ignorance, part five

While researchers dealing with biochemistry of the central nervous system were plagued by doubts, uncertainty and confusion, medical practitioners exhibited far more confidence. The distance between "this just might make you feel better" and "this will fix what ails you" is short enough to fit on a prescription pad.

Prescriptions which don't actually cure anything have the advantage of producing a steady stream of repeat customers. Snap judgments of what to do about a problem, delivered with confidence, also increase the rate at which physicians can "treat" patients, and generate corresponding cash flow.

(This does not imply that this is a conscious decision. People don't need to make detailed, elaborate and nefarious plans to exploit a resource any more than cats have to understand what fishing boats do over the horizon that makes it worthwhile to hang out at docks.)

Pharmacists have long known that far more prescriptions are written to make the patient (temporarily) go away than to cure disease. It was a pharmacist who developed the popular patent medicine called Coca-cola. Early versions did actually contain some cocaine, in addition to a heavy jolt of caffeine and sugar. This led to a need for a second invention of a formula which was not officially habit-forming.

(Despite urban legends, adding aspirin to Coke will not precipitate anything of recreational interest. Nonetheless, elderly southern relatives of mine continued to refer to the beverage as "dope" long after it moved from under-the-counter back to over-the-counter.)

Opium addiction had been known since ancient times. (You can find an indirect reference in Odysseus' stay with the 'lotus eaters' in the Odyssey.) The laudanum mentioned earlier in a quote from the 17th century was the name given by Paracelsus to a tincture of opium. Medical students had serious problems with opiate addiction in the period we covered in discussing the discovery of anesthesia.

Education of medical students still includes lectures with the same warnings about addiction. At one time, not too far in the past, about one doctor in ten could be expected to have a serious problem with substance abuse, probably involving opiates, (though I don't know if or how widespread testing has changed this.) Adding cocaine and amphetamine to the options widened possibilities for substance abuse. So did barbiturates. Even more bizarre experiments became possible in the last generation or two. What some medical students have survived would make your hair stand on end, even if you were not a patient of theirs. There are exclusive and discreet clinics specifically for rehabilitation of medical professionals.

(Arthur Conan Doyle was sufficiently familiar with cocaine dependence among medical doctors to provide a compelling description of Sherlock Holmes's struggle with cocaine.)

With this background, you can imagine what happened to patients with mysterious complaints as new pharmaceuticals appeared. Anything which produced an immediate reduction in complaints was a candidate treatment. One problem we now know about this is that anything which produces euphoria ahead of side effects is likely habit-forming. It took a long time to learn this. Some have not yet learned.

Skipping a great deal of unusually colorful history, let's move into the era of modern psychopharmaceuticals. The discovery that lithium salts could reduce mania was not accepted for well over a decade. Why was this?

An earlier experiment with lithium salts as a salt substitute for those with high blood pressure had been a disaster. Some patients with heart conditions simply dropped dead when their hearts stopped. To be effective, lithium salts have to be within a factor of two of the toxic threshold. This requires regular blood tests, and conscious awareness of possible interactions.

Unipolar depression was not considered an indication for lithium salts. The first modern antidepressant (apart from stimulants like amphetamines) was Iproniazid, a non-selective, irreversible monoamine oxidaze inhibitor (MAOI). It was only discovered in 1952, when patients receiving it for treatment of tuberculosis became "inappropriately happy". What's that?

With all I've said before, you might wonder why doctors would be worried about patients feeling good. This takes us back to yet another episode some would like to forget.

Many of the symptoms of illness are caused by immune response, not the disease itself. When corticosteroids became available they were tried on all kinds of illnesses where inflammation was a problem. In the case of tuberculosis, this led to another disaster when patients reported feeling much better even as the bacterial infection ran wild in their bodies. Steroids suppressed immune response, not infection. Doctors testing Iproniazid for its effects on tuberculosis were on the lookout for just this kind of problem. Some doctors do learn. Some patients do survive.

(You might well also ask why experimental treatments for tuberculosis with drugs of very questionable potential was going on in 1952. Hadn't Penicillin eliminated the disease?)

The discovery that there existed antidepressant chemicals which did not produce euphoria and addiction set off a gold rush. Several new classes of antidepressants were introduced. Earlier ones seldom disappeared, despite risks. A few patients always failed to respond to other drugs.

(Those who can't obey restrictions for MAOIs are in danger of hypertensive crises. This is not a property of the molecules, it comes from the context in which they are used. Other patients have tolerated the same drugs for decades.)

When you understand that the original antidepressant was being tested for treating infectious disease, you will gain some appreciation for the state of the art at the time it was introduced. Detailed study of the twists and turns of this vibrant growth industry would take us far afield. I want to concentrate on the mindset of medical doctors prescribing these drugs.

When you recall that many were trained before most neurotransmitters were discovered, (there are now hundreds) and had not kept up with the wild shifts in research, you will understand the need for a simplified model. Nobody could be very confident about research findings, patients needed reassurance they might understand. This was based on levels of biochemicals in the body.

If you were depressed the idea was that you had too little serotonin in your body, and the pills would raise this level until you felt happy. If you were schizophrenic, it was because you had too much dopamine, and so on.

Had this been true, the simple solution, for depression, would have been to ingest cheap generic L-tryptophan, a precursor of serotonin. (It was not true, and I don't recommend anyone do so, especially if they are taking antidepressants.)

Level-based models have an inherent problem: people don't go nuts every time they eat, or become hungry, or when their diet changes. When you ingest drugs, the concentration in the brain changes in hours, while the beneficial effects of many non-addictive psychoactive drugs require weeks. Brains have to keep working despite substantial changes in the internal biochemical milieu. This kind of robust stability is missing from simple models.

Evolution found a sophisticated solution long before humans existed. In engineering, it is called differential signaling. Biology takes this to heights seldom approached by humans. The significant feature is that strength of response depends on ratios of uptake rates at receptors. (Not reuptake rates, that is another story.) The dependence is also strongly non-linear, (which makes many aspects counterintuitive to people trained to use linear mathematics.) Robust stability requires this.

With this background, we have to ask why the above model became so popular. At one time, I guessed this was just a fable for patients. Long contact with a number of physicians, some personal friends, finally convinced me they really believed more or less what they were telling patients. (I can't speak for all, but I think this applies to the majority.)

Where did this model come from? Something with a close resemblance has been around for a very long time, the theory of humors. The difference is that doctors now talk about low serotonin or high dopamine instead of melancholy = black bile, excess phlegm = phlegmatic, too much blood = sanguine, yellow bile = feeling bilious, etc. The elements in this system were: earth, air, fire and water. The words changed, but the thinking behind them did not.

There is another kicker in research results since these explanations became popular. Receptor mapping now extends far outside the brain. We now know something like 80% of serotonin receptors are in the gut, with still more in the nervous system outside the brain. Inside the brain the distribution of receptors doesn't tell the whole story, because the vast majority of receptors are closed by glial blockade. (Those white cells of the brain that don't get respect do more than anyone had guessed.) The part of the nervous system which might be able to respond according to the simple model of antidepressant action uses only about 1% of all possible receptors of the given type.

Disclaimer: I don't want to stop anyone from taking medications which might keep them alive and out of hospitals. As has been said before, I don't refuse dinner because I don't understand how my stomach digests it. Quinine was used long before the cause of malaria was understood, and the molecular basis of the drug's action made clear.

If you don't feel like living, and no other treatment works, have a trial of antidepressants instead of taking more drastic action. I have seen people off their medication for other conditions, and it isn't pretty. If the price of being off medication is mania, terror or hallucinations, that is too much to pay for the privilege. In the absence of cures, palliative treatment may be needed to keep people alive until cures arrive. I want all of us to make it to that goal of a cure.

What I want everyone to understand is that the models in use in treatment are seriously flawed. Anyone reasoning on that basis who tells you they know exactly what a particular medication will do for a specific person is lying. By chance, they might turn out to be right some percentage of the time, but at this stage they cannot know.

When doctors say it would be unethical to experiment on patients, they are deliberately ignoring the fact that in large areas of medicine every new prescription is an experiment. Even if drugs are uniform commodities, patients are not. We live in a time when there is great change and uncertainty about what will be appropriate treatment next year. Treatment in the case of ME/CFS remains empirical. This is not as different from traditional practice as regularly claimed.

Find doctors who will check that they are not doing harm. Make sure you have one who understands that if he/she has been doing something for a reasonable time, with no evidence this is working, it is appropriate to try something else. One other thing, when you are in an area where treatment must, of necessity, be empirical, don't take anything on authority.


Hi ancientdaze, my take on the serotonin model is that it is all about marketing these days, primarily for Selective Serotonin Reuptake Inhibitors. Many drugs restore serotonin levels in hours, but as you point out the antidepressant action can take weeks.

The term "Selective" is not what a biochemist would recognize - SSRIs are not selective in biochemistry terms. Indeed, the only reason they work is that they are not selective.

If I recall my lectures on SSRI research correctly from 2002, the pharmaceutical companies have designed properly selective SSRIs. None made it to market, because none of them worked on depression, despite rapidly raising serotonin levels. This means the antidepressant property of SSRIs is not due simply to serotonin (but it could still be serotonin plus some other factor). This is because highly selective drugs wont work on other pathways.

On selectivity, a biochemist would say it has to be highly selective, and there are biochemical properties that go with this. SSRIs fail to meet those standards. It is highly likely they interact with other receptors or have other mechanisms. "Selective" is either a marketing term or an historical term that is kept because they like its implications.

Modern medicine is about statistical guesses. If most patients respond one way, then its standard practice to use that for all patients and correct later if there is a problem. Very little in drug treatment is not experimental medicine, its just that its experimentation that meets certain statistical requirements. That is fine if you are in the majority, it is not good if you are an under-responder. It can be lethal if you are an over-responder, or develop major side effects. Every drug prescribed is a throw of the dice.

My understanding of 'selective' in the case of SSRIs is that they mostly operate on a subset of synapses with a particular class of serotonin receptors, not that they are exclusive. Because they primarily affect the process of reuptake, they can't easily be highly selective about what receptors are on the post-synaptic side of the cleft. Beyond different classes of serotonin receptors we have very similar receptors for norepinephrine. When more research showed effects on both serotonin and norepinephrine, new drugs in this class were labeled SNRIs. In fact, earlier drugs just affected different percentages of different classes of receptors. The name SSRI is more a statement of intent than reality.

This follows a tradition in drug discovery. The same molecule may be marketed for several purposes, with primary effects and side effects changing places.

The whole business of SSRI effect remains controversial. The quote below comes from the Wikipedia article.
The efficacy of SSRIs is disputed. A 2010 meta-analysis states that "The magnitude of benefit of antidepressant medication compared with placebo ... may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial."
The research you mention, some of it unpublished, could be telling us something about the way the brain handles signaling. If it is true that changing serotonin uptake rates alone does not have the desired effect, but less selective manipulation of two or more neurotransmitters does, it is possible the nervous system is rejecting a signal on one circuit unless it correlates with another circuit involving a different particular neurotransmitter.

A separate question is on my mind right now, how many drugs would be profitable to manufacture if restrictions on 'off-label use' were enforced? For many pharmaceuticals, 'off-label use' predominates.
I have "MCS" whatever that is, and when I have tried and used snri's and other antideps over the years for pain and fatigue I always knew within a day or 2 the intended effect and it would be from a microdose......that is useful info to me that they technically raise your serotonin right away, perhaps some of us are tuned in where we can feel that, I could never tolerate a "therapeutic dose" and always used them sparingly and in my own way, they have gotten harder to tolerate over the years even in miniscule amounts so I stay away for now.
Very interesting anciendaze and take your points - so much still trial and error until more understood. At least my Neurologist could admit he did not understand (findings) and brother (Prof Neurology) - we do not know everthing (yet). A certain comfort in that admission but disappointing of course.
xrayspex;bt5295 said:
I have "MCS" whatever that is, and when I have tried and used snri's and other antideps over the years for pain and fatigue I always knew within a day or 2 the intended effect and it would be from a microdose......
No one has ever told me I have MCS, but the doctor who has known me longest has become very cautious about trials of medication. The phenomenon you report, of deducing the ultimate effect based on clues in the first 48 hours, (usually in the first 24,) has happened to me. The list of things I cannot tolerate is long. No one is telling me this is "all in my head" because discovering these included trips to the ER. This is supporting evidence for a neurological disease.
Interesting development in the BMJ (Study London/Norway on dementia treatments) revealing just how much there is to learn about the brain still. It appears the "chemical cosh" - antipsychotics blindly used are less effective than simple pain medication which reduced agitations more effectively. In no way related to ME of course but a step forward for Altzheimer patients. Some ignorance been righted.
I think most of the medical lore about neurotransmitters and depression is an incredibly over-simplified fantasy take on an extremely complex system. The side effects of the new "safe" antidepressants are largely ignored and unknown to most doctors. Did you know that SSRIs completely disrupt normal sleep architecture? They fragment REM sleep, so that it no longer occurs in regular cycles. Anyone who starts on an SSRI or SNRI should be advised that it may be very difficult for them to stop taking the drug due to a very unpleasant withdrawal syndrome. It doesn't happen to everyone, but can happen even if you've previously successfully gone off of one these meds. I know from personal experience. Once I stopped taking venlafaxine after years of using it without trouble. Started again, took it for a few years, and tried to stop: ouch! Took me 9 months to wean off it the second time.

I'm far from a Scientologist, I've been on many of these medications, and they can do a lot of good. But they are not benign and a great deal more consideration should go into when and how they are prescribed than is typical at present.
valentinelynx;bt5320 said:
I think most of the medical lore about neurotransmitters and depression is an incredibly over-simplified fantasy take on an extremely complex system. The side effects of the new "safe" antidepressants are largely ignored and unknown to most doctors...
Unfortunately, I know all too well what you mean. Twice, I've gotten involved in potential emergencies, where doctors treating people for serious medical problems decided they were depressed, and added their favorite anti-depressant to the mix. In one case they didn't tell the patient what to expect if it worked as advertised, or how long they might have to grit their teeth to get through initial side effects before getting benefits. In the other case, the patient was hospitalized for clear physical problems, and they did not tell either the patient or the other physicians treating the patient about the change. I had to go over each medication being administered (half a dozen) to find it. When I told one doctor, he went back and found the order in the chart. All doctors had missed the new order in the mass of material on that complex chart. A side-effect of the antidepressant resulted in a change of a different medication, on the grounds that it might have caused the problem. When you get into this kind of confusion, the patient's survival is a matter of luck.

My rule of thumb for identifying side effects is that interactions of three or more medications baffle the majority of doctors.

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