The new wave of SGAs: will high hopes for three new antipsychotics translate into better outcomes?
With the introduction of clozapine in 1989, the "second generation antipsychotic" (SGA) medications heralded the hope of avoiding or reducing many of the side effects that had been associated with their first generation antipsychotic (FGA) predecessors.
In my opinion, most of the SGAs, which included in order of appearance: Risperdal, Zyprexa, Seroquel, Geodon, Abilify, and Invega, reduced the risk of extrapyramidal side effects like tremors and stiffness. The evidence for my opinion can be seen in the reduced use of the antipar-kinson agents like Artane and Cogentin with the SGAs compared to the FGAs (1).
But following their introduction in the 1990s, two major concerns about the SGAs emerged. First, the occurrence of metabolic problems like weight gain, abnormal glucose levels, and elevated lipids overshadowed the concerns about extrapyramidal syndromes. Second, with the exception of clozapine, and possibly olanzapine, the SGAs did not show any particular advantage over the FGAs in symptom reduction.
Three new "second generation" antipsychotics
Since May, 2009, three new SGA medications have been introduced to practice (in order of approval date): No-vartis' Fanapt (Iloperidone), Merck's Saphris (Asenapine), and Sunovions Latuda (Lur-asidone). Two important questions not yet answered by empirical research are whether these newer SGAs offer any safety or efficacy advantages over the older SGAs and if they differ substantially from each other.
The best way to answer these questions, aside from properly designed studies and ongoing monitoring of individual patients, is to look at the product information provided by the manufacturers to the FDA.
At this time, the best that we are able to conclude about the relative efficacy of the three new SGAs is that all are superior to placebo in the acute treatment of acute schizophrenia, and, in the case of Saphris, manic or mixed episodes associated with bipolar I disorder.
Recently, Saphris received an FDA indication for maintenance in schizophrenia after it showed superiority to placebo over a 26-week trial; it also received an indication for adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder.
Fanapts labeling recommends that prescribes consider other antipsychotics first because Fanapt prolongs the QT interval of the heartbeat and requires a titrated dose. To date, studies have not yet demonstrated that any of these three agents hold any superior efficacy over the existing SGAs (Risperdal and Zyprexa have been the selected comparators thus far), but it is still too early to reach general conclusions.
Certainly, the pharmacologic "fingerprints" associated with Fanapt, Spahris and Latuda are different from each other and from predecessor SGAs. From our knowledge of the receptor binding profiles of the three agents, we are hoping that they might provide additional benefit for associated dimensions of illness like mood, aggression, cognition and negative symptoms. Long-term studies, especially extended for months to years, are needed to support this anticipation.
In selecting from the three news SGAs, I hold the hope that each of them might demonstrate efficacy benefits in individual patients, but I do not expect to see a "Clozaril effect" with any of them. There is no single antipsychotic medication that solves the problems of schizophrenia or bipolar disorder.
Weight gain: The biggest concern raised by clinicians who have had experience with the older SGAs is whether these three new agents cause weight gain. In reviewing the registration studies submitted to the FDA by the manufacturers of these three SGAs, I found one outcome measure--common to all--that provides an easy means of estimating weight-gain liability: the percentage of subjects who gained seven percent or more of their initial body weight after 4-6 weeks on the agent in question.
Table 1 illustrates these data for the three new SGAs along with four of the older SGAs. Remembering that these studies have different patient mixes, dosing strategies, etc., and also remembering that in some patients, weight gain is welcomed, it is apparent that Saphris and Latuda exhibit substantially less weight gain than Fanapt and most of the older SGAs, including Geodon and Abilify. If this "snapshot" holds true in practice, then Saphris and Latuda should become popular with prescribed and patients. Watch for long-term studies and, most importantly, well-designed comparative studies to see if these early observations hold true.
Number Needed to Harm: Leslie Citrome, MD, MPH recently published a review of the registration data for the three SGAs of interest2. As a part of his review, he calculated the "number needed to harm" (NNH) for the adverse events reported in each drug-placebo study. "NNH tells us how many patients one would need to treat with one intervention (i.e., the SGA) versus another (i.e., placebo) in order to expect to encounter one additional adverse outcome," said Dr. Citrome in an interview.
For example, Saphris dosed at 20 mg per day yields an NNH of 13 for the side effect akathisia (restlessness). This means that for every 13 patients treated with Saphris 20 mg/day rather than placebo, one would expect to see an additional case of akathisia.
Dr. Citrome maintains that NNHs over 10 may be more acceptable than NNHs under 10. "I looked for 'single-digit' NNHs because they represent adverse events attributable to the medication and that can be expected to occur commonly in practice," he explained. He found three instances of single digit NNHs:
* Fanapt 20-24 g/day exhibits dizziness (NNH of 8)
* Latuda at all doses caused somnolence (NNH of 9)
* Latuda at all doses caused akathisia (restlessness, NNH of 9)
"But remember to also consider the time it takes to develop the side effect versus the time it takes for the drug to work," said Dr. Citrome, who added, "If the patient sees the value of the medicine quickly, she may be more willing to tolerate the event." In addition, it is important to consider how long the adverse event lasts, since a short-lived event may not be clinically important.
It should be noted that Fanapt has virtually no risk of akathisia and extrapyramidal symptoms, unlike Saphris or Latuda, which have demonstrated dose-related effects.
Other distinguishing factors
In addition to different FDA indications described above, we see the following variations among the three agents:
Route of administration: Fanapt and Latuda are taken orally, with Latuda requiring intake 350 calories of food at the time of administration. Saphris is taken sublin-gually and, in some patients, can cause a bitter taste and numbness in the mouth. In addition, individuals should avoid food or liquids for ten minutes following administration of Saphris. It is important to review these administration issues with patients.
Dosing: Latuda requires once-a-day dosing, an advantage over both Fanapt and Saphris which require twice-a-day dosing. Both Latuda and Saphris are initiated in the target dose range, while Fanapt requires an initial four days of dose titration up to the target range. All three agents reach peak blood levels in less than four hours.
Drug-Drug interactions: All three agents have the potential to interact with other medications and clinicians must be familiar with these differences.
We have not yet found a best practice for medications in the treatment of schizophrenia or bipolar disorder. Our clinical challenge is to treat each patient--one at a time. The three newest SGA medications discussed here are therefore welcomed additions to the list of currently available medications. Concerns about weight gain may be diminished in the case of Latuda and Saphris but we need long-term studies and observation of treatment over time to validate this early impression taken from registration studies.
Given the financial and emotional costs of these illnesses, and given the relatively low contribution that the cost of these medications make to the overall cost of treating schizophrenia and bipolar disorder, payers and policy makers should strongly consider making these new medications easily accessible to patients.
Dr. Glazer receives funding from Eli Lilly and Merck, the manufacturers of two products discussed in this article.
(1.) Lieberman JA, Stroup TS, McE-voy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353:1209-1223, 2005).
(2.) Citrate L. Iloperidone, asenapine, and lurasidone: a brief overview of 3 new second-generation antipsychotics. Postgrad Med. 2011 Mar; 123(2):153-62
Questions? Comments? Ideas?
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Table 1. Percentage of schizophrenia patients in 4-8 week trials that gained > 7% in body weight Product Daily Dose Range Drug Placebo (Generic Name) Newest SGAs Fanapt 12-24 mg 12% (10-16 mg) 4% (lloperidone) (titration req'd.) 18% (20-24 mg) Latuda 40-80 mg 5.6% 4.0% (Lurasidone) Saphris 10-20 mg 4.9% 2% (Asenapine) Older SGAs Ability 10-30 mg 8% 3% (Aripiprazole) Geodon 40-160 mg (1) 10% 4% (Ziprazidone) Zyprexa 5-10 mg 22% 3% (Olanzapine) Source: PDR.net2011 edition
BY WILLIAM M. GLAZER, MD