18. Steering Clear of Tulip Futures.

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Blue daffodils – the next big thing.

If psychiatrists were football managers we’d have been fired hundreds of times over. Depression is still the biggest cause of disability in the developed world. Like football, Spurs in particular, our treatments don’t seem to have advanced much since the 1960s.

Nevertheless, we continue to live in a world where we feel the big breakthrough is just round the corner.

What if mental illness really was caused by abnormal chemicals in the brain? Would a whole generation of counsellors and therapists become unemployed?

And what if a real ‘happy pill’ was invented, that improved people’s mood and behaviour, without being addictive or dangerous?

Some very powerful vested interests would be upset: brewery companies, organised crime and drug companies – arguably all  the same people – who continue to make mind-altering drugs and antidepressants, whose sales would slump.

It could happen, but we are right to be sceptical.

Clearly, Depression is not one of those diseases like Smallpox or Cholera, that could be eradicated with a vaccination program or antibiotics. Is it?

There has only been one such development, which completely changed the game. This was the introduction of Chlorpromazine in the late 1950s.

Since then there have been so many promising avenues, which have turned out to be mere dead ends in the history of ideas.

Or rather, as we say in Europe, Cul de Sacs. Or is it Culs de sac? Or even Culs des Sacs? And that’s before we decide whether to hyphenate.

Whichever way, a good name for a Belgian jazz musician – probably one who has taken up a defunct form, such as Scat.

Cul de sac appears to mean ‘the arse of a bag’. No-one seems to know if Cul is a rude word in France. People I ask tell me the French don’t really have a concept of rude words in quite the same way as in English.

Culs de sac have occurred regularly in the history of Psychiatry. The best known example is the so called Pink Spot.

In the early 1960s, scientists thought they had found an abnormal chemical in urine samples from patients with schizophrenia, which made a pink spot on filter paper.

Eureka! The spot was thought to be DMPEA, a possible brain chemical that had an effect like LSD. The theory was that an abnormal gene produced an abnormal chemical that caused the brain to malfunction.

Sadly, not true.

It led indirectly to a large number of patients being given high doses of B and C vitamins, which were unhelpful. To some extent the sixties was the vitamin era (though we did not have them in Derbyshire) and mega doses were made popular by chemists such as Linus Pauling and advised for all kinds of ailments, particularly cancer. Megavitamin sites are all over the internet, even now.

A more recent cul de sac, which is still running in self help literature, is the idea that people with Depression have a deficiency of certain types of oil or fatty acid.

Quite a number of studies compared types of fish oil with placebo, and a brief overview suggests that the more rigorous the study method, the more limited the benefits, with many studies showing no significant effect from oils.

I’m not saying don’t try these oils, by the way. There’s just something fishy about them.

Another occasional ‘winter visitor’ is the notion that mental illnesses are caused by a virus. This theory seems half based on the admittedly interesting finding that people with certain mental illnesses are more likely to have been born in the winter.

Many illnesses may turn out to be caused by viruses, especially if we use the word ‘virus’, like ‘allergy’, to mean ‘tiny nasty thing we can’t see’. Famously, stomach ulcers turned out to be related to bacteria infection much more than stress.

There are vast numbers of micro-organisms yet to discover, many of them found in our own gut. There are a number of scientists working on pro-biotic remedies, using specially trained bacteria to impact upon the nervous system via the GI tract.

Mice fed with Lactobacillus rhamnosus JB-1 for instance, showed significantly fewer stress, anxiety and depression-related behaviours than those fed with just broth.

Scarily, the biggest organ in the body turns out not to be part of us at all, but zillions of bacteria.

This might be another cul de sac, or it might be a big breakthrough. Time will tell.

When it comes to therapeutic dead ends, Insulin coma therapy probably takes the sugar-free biscuit. It was popular in the 1950s, probably didn’t work, was quite labour intensive and was definitely barbaric. It was abandoned pretty soon after the invention of Chlorpromazine.

Psychiatrists aren’t the only doctors to jump on bandwagons though.

During the twentieth century everyone suddenly decided that people should have their tonsils out, leading to millions of unnecessary operations. This was despite excellent evidence that most people grew out of tonsillitis by their twenties.

Now it is very difficult to get your tonsils done at all, even when they look like Jackson Pollock has painted them.

How long before we see the Sunday Times run an exposé about backstreet tonsillectomy parlours? ‘A man with a huge soldering iron and bicycle pump sits in the half light of a tiny room in the alley behind Poundstretcher … etc’.

One of the longest running – nearly 2000 years – culs de sac was the idea that the body was made of four humours – blood, bile, black bile and phlegm. This itself was built on the philosophical dead end that there were four elements – Earth, Wind, Fire and Water.

Which must have made the Periodic Table very easy to learn compared with the version we learned in Chemistry.

And raises all sorts of questions. Did Earth, Wind and Fire ever think of getting Roger Waters to join? And were they formally known as Blood, Bile and Phlegm? And was that too similar to their horn – based rivals, Blood, Sweat and Tears?

The four humour system teaches us a lot about intellectual red herrings, just to mix up the metaphor for a moment. There’s a blind ending, but you can travel a long way down the road before you get there.

Like the M50 going west, there is just no destination.

We are probably still exploring a few, like the serotonin theory of Depression. But we cannot always know where these paths will lead.

Very clever people, like Isaac Newton, went along with humour-based medicine: ‘Trials are medicines which our gracious and wise Physician prescribes because we need them; and he proportions the frequency and weight of them to what the case requires. Let us trust his skill and thank him for his prescription.’

Isaac, you are most welcome in our clinic, with that excellent attitude. But please don’t believe everything you read on the internet. And watch out for Charlie’s men.

As mentioned above, Linus Pauling won two nobel prizes, and was the leading chemist of his generation. He became convinced that Vitamin C could cure cancer, even despite evidence to the contrary from large trials at the Mayo clinic.

Beyoncé is still looking towards the ‘four elements’ to inspire her new range of fashion: ‘we explore the different emotions of women represented by the four elements. Fire, water, earth and wind.’

If people like Isaac, Linus and Beyoncé can be taken in, what chance have mere mortals?

With a little hindsight though, generally we can see more clearly where trails have run cold. Such as the South Sea Bubble, or Soviet Communism.

My history advisor tells me that there was once an extraordinary Tulip craze in Amsterdam. At the peak of tulip mania, in March 1637, some single tulip bulbs sold for more than 10 times the annual income of a skilled craftsman.

Tulips of course persist, so they are not a cul de sac in terms of their role as flowers, but rather as investment products. Otherwise Spalding would be the financial capital of the UK, instead of just the style capital.

Shakers were a religious movement who mostly refused to procreate – the opposite approach to certain other religions – and hence died out. However, archaeologists have found a lot of illicit stuff in Shaker rubbish dumps, like whiskey bottles and tobacco pipes. No vibrators though.

On the commercial side, Sunny Delight was an attempt to create a modish new orange drink. It was launched in 1998 with a £10 million promotional campaign. Within months Sunny Delight had become the biggest selling soft drink in the UK behind Coke and Pepsi, with sales of £160 million a year.  Then it all went wrong. 8000 litres of Sunny D concentrate leaked into the River Parrett in 2006, creating a literal yellow river. A 5 year old child turned yellow after consuming 1.5 litres per day and the makers, Proctor and Gamble, had to put a health warning on the bottle advising moderation.

Sunny D seems still to be available, judging by its website, which makes the claim that it was ‘reverse engineered from the sun’. Wouldn’t that make it Hydrogen?

I don’t think we should be too hard on people for driving down blind turnings fast and furiously.

The reason we get carried away with a plausible new idea is our hunger to explain something very complicated with something we can grasp ourselves and even explain to others.

We are junkies for theories which seem to have Face Validity.

Writing in New Scientist recently, Prof Nick Craddock suggested that Psychiatry needs its ‘Higgs Boson moment’. He points out that mental illness research comprises only 5% of medical research. Despite this, he is optimistic that some of the newer strands of research are about to come together:

‘Psychiatry started the new millennium a few hundred years behind physics. But the decade that followed saw radical change, and set the stage for an intense period of catch-up. It is not fanciful to describe what will happen as the equivalent of some 200 to 300 years of progress being compressed into 20 to 30 years’.

So lets end on a positive note today, and enjoy waiting, as Spurs wait, for the Higgs Boson moment.

Meanwhile, don’t put all your money into Tulips, however plausible that might seem.

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16. Looking Out for Charlie’s Men.

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We could just wait and see. Or we could try taking these.

A man goes into Wetherspoon’s and orders a pint of Ruddles. He is handed a yellow Smartie instead. ‘Its a placebo’, says the barman. ‘We’re running a trial and it looks as though you’re in the control group.’

He winks, ‘don’t worry though, its probably just as effective’.

Few people realise that the naked emperor in the ‘Emperors New Clothes’ story was simply taking part in a controlled trial of Nylon.

King Canute famously tried to turn back the tide by issuing a command. Many think he was using irony to demonstrate the point that he had limitations. Even this would surely have been a massive mistake, in as far as the Vikings operated a ‘sticks and stones’ approach to verbal aggression, finding the axe more reliable than sarcasm.

In fact, misunderstood Canute was simply conducting a controlled experiment in Tide Management. Since kings used to think they might have divine powers, this was probably more reasonable than it sounds now.

Its a bit like Prince Charles testing whether he can destroy the South Bank Centre by telekinesis. From the look of the place he is slowly succeeding.

Sadly, modern Royalty don’t value controlled trials so much. Prince Charles, for instance is a big fan of Homeopathy.

Writers such as Ben Goldacre have issued warnings not to say anything rude about Homeopathy, for fear of ‘Charlie’s men’ finding you in a dark alley and rearranging your kneecaps.

Be assured, they can do it with a billionth of the force usually needed.

But now, there is no need for alternative practitioners to feel defensive, as we are entering the Age of the Placebo.

The reason is that it has become too difficult and expensive to invent ‘proper’ drugs and bring them on to the market. And it may not be necessary.

Alternative medicine used to be accused of being an expensive placebo. Now it is acclaimed as being an expensive placebo. The change has been an acknowledgement that placebos can be effective. Further, the more they cost, the better they work.

Even if the patient is told explicitly that the tablet contains no active ingredient.

Even if we write ‘placebo’ on the side of the tablet.

At least as shown in one study on Irritable Bowel Syndrome (IBS):

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015591

Think of that. You go to the doctors with a bad knee. Using a pin and a copy of the British National Formulary, he gives you an injection of vitamin B12 and tells you there is no possible way this should help.

But it does.

The word placebo is being rehabilitated slowly, in the light of evolving knowledge that our mind has a life of its own away from consciousness.

In fact the part of the mind that we think of as the Executive Board is more tiny and isolated than we thought and much less in control than we expected.

Much like the government really.

Depression is one of the conditions that responds quite well to placebo, making it difficult to test antidepressant treatments.

Some research has shown that brain function changes occur in depressed people as they respond to placebo treatment. This has been shown by the technique called QEEG, which is a special EEG technique designed to show regional brain activity.

All this comes as no surprise to regular readers of EP, who ‘got over’ the mind/brain problem several weeks ago.

We also know that people with Depression like their doctor or therapist to strike a positive and hopeful tone, but stop short of hype.

Much as we love evidence-based medicine, many of the treatments we offer do not have a strong evidence base. This is particularly true for resistant depression, where various combinations of antidepressants are added together.

Proving a drug therapy is effective is a tough challenge.

Firstly we need to be able to measure the condition itself, using some kind of rating scale that is valid and reliable.

Once we can measure it we can do a randomised controlled double blind trial, either against placebo, or against an established treatment. This is the gold standard test.

However, if the effect of the drug is small, a very large number of patients will be needed in the study to show a statistically significant difference.

Even then, the effect is usually only measured for a short period of time, say 3 or 6 months, before the trial ends.

This process is open to several kinds of bias, some intentional and some accidental. For instance, only trials which show a positive result tend to get published. And if we do enough trials, 5% of them will show a significant difference by chance.

If the trial contains 20 different measurement scales, one of them is likely to be significant by chance.

This has allowed companies to select data and use it out of context in support of their products.

All these problems have conspired to stop people testing products properly and led to the false conclusion that all antidepressants are equally effective, which is not as amazingly effective as we would like.

Randomised controlled trials are a relatively recent invention, so we have only recently discovered how powerful placebos can be in certain situations.

It is probably ethical to prescribe a placebo tablet if we tell the patient what they are getting. Presumably some part of the less-than-conscious mind responds to the treatment paradigm, even though another part has put on its sceptical face.

So, instead of developing new antidepressants and other drugs, we could try and develop better placebos. We might still need to test them though, if we are to suggest they are evidence based.

The reason is that some placebos might be more effective than others.

Instinctively, I know that a tiny purple tablet is better than a big white one. I would expect anything involving electricity, magnetism or machines that go beep to be more effective than anything made of plastic.

I’m sure there is scope for ‘steampunk’ designs, such as the old ECT boxes in mahogany and brass. Obviously, don’t plug them in.

Working specifically on the placebo effect rather than on supposed antidepressant properties based on neurotransmitters seems an easier way forward.

This is a highly convenient position for the alternative therapists, who can now argue that they are the reigning experts in the use of placebos. How long till we have a Professor of Placebo Studies at the University of (e.g) Mexborough?

This is a much better argument than trying to prove their therapies have specific active ingredients, such as water having a memory.

Even memory foam can’t remember anything – I’ve tested it. You don’t want your mattress knowing too much anyway. I subjected it to ruthless interrogation and can assure you it knows nothing.

‘Bigging up’ the treatment with a bit of hard sell seems a good idea.

Referencing a bogus system of how the body works – meridians, humours, animal magnetism, endorphins etc is always popular.

And, as mentioned, charge more to get more benefit. Money doesn’t just talk, it shouts loudly and eloquently.

A few years ago some friends and I devised the ideal placebo treatment, that would use tuning forks. The forks would be tuned precisely to resonate with the person’s brain waves.

This would enhance certain frequencies in the brain. The forks themselves would be very expensive, made of precious ceramics and metals and probably jewel encrusted. The pre-treatment diagnostic test would be an EEG.

Now we know, if we used QEEG instead of ordinary EEG, (note the Q) we could actually predict those likely to respond.

This gives us a business model similar to Harry Enfield’s ‘I saw you coming’ shop, which itself was based on the emperor’s new clothes principle.

How worried should ‘Big Pharma’ be about placebos? After all, if you can knock something useful up in your kitchen out of artichokes, why do we need huge research laboratories in Macclesfield?

Before you sell your Astrazeneca shares, note the Z, be aware that there are very few studies to support the use of explicit placebo.

The most famous is the Harvard study of IBS mentioned above.

With all due respect to IBS sufferers, this is quite a subjective type of health problem, which is very hard to measure. But not unlike Depression or Pain in this regard.

How far would a placebo go in treating a more biologically measurable disease, like hypertension or diabetes?

And attempts to give opiate addicts placebo instead of methadone failed to hit the spot. Opiate addicts are connoisseurs when it comes to pharmacology, much like the man in Wetherspoon’s.

He immediately discerned that the yellow Smartie did not have the same effects as the 22ml of ethanol contained in a pint of Ruddles Best.

The choice of a yellow Smartie is controversial, since yellow foodstuffs have been accused of toxicity. Yellow and blue Smarties were even removed from sale for a while in 2006, as the dyes Quinoline Yellow and Brilliant Blue were replaced with natural dyes.

Please, how can anything called ‘Brilliant Blue’ be bad for you?

My own preference for medication is a bit contrary to all this.

Firstly, if I am looking for placebo power, a bit like Scrabble, I’d go for a tablet with X, Z or Q in the name.

This is probably why ‘Xanax’ was so popular.

Otherwise, my favourite drug therapies are ones that were discovered by accident. The effect was not expected by anyone, it just happened.

That doesn’t really mean the effect was so barn-door obvious that it must be genuine, since people are very open to attribution errors.

Iproniazid was a TB drug that turned out to be an antidepressant, and Chlorpromazine was an antihistamine that turned out to be an antipsychotic. Note the Zs.

The history of drug therapies is fascinating and riddled with such discoveries.

Most of these were spin-offs from the German dye industry, so ironically the Yellow Smartie and mental health tablets share a lot of  heritage.

In the study of explicit placebo for IBS the patients were not told simply that they were taking sugar pills.

They were told they were taking ‘placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self- healing processes’.

That statement serves to stimulate the Suggestiveness Receptors.

So here’s the plan. In our kitchen, we count out Smarties, in non controversial colours like red and place them in proper tablet bottles with child-and-most-adult-proof lids.

With an eye to the potential central Asian market, we label the tablets QOZZAX.

In the small print we say: ‘These tablets contain no conventional western medicine. They work by lexicographic forces, based on the ancient Scrabble system’.

Going one further, for publicity, we get people to go on Radio 4, stating that their life had been ruined by scrabble tablets. They are trying to sue games giant Spear & Co.

I wonder how many placebos are already being used in different walks of life.  I’ve noticed that supermarkets can enhance the quality (and price) of foods simply by adding adjectives. Rhubarb would become Bohemian Wild Rhubarb for instance. As though rhubarb could ever be straight-laced or tame.

I’m certain (OK, I have no evidence) that one Honda garage I visited used to do nothing more for an annual service than apply bright red grease to the door hinges, so you could assume something had happened to the car during the day, apart from being raced along the ring road a few times, to KFC and back.

I spent a lot of time trying to convince our last pharmacist that he should make up a ‘proper mixture’ for each patient in a good strong colour, with a bit of bitter flavouring, in a proper fluted brown bottle with a glass stopper.

Sadly this suggestion was not met with the enthusiasm I felt it deserved.

I was not suggesting a complete sell-out to Charlie. Active antipsychotics and antidepressants are available in colourless liquids that can mix together, so this mixture would not be a placebo. Just an existing treatment with a bit of pzazz. Note the Zs .

It was just that I so wanted to make it Brilliant Blue.

But if the Mexborough department ever gets going, the  first development I would like to see is a dermatological version of Shake N Vac.