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.
Thought Broadcast 
I went to a Canadian Psychiatric Association workshop recently with Roger speaking. He has 13 companies in his disclosure so I take everything with a grain of salt. I only use Seroquel in the depression of a patient who is giving me a story for bipolar that I don’t trust but can’t disprove. The patient is happy when I explain it benefits everything and I feel safer because I can defend the indication.
“…it benefits everything…”
I don’t know if that says more about Seroquel or about psychiatry.
Says it all about psychiatry, including the misrepresentation to the patient.
Taryn, would you elaborate on what you mean by the phrase “giving me a story for bipolar that I don’t trust but can’t disprove”?
I work in crisis intervention and often get people in who give me a story of bipolar but my gut is telling me that it’s personality pathology. The patient often wants to be told it’s bipolar (you would not believe how often I get asked this!). I’m put in the position that a patient is asking for meds, they can’t get counseling any time soon, they’re convinced they have something and their story matches the diagnosis. So, I can’t go to an antidepressant with the risks and possibly no followup. They’re complaining of depressive symptoms. So I go through every side effect of Seroquel (quite thoroughly) and many like the idea that it could help sleep and mood. They often reject counseling or don’t follow up. Do I like this? No.
Taryn,
I, too, thank you for elaborating. This is precisely what I see several times a day in the community mental health setting. “They’re convinced they have something and their story matches the diagnosis” — I couldn’t have said it better myself. Our “diagnostic criteria” are so vague, diffuse, and nonspecific that virtually anyone with a history of mood lability, irritability, talkativeness, and impulsivity (all of which are common in the CMHC population) can be diagnosed as bipolar– particularly by our, ahem, less skilled colleagues. And, of course, given the street value of Seroquel and the benzos, that’s what they ask for. How can you say no?
Taryn, thanks for taking the time to reply.
Steve,
I’m not a doctor, but I have to say the use of antipsychotic (neuroleptic) drugs for depression (agitated, or otherwise) seems void of common sense.
If dopamine is a feel-good chemical, then how could inhibiting its reception (D-2 reception) possibly help someone who is depressed?
I can’t seem to get my head around this.
Actually, I’m not sure I want to get my head around it.
I don’t spend a lot of time with things that lack common sense, especially when drugmakers are involved, insisting that we ignore the obvious.
The other issue… the studies themselves.
The Truth about Antidepressant Studies, Timothy Scott, Ph.D. –
My best,
Duane Sherry, M.S.
Well said. When you don’t understand a drug’s mechanism of action, any explanation makes sense, er… or not.
True. But Duane’s comment about dopamine is precisely the selling point for using Abilify as an antidepressant. As a partial agonist of dopamine, it may actually “mimic” dopamine (esp. at low doses) and work for depression.
Never mind there’s no evidence for this mechanism. It just sounds good, so people will use it. (Also goes to show why Abilify has the market share it does: it can do anything you want it to.)
But I thought STATINS were the next panaceas! I should do a search, maybe they “work” on the dopamine axis too!
oops. maybe not.
http://www.medscape.com/viewarticle/521641_4
Steve,
Promoting Abilify’s “selling point?”
Maybe the drugmaker,
Not me.
Duane
I’m a patient that uses Seroquel xr. I went to the doctor with acute anxiety. I was having panic attacks every day, multiple times a day, and some lasting several hours. My mother is Bi-polar. She is on disability because of it. My doctor had recently been sold on Seroquel xr, by the drug reps. I had tried prozac and paxil, and neither one of them worked they only made me sick to my stomach. Seroquel xr worked, however, he never told me I could never go off of it without his help. I lost my insurance a few months after he started me on the meds. I had samples in different strengths so I stepped down in a couple weeks just as I had stepped up to the dose he wanted me on. My anxiety tripled, I could no longer sleep for more than a few minutes without waking up to an anxiety attack. I had horrible headaches. It was awful. After 3 months of it only getting worse, I finally broke down and went back to him. He put me right back on it. Since then I have had to buy my Seroquel xr overseas in order to remotely afford it. It is overly expensive, I can’t go off of it, I was told if I miss more than 1 or 2 doses I will have seizures or even a stroke. I feel chained to this drug. Now my canadian pharmacy is having problems with all the credit card companies. They have been holding my meds so long that I will run out before it gets to me. My doctor has to write a prescription for a local pharmacy and I’m told it’s going to cost 4 X’s the amount I pay in Canada. If I can barely afford it there how the hell am I gonna afford it here. I’m also hearing that if I’m able to get health insurance in the future, they won’t pay for that drug because it isn’t generic, and it won’t be generic till the end of 2016. This drug works, it’s amazing, but it is a chain around my neck that I can’t remove and can’t afford.
This is a great post, I enjoyed seeing you continue the discussion with more details, information and personal insight. I had not heard of the Quantia before! thanks for the hat tip and link too.
PS–Thinking abt agitation and depression with the drugs listed in this study, one has to consider that ppl can have agitation as a side effect of both of those drugs. 800mg wired my daughter when an inpatient doc placed her on it…agitation and increased psychosis!
I must be treating a different kind of patient. They will only keep taking a drug if it helps the symptoms so much as to make any side effects worth tolerating. Couldn’t care less about studies of other people, mechanisms, or FDA approval.
“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.”
I’m not anxious but I will be interested in the results of the trial for the following reasons:
1. The “major depression with prominent agitation” is, I think, what would be classified in the DSM-IV as “Bipolar II” or “Bipolar NOS.” By “agitation” I think they mean/are including “anxiety” or “hypomania” as they will be breaking out baseline to endpoint differences in anxiety in the trial.
As you mentioned, this trial will be done in Canada — which uses the ICD-10 diagnostic manual, so I think the language was chosen to “speak” to the overseas market using the ICD-10. The reason I bring up the DSM/ICD issue is that I just read a paper on how in Germany a group of symptoms that would be diagnosed here as Bipolar I is diagnosed there as “hyperkinetic conduct disorder.”
2. If the trial is about Bipolar II, then it’s about expanding the indication for Seroquel. At the moment, Seroquel is indicated for Bipolar II only in the acute phase of depression. The real purpose of this trial may be to test Seroquel for the maintenance treatment of Bipolar II/Bipolar NOS. I know that doctors can prescribe it off-label for maintenance of BP II — or prescribe it for acute treatment and then not want to take the patient off it again (as you discussed in your last post) but the big money for Pharma is having it “on label.”
Anyway, those are my two cents’ worth
Jackie,
Interesting point about the DSM vs ICD issue and the “Canada connection.”
As for your other comments, you might be jumping to an erroneous conclusion when you bring “bipolar” into the picture. (The protocol design is fairly clear about excluding other axis I diagnoses.) However, notice I said “might.” Even though “agitation” is one of the criteria distinguishing unipolar depression (more agitation) from bipolar depression (more retardation), according to the Task Force on Diagnostic Guidelines of the Intl. Society for Bipolar Disorders, it would not be unusual for a clinician to view “agitation” as a sign of “anxiety” or “hypomania” and see the patient as bipolar (or “bipolar spectrum”).
In psychiatry, diagnosis is in the eye of the beholder.
Seroquel is already being dumped on patients who show adverse reactions to antidepressants. Although “agitation” is a known adverse effect of many, including Lexapro — and indicates the medication should be discontinued post-haste — doctors widely misdiagnose it as emergence of bipolar disorder and proceed to medicate the patient up the wazoo.
Seroquel is a favorite, as among psychiatrists — including Taryn up above, apparently — it has the undeserved and undocumented reputation of being good for whatever. It’s the drug to prescribe when your patient falls under the DSM diagnosis “miscellaneous.” They might throw in Abilify as well and, oh yeah, maybe a benzo and another antidepressant, just to be safe.
And that is how drug-induced misdiagnosed bipolar disorder leads to disability, as outlined by Robert Whitaker in Anatomy of an Epidemic. QED.
Iatrogenia, whenever any kind of medical help is sought, the patient (or the patient’s parents and/or guardians) have a responsibility to become informed about the treatment options, including the side/adverse effects of any medicines. They should question the doctor, read the literature, and seek counsel from the pharmacist — indeed, in my state the pharmacist has to give counsel on any new prescriptions and “easy to read” info. is stapled to the bag as well.
None of that changes because the patient is seeing a psychiatrist. Psychiatric patients are no less capable than other patients — they can weigh the risk/benefits and make their own decisions on treatment. And that’s how it should be — we should all be free to make our own medical decisions.
Jackie,
I fundamentally agree with you that the patient has a responsibility to ask questions, but we must not ignore the fact that patients put immense trust (rightly or wrongly) in the wisdom of their physicians to do what is best for them– or, at the very least, primum non nocere. (OK, any Latin speakers can re-conjugate that verb for me.)
That said, it’s a daunting task for patients to figure out what’s best for them, as discussed in this NY Times article. When a medication’s side effects include both “diarrhea” and “constipation,” or both “insomnia” and “sedation,” what’s one to to? Trust the doctor? Get a second opinion? Google it? Go to a website like Iatrogenia’s?
Begging your pardon, Jackie, it is a doctor’s responsibility to weigh risk-benefit for each individual patient before laying out treatment options, at every stage of treatment. If the doctor is practicing medicine, that is.
If the doctor is prescribing a medication simply because Pfizer paid for lunch, the doctor is not practicing medicine, he or she is acting as a pharmaceutical distribution agent.
Psychiatrists should not be not operating out of a booth on the fairway, buyer beware.
Patients should be active in their own treatment and do their own research as well.
(Information provided with psychiatric drugs grossly understates risks — drug companies fight tooth and nail against every phrase added in this section.)
“When a medication’s side effects include both “diarrhea” and “constipation,” or both “insomnia” and “sedation,” what’s one to to?”
I wonder if the man in the NYT link was taking fluoxetine as those are some of its potential side-effects? … And were also some of the side-effects reported by those taking placebos in the fluoxetine clinical trials.
In our family, there wasn’t much of a dilemma: Possible remission from depression vs. chance of diarrhea or constipation?
Now, the stakes are much higher — and the decisions much more difficult — when the potential adverse effects are more serious, like stroke or metabolic syndrome. But people get informed and make those tough decisions every day as can be seen at the Crazy Meds site:
http://crazymeds.us/pmwiki/pmwiki.php/Main/HomePage
And people afflicted with every kind of ailment face difficult decisions.
Sure, the people on crazymeds make difficult decisions — people make decisions based on whatever kind of information they can find!
(crazymeds is not in any way pro-psychiatry. They do a pretty good job filling in the blanks about horrific and much-denied side effects.)
Unfortunately the advice from psychiatry is pretty hopelessly tainted, and the advice of individual psychiatrists — well, you know what flows downstream….
In a polite few words, garbage in, garbage out.
Psychiatrists with any kind of moral sense, like Dr. Balt, must be deeply mortified at state of their profession.
By the way, Jackie, if you are defensive because you are fighting a stigma against mental illness, allow me to point out that criticizing psychiatry is not the same as condemning mental illness.
Widespread incompetence among psychiatrists leaves the mentally ill in a quandary, though.
Not defensive, Iatrogenia. Not fighting a stigma — it’s the 21st century after all. That’s been the point of my posts — that psychiatry is like every other branch of medicine in that sometimes difficult decisions have to be made, often without a full understanding of what’s going on, with treatments that can have horrible, sometimes irreversible, side effects.
This was never more apparent to me than last week when a friend asked me to help research PSA velocity, prostate cancer, treatment options, etc. so he could make an informed decision on a potential life-and-death matter. I had no idea that that particular area of urology/oncology/radiology had so many unknowns, with pretty much all the points you are levelling against psychiatry — including urologists/oncologists/radiologists down-playing side-effects of ALL the treatments.
A must-read for all… medical, non-medical, patients, parents.
Marcia Angell, M.D. – The Epidemic of Mental Illness: Why?
From the New York Review of Books
Dr. Angell’s vitae (in part):
Harvard Medical School, Division of Medical Ethics
Former Editor-in-Chief, New England Journal of Medicine
http://www.nybooks.com/articles/archives/2011/jun/23/epidemic-mental-illness-why/?page=1
IMO, psychiatry was delivered another nail in its coffin.
It’s time for psychiatry to die.
We HAVE to find other methods of treatment!
Duane Sherry, M.S.
discoverandrecover.wordpress.com
Agreed, let us hope. From part 1, looks like Dr. Angell is doing an excellent job summarizing the most prominent criticisms of psychiatric treatment.
[…] were never discussed with the patient. And then there are other antipsychotics like Abilify and Seroquel XR, which are increasingly being used in primary care as drugs to “augment” […]
bipolar disorder can be managed by some medications but CBT also helps…
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I’ve lost the battle. I’ve had agitated depression since 15 (now 49) and have had all sorts of treatment (and yrs of misdiagnoses) including an ECT full trial. I’ve only had a couple very, very brief breaks with paxil, zyprexa and recently ritalin and adderall. I can not do a thing at all which includes socializing. I can not manage the irritability and/or agitation to save my life. Lexapro caused immense agitation, seroquel made me lightheaded, I passed out on first dose of ability. I’m at a loss. I’ve seen many Doctors from Pennsylvania Hospital (distinguished Psych Hospital, est. 1841) since 1991. And there’s no one to turn to. Family is baffled by me (and my daily complaints). Never dreamed this would happen to me.
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