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A Strange History

Is one of the oldest, cheapest drugs in the international pharmacopeia soon to become the medication that will block Alzheimer’s, Parkinson’s, and MS?    Work by Giovanna Mallucci’s laboratory at Britain’s Medical Research Council has shown – in mice – that trazodone and DBM, an anti-cancer drug, appear to stop a common neurodegenerative process which kills neurons in many major diseases, including  scourges like Alzheimer’s.  After studying over a thousand compounds, the group’s finding was announced with a headline on the BBC declaring “Experts Excited by Brain ‘Wonder Drug’”. 

My immediate reaction was to laugh out loud.  For like many medications that lack the sexiness of the new, trazodone has been multiply repurposed for uses very different than originally intended – when others let you use it.

What Is This For?

Developed in the 1960s in Italy, trazodone was created as a potential  antidepressant blocking serotonin receptors.  It worked.  However, rather quickly it developed a negative reputation.  It sedated people.  It caused orthostatic hypotension – producing fainting in some who get up quickly from a bed or chair.  It provoked some cardiac arrhythmias.  And perhaps strangest of all, it instigated priapism – uncontrolled penile erections that sometimes had to be surgically decompressed.  People complained of erections that persisted for hours,  decades before the appearance of Viagra.  When SSRIs like prozac came on the market, which supposedly worked through blocking reuptake of serotonin, they so eclipsed trazodone that hardly anyone used the drug for a quite a while.

For over three decades I have fought with internists, particularly cardiologists,  who do not want their patients to take the stuff.  They will immediately tell me it can cause torsade de points, a nasty cardiac arrythmia.  True, if you take truckloads of trazodone with other drugs.  When I would counter that the theoretical “therapeutic” dose was 300-600 mg and  I was suggesting 12.5 mg or less to start, given only at night, I would still be rebuffed.  The internists would immediately demand I use SSRIs, drugs they were familiar with and use frequently themselves.

A few of my colleagues did change their minds.  When I was a consult doc at Brown, many of the general internists gradually realized that low doses of trazodone could help with their most agitated, out of control psychotic patients, particularly those suffering from organic delirium.  Others found its sedative powers useful. But the general reference point, fanned by marketers of the SSRIs, was that such “dangerous, old line stuff” should not be used.

The SSRIs developers possessed a  strong economic point.  SSRIs can provoke weight gain over time.  Trazodone did not.  SSRIs produce a lot of sexual side effects, blocking ejaculation and erection.  Trazodone might cause erections, but the severe priapism, which happens in perhaps one in 6,000 to 10,000 patients, was more common among the young.  Some of the older folks on trazodone might find a little increase in sexual function, but most did not. SSRIs often provoked insomnia, a major problem for people with depression and anxiety.  Trazodone made many people sleepy. For  many years, SSRIs were far more expensive.

Here was a clear marketing task – a much cheaper drug existed than the SSRIs, the “wonder drugs” of the 80’s and 90’s (cue Peter Kramer’s bestseller “Listening to Prozac”) with approximately the same clinical efficacy for anxiety and depression, no weight gain, few negative sexual side effects, and the ability to put sleepless depressives into slumber.  A medication like that had to be stopped.

That the story got stranger.  People noticed that standard sleeping pills like ambien were associated with higher death rates, confusion, and sleepwalking.  So they started using trazodone as their sleeping pill of choice.  By some measures it is now the most commonly prescribed sleeping pill in the U.S.

Yet as I learned at a panel at the APSS, the FDA does not want it studied as a sleeping pill.  They won’t fund that research.  In many ways, they don’t want to know.  It’s an antidepressant, and as far as they’re concerned, it will remain an antidepressant.

These days many clinicians like me  very low doses – small fractions of the smallest 50 mg pill - for anxiety, depression, and insomnia, especially when the three are concomitant. You want to teach people to sleep without sleeping pills. But for the nearly 10% of the  population suffering from depression any given day, many of them with insomnia, dirt cheap trazodone has its uses.

The Funny Things You Learn

Will trazodone get repurposed again as the great preventer of Parkinson’s and Alzheimer’s disease?  To quote  Judah Folkman, “we can cure almost every tumor – in the mouse.”  What works in mice often does not succeed in people.  Clinical trials over the next three to five years should give everybody a better idea of clinical potential.  But what can be learned from the trazodone saga are several points:

1. Hype often overwhelms facts.  The superplacebo effect of “using new drugs before they lose their effectiveness” remains a common part of our lives.  Older drugs like MAOIs and tricyclics are often more effective antidepressants and antianxiety agents  than the commonly prescribed SSRIs, but new stuff is “always always” better than old.  Until you do the clinical trials.

2. People really don’t know how antidepressants truly work.  The Big Pharma marketing story that you are “rebuilding serotonin levels” or similar poppycock denies the complexity of what these drugs do.  Trazodone, often thought of as simply blocking serotonin receptors, also block alpha adrenergic receptors and serotonin transporter proteins, with knock on effects that remain very poorly understood.

3. Money talks.  Old line drugs have few “advocates,” as only Indian and Chinese generic manufacturers usually make money on them.

4. The brain is far more complicated than many researchers let on.  The layers and layers of information inside our head are more than not understood: we lack a conceptual framework to understand them.  Elon Musk may be eventually planning to profitably make billions of us into cyborgs, but lots of successful research will be required before that happens – "The Ghost in the Shell" still hasn't found the ghost. 

5. Biological intelligence is very powerful.  The body is an information system.  Medications – potent information transformers – often do very different things than theory suggests.  Luckily for us, many of these effects can be put to good use by biological systems built to sustain anything thrown at them.

Sometimes fortune likes to smile. 

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