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Antipsychotic Updates

Antipsychotic UpdatesHere is some selective coverage of interesting recent developments in antipsychotic medications.

Invega

TCPR gave Invega (paliperidone ER) a lukewarm review soon after it was first released (see March 2007: “Invega: Can you say ‘patent extender?’”). At that time we were able to pinpoint only two potentially meaningful advantages of Invega over its parent, Risperdal: first, more consistent blood levels could potentially lead to a smoother side effect profile (although there are no data demonstrating this), and second, Invega is not metabolized in the liver, allowing the drug to be given safely to patients with liver failure.

It has been over a year since that review. How has Invega held up? Hot off the press is a Cochrane Review of the Janssen drug (Nussbaum A and Stroup S,Schizophr Bull. 2008 May;34(3):419-22). The reviewers analyzed all five studies comparing paliperidone with placebo (three of which also compared it with Zyprexa 10 mg/day). On efficacy, they found that, indeed, Invega is more effective than placebo. Reviewing side effect profiles, Invega is similar to Risperdal, “with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo.” They also found that Invega “is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported.” While this is not different from Risperdal’s well known prolactin liability, one reviewer believes that Invega’s sustained release mechanism leads to more sustained hyperprolactinemia than seen with Risperdal, which could in turn lead to more side effects. Without direct comparative data, though, this is conjecture (Dopheide J, Am J Health-Syst Pharm 2008;65 (Mar):401). Finally, this author notes that Risperdal has the advantage of allowing the pill to be crushed and mixed into food, enhancing compliance in patients who are reluctant to take medication. Invega, on the other hand, must remain intact for bioavailability, making it an easier medication for reluctant patients to “cheek” and to spit out later.

The bottom line, according to Nussbaum and Stroup, is that “Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.” In other words, we’re still waiting for somebody to do the head-to-head trials that should logically have been done in the first place.

Abilify

Over the past year, Abilify (aripiprazole) has won two new FDA indications. In November of 2007, the Bristol-Myers Squibb medication received FDA approval as an addon treatment for major depression in patients who have not responded to a standard antidepressant. The approval was based on two studies, both of which compared Abilify with placebo augmentation in patients who had not responded to 8 weeks of an SSRI or Effexor XR (Berman RM et al., J Clin Psychiatry 2007;68(6):843-53; Marcus RN et al., J Clin Psychopharm 2008;28(2):156-165). After 6 weeks of augmentation, the remission rates for patients on Abilify ranged from 25.4% to 26% in both studies, while the remission rates on placebo were 15.2% to 15.7%. This 10% separation between Abilify and placebo means that the number needed to treat (NNT) to achieve a benefit from Abilify is 10. In other words, you would have to give Abilify to 10 patients in order to bring one additional patient to remission. In both studies, Abilify was started at 2 mg and titrated up to a final average dose of from 11 to 11.8 mg/day. The most common side effect on Abilify was akathisia, occurring in 23.1% to 25.9% of patients vs. 4.2% to 4.5% on placebo.

In May of 2008, the FDA approved Abilify for use as adjunctive treatment in patients whose manic episodes have not responded to lithium or Depakote. This approval was based on a trial in which 384 patients who had not responded to lithium or Depakote were randomly assigned to receive either adjunctive placebo or adjunctive Abilify, 15-30 mg (most patients received 15 mg). At the 6 week endpoint, the reduction in the Young Mania Rating Scale was statistically greater in patients on Abilify (-13.3) than on placebo (-10.7). However, 19% of patients on Abilify experienced akathisia, vs. 5% of patients on placebo (Vieta E et al., Am J Psychiatry 2008, May 9 (epub ahead of print)).

Seroquel XR

In June of 2007, Astra Zeneca received FDA approval for its extended release version of Seroquel, called Seroquel XR, for the treatment of schizophrenia. The drug is available in three dosage strengths: 200 mg, 300 mg, and 400 mg. The new formulation is advertised as being more convenient because it can be dosed daily, although, in truth, immediate release Seroquel is also commonly dosed once a day. As has been the case for other extended-release versions of old medications, drug reps imply that Seroquel XR might have fewer side effects than the immediate release version, because blood levels are more consistent. However, this theoretical advantage has not been tested in head-to-head studies, so it will be up to clinicians to see if this marketing claim holds up in their practices.

Meanwhile, because immediate release Seroquel will be losing patent protection in about 2011, the company has been funneling most of its R & D money into finding new indications for Seroquel XR. This appears to be paying off. At the 2008 annual meeting of the American Psychiatric Association, the company presented posters describing evidence that Seroquel XR may be helpful as monotherapy for both major depression and generalized anxiety disorder.

These studies have not been published, and therefore have not undergone the peer review process required to ensure that the research designs and statistics are legitimate, but here are some of their preliminary data (you can access this online at http://tinyurl.com/3v7heg). In one six week study of patients with major depression (without bipolar disorder), 723 patients were randomly assigned to one of three doses of Seroquel XR (50, 150, or 300) or to placebo. Patients on Seroquel XR improved their MADRS scale scores by 13.5 to 14.5 points, depending on the dose. Patients on placebo improved by about 11 points on the same scale. The differences between Seroquel XR and placebo were statistically significant for all doses, although one might wonder whether a 2.5 to 3.5 point improvement over placebo is very clinically significant.

In a 10 week study of generalized anxiety disorder (GAD), 951 patients were randomized to the same three doses of Seroquel XR as in the depression study (50 mg, 150 mg, or 300 mg) or placebo. Unlike the depression study, however, only one Seroquel XR dose did significantly better than placebo – 150 mg/day. The fact that neither the 50 mg dose nor the 300 mg dose were effective is odd, and implies that response to 150 mg may have been due to chance.

The bottom line is that the preliminary Seroquel XR depression data imply a small effect size, while the Seroquel XR data for GAD is unimpressive. We assume more studies will be forthcoming.

Meanwhile, before we consider treating depression or anxiety with Seroquel (IR or XR), we need to consider that the side effects are much less benign than those resulting from standard antidepressant treatment. Among other things, Seroquel can cause significant weight gain, metabolic disturbances, and severe sedation, not to mention a small but still present risk of tardive dyskinesia. For these reasons, Seroquel should be relegated toward the end of the list of treatment options for these disorders.

Antipsychotic Updates

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This article was published in print 6:2008 in Volume:Issue 6:6.


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APA Reference
Psychiatry Report, T. (2013). Antipsychotic Updates. Psych Central. Retrieved on December 12, 2018, from https://pro.psychcentral.com/antipsychotic-updates-2/

 

Scientifically Reviewed
Last updated: 6 Sep 2013
Last reviewed: By John M. Grohol, Psy.D. on 6 Sep 2013
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