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Our top story this month looks at a new study examining the QT prolongation risks with the antidepressant citalopram. Results about this potentially fatal side effect are presented, and we talk to lead author Dr. Roy Perlis.
Study of antidepressants finds modest effect on QT prolongation designed to offer prescribers A study additional guidance beyond federal prcis
regulators warnings about QT interval prolongation risk with use of the antidepressant citalopram (Celexa) has confirmed modest prolongation with citalopram and has found similar effects for some other antidepressants. This study also stands as noteworthy in its examination of data from electronic health records, a methodology that is seen as increasingly common as a complement to data collected through randomized clinical trials. Medication-induced prolongation of ventricular repolarization can lead to fatal arrhythmias, so a great deal of attention has been focused on reports of some antidepressants
Electronic medical records data for more than 38,000 patients were studied to examine QT intervals in individuals who were prescribed antidepressants. Increasing doses of citalopram, escitalopram, and amitriptyline were found to predict QT prolongation, while increasing doses of bupropion were associated with significant decreases in QTc. Effect sizes were modest overall; the authors suggested that several antidepressants could pose a lesser risk than citalopram for patients with other risk factors. QT Prolongation, continued on page 5
Inside
Drug-Drug Interactions . . 2
SSRIs and tramadol: Possible link to serotonin syndrome
Regulatory News
FDA Update
FDA offers new guidance on developing drugs for Alzheimers disease . . . . . . . . . . . . . . . . . . . . . . 6
prcis
News Notes
Common genetic variation and antidepressant efficacy . . . . . 7 Antipsychotics and weight change . 7 Pharmacogenetic study looks at cocaine abuse . . . 8 Polymorphism predicts 2011 escitalopram dose for depression . . . . . . . . 8
Silver
Food and Drug Administration T he (FDA) dealt Reckitt Benckiser Pharmaceuticals three setbacks in a single letter in February: 1) it denied the manufacturers request that all generic competition to Suboxone (buprenorphine plus naloxone) be designed to limit pediatric exposure; 2) it approved two generic competitors; and 3) it asked the Federal Trade Commission (FTC) to investigate
the company for anticompetitive practices related to its efforts to protect its patent on the buprenorphine-naloxone medication. Last September, Reckitt wrote the FDA that it intended to voluntarily stop distributing Suboxone tablets because of the risk of pediatric exposure a move many in the substance abuse treatment field saw as an attempt to safeguard the companys patent protection on the drug. At the same time, and in what treatment providers saw as similarly motivated, Reckitt asked the FDA to impose the same pediatric safety restrictions on any other similar medications in other words, on any generics that might be coming along. The company had already tried to transition
Reckitt, continued on page 6
Drug-Drug Interactions
Editor: Lawrence H. Price, M.D., Professor of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Vice-President of Medical Affairs and Medical Director, Butler Hospital, Providence, RI.
Executive Managing Editor..... Karienne Stovell Contributing Editor............................ Gary Enos Contributing Editor....................... Alison Knopf Production Editor................. Richard Reicherter Executive Editor....... Isabelle Cohen-DeAngelis Publisher............................................Sue Lewis Editorial Advisory Board: Linda L. Carpenter, M.D., Chief, Mood Disorder Program and Neuromodulation Clinic, Butler Hospital, Professor of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI; John H. Krystal, M.D., Robert L. McNeil Jr., Professor and Chair, Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Christopher J. McDougle, M.D., Director, Lurie Center for Autism, Massachusetts General Hospital, Nancy Lurie Marks, Professor of Psychiatry and Pediatrics, Harvard Medical School, Boston, MA.
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Literature review
Researchers searched English language studies and case reports from PubMed, Ovid MEDLINE, and International Pharmaceutical Abstracts from January 1990 to August 2012, with key words that included tramadol, antidepressive agents, antidepressants, drug interactions, selective serotonin reuptake inhibitors, and serotonin syndrome, and extracted summaries for review. A total of nine case reports of serotonin syndrome occurring with coadministration of tramadol and SSRI were published during the review time period. The dosage regimens of tramadol from these case reports ranged from 50 mg/day for a few days to 400 mg/day on a chronic basis. The SSRIs implicated included citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). The dosage
BottomLine
If concurrent SSRI and tramadol administration is needed, an SSRI with the least CYP2D6 inhibitory effect for example, citalopram, sertraline, or venlafaxine (Effexor) should be considered, as well as use of a lower dose of tramadol. Similarly, a patient who does not benefit from an appropriate analgesic dosage of tramadol could be a CYP2D6 poor metabolizer, with decreased formation of tramadols more potently analgesic metabolite, and an alternative analgesic might be necessary.
May 2013
the serotonin syndrome in association with increased concentrations of both drugs when prescribed concurrent citalopram 10mg/day and tramadol 50mg/day.4
Discussion
In addition to acting as an agonist at the mu-opioid receptor, tramadol inhibits the reuptake of serotonin and norepinephrine. While it is controversial to what extent tramadol can precipitate the serotonin syndrome, its metabolism is partially mediated
2. Alfaro C, Lam YWF, Simpson J, et al.: CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: Intraindividual variability and plasma concentration correlations. J Clin Pharmacol 2000; 40:5866. 3. Laugesen S, Enggaard TP, Pedersen RS, et al.: Paroxetine, a cytochrome P-450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther 2005; 77:312323. 4. Mahlberg R, Kunz D, Sasse J, et al.: Serotonin syndrome with tramadol and citalopram. Am J Psychiatry 2004; 161:1129.
prcis
ants effects over a 4-week study period in human subjects with primary insomnia.
Study details
The study took place between November 2008 and December 2009 at 29 sites in the United States and 12 sites in Japan. Patients ranged in age from 18 to 64 and met DSMIV-TR criteria for primary insomnia. Polysomnography assessments determined that each eligible patient experienced latency to persistent sleep (LPS) of greater than 20 minutes on the two tested nights, as well as mean wake after sleep onset (WASO) of at least 60 minutes on both nights. The randomized, double-blind, placebocontrolled study was designed to assess the effectiveness of suvorexant at doses of 10, 20, 40, and 80 mg. Patients received 1 of the 4 suvorexant doses and placebo in separate 4-week treatment periods, with a 1-week placebo washout in between. Polysomnography measurement of sleep over an 8-hour time in bed constituted the primary efficacy assessment in the study. Patients also used an electronic diary to record their assessments of the previous nights sleep and their functioning during the day. The authors examined subjects sleep efficiency on night 1 and at the end of week 4, as well as LPS and WASO at each of those time points. They also evaluated adverse events, vital signs, electrocardiograms, laboratory measures, and results of physical examinations.
orexin receptor antagonist suT he vorexant generated significant improvements in sleep efficiency at both evening 1 and at the end of a 4-week treatment period compared with placebo in a group of adult patients with primary insomnia, new research has found. Study results indicate that the drug could provide a novel and well-tolerated approach to the treatment of insomnia. Recent identification of pathways associated with circadian sleep/wake neurobiology has established the potential for alternatives to the benzodiazepine treatments currently used to address insomnia. One of these pathways is the orexin signaling pathway, originating within the lateral hypothalamus. With suvorexant acting on orexin receptors, and having resulted in a reduction in active wake time in animal studies, researchers led by Mercks W. Joseph Herring, M.D., Ph.D., set out to test suvorex-
Results
A total of 228 of the 254 patients who were randomized for the study completed the trial. At baseline, patients had an average LPS of 69 minutes and an average WASO of 101 minutes. Mean scores on the Insomnia Severity Index indicated moderate severity.
The authors found that all doses of suvorexant were more effective than placebo in improving sleep efficiency on the first night and at the end of week 4. All suvorexant doses also outperformed placebo in improving WASO at those two time points. Total sleep time also improved with suvorexant compared with placebo, with increases ranging from 22 to 62 minutes depending on the dose and the evaluation night. Total scores on the Insomnia Severity Index indicated greater improvement for suvorexant at the 20, 40, and 80 mg doses when compared with placebo. A doseresponse effect was evident overall, with the 40 and 80 mg doses showing the most pronounced effects on sleep outcomes, the authors reported. The study medication was generally well-tolerated, with only one suvorexant subject discontinuing treatment because of adverse events. The most common patientreported adverse event was somnolence, which not unexpectedly showed a doserelated increase. There was no significant evidence of insomnia rebound upon stopping the medication. The authors reported no clinically relevant changes in laboratory measures, vital signs, or electrocardiograms with the study treatment. While it has been suggested that orexin regulation might affect appetite and promote weight gain, the authors found no evidence of weight gain with suvorexant relative to placebo. In addition, there was no evidence of events that would indicate the possibility of abuse liability with the medication, the authors stated.
Implications
The authors acknowledged several limitations to the study, including a relatively
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4
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brief duration of treatment and the fact that elderly patients (who make up a large percentage of individuals with insomnia) were not part of the sample. However, they concluded, Efficacy of the orexin receptor antagonist suvorexant was demonstrated for [polysomnography] and patient-reported sleep end points at the first night after dosing and after 4 weeks of treatment.
*The majority of the studys authors are employees of Merck, maker of the study medication. Herring WJ, Snyder E, Budd K, et al.: Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant. Neurology 2012; 79:22652274. E-mail: william.herring@merck.com.
Study details
The study looked at data for all individuals enrolled in Taiwans single-payer national health insurance system in the period from 19972007. Specifically, authors looked at patients hospitalized for a primary diagnosis of a cerebrovascular event using ICD-9-CM codes for hemorrhagic stroke, ischemic stroke, or other stroke. Three groups were excluded from the analysis: those with any previous inpatient or outpatient diagnosis using the ICD9-CM codes; those who had a head injury at the time of first hospitalization for stroke; and those who had been hospitalized during the previous year. This left a data set of 334,249 patients, with 8.9% of them having received at least one antipsychotic prescription within a year of stroke onset. The authors also excluded some other patients, such as those who had been prescribed long-acting injection antipsychotic formulations that have different pharmacokinetic properties from conventional antipsychotics. The authors included 13 frequently prescribed antipsychotics in their analysis, and used the National Institute of Mental Health Psychoactive Drug Screening Programs Ki Database to establish the binding affinity of each drug for a number of neurotransmitter receptors. Patients exposure to antipsychotics was defined as the prescribing of antipsychotics for at least 1 day during the case or control periods.
prcis
Study examined a database of stroke patients in Taiwan to analyze the association between stroke risk and antipsychotic exposure, and to determine how receptor binding profiles affect stroke risk. Antipsychotic use in the two weeks before a stroke was associated with a 1.6-fold increased risk of stroke, and stroke risk also increased in older subjects and in individuals with dementia. Antipsychotics with high binding affinity for serotonin, dopamine, histamine, muscarinic, and alpha-adrenergic receptors were associated with greater stroke risk.
se of antipsychotic medications that have a high binding affinity to certain specific receptors (especially M1 muscarinic and 2 adrenergic receptors) carries a greater risk of stroke than does use of other antipsychotics, a case-crossover study conducted in Taiwan has found. The use of antipsychotics to treat behavioral symptoms in dementia is discouraged because of increasing concern about cerebrovascular adverse events associated with antipsychotic use. In addition, it has been found that the receptor binding profiles of various antipsychotics may be associated with the occurrence of specific side effects.
Results
The study population of 14,584 stroke patients had a mean age of 68.5 years; 50.8% were women. The mean number of cumulative days of antipsychotic use in the previous year was 66.9. Antipsychotic use in the 2 weeks before a stroke was associated with a 1.6-fold increased risk of stroke, after adjusting for health system utilization and confounding medications. Stroke risk increased in older subjects and in those with dementia; 17.5% of the study sample had dementia. Use of a higher dose of antipsychotics was associated with a greater stroke risk.
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May 2013
QT Prolongation
continued from page 1
prolonging QT interval. In August 2011, the Food and Drug Administration (FDA) announced that citalopram, a selective serotonin reuptake inhibitor (SSRI), causes dose-dependent QT prolongation. The federal agency first stated that the medication should not be prescribed at doses higher than 40 mg/day, and then in 2012 offered further details by stating that the maximum dose should be limited to 20 mg/day for groups such as individuals over age 60. Because the FDA guidance did not offer comparative information on the effects on QT interval from other antidepressants, the warnings on citalopram left prescribers unclear about how they should proceed with medication strategies. As a result, a research team led by Victor M. Castro, of Partners HealthCare System in Massachusetts, launched a broader examination of QT intervals in individuals who were prescribed antidepressants. In order to gain a better grasp of the extent of QT prolongation in a general clinical population, the authors of this study examined electronic health records from a Partners HealthCare database that encompasses more than 4 million individuals.
in the study overall were modest. Our Celexa effect sizes were similar to what the FDA saw in the studies it had called for, Perlis told The Update.
Implications
The comparative results between citalopram, the subject of the FDA warnings in 2011 and 2012, and the other antidepressants shed light on variations in risk, according to the authors. They reported that SSRIs such as sertraline might pose a lesser risk than citalopram, and therefore might serve as a viable option for patients with other cardiac risk factors. The authors added, Our results suggest that, given its capacity to shorten QT interval, bupropion treatment might be a reasonable next step for patients partially responsive to citalopram who would otherwise require a dose increase. In his comments to The Update, Perlis pointed out that studies such as this one that rely on data from electronic health records might offer advantages over other approaches. For example, studies that depend on information from Medicare and Medicaid claims data lack the ability to dig deeper into patient-level detail, he said. Use of electronic health record data is going to become more common in all of medicine, Perlis said. But because these analyses are not randomized trials, he added, those who interpret the data derived from these studies will have to look closely at how the authors confront issues of confounding, he said. The authors of this study cite this issue as a key limitation of their study. In addition, they acknowledged that the non-random ascertainment of electrocardiograms likely resulted in a bias of results toward greater mean QTc. Still, they concluded, Taken together, the present findings demonstrate the potential advantages of using electronic health records for post-marketing surveillance.
*Several co-authors of the study report receiving research support or consulting fees from pharmaceutical companies. Castro VM, Clements CC, Murphy SN, et al.: QT interval and antidepressant use: A cross sectional study of electronic health records. BMJ 2013; 346:f288. Doi: 10.1136/bmj.f288. E-mail: rperlis@ partners.org.
Results
A total of 38,397 Partners HealthCare patients had received an electrocardiogram within the studys time window. For each medication studied, dosecorrected QT interval (QTc) curves were plotted and tested for dose-response relation. Dose was found to be a significant predictor of QT prolongation for the antidepressants citalopram, escitalopram, and amitriptyline, and increasing methadone dose also was associated with increased QTc. By contrast, increases in dosage of bupropion were associated with significant decreases in QTc.
Our Celexa effect sizes were similar to what the FDA saw in the studies it had called for.
Roy H. Perlis, M.D.
Study details
The data set for this study included adult patients who received at least one prescription for an antidepressant or methadone between February 1990 and August 2011; methadone was included in the analysis for comparative purposes because it is also known to contribute to QT prolongation. Antidepressants included in the analysis were citalopram, escitalopram, fluoxetine, paroxetine, sertraline, amitriptyline, bupropion, duloxetine, mirtazapine, nortriptyline, and venlafaxine. The authors selected for examination the most recent electrocardiogram (within 90 days) occurring at least 14 days after a prescription; this ensured that the antidepressant had reached steady state at the new dose. QT measurements were categorized as normal, borderline, abnormal, or high, based on published thresholds. The authors also performed three sensitivity analyses in the study. They excluded individuals who did not have a follow-up prescription after their initial Among 467 patients for whom electrocardiogram data were available for multiple doses of citalopram, escitalopram, amitriptyline, bupropion, and methadone, statistically significant increases in QT interval were found in 59 patients whose daily dose of citalopram increased from 10 mg to 20 mg, as well as for 107 patients whose daily dose of citalopram increased from 20 mg to 40 mg. Significant decreases in QT interval were seen in 13 patients whose daily dose of bupropion increased from 100 mg/day to 200 mg/day. Among patients who had a QTc in the normal range upon starting citalopram, 13.1% moved to an abnormal reading after dose increase, the authors stated. The authors wrote that our results show that several of the antidepressants may be associated individually with lengthening of QT intervals with increasing dose. The studys corresponding author, Partners HealthCares Roy H. Perlis, M.D., stressed that the effect sizes seen
Reckitt
all patients from tablet to film. As the patent expired on the tablet in October 2009 and the film is patented until 2023, observers speculated that the company was worried about generic competition.
FDA Update:
May 2013
in which generic competition for this product was expected to begin, cannot be ignored, the FDA said. The FDA referred the matter to the FTC, which has the administrative tools and the expertise to investigate and address anticompetitive business practices. In a February 25 press release, Reckitt said it was disappointed with the FDAs decision, but it would continue to work with the FDA on safety enhancements and will carry on with the decision to discontinue the sale of its loose tablet bottles of Suboxone in the United States.
Generics
The approval of the generics was very good news for patients taking buprenorphine, said Junig. Many patients lose insurance coverage as part of the fallout of their addiction, and the high price of Suboxone has encouraged improper use of the medication, such as using small pieces of one dose for many
days, rather than taking a sufficient dose, he said. Hopefully price competition will result in greater access to allow for appropriate dosing. Its easy to interchange between film and tablet, said Junig. The transition is a no-brainer, he said. The film and the tab have the same ingredients, and each dissolves in the mouth to yield the exact same mix of molecules, which are then absorbed through the oral mucosa and into the bloodstream. Its also simple to transfer from Suboxone to generic buprenorphine-naloxone, he said. Both the film and the tablet must be allowed to dissolve under the tongue and be absorbed that way. If swallowed instead of taken sublingually, the buprenorphine is metabolized by the liver during the first pass and never gets into the circulation. The approval of the generics the sponsors are Actavis and Amneal is also significant because of the greatly increased demand that is expected for buprenorphine, now that opioid treatment programs can dispense take-homes without a long waiting period.
News Notes
Common genetic variation and antidepressant efficacy
Indirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but data are limited. Researchers performed a meta-analysis on data from three genome-wide pharmacogenetic studies: 1) the Genome-Based Therapeutic Drugs for Depression [GENDEP] project; 2) the Munich Antidepressant Response Signature [MARS] project; and 3) the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study. The total study sample included 2,256 individuals of Northern European descent with major depressive disorder, and researchers prospectively collected antidepressant treatment outcomes. They tested a total of 1.2 million single-nucleotide polymorphisms and captured common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment. Results indicated that no individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, which suggested a weakly concordant signal distributed over many polymorphisms. The analysis of 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment. Despite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response, concluded the authors. [GENDEP Investigators, MARS Investigators, STAR*D Investigators: Am J Psychiatry 2013 Feb 1; 170(2):207217. Doi: 10.1176/appi. ajp.2012.12020237.] (BMI) changes by baseline BMI in patients completing three years of monotherapy with first- and second-generation antipsychotics. Researchers analyzed data by antipsychotic and three baseline BMI bands: 1) underweight/normal weight (BMI <25); 2) overweight (BMI=2530); and 3) obese (BMI >30). They found that baseline BMI was linked to subsequent weight change irrespective of the antipsychotic given. With increasing baseline BMI, a smaller proportion of patients gained 7% baseline body weight and a greater proportion of patients lost 7% baseline body weight. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining 7% baseline weight was 45% (95% CI: 4348) in the underweight/normal weight BMI cohort and 20% (95% CI: 1527) in the obese BMI cohort; 7% (95% CI: 68) of the underweight/ normal cohort and 19% (95% CI: 1327) of the obese cohort lost 7% baseline weight. BMI has an association with the likelihood of weight gain or loss and
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News Notes
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should be considered in analyses of antipsychotic weight change, conclude the authors. [Bushe CJ, et al.: JPsychopharmacol 2013 Apr; 27(4):358365. Doi: 10.1177/0269881112473789. Epub 2013 Jan 23.]
rs1045642 of ABCB1 have been linked to efflux pump efficiency, possibly explaining interindividual dose variation of antidepressant needed to be effective. Researchers treated 113 patients with major depressive disorder (MDD) with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. SNP rs1045642 of ABCB1 and 2 other SNPs were genotyped. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (p=0.0001). Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype. This suggests that the antidepressant dose needed to remit can be predicted by an ABCB1 SNP. The authors conclude that this has potential clinical translation implications for dose selection and remission from MDD. [Singh AB, et al.: Transl Psychiatry 2012 Nov 27; 2:e198. Doi: 10.1038/tp.2012.115.]
for preclinical and clinical publications related to SSRIs and ischemic heart disease (IHD) or congestive heart failure (CHF) in March 2011. They identified and discussed a number of mechanisms by which SSRIs may influence cardiovascular functioning and health outcomes in patients with heart disease, many of which have received little attention in previous reviews. SSRIs influence cardiovascular functioning and health through several different mechanisms: they inhibit serotonin-mediated and collagenmediated platelet aggregation; they reduce inflammatory mediator levels; they improve endothelial function; and they improve indices of ventricular functioning in IHD and heart failure without adversely affecting electrocardiographic parameters. SSRIs may also be involved in favorable or unfavorable drug interactions with medications that influence cardiovascular functions. The research suggests that SSRIs are safe in patients with IHD and may exert a cardioprotective effect. The clinical data are less clear in patients with heart failure, where the evidence for benefits with SSRIs is weak, note the authors. [Chittaranjan A, et al.: Int Clin Psychopharmacol 2013 Jan 15. Epub ahead of print]
From the
FDA
Labeling revision for Wellbutrin
The FDA announced labeling revisions for Wellbutrin (bupropion hydrochloride) 75 mg and 100 mg Tablets and Wellbutrin Sustained-Release 100 mg, 150 mg, and 200 mg Tablets in the CONTRAINDICATIONS, WARNINGS, DOSAGE AND ADMINISTRATION section. The new information describes the increased risk of hypertensive reactions when bupropion is used concomitantly with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism (e.g., MAOIs). [www.accessdata.fda.gov]