ou’ve probably heard aboutFanapta (iloperidone), a newantipsychotic marketed by Vanda

Pharmaceuticals. No, it hasn’t been approvedofficially yet, but it is likely to win approvalin 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 overiloperidone’s original trade name, whichwas – 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 toVanda. These studies were summarized ina recent industry-supported supplement to

the Journal of Clinical Psychopharmacology(Potkin SG, et al., J Clin Psychopharmacology2008;28 (Suppl 1):S4-S11).

In Study 1, schizophrenic patientswere 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/daydid not statistically outperform placebo(this was the prespecified outcome variable)whereas Haldol 15 mg/day was robustlysuperior 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 statisticallysuperior to placebo in three of the fourdoses tested. None of these studies reportedthe statistical significance of the numericaladvantages of Haldol and Risperdal overFanapta. This omission might be becausethe active comparator drugs were includedfor assay sensitivity only – that is, to ensurethe integrity of the overall study design. Less

charitably, 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 Roundup

2008

VOLUME 6, NUMBER 6 WWW.THECARLATREPORT.COM JUNE 2008

AN UNBIASED MONTHLY COVERING ALL THINGS PSYCHIATRIC

PAG E 1May 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 Updatesere is some selective coverage ofinteresting recent developmentsin antipsychotic medications.

Invega

TCPR gave Invega (paliperidone ER) alukewarm review soon after it was firstreleased (see March 2007: “Invega: Canyou say ‘patent extender?’”). At that time wewere able to pinpoint only two potentiallymeaningful advantages of Invega over itsparent, Risperdal: first, more consistentblood levels could potentially lead to asmoother side effect profile (although

there are no data demonstrating this), andsecond, Invega is not metabolized in theliver, allowing the drug to be given safelyto patients with liver failure.

It has been over a year since thatreview. How has Invega held up? Hot offthe press is a Cochrane Review of theJanssen 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 effective than

placebo. Reviewing side effect profiles,Invega is similar to Risperdal, “with move-ment disorders, weight gain, and tachycardiaall more common with paliperidone thanplacebo.” They also found that Invega “isassociated with substantial increases inserum prolactin that may be associatedwith sexual dysfunction, although sexualfunctioning outcomes were not reported.”While this is not different from Risperdal’swell known prolactin liability, one reviewerbelieves that Invega’s sustained releasemechanism leads to more sustained hyper-

H

Continued on Page 2

Schizophr Bull . 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 JHealth-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 anyadvantages or disadvantages compared to itswell-known parent compound.” In otherwords, we’re still waiting for somebody to dothe head-to-head trials that should logicallyhave 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 comparedAbilify with placebo augmentation in patientswho had not responded to 8 weeks of anSSRI or Effexor XR (Berman RM et al., J ClinPsychiatry 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 Abilifyand placebo means that the number neededto treat (NNT) to achieve a benefit fromAbilify 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 approvedAbilify 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 oradjunctive Abilify, 15-30 mg (most patientsreceived 15 mg). At the 6 week endpoint, thereduction in the Young Mania Rating Scalewas 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, May9 (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 commonlydosed once a day. As has been the case forother extended-release versions of oldmedications, drug reps imply that SeroquelXR 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 been funneling 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 PsychiatricAssociation, the company presentedposters describing evidence that SeroquelXR may be helpful as monotherapy forboth major depression and generalizedanxiety disorder.

These studies have not been published,and therefore have not undergone the peerreview process required to ensure that theresearch designs and statistics are legitimate,but here are some of their preliminarydata (you can access this online athttp://tinyurl.com/3v7heg). In one six weekstudy of patients with major depression(without bipolar disorder), 723 patientswere randomly assigned to one of threedoses of Seroquel XR (50, 150, or 300) or to placebo. Patients on Seroquel XRimproved their MADRS scale scores by13.5 to 14.5 points, depending on thedose. Patients on placebo improved byabout 11 points on the same scale. Thedifferences between Seroquel XR andplacebo were statistically significant for all doses, although one might wonderwhether a 2.5 to 3.5 point improvementover placebo is very clinically significant.

In a 10 week study of generalized anxiety disorder (GAD), 951 patients wererandomized to the same three doses ofSeroquel XR as in the depression study(50 mg, 150 mg, or 300 mg) or placebo.Unlike the depression study, however, onlyone Seroquel XR dose did significantlybetter 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 preliminarySeroquel XR depression data imply a smalleffect size, while the Seroquel XR data forGAD 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.

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Continued from Page 1Antipsychotic Updates

schedule, which specified a gradual rampingup of Fanapta over a two week period. Incontrast, the patients on the comparatormedications 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 twoweeks. This led to abetter result for thecompany – now, alldose ranges ofFanapta 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 theirresearch methods, either to more accurate-ly test Fanapta’s efficacy, or to simplymake 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 JPsychiatry 2006;163:185-194).

At any rate, in the new studies, thecompany chose to compare Fanapta withGeodon. Why Geodon? In an email

response, 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 canwiden the QT interval in the EKG. From amarketing perspective, what better way todistract attention from these disadvan-tages than to compare the drug with

Geodon, a medication sharing these liabil-ities?

In the only Fanapta vs. Geodon studyto 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 Psychopharmacology2008;28 (Suppl 1):S20-S28). After fourweeks of treatment, Fanapta and Geodonimproved symptoms by the same amount(Fanapta, 12 point PANNS (Positive andNegative Syndrome Scale) improvement;Geodon 12.3 points) and significantlymore than placebo (7.1 points).

In terms of side effects, Geodon caused

more 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 antipsychoticwhich 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 willget excited about is thepossibility that it mayhave developed a wayof predicting patientswho will respond.

An article in thejournalPharmacogenomics

reported that patientswho had two copies of a

specific gene responded differently in thestudy than patients with only copy(Lavedan C et al., Pharmacogenomics2008;9:289-301). The gene in questionencodes for a protein called CiliaryNeurotrophic Factor (CNTF), which is a neu-roprotectant molecule for 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 homozygous to thosewho were heterozygous (only one copy ofthe CNTF gene). As it turned out, there

Fanapta Placebo Statistics Fanapta Placebo Statistics12.0 (218)* 5.7 (107) P=0.002 12.2 (61) 12.2 (31) P=0.98*Number in parentheses = number of subjects in each group.

EDITORIAL INFORMATIONPublisher and Editor-in-Chief: Daniel J. Carlat, M.D., is assistant clinical professor of psychiatry at Tufts University School of Medicine and maintains 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 FranciscoIvan Goldberg, M.D., creator, Depression Central Web Site, psychopharmacologist in private practice, New York CityAlan D. Lyman, M.D., child and adolescent psychiatrist in private practice, New York CityRobert L. Mick, M.D., medical director, DePaul Addiction Services, Rochester, New YorkMichael Posternak, M.D., staff psychiatrist, Massachusetts General Hospital, assistant professor of psychiatry, Harvard Medical School, Boston

Dr. 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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Continued from Page 1Introducing...Fanapta!

Continued on Page 6

Improvement in PANNS Score in Patients with two different Genotypes on Fanapta vs. Placebo

Two Copies of CNTF (homozygous) One Copy of CNTF (heterozygous)

This Month’s Expert:

Antipsychotics and Meta-analyses: A Basic SurveyMichael Jibson, M.D., Ph.D. Associate Professor of PsychiatryDirector of Residency Training, University of Michigan Health System, Ann Arbor

Dr. Jibson has disclosed that he is on the speaker’s bureau for Astra Zeneca, and gives talks regarding the use of quetiapine for bothschizophrenia and bipolar disorder. Dr. Jibson has disclosed that he has made between $20,000 and $50,000 from these activitiesover the past year. Dr. Carlat has reviewed and edited the content to ensure a balanced and unbiased presentation.

PAG E 4June 2008

Withthe Expert

TCPR: Dr. Jibson, there have been several meta-analyses comparing atypical antipsychotics published over the last fewyears. They are all long, complicated papers, and the conclusions are often controversial. Can you help us understandthis literature?Dr. Jibson: First, it’s important to distinguish a meta-analysis from a large comparative study. For example, the CATIE trial was alandmark comparative study of several antipsychotics. But it was not a meta-analysis. A meta-analysis is a way of summarizing theresults of many different clinical studies. TCPR: And are there different types of meta-analyses?Dr. Jibson: There are two kinds of meta-analyses. First, there are those that focus narrowly on a specific question, and are strict interms of which studies are included in the analysis. The Cochrane reviews are the best example of this. These reviewers typically setthe bar high in terms of which studies are “good enough” to qualify for the analysis. This means that they have a high threshold todemonstrate an effect. Consequently, Cochrane reviews often conclude that there is not enough evidence to demonstrate a differencebetween drugs. TCPR: Yes, I’ve noticed that. On the other hand, I suppose that when a Cochrane review concludes that one drug is betterthan another, you can be very certain that this is true. Dr. Jibson: Yes, and that is one of the advantages of this restrictive approach to doing these analyses. The other type of meta-analysis isa more broad survey of as many studies as you can include. The goal here is to try to gather together data on as many patients aspossible. This may allow for more interesting conclusions, although the quality of the studies may not be as high as one would like.These might best be described as hypothesis generating, that is, they may suggest a trend that should be investigated with morerigorous clinical studies. It is important to recognize that a meta-analysis cannot be any better than the studies that go into it. A meta-analysis comprised of poorly designed or poorly conducted studies, for example studies in which drugs are used at inappropriate dosesor which lack systematic outcome measures, will not be able to reach a meaningful conclusion. Meta-analyses are useful, however,in some situations in which individual studies may be limited not by quality but by size. For example, a well-conducted study maynot have a large enough sample size for group differences to reach statistical significance, but a meta-analysis of several studiestogether may correct that problem. Second, a group of well-conducted studies may each have an effect size that is too small to bedetected in any one study, but a collection of studies that show a small but uniform effect may reach statistical significance. Finally,high quality studies may differ in outcomes and a meta-analysis would allow a weighted average of studies to demonstrate if therewere a trend in one direction or another.TCPR: Can you go through the most important of these studies for schizophrenia?Dr. Jibson: The largest meta-analysis was the John Davis study of 2003 (Davis JM, et al., Arch Gen Psychiatry 2003; 60:553-64).Davis combined results from 124 clinical trials, including some unpublished material that was submitted to the FDA. He computedeffect sizes between second generation antipsychotics (SGAs) and first generation antipsychotics (FGAs). An effect size is a measureof the advantage of one drug over another. TCPR: And what did the Davis study conclude?Dr. Jibson: The investigators concluded two things. The first conclusion was expected: clozapine is more effective than FGAs. (They didnot compare clozapine with SGAs.) But the second finding was surprising: only two of the newer atypicals – olanzapine and risperidone– separated statistically from FGAs. In 2003, most of us assumed that all atypicals were equally effective, but this finding appearedto challenge this idea. TCPR: I recall there was some controversy about this conclusion, however. Dr. Jibson: Yes, there were two criticisms that emerged. First, the dosing used in the studies may have put some drugs at a disadvantage.Studies of risperidone were limited to those using a minimum dose of 4 mg/day, which is equal to the average dose in the community; the

Continued on Page 5

minimum allowed dose of olanzapine was 11 mg/day, about half the average community dose of 20 mg/day. But for studies of aripipra-zole, which has an average dose in the community of about 20 mg/day, and ziprasidone, which averages around 120 mg/day in thecommunity, no minimum dose was specified, and for quetiapine, the required minimum dose was 150 mg, far below the manufac-turer’s recommendation of 400-600 mg/day for schizophrenia. So it may be that these three drugs didn’t separate from FGAsbecause they were dosed too low. TCPR: And what was the other problem? Dr. Jibson: The second criticism was more global, and more interesting in some ways. Over the past couple of decades, it hasbecome harder and harder for clinical trials to demonstrate a separation between antipsychotics and placebo. I do not believe thisis because antipsychotics are ineffective, because we have an enormous body of data to indicate that they are, indeed, effective. Theproblem seems to be that it is getting harder to recruit patients for studies of antipsychotics, presumably because more and morepatients are finding their current treatment satisfactory. So there is a smaller group of patients willing to roll the dice on a placebovs. active drug study, and the patients who enroll tend to be less responsive to standard treatments.TCPR: And shortly after the Davis study, a “competing” meta-analysis was published. Dr. Jibson: Yes, that was the Leucht study, published in Lancet (Leucht S, et al., Lancet 2003; 361,1581-89). This meta-analysis concludedthat, in fact, there are no meaningful efficacy differences between the SGAs. But there were critiques of this study as well. It wasmuch smaller than the Davis paper, including only 31 studies, and it included several drugs in the analysis that were not includedin the Davis study, including Sertindole, amisulpride, and clozapine. TCPR: And then the CATIE trial came along and caused quite a splash. Dr. Jibson: Yes, the CATIE study showed that olanzapine appeared to be more effective than the other SGAs in maintenance treatmentof schizophrenia. The main problem with CATIE was that more patients came into the study already on olanzapine than any otherdrug, potentially enriching the study with olanzapine-responsive patients. Later, when the authors reanalyzed the results by removingany patients who were randomized to the same drug they were already taking, the effect size of olanzapine was cut in half. It wasstill numerically better than the other SGAs, but it dropped below the 0.05 level of statistical significance to 0.09, leaving only a“trend” toward superior effectiveness for olanzapine, a point not included in the paper’s abstract (Essock SM, et al., Am J Psychiatry2006; 163:2090-95).TCPR: What about the most recent meta-analyses?Dr. Jibson: A recently updated Cochrane review by Hunter (Hunter RH, Cochrane Database Syst Rev 2003; CD000440) comparedrisperidone with the FGAs. They found that there was slightly better patient acceptance of risperidone, which they attributed to“marginal benefits in terms of clinical improvement” and a side effect profile that “may be better” than haloperidol, but that theseadvantages were offset by the higher cost. They also made an intriguing observation: earlier studies showed a much clearer advantagefor risperidone than later studies. They suggested that this was because most early studies were industry-sponsored, while laterstudies were publicly sponsored. We know that industry-sponsored studies have a higher probability of showing a benefit of thesponsor’s drug, although the reason for this is not always clear. TCPR: I think many clinicians are reluctant to prescribe FGAs because of the fear of causing tardive dyskinesia (TD). Dr. Jibson: That’s a realistic concern, although this has to be weighed against the problems with metabolic side effects of the SGAs.

specifically to prevent cases of TD, and found the cost of preventing each case of TD so exorbitant that most public policy officialswould conclude that health systems could not afford it. TCPR: In the end, it seems that the meta-analyses are pretty mixed. How have the studies affected your choices ofantipsychotics?Dr. Jibson: I don’t think these studies support the preferential selection of any one drug for first-line treatment, and I start aboutequal numbers of patients on each of the atypicals and a few patients on first-generation drugs, usually based on side-effect profile,insurance coverage, need for depot medication, or patient preference. Since the CATIE study, however, I make sure that any patientwho has not had a satisfactory response to another drug has had a trial of olanzapine before I consider clozapine treatment. So I’mtending to give olanzapine the benefit of the doubt for a slight edge in effectiveness.TCPR: We’re starting to see the SGAs becoming available as generics. How will this change clinical practice?Dr. Jibson: I think that much of the heat of the debate on this issue will dissipate when the atypicals go generic. I predict that itwill be similar to what happened in the antidepressant world. When SSRIs were first introduced, there was debate about whetherthey should be preferentially prescribed over tricyclics, and whether their better side effect profile made up for their increased cost.But once the SSRIs went generic, and the cost of the two classes were the same, everyone lost interest in that debate, and the SSRIswon in terms of popularity. My guess is that the same thing will happen with atypicals.

PAG E 5June 2008

Continued from Page 4Q & A With the Expert

A review by Robert Rosenheck (Rosenheck RA, Br J Psychiatry 2007; 191, 238-45) looked at the cost vs. benefit of choosing SGAs

New report details additional Chantix side effects.A non-profit agency called the Institute for Safe Medication Practices (ISMP) has

released an analysis of the side effects of Chantix (varenicline), and the news is notgood. They found that in the 4th quarter of 2007, Chantix accounted for 988 seriousinjuries, more than any other single medication. To put this in perspective, the mediannumber of injuries reported per drug in that same quarter was five. This analysis isimportant because, while the FDA has issued a public health advisory about psychi-atric side effects of Chantix (see TCPR March 2008), the agency did not describethe data in any detail. ISMP obtained and analyzed data for all adverse eventsreported since Chantix was approved in 2006. They found 227 reports of suicidalacts, 397 cases of possible psychosis, and 525 cases of hostility or aggression. Inaddition, they found many cases of seizures, cardiac arrhythmias, and accidentsthat were associated with Chantix use. As a result of this report, the FAA hasbanned Chantix use for air traffic controllers and pilots, while the Federal MotorCarrier Safety Administration has banned its use in truckers. (The ISMP report isavailable online at http://www.ismp.org/docs/vareniclineStudy.asp.)

TCPR’s Take: It is becoming increasingly clear that Chantix causes psychiatric symp-toms in many people, and this latest data is making the drug look even more problemat-ic. Smoking, too, is problematic, so this remains a very tricky risk/benefit analysis. Thekey is full disclosure of this data to your patients, and very close follow-up.

An approach to treating comorbid anxiety disorder and bipolar disorder. How should we treat patients with both bipolar disorder and a comorbid anxiety

disorder? The answer is not straightforward. Antidepressants, especially SSRIs andSNRIs are generally our first line medication for anxiety disorders, but they cansometimes destabilize patients with bipolar disorder. Benzodiazepines are fine, butthey present their own potential problems with dependency and sedation. In thisstudy, researchers enrolled patients with bipolar disorder who were stable on lithi-um, but who also had a specific DSM-4 anxiety disorder. 47 patients were randomlyassigned to add-on treatment with either Zyprexa (N=24, mean dose 7.7 mg/day)or Lamictal (N=23, mean dose 96.7 mg/day). This was a single blind study, inwhich the patients did not know the identity of their pills, but the investigatorsdid. After 12 weeks, both medications were helpful in decreasing anxiety scores onthe Hamilton Anxiety Scale, but Zyprexa was significantly more effective than Lamictal.Lamictal had the unfortunate side effective of increasing anxiety in 8 of 23 patients(35%), vs. 0 of 24 on Zyprexa (Maina G, J Clin Psychiatry 2008;69:609-616).

TCPR’s Take: Zyprexa beat Lamictal, partly because the dose of Lamictal wastitrated so slowly that more Lamictal patients dropped out before the end of thetrial. Using the LOCF (last observation carried forward) approach, these scores atdropout were included in the final data analysis, making Lamictal look particularly bad.When only those patients who completed the trial were analyzed, there was no longera statistically significant difference. The bottom line is that Zyprexa is likely to bemore effective more quickly in anxious bipolar patients, but Lamictal will eventuallycatch up, if you can convince such patients to stay the course.

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Research UpdatesI N P S Y C H I A T R Y

TOBACCO DEPENDENCE

BIPOLAR DISORDER

Fanapta! Continued from Page 3

was no difference in response to Fanaptabetween these two groups, with bothshowing about a 12 point improvement onthe PANNS score. So how is the gene testvaluable? The patients who were homozy-gous responded much more poorly toplacebo (5.7 point improvement) than toFanapta, while heterozygous patients hadidentical responses to placebo and activedrug (see table).

Thus, it’s not really accurate to say thatthe genetic test predicts a better responseto the medication; rather, it predicts aworse response on placebo. While this isintriguing data, it’s not clear how clinicianswould actually use it. If my patient ishomozygous for CNTF, I would go aheadand prescribe Fanapta. But what if mypatient is heterozygous? According to thispaper, such a patient will still respond toFanapta, as well as to placebo. Since it isunethical to prescribe placebos in clinicalpractice, I’ll still be likely to prescribe amedication. Or, it might be that thesegenetically identified placebo-responderswill end up doing fine with no treatmentat all – but the study did not include a “notreatment” arm, so we do not know if thisis true.

Finally, does this genetic test predictplacebo response to antipsychotics other

paper did not discuss

Fanapta: Genomic Advance orGenomic Snow Job? Crucial

data is yet to come.

TCPR VERDICT:TCPR VERDICT:

this crucial question, Vanda told me that, yes, “the same trend appears to hold for Geodon.” Because of this, the test appears to provide no

Fanapta over Geodon, or, by extension, over any other atypical. The company says it plans to

may be

rationale for choosing

test other genetic markers that specific predictors of response to

than Fanapta? While the

Fanapta.

Pharmocogenomics

CME Post-TestTo earn CME or CE credit, you must read the articles and complete the quiz below, answering at least four of the questions correctly. Mail a photocopyor fax the completed page (no cover sheet required) to Clearview CME Institute, P.O. Box 626, Newburyport, MA 01950; fax (978) 499-2278. Forcustomer service, please call (978) 499-0583. Only the first entry will be considered for credit and must be received by Clearview CME Institute by May31, 2009. Acknowledgment will be sent to you within six to eight weeks of participation.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing MedicalEducation (ACCME) through the sponsorship of the Clearview CME Institute. Clearview CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Clearview CME Institute is also approved by the American Psychological Association to sponsor continuingeducation for psychologists. Clearview CME Institute maintains responsibility for this program and its content.

Clearview CME Institute designates this educational activity for a maximum of one (1) AMA PRA Category 1 CreditTM or 1 CE for psychologists.Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.

Please identify your answer by placing a check mark or an X in the box accompanying the appropriate letter. Note: learning objectives are listed onpage 1.

1. The genetic test reported in the recent Fanapta (iloperidone) study predicts: (Learning objective #1) [ ] a. Greater improvement for patients on Geodon.[ ] b. Greater improvement for patients on Fanapta.[ ] c. Differential response to placebo.[ ] d. Worse response to Geodon.

2. Abilify (aripiprazole) has a new FDA approval for: (L.O. #2) [ ] a. Antidepressant augmentation in bipolar depression.[ ] b. Antidepressant augmentation in unipolar depression. [ ] c. Monotherapy for unipolar depression. [ ] d. Monotherapy for bipolar depression.

3. Fanapta causes more akathisia and EPS than Geodon. (L.O. #1)[ ] a. True [ ] b. False

4. Seroquel XR is available in the following doses: (L.O. #2)[ ] a. 200 mg, 300 mg and 400 mg. [ ] b. 50 mg, 100 mg and 200 mg.[ ] c. 200 mg, 400 mg and 800 mg.[ ] d. 25 mg, 50 mg, and 100 mg.

5. According to Dr. Jibson, more recent studies have shown a more robust effect of antipsychotics than older studies. (L.O. #3)[ ] a. True [ ] b. False

PAG E 7June 2008

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PAG E 8June 2008

This Month’s Focus:Antipsychotic Roundup

2008

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The First Antipsychotiche first antipsychotic medication was discoveredby a French naval surgeon named Henri

Laborit. Dr. Laborit had little interest in psychiatry,but was avidly seeking a way to better treatwounded soldiers who were in shock. In June of1951, he obtained a medication from the FrenchPharmaceutical firm Rhone-Poulenc that was billedas effective in “potentiating” anesthetic agents usedduring surgery. He found it quite helpful, but noted astrange sense of psychological apathy as a sideeffect. The compound, a phenothiazine dubbed“4560 RP”, was later named “chlorpromazine”,and Laborit persuaded some psychiatrist colleaguesto try it on their patients. The first patient to receiveit was Jacques L, a 24 year old in the midst of amanic episode., on January 19, 1952. Soon, newsof the drug had spread throughout France, and thefollowing year American psychiatrists discovered it.

Source: Edward Shorter, A History of Psychiatry, New York: John Wiley and Sons, Inc., 1997.

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