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.

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.

Lilly turned back to duloxetine and turbo charged 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 Alaskato Australia (see Petra’s story) rushed to prescribe it.

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.

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.

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.

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?

Readers can also view my blog posts (A Symbolta of Sorts) and find further information at www.davidhealy.org or visit my Facebook page.

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