A Symbolta of Sorts

In the early 1990s, Prozac was riding high but Lilly were planning its successor. The leading candidate was duloxetine – a dual inhibitor of both serotonin and norepinephrine reuptake as the older tricylic antidepressants (TCAs) had been. The company approached me in 1992 to recruit patients to a clinical trial of the new drug but before the trial could start duloxetine was pulled from development as an antidepressant. There were problems I was led to believe.

Some years later I heard duloxetine had been brought on the market in Europe as a bladder stabilizer. It is marketed as Yentreve.

To solve their successor to Prozac problem, Lilly turned instead to an isomer of Prozac. R-fluoxetine. This would emerge as Zalutria. The company was blazing a trail that Lundbeck (Forest) have followed since with Celexa becoming Lexapro, and Wyeth with Effexor becoming Pristiq and Astra Zeneca with Prilosec becoming Nexium.

 Heart-stopping moments

But Zalutria ran into problems around 2000 when the data were sent to FDA. It interfered with cardiac QT interval on EKG tracings. When this happens those affected are at risk of simply dropping dead. If Zalutria does it badly enough to make it unmarketable, it has to be presumed Prozac does it also.

Since then other SSRIs such as Celexa and Lexapro have been reported to cause QT problems, and are running into problems for just this reason. In some cases companies appear to ‘discover’ QT interval problems in order to get some of their older drugs removed from the market. But while there were other reasons why they might have wanted to abandon it, in this case Zalutria’s interference with QT intervals was probably a major inconvenience for Lilly.

$3-4 billion per year is nothing to be sneezed at.

Lilly turned back to duloxetine and turbocharged their clinical trial program. It was during this program that one healthy volunteer on duloxetine, Traci Johnson, committed suicide. Lilly submitted an application to FDA to bring the drug on the US market for both depression as Cymbalta and for bladder stabilization. The FDA were not prepared to license it for bladder stabilization – there had been too many suicidal acts of women on duloxetine in bladder stabilization trials. But Cymbalta was let on the market for depression.

So how would a drug that the company at one point had abandoned, that had significant side effects – such as marked urinary retention, suicidality along with physical dependence – do in a market where the parent company were also trying to persuade doctors that many of their cases of depression were in fact bipolar disordered and should be prescribed Zyprexa. Well $3-4 billion per year is nothing to be sneezed at. Doctors from Alaska to Australia (see Petra’s story) rushed to prescribe it.

Why do doctors roll over in the face of good marketing?

How does a company manage to turn a drug they had written off into a blockbuster? Why do doctors roll over in the face of good marketing? It all hinges on good stories. In the case of Cymbalta, the story was that this was helpful for pain. There was nothing about Cymbalta to recommend it for pain beyond other antidepressants. The marketing campaign might have even been worked out for Zalutria and just seamlessly transferred to Cymbalta. It makes little difference what the drug does. Companies listen to what doctors say they want and this is what they give them pretty well whether there is anything significant about the drug that would support these claims or not.

In this case Lilly were lucky, this story emerged just when the pain-killer Vioxx ran into trouble, and doctors were looking around for another new drug to help with one of the commonest problems in clinical practice – chronic pain syndromes. But it’s the listening to doctors and repeating back to them what they say they want that works every time. These are soothing not challenging stories.

I feel it in my waters

Cymbalta brings out another story that doctors have been totally sold on for 40 years – a perfect symbol of modern biobabble. From early on the first of the tricyclic antidepressants, imipramine, was used to stop bed-wetting in children. The tricyclics got a reputation as bladder stabilizers – sometimes too much so as they could cause urinary retention.

How did tricylics stabilize bladders? Well in the 1960s the story emerged that the antidepressants fixed the lowering of norepinephrine that was at the heart of depression. If this was what they did to treat depression, something else they did must lead to urinary retention. The field settled on the anticholinergic actions of the tricyclics as the culprit. Every single text on antidepressants trots this out. This led to the marketing copy for the SSRIs, 20 years later, the new kids on the block that didn’t have the nasty anticholinergic side effects of the tricylics.

It was and still is almost impossible to find a psychiatrist to say anything other than this even though all of them prescribe much more potently anticholinergic drugs than the tricylics to patients within the mental health system to stop some of the side effects of antipsychotics, but these potent anticholinergics rarely if ever cause urinary retention.

The mismatch between what the books say and what the drugs do is extraordinary.

Imipramine and duloxetine in fact cause urinary retention because they act on the norepinephrine system. The mismatch between what the books say and what is going on here is extraordinary. The story that it’s the anticholinergic effects of antidepressants that cause urinary retention is a myth in service to another myth, the catecholamine hypothesis of depression, the source of all later myths about chemical imbalances.

In fact if a group of 10 healthy volunteers were given an SSRI, a norepinephrine reuptake inhibitor or an anticholinergic, we know that on the SSRI there is a good chance that 1 would be suicidal, most would have impaired sexual function and other problems. Those on the norepinephrine reuptake inhibitor would have erectile failure, bladder stabilization, constipation, chilblains and other problems. What would those on the anticholinergic have? If the dose was not too high, the answer is euphoria. Of the three groups of drugs, the anticholinergics have the highest street value.

Masturbation and myths

What’s the moral? You should believe little you hear about drugs and biology across medicine. What is peddled is for the most part a set of stories or myths. In the case of the antidepressants there is almost nothing but myths from chemical imbalances to lowered serotonin levels.

As with the myth that insanity was cause by masturbation, with mythologies in general the issue is whose interests are being served?


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Pharmageddon

Pharmaceutical companies have hijacked healthcare in America, and the results are life-threatening.

 

Dr. David Healy documents a riveting and terrifying story that affects us all.

 

University of California Press (2012)

 

Available on Amazon.com

 

Comments

  1. Since the advent of the Internet, it is a simple matter for both physicians and patients to find out much that is required in order to make an informed decision about undergoing any recommended treatment be it medication or surgery. For example:
    Cymbalta : Information from the manufacturer:
    “Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults.
    Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term and one maintenance trial in adults.
    Cymbalta is indicated for the management of diabetic peripheral neuropathic pain and fibromyalgia.
    Cymbalta is indicated for the management of chronic musculoskeletal pain due to chronic osteoarthritis pain and chronic low back pain.”
    According to this, we have an actual panacea for the ills of the elderly. However:
    “Important Safety Information About Cymbalta
    The most important information you should know about Cymbalta:
    Antidepressants can increase suicidal thoughts and behaviors in children, teens, and young adults. Suicide is a known risk of depression and some other psychiatric disorders.
    (So, it doesn’t cause suicide, just makes it more likely if you’re already depressed.)
    “Before taking Cymbalta, talk with your healthcare provider:
    about all your medical conditions, including kidney or liver problems, glaucoma, diabetes, seizures, or if you have bipolar disorder. Cymbalta may worsen a type of glaucoma or diabetes
    about all your prescription and nonprescription medicines. A potentially life-threatening condition has been reported when Cymbalta was taken with certain drugs for migraine, mood, or psychotic disorders
    if you are taking NSAID pain relievers, aspirin, or blood thinners. Use with Cymbalta may increase bleeding risk
    about your alcohol use
    about your blood pressure. Cymbalta can increase your blood pressure. Your healthcare provider should check your blood pressure prior to and while taking Cymbalta
    if you are pregnant or plan to become pregnant during therapy, or are breast-feeding
    Severe liver problems, sometimes fatal, have been reported”
    if you experience dizziness or fainting upon standing. This tends to occur in the first week or when increasing the dose, but may occur at any time during treatment
    if you experience headache, weakness, confusion, problems concentrating, memory problems, or feel unsteady, which may be signs of low sodium levels
    if you develop problems with urine flow”
    Oops! That lets out most of the old and very old. Why would anyone prescribe or take a drug that indicated it could kill you and you can’t predict whether or not you might be drawing the short straw?
    “People age 65 and older who took Cymbalta reported more falls, some resulting in serious injuries.”
    Perhaps related to blood pressure changes?
    So, if physicians are aware of all of these adverse effects and take a responsible attitude, who’s left to prescribe for?
    p.s. Let’s not forget we have “ The Cymbalta Promise 60-Day Money-Back Offer” – if you survive that long.

  2. Cymbalta comes in dead last in a patient survey of treatments for fibromyalgia: http://curetogether.com/blog/2011/08/10/patients-say-fibromyalgia-drugs-make-things-worse-rest-is-best/

  3. Neil Carlin says:

    In 2011 Eli Lilly Canada announced that Health Canada had approved Cymbalta (duloxetine) for the management of low back pain.

    http://www.digitaljournal.com/pr/292994

    In the recent past, a close family member was prescribed Cymbalta for low back pain and had no idea that it is an SNRI-antidepressant – GP did not give any warnings on possible adverse effects. It was simply described as a pill for pain??

    After we spoke, this person, who is near & dear to me, did not fill the prescription. Their back pain resolved within 6 weeks or so with some exercises and physiotherapy.

    So big question is, are people who are properly informed of risks, willing to trade an episode of low back pain for a potential heart attack or perhaps death by suicide?

    I don’t think so.

  4. Interestingly, I found these two stories about the launch of Cymbalta in the UK and you can see the way the drug company was positioning its product.

    http://seroxatsecrets.wordpress.com/2007/05/24/cymbalta-marketing-by-the-back-door-re-post/

    http://seroxatsecrets.wordpress.com/2007/05/06/depression-alliance-and-cymbalta-launch-2/

  5. Neil Carlin says:

    To highlight what I said in my previous comment regarding Cymbalta induced “heart attack”. I should have said severe heart problems as “heart attack” is a vague term. Here is a case example of what I meant.

    A 60 year-old lady with a 5 day history of dizzy spells and 1 day of chest pain had been prescribed Cymbalta that week for the treatment of diabetic neuropathic pain- one of the reasons the drug is prescibed here in Canada..

    One day after starting Cymbalta, she began experiencing shortness of breath and had multiple falls at home. Heart tests showed normal coronary arteries, but showed the left side of her heart (the extremely important part of the heart) ballooning or getting much larger than is normal.

    She was told to stop the Cymbalta and further repeat tests after stopping the drug showed her heart had returned to normal. A diagnosis of cardiomyopathy (enlargement of the heart) caused by Cymbalta was given.

    How many others have not been as fortunate as this lady and have died because of this Cymbalta-induced heart problem?

    God only knows.

    Reterence:
    Bergman BR, Reynolds HR, Skolnick AH, Castillo D. A case of apical ballooning cardiomyopathy associated with duloxetine. Ann Int Med 2008;149(3):218–9.

  6. Johanna says:

    The mass prescribing of Cymbalta for chronic pain may be one of the worst uncontrolled experiments on human beings imaginable. Psychiatrists are ignorant enough about its range of adverse effects, but GPs, orthopedic surgeons and physiatrists who have been sold this stuff as a pain pill are even less prepared to warn their patients. This is particularly scary with the psychiatric side effects. I had godawful nightmares while coming off this drug — stuff right out of the worst Hollywood splatter movie — and while they were upsetting enough for someone who actually knew this was the drug talking, I shudder to think how a person must feel who believes these impulses are a sign of her underlying illness or her subconscious “true feelings.”

    I ran across this post on Cymbalta withdrawal from an MD physiatrist who blogs for Health Central:

    http://www.healthcentral.com/chronic-pain/c/27148/146506/cymbalta

    About halfway through her article, she provides a link to a 2009 FDA Advisory Ctte meeting on the question which is really shocking. Given how much is known, why are docs and patients being told so little?

  7. Perhaps one of the ways to ensure that patients are given all requisite information would be to force physicians to obey the law. Consent is the principle that a person must give permission before receiving any type of medical treatment from a blood test to an organ donation. There is a tendency to think of written consent as being required only before invasive procedures. Not so. The principle of consent is one of the cornerstones of medical ethics. It is also enshrined in international human rights law.
    What would happen if, when faced with a recommended prescription, we presented the physician with the following:

    It has been suggested to me by Dr……………….. that I have a condition called…………..and that I should take a medication called……………for a period of………. …………at a dosage of…………….The expected effects and adverse effects are described by Dr………… below:
    …………………………………………………………………………………
    …………………………………………………………………………………

    Signed: Dr …………………… Date…………………………..Witness…………….

    Having been made aware of the expected results as well as all possible effects of this medication, positive and negative, I consent/refuse to take the recommended drug.

    Signed……………………….Date…………………………Witness…………….

    I suspect hordes would be seeking new doctors for quite a while but should the politicians not be forced into protection of the public by making something of this nature mandatory?.

  8. If the resulting effect was suicide from a prescription drug and the patient signed the consent note, then, I am afraid, the patient takes the consequences. The doctor was given information that the prescribing drugs were safe by the manufacturers, so, regretfully this would not solve the problem.

    I could have signed all the forms going for all the drugs I was given but at the end of the day, most gps and psychiatrists are oblivious to the dangers.

    Most of the gps and psychiatrists are not on the internet looking into all this menace either.

    At the moment, it is criticism of prescription drugs on the internet only.

    All this colossal amount of information that we have, Irene, should be in the press on a daily basis and it is not. Why not? And why, despite legions of court cases and damages, particularly in the US, are all these manufacturers of prescription drugs, which have a propensity to kill, a few, allowed to get away with it?
    The same old story, it is good for the majority but the rest can go hang!

    • There is one notion that needs to be corrected here – the notion that the drugs kill a few. The data that we have indicates they kill more than they save. If that’s a few dead, it still begs the question as to whether the benefits warrant these risks.

  9. No. It doesn’t beg the question. Not when we know that ‘lyrics’ in the pil leaflets are words and statements massaged to suit the end goal.
    Benefits of ssris are either placebo or sedation. Both of which work to suit the manufacturers’ end goal. The same with other drugs; massage and distortion of medical facts have taken hold of all pil leaflets and ensure that they are covered from every angle which is now their protection from being sued.
    You have the data, you have the expertise, you have it all and yet, they kill more than they save, is not released into the public domain.
    Yet.
    Unless I had experienced all this first hand myself, I would not have believed it posssible, so I understand the laborious and yet, necessary, need to gather all the evidence before the siege of upending it all.
    Thanks for correcting my notion that drugs kill a few.
    They’ kill more than they save’.
    An extremely professional, extremely intuitive and vital blog.

  10. The lethal effects of drugs are most evident in the older person for several reasons and I would have to agree that they kill more than they save, not only by individual adverse effects of a drug but by the common, appalling “drug cascade” seen all too often. As we age, our ability to clear the system of medications slows dramatically because of the reduced function of liver and kidneys so that overdose is the norm. It’s not uncommon to find patients in their 80s on more than 10 prescribed drugs, often with two versions of the same medication at the same time. A recent consult of mine was for an 85 year old gentleman who was on two drugs to lower blood pressure, three statins, pantaloc, two medications to reduce the progression of Alzheimer disease, citalopram for “depression”, aspirin, nitro for angina (x2), Abilify and the family was concerned because he appeared to be confused. On this list, I doubt I’d have been able to get out of bed or remember my own name.
    In the older patient, in general, the fewer the medications the better and at the lowest dosage possible. It would take too long to go through the adverse effects of each of these individually but collectively we have the potential for the following: drowsiness, confusion, muscle twitching due to lowered sodium. Bradycardia, a slowing of the heart rate. Abnormal bleeding, headache , nausea, diarrhea, abdominal pain, fatigue, dizziness, depression and anxiety. Reduction in blood magnesium affecting heart function. Vitamin B12 deficiency which can cause fatigue and confusion. Increased risk of community-acquired pneumonia. Increased risk of Clostridium difficile infection (a very serious colon infection with severe diarrhea) which this gentleman has already had and suffers after-effects including dehydration. Increased risk for breaking a hip. Elevated levels of homocysteine in the blood, associated with atherosclerosis (hardening and narrowing of the arteries) which this gentleman has in the form of coronary artery disease. Dangerous changes in pH, potassium, and calcium levels in the heart. Shortness of breath; cold, tingling, or numbness in the hands or feet; dizziness, chest pain, or irregular heartbeat. And of course, let’s not forget the drugs such as Aricept, intended to control the progression of Alzheimer disease that are given to any older person who seems to be even moderately “confused”. If you survive all of that, it’s a wonder.

  11. Oh, Irene. Physicians like you are a wonder, who speak such total common sense.
    Not many like you around and why, I know not.
    Why are are most doctors and psychiatrists not aware that drugging children and elderly folk and middle aged people like me, is such a terrible thing to do.

    The children and the elderly folk cannot stand up for themselves. I think half the problem is to do with the utter respect which families have for their physicians.

    But when the physicians have been brainwashed, then Pharmageddon steps in.

    Drugs are good when they give cancer and other serious conditions the goodbye and more time, but drugs which change the mindset are criminally dangerous and those prescribing such should, by right, be stuck off the register of general practice for deliberately and knowingly giving drugs which are not proven, not regulated, not having had honest clinical trials, and not understood at all as to the way they distort the mind.
    Heinous.

  12. Neil Carlin says:

    Do Not Use: Duloxetine (CYMBALTA)

    Worst Pills Best Pills Newsletter article June, 2012

    After previously concluding that duloxetine (CYMBALTA) should not be used for major depressive disorder (MDD), Public Citizen’s Health Research Group has now classified the drug as “Do Not Use” for any form of depression as well as for all other uses for which it has been approved (for example, generalized anxiety or any form of pain, including fibromyalgia). For none of the approved indications is there evidence that the benefits outweigh the multiple serious risks discussed in this article…..

    Full article at http://www.worstpills.org/results.cfm?drug_id=1226

  13. bemused says:

    “What’s the moral? You should believe little you hear about drugs and biology across medicine. What is peddled is for the most part a set of stories or myths.”

    Indeed. And the lesson should be applied to what you read here as well.

    Dr. Healy, would you explain for your audience what happens, or what might happen, when an oldster with BHP and compromised urinary function takes an ordinary over the counter antihistamine?

    • David_Healy says:

      Bemused – it depends on which antihistamine. Part of the problem you will have here though if finding out exactly what your antihistamine does. Whichever one you are having it will do far more than act on the histamine system – and the next issue is that it is almost certain that many of its significant effects are either not known – or not easily available.

  14. bemused says:

    Sorry BPH, not BHP.

    The answer I was looking for is that the oldster might very well end up with acute urinary retention, requiring emergency room treatment. Perhaps that is also a myth, but somehow I don’t wish to run the experiment on myself.

    The point is that a lot of medications can cause urinary retention (because the control of urination is complicated), among them antihistamines, which are, I believe, lumped together with anticholinergics.

    • David_Healy says:

      Depends on the antihistamine – their anticholingergic effects are weak. And potent anticholinergics do not cause a problem. Antihistamines commonly have effects on the catecholamine system – if they cause urinary retention this is likely to be the reason. But it depends on the antihistamine. Some act on the serotonin system others don’t etc

  15. bemused says:

    That’s very interesting, thanks. As far as I understand, you assert that for both (certain) antidepressants and for antihistamines, when they do cause urinary retention, that is unlikely to be an anticholinergic effect, as is commonly asserted for both types of medications. I wonder how one would actually know that? I wonder (aside from pure scientific interest) whether the assertion has practical implications. For example, if one treatment causes urinary retention for a particular person, would anyone be able to predict with reasonable accuracy what other treatments might do the same?

    Actually, I care nothing about antihistamines. I thought it was a known point of reference that antihistamines were anticholinergic and that antihistamines cause urinary retention (in vulnerable populations).

  16. when i was 12 i met an old man walking by the lake where i went to camp. he said his name was eli lilley and he made medicine. i thought it was odd that the pillar capitols on his garage ( out in the middle of nowhere) had corinthian capitals. if i knew then what i know now, i wouldve thrown the old geezer in the drink! Cymbalta has caused me all kinds of misery, but i just CANNOT get off the darn stuff. first theres crying over everything good and bad and in between, and then theres withdrawal symptoms that mustve been designed in the pits of hell that will NOT diminish or go away. can somebody please help me? thanks, kate bazner

  17. It is important to note that not all people will have the adverse reactions and these meds do help many people.
    I have had good luck with some meds and bad with others. It is important to keep your relationship with your doctor is the main thing and not try to medication yourself. If it isn’t working, call right away and tell your doctor so they can help you immediately.
    I have taken these medications and many others as my doctors strive to find me the best “cocktail” of the day, week, month, etc. since a car accident left me disabled several years ago. I have to say that not only have I experienced the phenomena of onset of depressive symptoms from starting a medication, but I have indeed become actively suicidal as one of those symptoms.
    In my “former life” prior to the accident I educated others on mental health including suicide prevention and I basically promoted the use of these medications, but I really have had a complete change of heart after being on many of them.
    I still believe the benefits have been necessary in my case, but I would be far more cautionary in my teaching now because I know how unlikely others are to stay in close contact with their doctors when on these medications which is why the deaths occur. They do not seek support when they begin to feel these symptoms, and contact their doctor to go off of the medication in the prescribed manor which is vitally important as well because both taking the med and how your taking the med can be causing the adverse affects. Going off a medication all at once can cause more complications and even death, so it is very important to talk to the doctor.
    In my case, I have also experienced increased blood pressure, heart murmurs, decreased kidney function, serotonin syndrome and other complications which led to permanent physical health problems. I have stage 3 chronic kidney failure, chronic fatigue and muscle weakness, and was diagnosed with diabetes recently. I also have developed a blistering under the my skin on my head, neck and face, in my ears, throat and mouth that began after a change in antidepressants nearly 3 years ago. It creates a horrible pressure and burning beneath my skin and eventually breaks the surface of my skin emitting a clear sticky substance, and sometimes bleed, but in no clear boundary but forms scabs that peel and have left my previously clear complexion with ugly scarring. I have not been able to find any diagnosis or relief from this miserable affliction that is progressively getting worse. It had given me some weeks of relief, but now is constantly recurring since last July 2013. The exposed skin left behind appears as though it is burned and a biopsy of a blistered area reported that exact wording that the skin cells appeared as though they had been burned. I have tried all manor of treatments from acne treatments to both oral and topical antibiotics. I have seen 3 dermatologists.
    Unfortunately for me, I truly feel that it is possible the medications or my mix of medications could have caused a new and/or resistant skin issue. I would be very interested if any licensed physician or pharmacologist had an idea for me.
    I also feel though, I needed the medications because my situation was dire. I continue to work with my doctors to keep myself on the best treatment plan for me and I keep abreast of the newest and least invasive treatment options. I pray for new research to continue and thank all of those who help those of us who need it!

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