Experts by Experience and Nobel Prizes

 

In the mid-1980s, I gave a very nice man, an in-patient, weekend leave.  He hung himself. Everyone was shocked. The drug I’d put him on was the trigger to his suicide.

Soon after, a medical resident called me to a case she was handling. She seemed exceptionally impressive, so I was surprised to hear afterwards she was taking an antidepressant. She told me about the main problem this caused her – urinary retention. I had the usual view – urinary retention is an issue for older men with prostate problems with an antidepressant’s anticholinergic effects potentially being the straw that broke the camel’s back. This woman, who was even younger than me, didn’t fit the bill.

I can still see in my mind’s eye, an older lady who came to see me a few years later. She had been admitted and put on a rake of heavy duty drugs, out of all proportion to some quirky episodes. She now had tardive dyskinesia. I suggested trimming some meds. She was all for this but laying them out on the table, she said, ‘I don’t want you to stop this one’.  The only helpful drug in the mix as far as she was concerned was benztropine.

Soon after, Eli Lilly engaged me as a clinical trialist for duloxetine, their intended post-Prozac block-buster. Having gone through the trouble of filing applications for ethics approval and other paperwork, I was disappointed when they terminated the trial before it began. The drug had some problem. A few years later, duloxetine came on European markets as a bladder stabilizer – Yentreve.

Zalutria, r-fluoxetine, replaced duloxetine as Prozac’s heir apparent. But it too ran into problems. Lilly resurrected duloxetine in a rush.  In the course of a healthy volunteer trial, 19 year-old Traci Johnston committed suicide. Lilly applied to FDA to license duloxetine as Cymbalta for depression, and as Yentreve for bladder stabilization.  FDA said no to Yentreve – too many women with no nervous problems had attempted suicide on it.

Long before this, Psychiatric Drugs Explained had been published with a message that ties these vignettes together.  See below.

Yes antidepressants can cause urinary problems – much more than just retention – but the conventional story that retention is due to an anticholinergic action is just plain wrong.  Not just wrong, but rapidly becoming psychotic.  Here’s how the psychosis developed

The Background Story

In 1965, the Catecholamine Hypothesis of Depression was born. This was the original chemical imbalance hypothesis.

In 1958, the first antidepressants, imipramine, a tricyclic, and iproniazid, a monoamine oxidase inhibitor (MAOI), had appeared triggering efforts to work out whether their mechanism of action could tell us something about the biology of depression. The work of Julie Axelrod, who won a Nobel Prize for demonstrating that noradrenaline (aka norepinephrine), adrenaline and serotonin have reuptake mechanisms and that imipramine acted on noradrenaline reuptake, provided the key.

(Axelrod is in the light jacket in the photo – getting his Nobel Prize in 1970).

The catecholamine hypothesis, a 1960s update on Freud’s Interpretation of Dreams in terms of its impact on how we thought about nervous problems, claimed depression stemmed from lowered noradrenaline and increasing this, which both tricyclics and MAOIs were now known to do, was how antidepressants worked.

This hypothesis put a premium on creating pure noradrenaline reuptake inhibitors. These would be much more effective. And free of side effects.  The original tricyclic antidepressants, imipramine and amitripytline, are antihistamines, act on other receptor systems, and are serotonin reuptake inhibitors. A second generation of noradrenaline reuptake inhibitors, desipramine, nortriptyline and lofepramine, close to eliminated the serotonin reuptake inhibiting effects which Axelrod regarded as irrelevant, a primitive relic of our marine past.

Lofepramine was the drug I had prescribed for the man who hung himself. In the mid-1980s it was the best-selling antidepressant in Britain. You couldn’t die from an overdose on it. He had gone into urinary retention and this triggered his suicide by hanging. Nortriptyline was the drug that put the medical resident into retention.

Listening to Patients

In 1969, Arvid Carlsson comparing what patients said about the effects of desipramine, and nortriptyline to imipramine, amitriptyline and clomipramine, came up with the idea of a serotonin reuptake inhibitor. The serotonin reuptake inhibiting effects of imipramine and amitriptyline seemed helpful in OCD, whereas desipramine and nortriptyline were not. What would a drug which inhibited serotonin but not noradrenaline reuptake look like?

Carlsson’s zimelidine was the first of these.  One of the early hopes was that serotonin reuptake inhibitors would not have the activating effects noradrenaline reuptake inhibitors had, which some people were blaming for the suicides imipramine, amitriptyline and clomipramine caused.  Carlsson accepted from early on that his SSRIs could cause suicide.

Carlsson also won a Nobel Prize.

The Crack and the Light

The tricyclics also had anticholinergic effects. It was likely a semi-marketing department move to blame this anticholinergic action as the source of all side effects – urinary retention, constipation, a dry mouth, dizziness, vision problems, memory problems, confusion, even dementia.

Quite extraordinarily in retrospect, by the early 1960s imipramine was being give in a low 10 mg dose – the antidepressant dose is 150 mg – to young boys who had enuresis (bedwetting). It contributed a little bit of urinary retention that worked well. This, it was claimed, had to be an anticholinergic effect – even though cleaner anticholinergic drugs like benztropine or procyclidine were never used for this purpose.

Getting rid of the anticholinergic effects was the key to producing drugs that would sell by the billion. The SSRIs weren’t bad in this respect, but they also cause dry mouth, constipation and not just constipation but functional dysnergia syndrome, lots of urinary problems like interstitial cystitis, prostatis, vision problems (see Visual Snow and Visual Problems), dizziness (see PPPD), confusion and even dementia.  Along with far more suicide, sexual problems, and dependence than noradrenaline reuptake inhibitors cause.

The SSRIs are also weak antidepressants. The dual in duloxetine meant it inhibited both noradrenaline and serotonin reuptake – by then it was agreed that this would make it a stronger antidepressant.

The Crack through which the Light gets in is that duloxetine and reboxetine, a relatively pure noradrenaline reuptake inhibitor with no anticholinergic effects, along with desipramine, imipramine, nortriptyline, amitriptyline or lofepramine, are the drugs for you if you want urinary retention.  Benztropine, procyclidine or any potent anticholinergic drug are useless for this – but bladder stabilization is a different matter (See The Making of Anticholinergic Maleficence).

Or noradrenaline reuptake inhibitors can help if you want to be constipated or your entire pelvic floor to stop coordinating properly.

An SSRI is a good bet, if you want your vision compromised, your love life wiped out, to be made suicidal, homicidal or to end up unable to part company with your drug. Duloxetine, which is also a potent serotonin reuptake inhibitor, is pretty good at all this as well as having noradrenergic problems.

Why An Anticholinergic?

So what use if any are drugs like Benztropine?  Why did my Lady of the Quirks want to hang onto it?

The good thing about noradrenaline reuptake inhibitors, if they are doing what they are supposed to be doing, is that they enhance drive, vigilance and maybe sensitivity.  The good thing about SSRIs when they work is that they are serenic – anxiolytic.  A smidgen of the dose typically dished out and you can have a useful degree of emotional numbing.

The good thing about benztropine?  Compared to the others its euphoriant and may be why tricyclic antidepressants are so much better for depression than noradrenaline reuptake inhibitors or SSRIs.

My Quirky Lady was just like many patients in the 1980s who figured that their anticholinergics had more commercial value than anything else they were being given – even benzodiazepines.

In her case and many others, far from causing confusion and other cognitive effects, they were speeding up thinking, making it clearer and all without causing a fraction of the memory and cognitive problems antipsychotics and benzodiazepines cause.

Doctors meanwhile were horrified at the rates their patients were smoking. The excess mortality of schizophrenia was put down to smoking rather than to the metabolic and cognitive effects of the antipsychotics. But in addition to nicotine’s cognitive benefits, it controls the appetite that antipsychotics make voracious causing weight to balloon.  Being a patient at the hands of a doctor can often involve a pretty desperate calculus.

Anticholinergic drugs are famous for their euphoriant effects.  The use of Henbane, the main ingredient in Witches’ Brew gave rise to the pictures of witches riding broomsticks. Atropine, the original anticholinergic drug, put into clinical trials for melancholia – the severe depression for which SSRIs are useless – has been reported as effective.

The very racy history of Witches on Broomsticks and sex is in this link.

Sex – for the most part cholinomimetic drugs seem a good thing.  See Witches.

Anxiety – why did we ever smoke if not for the stress relieving effects of nicotine? Nicotine acts on a different part of the cholinergic system to the antimuscarinic anticholinergics but the two cholinergic drug groups produce many similar cognitive and other effects.

A very likeable man with crippling OCD came my way recently. We tried the usual option for OCD, an SSRI. It didn’t work. We switched to clomipramine – no good. We added an antipsychotic – no joy. I was very upset at not being able to help. Some weeks later he came back much better. I was relieved. He had stopped the drugs I’d put him on. I was fine with this. I’d have been happy with anything that gave him a little peace. And was very happy when he told me what had made the difference.

Nervous about telling me that he had taken up smoking, he had googled nicotine and OCD before coming to see me. He had found good studies showing nicotine and other drugs working on the cholinergic system, like donepezil and rivastigmine, have effects on OCD as good as the SSRIs. He had printed them off. The first study he handed me had Arvid Carlsson on its authorship line – Nicotine and OCD. He had no idea who Carlsson was.

Therapeutic Principles

Why would nicotine rather than SSRIs help this man. This goes back to a way of thinking that helped Carlsson discover the SSRIs.

He didn’t see an SSRI as a Magic Bullet that was going to fix the problem in Depression. He listened to what patients said and worked out that they were more likely to say there was an anxiolytic effect from a drug that acted on serotonin compared to a drug that didn’t.  Reliably producing an anxiolytic or serenic effect meant that the serotonin system was normal and that a normal serotonin system could produce an effect that might be useful in nervous disorders – for some people but not necessarily for all.

Rather than a Magic Bullet for all, an SSRI could be a Therapeutic Principle for some.

One way to understand this is to look at this image of Constipation and Laxatives.  There are 4 four different ways we can get constipated and it four different kinds of drugs can help. The clinical skill lies in picking the right drug for the problem you or I have.  Put us on a drug just because its called a laxative and we may end up on our way to treatment resistant constipation.

(There are of course 5 ways – take a noradrenaline reuptake inhibitor is another with a stop the drug therapeutic principle).

It’s the same with treating hypertension, diabetes, and most things in medicine, including depression and other nervous disorders. Its even the same with Cognitive Behaviour Therapy which has a number of different therapeutic principles in it – cognitive restructuring, behavioral activation, homework – one of which may be the thing that helps me and another helps you.

It is, or until recently was, mainstream medicine to think that nicotine (not smoking) or benztropine might work wonderfully for some us. Magic Bullet thinking has thrown us off course with its idea that there is a known simple abnormality at the heart of our problems that can be exterminated the way we exterminate bacteria.

The catecholamine and later serotonin hypotheses were Magic Bullet hypotheses – marketing copy rather than real hypotheses. Drug companies want Magic Bullets, as in this antibiotic image, which give control of how we think over to them. This citalopram adverts shows the same kind of thinking.

They do not want Therapeutic Principles, which hand control of the treatment process over to doctors and to us.

The Magic Bullet idea, a drug than can only do good, has spun off a Maleficent Twin – a drug that can only do bad. More than any other group of drugs in medicine, the anticholinergics have become Maleficent – blamed for the hedge of thorns that keeps our inner beauty asleep until some medical prince can fight his way through and put a Magic Wafer on our lips.

This has been a disaster. Anticholinergics now look like they might stimulate peripheral nerve regeneration, which may treat diabetic neuropathy, antidepressant dependence and withdrawal, PSSD, PRSD, PFS and PGAD, along with PPPD, Visual Snow and other problems. This factor may have made older tricyclics less damaging than SSRIs.

No drug suits everyone. Every drug is a poison, and the skill lies in bringing good out of its use. The anticholinergic group of drugs come with their own problems but on balance these drugs look less poisonous than the SSRIs, antipsychotics, most anticonvulsants and perhaps the benzodiazepines.

My quirky lady and man with OCD knew and know more than many of the doctors treating them.  As drug companies proudly boast, many doctors today have no thoughts in their heads that are not put there by our company or our competitors. As a consequence of doctors being more manipulable by marketing campaigns than teenage boys and designer clothes, anyone who want to get the benefits of a cholinomimetic or anticholinergic drug now is up against a full-blown psychosis.

How company marketing can generate psychoses like this is explained in a sister post The Marketing of Anticholinergic Maleficence on DavidHealy.org

The academic version of these two posts is in The Past, Present and Future of Anticholinergic Drugs  which can be accessed here and on DH.

The history of all this is in The Antidepressant Era.  Interviews with Julie Axelrod and Arvid Carlsson can be found on The Psychopharmacologists where on the Samizdat Website these and 98 others including the discoverers of amitriptyline, and imipramine and the discovery of the sexual side effects of clomipramine and later SSRIs can be found.