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    <recommendedItem id="20100101_19_450"
                     title="SSRI and Tamoxifen Increase Mortality Risk (CME/CE)"
                     score="0.014"
                     href="http://www.medpagetoday.com/HematologyOncology/BreastCancer/tb/18376?impressionId=1265788244211"
                     
      Overlapping use of tamoxifen and the antidepressant paroxetine (Paxil) significantly increases the risk of breast cancer mortality, data from a large cohort of breast cancer patients showed.&lt;br&gt;
&lt;br&gt;The excess breast-cancer mortality risk ranged as high as 91%, depending on the duration of simultaneous use, researchers reported online in &lt;em&gt;BMJ.&lt;/em&gt;&lt;br&gt;
&lt;br&gt;Women taking other antidepressants with tamoxifen, including other selective serotonin reuptake inhibitors (SSRIs), did not have an increased risk of breast cancer death.&lt;br&gt;
&lt;br&gt;&quot;We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 patients so treated; the risk with more extensive overlap would be greater,&quot; David Juurlink, MD, PhD, of Sunnybrook Health Sciences Center in Toronto, and colleagues concluded.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;The findings add to an accumulation of evidence suggesting that inhibition of the cytochrome P450 2D6 isozyme (CYP2D6) may adversely affect outcomes in breast cancer patients taking tamoxifen. CYP2D6 is the principle catalyst for converting tamoxifen into endoxifen, a metabolite with 100-fold greater affinity for the estrogen receptor.&lt;/p&gt;
&lt;p&gt;Multiple studies have shown that women who have a poor-metabolizer phenotype have lower levels of endoxifen, as do women treated with drugs that inhibit CYP2D6.&lt;/p&gt;
&lt;p&gt;&quot;Indeed, in patients who receive tamoxifen in addition to a CYP2D6 inhibitor, endoxifen concentrations vary inversely with the degree of CYP2D6 inhibition,&quot; the authors wrote.&lt;/p&gt;
&lt;p&gt;Paroxetine is used to treat depression and vasomotor symptoms in breast cancer patients treated with tamoxifen. Paroxetine is not the only SSRI antidepressant used by breast cancer patients, but it is the only SSRI that irreversibly inhibits CYP2D6.&lt;/p&gt;
&lt;p&gt;Whether the metabolic effects of CYP2D6 inhibition translated into adverse breast cancer outcomes had not been determined.&lt;/p&gt;
&lt;p&gt;To examine the issue, Juurlink and colleagues compared prescribing data with clinical records of 24,430 breast cancer patients, ages 66 and older, who initiated tamoxifen therapy from 1993 to 2005. Of those, 7,500 also received an antidepressant.&lt;/p&gt;
&lt;p&gt;Ultimately, the investigators narrowed the study population to 2,430 women who took a single SSRI during tamoxifen therapy. The most commonly prescribed SSRI was paroxetine (25.9%), followed by sertraline (22.3%), citalopram (19.2%), venlafaxine (15%), fluoxetine (10.4%), and fluvoxamine (7.2%).&lt;/p&gt;
&lt;p&gt;During a mean follow-up of 2.38 years, 1,074 patients died, including 374 breast cancer deaths.&lt;/p&gt;
&lt;p&gt;The analysis showed an increased risk of breast cancer death only among women taking paroxetine.&lt;/p&gt;
&lt;p&gt;The breast cancer mortality risk increased with the duration of concomitant use of paroxetine and tamoxifen. As the duration of therapeutic overlap increased from 25%, to 50%, to 75% of time on tamoxifen, the excess risk of breast cancer death increased from 24%, to 54%, to 91%.&lt;/p&gt;
&lt;p&gt;Investigators repeated the analysis, using death from any cause. Overlapping treatment with tamoxifen and paroxetine led to an increased mortality risk of 13%, 28%, and 46% as the duration of overlap increased from 25% to 75%.&lt;/p&gt;
&lt;p&gt;The results suggest clear implications for use of SSRIs in breast cancer patients on tamoxifen, Frank Andersohn, MD, and Stefan Willich, MD, of Charite University in Berlin, wrote in an accompanying editorial.&lt;/p&gt;
&lt;p&gt;&quot;The straightforward answer is to avoid prescribing strong CYP2D6-inhibiting SSRIs (such as paroxetine or fluoxetine) for women with breast cancer who are prescribed tamoxifen, and to consider instead drugs with low potential to inhibit CYP2D6 (such as citalopram or venlafaxine),&quot; they wrote.&lt;/p&gt;
&lt;p&gt;For women who are already taking a potent inhibitor of CYP2D6, doctors should consider switching to a drug that does not inhibit the enzyme, they added. However, any switch should be accomplished gradually, as abrupt discontinuation of an antidepressant confers risk, as well, they noted.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;Co-author Kathleen Pritchard disclosed relationships with sanofi-aventis, AstraZeneca, Roche, Pfizer, Ortho-Biotech, YM Biosciences, Novartis, Abraxis, Amgen, GlaxoSmithKline, Bristol Myers Squibb, and Roche&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_358"
                     title="Poststroke Antidepressant Boosts Mental Agility (CME/CE)"
                     score="0.009"
                     href="http://www.medpagetoday.com/Cardiology/Strokes/tb/18240?impressionId=1265788244211"
                     
      &lt;p&gt;Antidepressants in the first months after a stroke may aid cognitive recovery for patients without depression, according to a randomized trial analysis.&lt;/p&gt;
&lt;p&gt;Global cognitive function scores improved significantly more with escitalopram (Lexapro) than with problem-solving therapy or placebo (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01), according to Ricardo E. Jorge, MD, of the University of Iowa in Iowa City, and colleagues.&lt;/p&gt;
&lt;p&gt;Memory scores rose significantly higher with the antidepressant as well (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01), with both effects independent of those on depression, they reported in the February &lt;em&gt;Archives of General Psychiatry&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;&quot;Adjunctive restorative therapies administered during the first few months after stroke, the period with the greatest degree of spontaneous recovery, reduce the number of stroke patients with significant disability,&quot; the researchers concluded.&lt;/p&gt;
&lt;p&gt;The &lt;a href=&quot;http://www.medpagetoday.com/Cardiology/Strokes/9621&quot; mce_href=&quot;http://www.medpagetoday.com/Cardiology/Strokes/9621&quot; target=&quot;_blank&quot;&gt;primary analysis&lt;/a&gt; of the trial, reported in the &lt;em&gt;Journal of the American Medical Association on&lt;/em&gt; May 28, 2008, showed that prophylactic escitalopram treatment would prevent poststroke depression in one patient for every 7.2 treated &lt;em&gt;(P&lt;/em&gt;&amp;lt;0.001 compared with placebo). That article ultimately raised a controversy over an undisclosed conflict of interest.&lt;/p&gt;
&lt;p&gt;Escitalopram is a selective serotonin reuptake inhibitor (SSRI). Since serotonin plays a role in neuroplastic changes in the developing brain as well as in depression, Jorge&apos;s group analyzed whether there might be such an effect after a stroke.&lt;/p&gt;
&lt;p&gt;The study randomized patients to double-blind treatment with escitalopram (10 mg/d under age 65 or 5 mg/day age 65 and older) or placebo or unblinded problem-solving therapy (12 sessions of going through steps to arrive at a course of action for a patient-selected problem).&lt;/p&gt;
&lt;p&gt;The intent-to-treat analysis included 129 patients treated starting within the first three months after their mild to moderate severity stroke and who did not meet criteria for major or minor depression.&lt;/p&gt;
&lt;p&gt;Overall, global cognitive functioning was significantly changed between groups as measured on the Repeatable Battery for the Assessment of Neuropsychological Status (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;After controlling for change in depression score and type of stroke, escitalopram was associated with the best cognitive recovery, an adjusted mean change of 9.9 points compared with 1.9 for problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01) and 4.0 for placebo (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;Similarly, for delayed memory scores on the same test battery, escitalopram came out on top (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;After adjustment for depression score change and stroke mechanism, the antidepressant was associated with an 11.2 point improvement in delayed memory, compared with a change of -0.7 with problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) and 3.9 with placebo (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;On test of immediate memory, escitalopram again yielded the best recovery.&lt;/p&gt;
&lt;p&gt;The researchers found mean improvement of 13.4 points with the antidepressant compared with 2.0 with problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) and 7.2 with placebo (&lt;em&gt;P&lt;/em&gt;=0.04), after adjustment for time between stroke and treatment, depression score change, and stroke type.&lt;/p&gt;
&lt;p&gt;These mental benefits appeared to have an impact on functional status as well.&lt;/p&gt;
&lt;p&gt;Cognitive domain scores on the Functional Independence Measure were better for escitalopram-treated patients than those who didn&apos;t get the drug (&lt;em&gt;P&lt;/em&gt;=0.05), as were memory domain scores on the same measure (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;At baseline, the global cognitive functioning and delayed and immediate memory scores were nonsignificantly lower in the antidepressant group than in the other two groups, which could have biased the results.&lt;/p&gt;
&lt;p&gt;However, the treatment effects appeared to be real, Jorge explained in an interview.&lt;/p&gt;
&lt;p&gt;In an unpublished regression analysis, the baseline scores were not a significant covariate. &quot;If [the results were] related only to the difference in baseline, this would be significant but it wasn&apos;t,&quot; he told &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Moreover, with an initially lower score it might have been expected that the escitalopram-treated group would have had a lower score at the end of the study than the other groups, added co-author Robert G. Robinson, MD, also of the University of Iowa.&lt;/p&gt;
&lt;p&gt;But that wasn&apos;t the case, he said in an interview. With regard to delayed memory, for example, &quot;the escitalopram-treated group went from the most impaired to the best performing.&quot;&lt;/p&gt;
&lt;p&gt;The researchers didn&apos;t compare end scores for the escitalopram, problem solving therapy, and placebo groups, but they were: &lt;ul&gt; &lt;li&gt;For global cognitive functioning 89.8, 89.1, and 91.0 points, respectively&lt;/li&gt; &lt;li&gt;For delayed memory, 96.6, 89.1, and 94.2, respectively&lt;/li&gt; &lt;li&gt;For immediate memory, 95.1, 94.9, and 98.5, respectively&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The treatment showed no effect on other individual cognitive measurements, including those for attention, language, and IQ. Nor were there significant differences in changes in occupational or living conditions.&lt;/p&gt;
&lt;p&gt;Although SSRIs such as escitalopram have been associated with hospitalization for GI bleeding and falls in prior studies, these complications did not occur in Jorge&apos;s study.&lt;/p&gt;
&lt;p&gt;&quot;Long-term administration of SSRIs appears to be an effective and safe treatment option to improve cognitive outcomes among patients with cerebrovascular disease,&quot; they concluded in the &lt;em&gt;Archives&lt;/em&gt; paper.&lt;/p&gt;
&lt;p&gt;The researchers cautioned that the study was limited by lack of CT or MRI scans and the younger age of escitalopram-treated patients, compared with other groups. That may have been a source of bias, although age did not appear to be a significant factor in the trial results.&lt;/p&gt;
&lt;p&gt;In this analysis, the researchers emphasized that the trial was not financially supported in any way by any drug company  --  a declaration hinting at the controversy that brewed last year over failure of one of the authors of the original &lt;em&gt;JAMA&lt;/em&gt; article to &lt;a href=&quot;http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/13391&quot; mce_href=&quot;http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/13391&quot; target=&quot;_blank&quot;&gt;properly disclose ties&lt;/a&gt; to Forest Pharmaceuticals, which makes escitalopram.&lt;/p&gt;
&lt;p&gt;Another scientist who discovered that omission published the information in a competing journal, inducing &lt;em&gt;JAMA&lt;/em&gt; to issue a gag rule on reporting of undisclosed conflicts of interest. That policy encourages those who discover such conflicts to report them to &lt;em&gt;JAMA&apos;s&lt;/em&gt; editors but prohibits them from disclosing the conflicts publicly pending an investigation by the journal.&lt;/p&gt;
&lt;p&gt;In the current analysis, the disclosure statement indicated that co-author Robertson, had received honoraria and speakers&apos; bureau fees from Forest, with the caveat that &quot;none of the design, analysis, or expenses (including the cost of medications) of this study were supported by monies, materials, or any intellectual input from Forest Laboratories.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported solely by a grant from the National Institute of Mental Health.&lt;/p&gt;&lt;p&gt;Jorge reported having received travel awards to participate in national meetings from the former Hamilton Pharmaceutical Company and Avanir Pharmaceutical Company.&lt;/p&gt;&lt;p&gt;Co-authors reported financial conflicts of interest with Merck, NMT Medical, Eli Lilly, Centocor, Sanofi-Bristol-Meyers-Squibb, Boerhringer-Ingelheim, Schering-Plough, AstraZeneca, and GlaxoSmithKline, the former Hamilton Pharmaceutical Company, Avanir Pharmaceutical Company, Lubeck, Forest Laboratories, and Pfizer.&lt;/p&gt;&lt;p&gt;No pharmaceutical company donated medications for or had any financial interest in the study.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_3_723"
                     title="Hostility Events Dog Small Minority of SSRI Users"
                     score="-0.005"
                     href="