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 antiparkinson agents like Artane and Cogentin with the SGAs compared to the FGAs1.
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): Novartis' Fanapt (Iloperidone), Merck's Saphris (Asenapine), and Sunovion's Latuda (Lurasidone). 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.
Fanapt's labeling recommends that prescribers 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 prescribers and patients. Watch for long-term studies and, most importantly, well-designed comparative studies to see if these early observations hold true.
Table 1. Percentage of schizophrenia patients in 4-8 week trials that gained > 7% in body weight
Product (Generic Name)
Daily Dose Range
Source: PDR.net 2011 edition
12% (10-16 mg)
18% (20-24 mg)