Here’s a scenario for you. You have five medications to choose from. They are all FDA approved for the same indications. Any head-to-head study among them has shown equivalent efficacy. Three of them are associated with significant weight gain, hypercholesteremia, and diabetes risk. Two of them are not. Your job is to take a stand on what you would recommend as "first-line" medication for the disorder in question.

Sound familiar?

We are referring, of course, to the quintet of what are now sometimes referred to as "NGAs," or "new-generation antipsychotics." Also known as the "atypicals," they include, in order of FDA approval, Risperdal (risperidone), Zyprexa (olanzapine), Seroquel (quetiapine), Geodon (ziprasidone), and Abilify (aripiprazole).

We have tackled the issue of metabolic side effects in two prior February issues (TCR 1:2 and 2:2). After each of these literature reviews, we came to the same conclusions, the bunch, followed by Risperdal and Seroquel, which are roughly equal metabolic messer-uppers, followed finally by Geodon and Abilify, which appear to cause no more weight gain or diabetes than placebo.

Shortly after our last pass at this topic, the American Diabetes Association (ADA) published their long awaited Consensus Statement on antipsychotics and obesity and diabetes (Diabetes Care 27: 596-601, 2004). They essentially came to the same conclusion as TCR, ranking in this way: Clozapine/Zyprexa (worst for weight gain/diabetes/hyperlipidemia risk); Risperdal/Seroquel (intermediate); Geodon/Abilify (little or no effect).

While these recommendations were something of a yawner for those who have been reading the epidemiological studies over the years, they elicited surprising venom from just about everyone else (see Diabetes Care 2004; 27: 2086 for all of the responses to the Consensus Statement). While it was not surprising that industry-funded hired guns trashed the conclusions (see letters by Holt and Citrome), the FDA took the uncommon action of publishing a critical letter in Diabetes Care in which they chose not to offend any particular company, instead lumping all the antipsychotics together into one risky basket, saying that they "recommend that clinicians remain vigilant in monitoring all patients treated with SGAs (second-generation antipsychotics) to assure their safe use." In other words, Abilify’s no safer metabolically than Zyprexa. This view was reflected in the fact that the FDA required all makers of atypicals, including Pfizer (Geodon) and Bristol-Myers Squibb (Abilify), to add wording to their package inserts warning of a possible link between their drugs and diabetes.

In another era, the FDA’s opinions would have been considered more legitimate than those of the hired guns, but unfortunately, much has changed over the last few years. According to the New York Times, since 1992 the FDA has been accepting $200 million per year from the pharmaceutical industry in what amounted to a deal with the devil: the cash-strapped agency needed the money, and in return, promised to speed up the drug approval process according to new timelines. Over the years, in order to meet these rigid schedules, the FDA has been forced to siphon money from its drug safety monitoring programs, ultimately slashing monitoring budgets by over 50% (See NY Times, December 6, 2004, front page). In retrospect, this deal was a poor choice, as it has blown up in the FDA’s face in the Vioxx affair and the antidepressants-in-children cover-up (see TCR November 2004 for coverage of the suicidality in children data).

The FDA’s argument for fencesitting on atypicals is that the only evidence for differences in risk comes from retrospective studies, in which researchers sift through medical records after the fact, looking for differences in diabetes rates in patients on different drugs. As covered in TCR February 2004, these studies overwhelmingly implicate Zyprexa as being more risky than Risperdal, which is the drug usually used for comparison.

There is no question that prospective, head-to-head trials are the way to go to really answer these questions. Thus far, TCR has been able to locate only two published randomized headto- head trials looking specifically at Geodon or Abilify.

One study was a comparison of Geodon with Zyprexa that randomly assigned 269 patients with schizophrenia or schizoaffective disorder to receive either Geodon (mean dose 130 mg QD) or Zyprexa (mean dose 11 mg QD). Efficacy was identical at the end of the six week trial, but Zyprexa caused predictable metabolic problems, with mean increases in cholesterol of 19.5 mg/dl, in triglycerides by 26 mg/dl, in LDL cholesterol by 13 mg/dl, in fasting insulin level by 3.3 U/ml, and in weight by 3.5 kg. In comparison, patients taking Geodon had either decreases or trivial increases in all these parameters (Am J Psychiatry 2004; 161:1837-1847).

The other prospective study compared Abilify (20-30 mg QD) with Risperdal (6 mg QD) in the treatment of schizophrenia and schizoaffective disorder. The two medications were equivalentally effective on the PANSS scales. In terms of side effects, Risperdal caused more hyperprolactinemia than Abilify (90% of Risperdal patients vs. 3 to 4% of Abilify patients). Otherwise, there were no significant side effect differences, with both meds causing about 1 kg of weight gain over four weeks, significantly more than placebo, but not really clinically significant. Unfortunately, researchers did not assess lipid or glucose levels in this study (JAMA 2003; 60:681-690).

More comparative trials will be published soon, because the NIMHfunded CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) project is nearing completion. This data will provide unbiased comparisons of Zyprexa, Risperdal, Geodon, and Seroquel, and may finally knock the FDA off the fence. In the meantime, TCR believes that we already have enough data to minimize metabolic harm to our patients by using Abilify and Geodon when we can, turning to Risperdal and Seroquel when they are not effective, and avoiding Zyprexa if possible.

TCR VERDICT: When will the FDA take a stand on Zyprexa?