Abilify (aripiprazole) is out! But you probably already know this, if your mailbox and fax machine have become as saturated with BMS-funded missives from CME, Inc. as mine have been. The hired guns are out in force once again, and so we front-line clinicians are faced with the task of separating the authentic wheat from the hyped-up chaff.

The buzz is about its mechanism of action, which is unique among currently approved antipsychotics. Rather than being a dopamine blocker, it is a “dopamine system stabilizer”. What does this fancy moniker actually mean?

Let’s go back to the basics of antipsychotics. Conventional agents are dopamine antagonists throughout the brain, not distinguishing between the mesolimbic regions (where too much dopamine causes psychosis, we hypothesize) and the nigrostriatal region (where dopamine normally modulates fluidity of movement). Thus, far from “stabilizing” dopamine, conventional neuroleptics shut down on dopamine indiscriminately, leading to the movement disorders for which they are infamous.

So, along came the atypicals, first Clozaril, and subsequently the “first-line atypicals” (Risperdal, Zyprexa, Seroquel, and Geodon). Like conventionals, atypicals block dopamine receptors, but they also do something to modulate this effect: they block serotonin 2A receptors, especially in the nigrostriatal cortex. Since decreasing serotonin tends to increase dopamine, blocking 5HT 2A has the effect of releasing more dopamine where it is needed to prevent movement problems. Thus, atypicals tend not to cause EPS or TD. In a very real sense, then, current atypicals already are dopamine system stabilizers. So why the hullabaloo over Abilify?

It is not entirely clear. It may be because Abilify’s mechanism of stabilizing the dopamine system is more elegant. Rather than blocking dopamine in one area, then relying on also blocking serotonin to normalize levels, Abilify is a “partial agonist” of D2 in the first place, meaning that it sits on the dopamine receptor strongly enough to bat away the excess dopamine that causes psychosis, while at the same time exerting enough mild dopamine-like activity to prevent movement disorders. So its dopamine stabilizing mechanism is more direct. But does that make it a better antipsychotic? Probably not.

“Currently available atypicals do a pretty good job of ‘stabilizing’ the dopamine system already. Abilify is just more elegant in its mechanism.”

In fact, the clinical trials very clearly show that Abilify is no more effective than either Haldol or Risperdal. The most widely read study, by Kane and colleagues, randomized 414 acutely relapsed schizophrenic patients to one of four groups: Abilify 15 mg, Abilify 30 mg, Haldol 10 mg, and Placebo. All three active treatments improved both positive and negative symptoms equivalently. The only significant benefit of Abilify was in its better side effect profile.

In terms of side effects, Abilify may very well be the most perfect antipsychotic yet developed. No EPS, no weight gain, no hyperprolactinemia, less sedation than any of its competitors (but watch out for insomnia, which is common). Abilify is Geodon without QT prolongation, and for this reason TCR predicts that it will become very popular, very quickly.

Dose it like this: Start at 15 mg Q AM, aim for 15 mg to 30 mg for best therapeutic effect. Try to stay at 15 mg though, because at 30 mg there is more sedation. It’s a very easy drug to use.

If only the Abilify-boosters would stop harping on its pseudo-unique mechanism of action and emphasize what makes it truly unique—the best side effect profile in its class.

TCR VERDICT: The most perfect atypical—but enough about its mechanism!

_{1. Kane JM, Carson WH, Saha AR: Efficacy and safety of aripiprazole and haloperidal versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-771.}