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ou’ve probably heard aboutFanapta (iloperidone), a new antipsychotic marketed by VandaPharmaceuticals. No, it hasn’t been approvedofficially yet, but it is likely to winapprovalin July, and the company has already beentaking out teaser ads in the journals andhas even sponsored a touring promotionalCME program run by Stephen Stahl.Is it likely to represent an advance inantipsychotic treatment? Well…maybe. Is itlikely to represent a low point in the namingof new drugs? Definitely. And in fact,Fanapta is a slight improvement over iloperidone’s original trade name, which was – get ready – “Fiapta.”Before Vanda purchased the right todevelop iloperidone in 2004, the drug wasowned by Novartis, which conducted thefirst three controlled trials. Apparently,they were not dazzled by the results,because they promptly sold the drug to Vanda. These studies were summarized ina recent industry-supported supplement tothe Journal of Clinical Psychopharmacology (Potkin SG, et al.,
 J Clin Psychopharmacology
2008;28 (Suppl 1):S4-S11).In Study 1, schizophrenic patients were randomized to five treatment arms:Fanapta at one of three doses (8, 10, 12mg/day), Haldol 15 mg/day, or placebo. Atthe 6 week endpoint, Fanapta 8-12 mg/day did not statistically outperform placebo(this was the prespecified outcome variable) whereas Haldol 15 mg/day was robustly superior to placebo. In both Studies 2 and3, patients were randomized to Fanapta,Risperdal or placebo. Risperdal yielded morerobust improvements over placebo thanFanapta, but at least Fanapta was statistically superior to placebo in three of the four doses tested. None of these studies reportedthe statistical significance of the numericaladvantages of Haldol and Risperdal over Fanapta. This omission might be becausethe active comparator drugs were includedfor assay sensitivity only – that is, to ensurethe integrity of the overall study design. Lesscharitably, the data may have been left outbecause Fanapta would have looked bad.Only the company knows for sure….The Vanda-funded authors went togreat lengths to explain why Fanapta didso poorly in comparison to Haldol andRisperdal. Mostly, they blamed the dosing
IN THIS ISSUE
• Introducing...Fanapta!• Antipsychotic Update•Research Updates•Expert Q & A:
Michael Jibson, M.D., Ph.D. Antipsychotics and Meta-analyses: A Basic Survey 
 Focus of the Month:
 Antipsychotic Roundup2008
 VOLUME 6, NUMBER 6
 WWW.THECARLATREPORT.COM
 JUNE 2008
AN UNBIASED MONTHLYCOVERING ALLTHINGS PSYCHIATRIC
PAGE 1
May 2008
Continued on Page 3
Introducing...Fanapta!
Learning objectives for this issue:
1. Summarize the clinical trials evidence regarding Fanapta (iloperidone); 2. Describe recent data on Invega, Seroquel XR,and Abilify; 3. List recent meta-analyses regarding antipsychotics for the treatment of schizophrenia.This CME/CE activity is intended for psychiatrists, psychiatric nurses, psychologists and other health care professionals with an interest in the diagnosisand treatment of psychiatric disorders.
 Y 
Antipsychotic Updates
ere is some selective coverage of interesting recent developmentsin antipsychotic medications.
Invega
TCPR
gave Invega (paliperidone ER) alukewarm review soon after it was firstreleased (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 itsparent, Risperdal: first, more consistentblood levels could potentially lead to asmoother side effect profile (althoughthere are no data demonstrating this), andsecond, Invega is not metabolized in theliver, allowing the drug to be given safely to patients with liver failure.It has been over a year since thatreview. How has Invega held up? Hot off the press is a Cochrane Review of the Janssen drug (Nussbaum A and Stroup S,The reviewers analyzed all five studiescomparing paliperidone with placebo(three of which also compared it withZyprexa 10 mg/day). On efficacy, they foundthat, indeed, Invega is more effectivethanplacebo. Reviewing side effect profiles,Invega is similar to Risperdal, “with move-mentdisorders, weight gain, and tachycardiaall more common with paliperidone thanplacebo.” They also found that Invega “isassociated with substantial increases inserum prolactin that may be associated with sexual dysfunction, although sexualfunctioning outcomes were not reported.” While this is not different from Risperdal’s well known prolactin liability, one reviewer believes that Invega’s sustained releasemechanism leads to more sustained hyper-
H
Continued on Page 2
S ch iz o  ph r B u ll 
. 2008 May;34(3):419-22).
 
prolactinemia than seen with Risperdal, which could in turn lead to
more
sideeffects. 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 hasthe advantage of allowing the pill to becrushed and mixed into food, enhancingcompliance in patients who are reluctant totake medication. Invega, on the other hand,must remain intact for bioavailability, makingit an easier medication for reluctant patientsto “cheek” and to spit out later.The bottom line, according to Nussbaumand Stroup, is that “Regarding the criticalcomparison of oral paliperidone to risperi-done, we have no information and are thusunable 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 dothe 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. InNovember of 2007, the Bristol-Myers Squibbmedication received FDA approval as an add-on treatment for major depression inpatients who have not responded to a stan-dard antidepressant. The approval was basedon two studies, both of which compared Abilify with placebo augmentation in patients who had not responded to 8 weeks of anSSRI or Effexor XR (Berman RM et al.,
 J Clin Psychiatry
2007;68(6):843-53; Marcus RN etal.,
 J Clin Psychopharm
2008;28(2):156-165). After 6 weeks of augmentation, the remissionrates for patients on Abilify ranged from25.4% to 26% in both studies, while theremission rates on placebo were 15.2% to15.7%. This 10% separation between Abilify and placebo means that the number neededto treat (NNT) to achieve a benefit from Abilify is 10. In other words, you would haveto give Abilify to 10 patients in order to bringone additional patient to remission. In bothstudies, Abilify was started at 2 mg and titrat-ed up to a final average dose of from 11 to11.8 mg/day. The most common side effecton Abilify was akathisia, occurring in 23.1%to 25.9% of patients vs. 4.2% to 4.5% onplacebo.In May of 2008, the FDA approved Abilify for use as adjunctive treatment inpatients whose manic episodes have notresponded to lithium or Depakote. Thisapproval was based on a trial in which 384patients who had not responded to lithiumor Depakote were randomly assigned toreceive either adjunctive placebo or adjunctive Abilify, 15-30 mg (most patientsreceived 15 mg). At the 6 week endpoint, thereduction 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 experiencedakathisia, 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 receivedFDA approval for its extended release versionof Seroquel, called Seroquel XR, for the treat-ment of schizophrenia. The drug is availablein three dosage strengths: 200 mg, 300 mg,and 400 mg. The new formulation isadvertised as being more convenient becauseit 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 oldmedications, drug reps imply that Seroquel XR might have fewer side effects than theimmediate release version, because bloodlevels are more consistent. However, thistheoretical advantage has not been tested inhead-to-head studies, so it will be up to clini-cians to see if this marketing claim holds upin their practices.Meanwhile, because immediate releaseSeroquel will be losing patent protectionin about 2011, the company has beenfunneling most of its R & D money intofinding new indications for Seroquel XR.This appears to be paying off. At the 2008annual meeting of the American Psychiatric Association, the company presentedposters describing evidence that Seroquel XR may be helpful as monotherapy for both major depression and generalizedanxiety disorder.These studies have not been published,and therefore have not undergone the peer review process required to ensure thattheresearch designs and statistics are legitimate,but here are some of their preliminary data (you can access this online athttp://tinyurl.com/3v7heg). In one six week study of patients with major depression(without bipolar disorder), 723 patients were randomly assigned to one of threedoses 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 thedose. Patients on placebo improved by about 11 points on the same scale. Thedifferences between Seroquel XR andplacebo were statistically significant for all doses, although one might wonder  whether a 2.5 to 3.5 point improvementover placebo is
very
clinically significant.In a 10 week study of generalizedanxiety disorder (GAD), 951 patients wererandomized 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 factthat neither the 50 mg dose nor the 300mg dose were effective is odd, and impliesthat response to 150 mg may have beendue to chance.The bottom line is that the preliminary Seroquel XR depression data imply a smalleffect size, while the Seroquel XR data for GAD is unimpressive. We assume morestudies will be forthcoming.Meanwhile, before we consider treat-ing depression or anxiety with Seroquel(IR or XR), we need to consider that theside effects are much less benign thanthose resulting from standard antidepres-sant treatment. Among other things,Seroquel can cause significant weight gain,metabolic disturbances, and severe seda-tion, not to mention a small but still pres-ent risk of tardive dyskinesia. For thesereasons, Seroquel should be relegatedtoward the end of the list of treatmentoptions for these disorders.
PAGE 2
 June 2008
Continued from Page 1
Antipsychotic Updates
 
schedule, which specified a gradual rampingup of Fanapta over a two week period. Incontrast, the patients on the comparator medications achieved the therapeuticdose within a couple of days, puttingFanapta at a therapeutic disadvantage.(True, but in the real world, a drug thattakes two weeks to ramp up is, in fact,less desirable than others.)In order to correct for this imbalance,the authors did a revised analysis in whichthey deleted data on all patients who haddropped out of the study before two weeks. This led to abetter result for thecompany – now,
 all 
dose ranges of Fanapta beat place-bo, althoughFanapta’s perform-ance was still numer-ically inferior toHaldol and Risperdal. Which brings us tothe most recent Fanapta data. Once Vandatook over the drug, they revamped their research methods,either to more accurate-ly test Fanapta’s efficacy, or to simply make certain that it would look good thistime. The cynicism is not capricious: onestudy showed that in 90% of industry-funded comparisons of atypical antipsy-chotics, the sponsor’s drug came outahead due in part to manipulations of theresearch design (Heres S et al.,
 Am J  Psychiatry
2006;163:185-194). At any rate, in the new studies, thecompany chose to compare Fanapta withGeodon. Why Geodon? In an emailresponse, Vanda said they made the choicebecause of “similar tolerability profiles”between the two drugs, thereby prevent-ing researchers from guessing whichpatients were assigned to which drug – animportant issue in double-blind trials. Wesuspect that this is only part of the story.Fanapta has two distinct disadvantages: itrequires a gradual dose titration,and it can widen the QT interval in the EKG. From amarketing perspective, what better way todistract attention from these disadvan-tages than to compare the drug withGeodon, a medication sharing these liabil-ities?In the only Fanapta vs. Geodon study to be published thus far, a total of 593patients were randomized to either Fanapta24 mg/day, Geodon 160 mg/day or placebo(Cutler AJ et al.,
 J Clin Psychopharmacology
2008;28 (Suppl 1):S20-S28). After four  weeks of treatment, Fanapta and Geodonimprovedsymptoms by the same amount(Fanapta, 12 point PANNS (Positive andNegative Syndrome Scale) improvement;Geodon 12.3 points) and significantly more than placebo (7.1 points).In terms of side effects, Geodon causedmore akathisia, EPS, and sedation thanFanapta, while Fanapta caused more dizzi-ness, orthostatic hypotension, weight gain,and tachycardia.The two drugs lengthenedthe QT interval by about 11 millisecondsafter 14 days of treatment, but this less-ened by nearly half after four weeks.Thus far, then, we have an antipsychotic which appears to work as well as Geodonand which appears to cause less EPS andsedation, but more orthostasis, tachycar-dia, and weight gain, and the same EKG lia-bility. Not much to get excited about. What Vanda is hoping we
will 
get excited about is thepossibility that it may have developed a way of predicting patients who will respond. An article in the journal
 Pharmacogenomics
reported that patients who had two copies of aspecific gene responded differently in thestudy than patients with only copy (Lavedan C et al.,
 Pharmacogenomics
2008;9:289-301). The gene in questionencodes for a protein called Ciliary Neurotrophic Factor (CNTF), which is a neu-roprotectant moleculefor nerve cells andmay theoretically improve responses toantipsychotics. About 75% of Caucasiansare homozygous for CNTF (meaning thatthey carry two copies of the gene).The researchers compared the responseof patients who were homozygousto those who were heterozygous (only one copy of the CNTF gene). As it turned out, there
FanaptaPlaceboStatisticsFanaptaPlaceboStatistics12.0 (218)*5.7 (107)P=0.00212.2 (61)12.2 (31)P=0.98*Number in parentheses = number of subjects in each group.
 EDITORIAL INFORMATION 
 Publisher and Editor-in-Chief:
Daniel J. Carlat, M.D.,
is assistant clinical professor of psychiatry at Tufts University School of Medicine andmaintains a private practice in Newburyport, Massachusetts. He graduated from the psychiatric residency at Massachusetts General Hospital in1995 and is founding editor of 
The Practical Guide Series in Psychiatry
, published by Lippincott Williams & Wilkins.
 Associate Editor:
Marcia L. Zuckerman, M.D.,
practices psychiatry at HRI/Arbour in Brookline, Massachusetts.
 Editorial Board:
Ronald C. Albucher, M. D.,
chief medical officer, Westside Community Services, San Francisco
Ivan Goldberg, M.D.,
creator, Depression Central Web Site, psychopharmacologist in private practice, New York City 
 Alan D. Lyman, M.D.,
child and adolescent psychiatrist in private practice, New York City 
Robert L. Mick, M.D.,
medical director, DePaul Addiction Services, Rochester, New York 
Michael Posternak, M.D.,
staff psychiatrist, Massachusetts General Hospital, assistant professor of psychiatry, Harvard Medical School, BostonDr. Carlat, with editorial assistance by Dr. Zuckerman, is the author (unless other authorship is specified) of all articles and interviews for 
The Carlat Psychiatry Report 
. All editorial content is peer reviewed by the editorial board. Dr. Albucher, Dr. Carlat, Dr. Goldberg, Dr. Lyman, Dr.Mick, Dr. Posternak, and Dr. Zuckerman have disclosed that they have no relevant financial or other interests in any commercial
companies per-taining to this educational activity.
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 June 2008
Continued from Page 1
Introducing...Fanapta!
Continued on Page 6
Improvement in PANNS Score in Patients withtwo different Genotypes on Fanapta vs. Placebo
Two Copies of CNTF (homozygous) One Copy of CNTF (heterozygous)
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