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Lexapro, Hot Flashes, and Doing What Works

June 15, 2011

One of the most common—and distressing—symptoms of menopause is the “hot flash.”  As many as 85% of perimenopausal women complain of hot flashes, characterized by a sensation of intense heat, a flushed appearance, perspiration, and pressure in the head.  An effective remedy for hot flashes over the years has been hormone replacement therapy, but many women shun this treatment because of the increased risk of breast cancer, heart disease, and stroke.  In its place, antidepressants like SSRIs and SNRIs have become more commonly prescribed for hot flashes.  Many women report great improvement in symptoms, both anecdotally and in some small open-label trials, with antidepressant therapy.

But do antidepressants actually do anything at all?

Jim Edwards covers this story in a post today on bnet’s “Placebo Effect” blog. Edwards describes a study published in the Journal of the American Medical Association (JAMA) in January 2011 (PDF here).  The study showed the clear benefit of Lexapro (an SSRI made by Forest Labs) relative to placebo in a randomized clinical trial of more than 200 menopausal women with hot flashes.  However, Edwards also reports that a brand new study (which he calls “elegant”) published in the journal Menopause found NO effect of Lexapro.  This second study measured hot flashes not by patient report, but instead by a “battery-powered hot flash detector” worn by women participating in the research.

Does Edwards conclude that the first study was bogus?  Well, not quite.  Edwards argues that the integrity of the JAMA study was dubious from the start because its lead author, Ellen Freeman, received money (honoraria and research support) from Forest Labs, while the paper in Menopause was not tainted by drug company money.  (Note: he neglected to point out that the author of the second study, Robert Freedman, holds a patent, US # 60,741,376, on the “hot flash detector” used in his study.  Yeah, that’s “elegant.”)

Now, I understand that pharmaceutical company funding has a potential to bias research (sometimes a great deal), even when the researchers swear by their objectivity.  But in this case, Edwards’ axe-grinding seems to have obscured some more relevant arguments.  In his zeal to criticize Freeman for her nefarious Forest ties, he ignores the fact that patients often do report a benefit of Lexapro.  A more relevant (and convincing) argument might have been: What makes Lexapro that much better than a generic SSRI—which would be significantly cheaper—in the treatment of hot flashes?  But no, that question was overlooked.

It’s also important to consider the methods used in the Menopause study.  Freedman and his colleagues used “objective” measures of hot flashes (using a device patented by the author, remember) instead of patients’ self-report.  What did these ambulatory monitors measure?  “Humidity on the chest”—that’s it.  (Hmmm… maybe the Exmovere Corporation could build an “Exmobaby garment” for menopausal women??)  Lexapro had no significant effect on this objective measurement.

But the problem is, hot flashes are subjective experiences.  Just like depressed mood, fatigue, pain, gastrointestinal upset, and many other symptoms we treat in medicine.  There’s probably a physiological explanation, but we don’t know what it is.  I’m sorry, but it seems presumptuous (if not downright arrogant) to say that a biometric device is an “accurate” detector of hot flashes, regardless of what the woman reports.  It’s like saying that a person is depressed because his ethanolamine phosphate level is high, or that another has OCD because she has a thicker right superior parietal gyrus in an MRI scan.

Anyway, back to Edwards’ blog post:  His opening sentence, dripping with obvious sarcasm, is “Never mind the evidence; just treat patients’ complaints.”  He then proceeds to completely downplay (if not ridicule) the fact that women frequently report a benefit of Lexapro and other SSRIs.

I wonder whether Edwards has paid any attention to what we’ve been doing in psychiatry for the last several decades.  Trust me, I would love to understand the biological basis of my patients’ symptoms—whether depression, psychosis, anxiety, or hot flashes—in order to develop more “targeted” medical treatment.  But the evidence is just not there (yet?).  In the meantime, we have to use what we’ve got.  If a woman reports improvement on Lexapro without any side effects (in other words, if the benefit exceeds the risk), I’ll prescribe it.

Let me be clear.  I’m not defending Lexapro:  if there’s a cheaper generic alternative available we should use it.  Similarly, I’m not defending Ellen Freeman: pharmaceutical funding should be fully disclosed and, moreover, it does skew what gets published (or not).  And I’m not criticizing Dr Freedman’s Hot Flash Detector (why does that sound like something out of a 1920’s Sears Catalog?): objective measures of subjective complaints help us to understand complicated pathophysiology more clearly.

But if patients benefit from a treatment (and aren’t harmed by it), we owe it to them to provide it.  Arguments like “the research is biased,” “it’s not scientific enough,” or “doctors don’t know how it works anyway” are valid, and should not be ignored, but should also not keep us from prescribing treatments that alleviate our patients’ suffering.

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Another Day, Another Seroquel XR Indication?

June 1, 2011

Just when you thought the antipsychotic drug Seroquel had fully penetrated doctors’ offices and patients’ medicine chests (not to mention law offices and children’s tummies) all across America, a new clinical trial is recruiting subjects for yet another indication for this ubiquitous drug.

Technically, the trial is of Seroquel XR, not Seroquel.  (Because, you know, the two are COMPLETELY different drugs, as described in this YouTube video.)  But you get the idea.  Anything to keep the money flowing for Astra-Zeneca, especially after Seroquel goes generic in 2012.

Thanks to a tip from Stephany at Soulful Sepulcher, you can read all the details of this study here.  It’s called the “Quietude Study,” a trial of Seroquel XR for the treatment of agitated depression.  Specifically, they want to compare Seroquel XR (at doses up to 150 or 300 mg/day) with Lexapro (up to 20 mg/day), and the investigators predict that Seroquel XR will be more effective in the management of depression “with prominent agitation.”

Two things caught my eye right away:  First, the name of the study (“Quietude”) is obviously a play on words, since the generic name for Seroquel is quetiapine.  How cute.  I also noticed that the study is being conducted by Roger McIntyre, MD, whom I saw just yesterday on the medical website QuantiaMD giving a blatantly obvious “infomercial” for Geodon (for Quantia members, here’s the link), a competitor’s drug.  [And for more info on QuantiaMD, see Daniel Carlat’s recent post about this site.])

But let’s get more substantive, shall we?  A look at the details of this new “Quietude” study is revealing.  For one thing, the opening statement of the study’s “Purpose” is:  “Most individuals with major depressive disorder manifest clinically significant agitation.”  Really?  I’ve certainly seen cases of agitated depression, but are “most” depressed patients agitated?  Not in my experience.  Maybe when they say “agitation” they’re including patients with akathisia, an occasional side effect of some antidepressant medication.  I understand research proposals always have to start with a statement about how widespread the problem is, but this one seems a bit of a stretch.

The inclusion and exclusion criteria are also included in the study design.  One of the inclusion criteria, along with the typical symptomatic measures (i.e., HAM-D >20 and CGI-S >4), is “significant agitation.”  That’s it.  By whose measure?  Patient report?  Clinician’s evaluation?  I’d really like to know more about how the “agitated” folks are going to be selected.

Some interesting exclusion criteria are (a) “known lack of antidepressant response to escitalopram [Lexapro]” and (b) “known lack of antidepressant response to quetiapine [Seroquel].”  So they’re enriching their population for individuals who have not already tried Lexapro or Seroquel and failed to respond to the antidepressant effect. Perhaps this isn’t a huge problem, but Seroquel XR is not the greatest antidepressant (see below), and this exclusion criterion will probably weed out the patients who gained weight on Seroquel or “felt like a zombie”—two common complaints with this medication which often lead to its discontinuation.

But what disturbs me the most about this trial is the fact that it seems entirely unnecessary.  The fact of the matter is that Seroquel XR is–for better or for worse—already used for many cases of “agitated depression.”  And it’s not even entirely off-label, because Seroquel XR is approved for bipolar depression and for the adjunctive treatment of MDD (whether it actually works as an antidepressant is another story).  As mentioned above, quetiapine is a sedating drug in many patients, so of course a psychiatrist is going to think about it for “agitated depression.”  (Unless he/she wants to take the time to determine the causes of the patient’s agitation, which, unfortunately, often does not happen.)

But there’s more.  When Seroquel XR was first introduced, with much fanfare, for the treatment of depression, I remember being somewhat skeptical and asking my local AstraZeneca sales force whether it had any “antidepressant effect” other than its well-known sedative and appetite-enhancing effects (because, after all, those are two of the symptoms of depression typically measured in clinical trials).  I was reassured that, no, no, Seroquel XR is more than that; it acts on all depressive symptoms, probably through its metabolite norquetiapine.

In fact, a year ago I emailed a local “key opinion leader” who spoke extensively for AstraZeneca and was told the following (emphasis added; BTW, if it’s too technical for you, don’t worry, go ahead and skip):

I think the concept is that quetapine at low doses (25-50-100 mg) is almost entirely anti-histaminergic and anti-muscarinic. However at the 150-300 mg doses there is significant norepinephrine transporter inhibition from the metabolite norquetapine as well as 5HT 1A agonism and 5HT2A AND 5HT2-C antagonism which all increase dopamine. Thus at the higher doses of 150-300 mg there is significant antidepressant activity but also increases in frontal, limbic and striatal dopamine which can be stimulatory (as well as having anti-depressant effects). At the 600-800 mg doses there is significant D-2 antagonism which is where the antipsychotic effect (D-2 antagonism) kicks in. Thus as the doses escalate patients go from pure sedation to antidepressant to antipsychotic effects.  At least this is the theory based on the dose related relative strength and affinities for its respective receptors.

The premise of the “Quietude” study seems to be telling us something different—even though it’s what we already knew if we only paid attention to what our patients tell us (and not necessarily to AstraZeneca): namely, that the primary advantage of intermediate-dose Seroquel XR does seem to be its sedative effect.  And this might indeed make it effective for the treatment of the “psychological and physical restlessness” associated with depression.

Anyway, because the trial is only being run in Canadian sites, I won’t have to worry about whether to refer my patients to it.  But it’s also a trial whose results I won’t exactly be anxiously awaiting.


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