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VOLUME 6, NUMBER 6
ou’ve probably heard about Fanapta (iloperidone), a new antipsychotic marketed by Vanda Pharmaceuticals. No, it hasn’t been approved officially yet, but it is likely to win approval in July, and the company has already been taking out teaser ads in the journals and has even sponsored a touring promotional CME program run by Stephen Stahl. Is it likely to represent an advance in antipsychotic treatment? Well…maybe. Is it likely to represent a low point in the naming of 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 to develop iloperidone in 2004, the drug was owned by Novartis, which conducted the first three controlled trials. Apparently, they were not dazzled by the results, because they promptly sold the drug to Vanda. These studies were summarized in a recent industry-supported supplement to
the 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, 12 mg/day), Haldol 15 mg/day, or placebo. At the 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 and 3, patients were randomized to Fanapta, Risperdal or placebo. Risperdal yielded more robust improvements over placebo than Fanapta, but at least Fanapta was statistically superior to placebo in three of the four doses tested. None of these studies reported the statistical significance of the numerical advantages of Haldol and Risperdal over Fanapta. This omission might be because the active comparator drugs were included for assay sensitivity only – that is, to ensure the integrity of the overall study design. Less
IN THIS ISSUE
Antipsychotic Roundup 2008
• Introducing...Fanapta! • Antipsychotic Update • Research Updates • Expert Q & A: Michael Jibson, M.D., Ph.D. Antipsychotics and Meta-analyses: A Basic Survey
charitably, the data may have been left out because Fanapta would have looked bad. Only the company knows for sure…. The Vanda-funded authors went to great lengths to explain why Fanapta did so poorly in comparison to Haldol and Risperdal. Mostly, they blamed the dosing
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Focus of the Month:
ere is some selective coverage of interesting recent developments in antipsychotic medications. 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 hyperContinued on Page 2
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
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 diagnosis and treatment of psychiatric disorders.
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prolactinemia 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.
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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.
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Publisher 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 in 1995 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, 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 pertaining to this educational activity.
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schedule, which specified a gradual ramping response, Vanda said they made the choice more akathisia, EPS, and sedation than up of Fanapta over a two week period. In because of “similar tolerability profiles” Fanapta, while Fanapta caused more dizzicontrast, the patients on the comparator between the two drugs, thereby preventness, orthostatic hypotension, weight gain, medications achieved the therapeutic ing researchers from guessing which and tachycardia. The two drugs lengthened dose within a couple of days, putting patients were assigned to which drug – an the QT interval by about 11 milliseconds Fanapta at a therapeutic disadvantage. important issue in double-blind trials. We after 14 days of treatment, but this less(True, but in the real world, a drug that suspect that this is only part of the story. ened by nearly half after four weeks. takes two weeks to ramp up is, in fact, Fanapta has two distinct disadvantages: it Thus far, then, we have an antipsychotic less desirable than others.) requires a gradual dose titration, and it can which appears to work as well as Geodon In order to correct for this imbalance, widen the QT interval in the EKG. From a and which appears to cause less EPS and the authors did a revised analysis in which marketing perspective, what better way to sedation, but more orthostasis, tachycarthey deleted data on all patients who had distract attention from these disadvandia, and weight gain, and the same EKG liadropped out of the study before two tages than to compare the drug with bility. Not much to get excited about. What weeks. This led to a Vanda is hoping we will better result for the get excited about is the Improvement in PANNS Score in Patients with company – now, all possibility that it may two different Genotypes on Fanapta vs. Placebo dose ranges of have developed a way Fanapta beat placeof predicting patients Two Copies of CNTF (homozygous) One Copy of CNTF (heterozygous) bo, although who will respond. Fanapta Placebo Statistics Fanapta Placebo Statistics Fanapta’s performAn article in the ance was still numerjournal 12.0 (218)* 5.7 (107) P=0.002 12.2 (61) 12.2 (31) P=0.98 ically inferior to Pharmacogenomics Haldol and Risperdal. *Number in parentheses = number of subjects in each group. reported that patients Which brings us to who had two copies of a the most recent Fanapta data. Once Vanda Geodon, a medication sharing these liabilspecific gene responded differently in the took over the drug, they revamped their ities? study than patients with only copy research methods, either to more accurateIn the only Fanapta vs. Geodon study (Lavedan C et al., Pharmacogenomics ly test Fanapta’s efficacy, or to simply to be published thus far, a total of 593 2008;9:289-301). The gene in question make certain that it would look good this patients were randomized to either Fanapta encodes for a protein called Ciliary time. The cynicism is not capricious: one 24 mg/day, Geodon 160 mg/day or placebo Neurotrophic Factor (CNTF), which is a neustudy showed that in 90% of industry(Cutler AJ et al., J Clin Psychopharmacology roprotectant molecule for nerve cells and funded comparisons of atypical antipsy2008;28 (Suppl 1):S20-S28). After four may theoretically improve responses to chotics, the sponsor’s drug came out weeks of treatment, Fanapta and Geodon antipsychotics. About 75% of Caucasians ahead due in part to manipulations of the improved symptoms by the same amount are homozygous for CNTF (meaning that research design (Heres S et al., Am J (Fanapta, 12 point PANNS (Positive and they carry two copies of the gene). Psychiatry 2006;163:185-194). Negative Syndrome Scale) improvement; The researchers compared the response At any rate, in the new studies, the Geodon 12.3 points) and significantly of patients who were homozygous to those company chose to compare Fanapta with more than placebo (7.1 points). who were heterozygous (only one copy of Geodon. Why Geodon? In an email In terms of side effects, Geodon caused the CNTF gene). As it turned out, there
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This Month’s Expert: Antipsychotics and Meta-analyses: A Basic Survey Michael Jibson, M.D., Ph.D.
Associate Professor of Psychiatry Director 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 both schizophrenia and bipolar disorder. Dr. Jibson has disclosed that he has made between $20,000 and $50,000 from these activities over the past year. Dr. Carlat has reviewed and edited the content to ensure a balanced and unbiased presentation.
With the Expert
TCPR: Dr. Jibson, there have been several meta-analyses comparing atypical antipsychotics published over the last few years. They are all long, complicated papers, and the conclusions are often controversial. Can you help us understand this literature? Dr. Jibson: First, it’s important to distinguish a meta-analysis from a large comparative study. For example, the CATIE trial was a landmark comparative study of several antipsychotics. But it was not a meta-analysis. A meta-analysis is a way of summarizing the results 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 in terms of which studies are included in the analysis. The Cochrane reviews are the best example of this. These reviewers typically set the bar high in terms of which studies are “good enough” to qualify for the analysis. This means that they have a high threshold to demonstrate an effect. Consequently, Cochrane reviews often conclude that there is not enough evidence to demonstrate a difference between drugs. TCPR: Yes, I’ve noticed that. On the other hand, I suppose that when a Cochrane review concludes that one drug is better than 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 is a 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 as possible. 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 more rigorous clinical studies. It is important to recognize that a meta-analysis cannot be any better than the studies that go into it. A metaanalysis comprised of poorly designed or poorly conducted studies, for example studies in which drugs are used at inappropriate doses or 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 may not have a large enough sample size for group differences to reach statistical significance, but a meta-analysis of several studies together may correct that problem. Second, a group of well-conducted studies may each have an effect size that is too small to be detected 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 there were 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 computed effect sizes between second generation antipsychotics (SGAs) and first generation antipsychotics (FGAs). An effect size is a measure of 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 did not 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 appeared to 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
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Q & A With the Expert
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minimum allowed dose of olanzapine was 11 mg/day, about half the average community dose of 20 mg/day. But for studies of aripiprazole, which has an average dose in the community of about 20 mg/day, and ziprasidone, which averages around 120 mg/day in the community, no minimum dose was specified, and for quetiapine, the required minimum dose was 150 mg, far below the manufacturer’s recommendation of 400-600 mg/day for schizophrenia. So it may be that these three drugs didn’t separate from FGAs because 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 has become harder and harder for clinical trials to demonstrate a separation between antipsychotics and placebo. I do not believe this is because antipsychotics are ineffective, because we have an enormous body of data to indicate that they are, indeed, effective. The problem seems to be that it is getting harder to recruit patients for studies of antipsychotics, presumably because more and more patients are finding their current treatment satisfactory. So there is a smaller group of patients willing to roll the dice on a placebo vs. 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 concluded that, in fact, there are no meaningful efficacy differences between the SGAs. But there were critiques of this study as well. It was much smaller than the Davis paper, including only 31 studies, and it included several drugs in the analysis that were not included in 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 treatment of schizophrenia. The main problem with CATIE was that more patients came into the study already on olanzapine than any other drug, potentially enriching the study with olanzapine-responsive patients. Later, when the authors reanalyzed the results by removing any patients who were randomized to the same drug they were already taking, the effect size of olanzapine was cut in half. It was still 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 Psychiatry 2006; 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) compared risperidone 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 these advantages were offset by the higher cost. They also made an intriguing observation: earlier studies showed a much clearer advantage for risperidone than later studies. They suggested that this was because most early studies were industry-sponsored, while later studies were publicly sponsored. We know that industry-sponsored studies have a higher probability of showing a benefit of the sponsor’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. A review by Robert Rosenheck (Rosenheck RA, Br J Psychiatry 2007; 191, 238-45) looked at the cost vs. benefit of choosing SGAs specifically to prevent cases of TD, and found the cost of preventing each case of TD so exorbitant that most public policy officials would 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 of antipsychotics? Dr. Jibson: I don’t think these studies support the preferential selection of any one drug for first-line treatment, and I start about equal 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 patient who has not had a satisfactory response to another drug has had a trial of olanzapine before I consider clozapine treatment. So I’m tending 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 it will be similar to what happened in the antidepressant world. When SSRIs were first introduced, there was debate about whether they 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 SSRIs won in terms of popularity. My guess is that the same thing will happen with atypicals.
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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 not good. They found that in the 4th quarter of 2007, Chantix accounted for 988 serious injuries, more than any other single medication. To put this in perspective, the median number of injuries reported per drug in that same quarter was five. This analysis is important because, while the FDA has issued a public health advisory about psychiatric side effects of Chantix (see TCPR March 2008), the agency did not describe the data in any detail. ISMP obtained and analyzed data for all adverse events reported since Chantix was approved in 2006. They found 227 reports of suicidal acts, 397 cases of possible psychosis, and 525 cases of hostility or aggression. In addition, they found many cases of seizures, cardiac arrhythmias, and accidents that were associated with Chantix use. As a result of this report, the FAA has banned Chantix use for air traffic controllers and pilots, while the Federal Motor Carrier Safety Administration has banned its use in truckers. (The ISMP report is available online at http://www.ismp.org/docs/vareniclineStudy.asp.) TCPR’s Take: It is becoming increasingly clear that Chantix causes psychiatric symptoms in many people, and this latest data is making the drug look even more problematic. Smoking, too, is problematic, so this remains a very tricky risk/benefit analysis. The key is full disclosure of this data to your patients, and very close follow-up.
was no difference in response to Fanapta between these two groups, with both showing about a 12 point improvement on the PANNS score. So how is the gene test valuable? The patients who were homozygous responded much more poorly to placebo (5.7 point improvement) than to Fanapta, while heterozygous patients had identical responses to placebo and active drug (see table). Thus, it’s not really accurate to say that the genetic test predicts a better response to the medication; rather, it predicts a worse response on placebo. While this is intriguing data, it’s not clear how clinicians would actually use it. If my patient is homozygous for CNTF, I would go ahead and prescribe Fanapta. But what if my patient is heterozygous? According to this paper, such a patient will still respond to Fanapta, as well as to placebo. Since it is unethical to prescribe placebos in clinical practice, I’ll still be likely to prescribe a medication. Or, it might be that these genetically identified placebo-responders will end up doing fine with no treatment at all – but the study did not include a “no treatment” arm, so we do not know if this is true. Finally, does this genetic test predict placebo response to antipsychotics other than Fanapta? While the Pharmocogenomics paper did not discuss 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 rationale for choosing Fanapta over Geodon, or, by extension, over any other atypical. The company says it plans to test other genetic markers that may be specific predictors of response to Fanapta.
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 and SNRIs are generally our first line medication for anxiety disorders, but they can sometimes destabilize patients with bipolar disorder. Benzodiazepines are fine, but they present their own potential problems with dependency and sedation. In this study, researchers enrolled patients with bipolar disorder who were stable on lithium, but who also had a specific DSM-4 anxiety disorder. 47 patients were randomly assigned 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, in which the patients did not know the identity of their pills, but the investigators did. After 12 weeks, both medications were helpful in decreasing anxiety scores on the 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 was titrated so slowly that more Lamictal patients dropped out before the end of the trial. Using the LOCF (last observation carried forward) approach, these scores at dropout 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 longer a statistically significant difference. The bottom line is that Zyprexa is likely to be more effective more quickly in anxious bipolar patients, but Lamictal will eventually catch up, if you can convince such patients to stay the course.
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Fanapta: Genomic Advance or Genomic Snow Job? Crucial data is yet to come.
To 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 photocopy or fax the completed page (no cover sheet required) to Clearview CME Institute, P.O. Box 626, Newburyport, MA 01950; fax (978) 499-2278. For customer service, please call (978) 499-0583. Only the first entry will be considered for credit and must be received by Clearview CME Institute by May 31, 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 Medical Education (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 continuing education 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 on page 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. Visit Our [ ] 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.
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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
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The First Antipsychotic
medication was T he first antipsychoticsurgeon named discovered by a French naval Henri Laborit. Dr. Laborit had little interest in psychiatry, but was avidly seeking a way to better treat wounded soldiers who were in shock. In June of 1951, he obtained a medication from the French Pharmaceutical firm Rhone-Poulenc that was billed as effective in “potentiating” anesthetic agents used during surgery. He found it quite helpful, but noted a strange sense of psychological apathy as a side effect. The compound, a phenothiazine dubbed “4560 RP”, was later named “chlorpromazine”, and Laborit persuaded some psychiatrist colleagues to try it on their patients. The first patient to receive it was Jacques L, a 24 year old in the midst of a manic episode., on January 19, 1952. Soon, news of the drug had spread throughout France, and the following year American psychiatrists discovered it.
Source: Edward Shorter, A History of Psychiatry, New York: John Wiley and Sons, Inc., 1997.
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This Month’s Focus: Antipsychotic Roundup 2008
Next Month in The Carlat Psychiatry Report: Update on Bipolar Disorder, including reviews of mood stabilizers, the diagnosis of bipolar disorder in children, and neurobiological findings.
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