative reactions.

In the end, "participants in the FGA arm tended to have greater improvements in QLS and symptom measures than those in the SGA arm, suggesting that the failure to find an advantage for SGAs was not due to the sample simply being too small. We emphasize that we do not present a null result; the hypothesis that SGAs are superior was clearly rejected," the researchers wrote.

Manufacturers of the newer drugs were quick to respond to the study. "I see at least design flaws with the study," said James Minnick, a spokesman for AstraZeneca, which makes the SGA Seroquel (quetiapine). "Patients were randomized to either first-generation or second-generation treatment, but the choice of medication wasn't random. Patients weren't blinded to what they were taking. The other point might be that every medication is different, and by lumping all second-generation drugs together and inferring they are the same, their unique attributes are undermined."

But Robert W. Baker, MD, group director of global product safety in therapeutic areas for Eli Lilly and Company, put a more positive face on the results. "It's valuable and interesting information for clinicians," he said. "It is useful if they . . . [learn] from this study and the vast existing literature on antipsychotics. It reinforces the notion that because individual drugs and patients differ from each other, clinicians can help their patients best if they are well informed and aggressively pursue the best choice."Eli Lilly's Zyprexa (olanzapine) was one of the SGAs included in the study and fared reasonably well in terms of acceptance. At the end of the study, 74% of the SGA patients for whom olanzapine had been prescribed were still taking the drug.

While quality of care was a principal focus of the study, the cost of care was clearly the driving force. "The key question was whether the additional acquisition costs of SGAs over FGAs would be offset by improvements in health-related quality of life or savings in the use of other health and social care services in people with schizophrenia for whom a change in drug treatment was being considered for clinical reasons, most commonly suboptimal efficacy or adverse effects," the researchers wrote.

In their findings, however, they note that although the mean costs for patients in the FGA arm of the study were lower, the "major cost in both groups was psychiatric hospital inpatient admissions: 93.2% of total costs in the FGA arm and 81.5% in the SGA arm. Antipsychotic drug costs accounted for a small proportion of total costs (2.1% in the FGA arm and 3.8% in the SGA arm).

"This calls into question how valuable it is to think of these drugs as a class as opposed to trying to think about the right treatment for each individual," Baker noted. "Some people may take a headline, just choose only cost, but [this applies] only the farther away you are from patients and clinical realities. This signals how much you have to individualize the choices."

Lehman also worries that policy makers will use cost considerations as a way of restricting treatment options. "When we go for treatment, we don't want our choices to be constrained by costs. It would be a shame for someone not to have access to a treatment that might be better for them because of a policy decision only to have the cheaper drugs or to have to fail with a cheaper drug first. That's true for other medical conditions, as well. We are balancing a range of choices with cost.

"Instead we should look at prescribing practices that tend to drive costs up more, such as inappropriate prescribing for other indications. This is not always done by mental health practitioners but by family physicians and others who are not as familiar with the literature. We see people using multiple drugs in the same class. Why do you need to take 3 antipsychotics?

"There are lots of ways of reducing costs without restricting the nature of drugs available. That's just a blunt instrument, although policy often uses blunt instruments."