Workshop on Drug Therapy in Mental Retardation

Renato Cocchi M.D., Ph.D. (Sociology)
X World Congress on the International Association for the Scientific Study of Intellectual Disabilities
July 1996
Helsinki, Finland

Reprinted with the permission of Renato Cocchi
Via A. Rabbeno, 3
42100 Reggio Emilia, Italy
+39 0522 320 716
Mobile +39 348 5145 520
URL: http://www.stress-cocchi.net

We need starting this workshop by a definition of stress.
Waiting for a more precise one we can get this as an operational definition.
We term stress a set of relations linking external or internal stressors of physical, chemical biological/metabolical and psychological/social origin, to nonspecific reactions of a living organism. These reactions come out from the modification of homeostasis made by the stressor or stressors. In facts, we can find one or more external or internal stressors, or external and internal stressors acting in the same time.
This concept of stress has been more precisely defined by Loo et al.,[29] who assert that today it would be irresponsible not to consider an illness as the sum of three factors:

the causal agent
the organism's specific response
the organism's aspecific response, which is a stress response to the condition of the illness in course.

If you prefer so, every illness is a stressor that induces also a response - stress reactions - of the body.
It is easy to add that this response will differ from individual to individual and depends on constitutional, hereditary and acquired characteristics.
The stress reactions the organism immediately set off go along the neurochemical pathway glutamate-GABA with its collaterals. (Fig. 1)
In Downs subjects I shall speak of metabolic stress, that is a stress produced by metabolic stressors.
Now the question raises of whether other stress, of an internal biological origin, exist in the human organism, which may justify a mechanism analogous to the one involved here in Down's syndrome.
One such example is the well known pre-menstrual syndrome. In women of a fertile age, the falling of progesterone - a hormonal cyclic variation, which is normal to these women -, produces an internal biological stress. The effects of this may be manifested in aspecific symptoms: cephalalgia, irritability, depression, bulimia, and so on.
Those women having an adequate response to stress feel the consequences of this stress very little. Those who are constitutionally more fragile, or at that moment are so because they are subject to other stress, suffer more.
Even though this stress derives from a normal, physiological phenomenon, it cannot be too unimportant given that it is also considered a factor which helps to bring on fits in epileptic women.

Cocchi R.: Drug Therapy in Down's Syndrome: A Theoretical Context. It. J. Intellect. Impair. 1993, 2: 143-154
My encounter with drug therapy in Down subjects came about roughly 18 years ago and was completely by chance.
In 1979 I was treating cases of childhood depression and I had found that depressed children were more susceptible to colds and related illnesses. I found that the vast majority of them grew more resistant to such illnesses if treated with a certain combination of drugs [2].
One day a mother arrived with her Down child in my outpatient clinic asking for my help. He was continually affected by this type of illness and was virtually always under antibiotic treatment. Having asked all my questions, I prescribed a cure. Six months later, at the check up, the mother told me he was much better, and that his school performance had improved too. Furthermore, she informed me that some said his face had improved. This made me curious.
I must confess that I was lucky. At that time I was convinced that small Down children caught colds easily.
Later, I was to realize that this is in fact not true [3], as indeed are untrue many other assertions concerning so called 'typical' characteristics of Downs.
I was also fortunate because that particular child was one of those who improved immediately as regards susceptibility to colds, using the therapy which I prescribed.
I now know that in 15% of these cases there is no short-term improvement [4].
The third element in my favour was that I had begun to take an interest in GABA, a CNS neurotrasmitter.
At that time, very few clinical researchers were interested in it while it has since been proved to be the most important inhibitory neurotransmitter in the Central Nervous System.
I had been working on it, using more than one pharmacological substance, since 1973.
GABA, as is beginning to be understood now, is what becomes primarily involved in every stress response.
After the first, two other Down cases presented themselves and the therapies I prescribed continued to work, even if they were less refined than any I would administer today.
I always acted very cautiously, using low dosages, and modifying only when the organism had become used to the drug (which does not mean dependant).
I still work in this manner so as to avoid stressful reaction to the massive introduction, in that particular organism, of foreign substances, even if they are almost always physiological.
In an organism with a low level of stress response such as that of Down subjects [7-8], aspecific side effects to the pharmacological substance are more easily produced, effects which are stress responses.
Despite this, the odd reaction continues to appear, even if rarely.
One of the symptoms I described as being frequently found in this syndrome of possible GABA deficiency is feeling the cold very much.
When I asked the Down children parents about this most of them replied in the negative and that the exact opposite was true, that is the child suffered the heat. I later verified this symptom statistically over a wide sample [11].
The problem of greediness for sweet things was even more indicative.
In 1980, again concerning childhood depression and the possible GABA deficiency syndrome, I had published in Switzerland a work about the fact that a number of depressed children, which I considered to be GABA deficient, showed a high consumption of sweets [12]. This symptom could be explained easily from a biochemical point of view.
Glucose is the precursor of GABA through the metabolic pathway of the Krebs cycle. By eating more sweet things more glucose is introduced which in turn synthesizes more GABA. This constitutes a non-rationally conscious automemedication.
The bodies of these type of individuals force them into certain kinds of alimentary habits aimed at improving a neurochemical imbalance.
If GABA is excessively consumed, more must be produced to keep a correct balance. One way of producing more is to have more glucose at hand, being one of its precursors.
To have more glucose at hand it is sufficient to eat foods rich in that substance and the richest in this respect are in fact sweets and cakes.
When I came to check the symptom 'greediness for sweet foods' in Down subjects, not only was it reported infrequently, but the alimentary habits of the child on this point were usually the opposite; the child did not enjoy such foods. This symptom was also verified using a large sample group [13].
I was still however quite certain that the Down child was basically in a stress situation, but I could not work out the origins of this stress.
In Downs, I did not believe in stress of psychological origin. Stress deriving from pregnancy, birth or neo-natal complications, a topic which I was looking into even at that time [14-15] and which are all indeed very frequent in Down's syndrome, [16], was not justifiable in all cases.
I found the key to understanding this riddle in what is known as the 'dosage effect'. In chromosomic anomalies, metabolisms which normally depend on two genes, one per chromosome, reduce by 50% in monosomic forms.
Likewise, when there is one extra chromosome, as in trisomy, those metabolisms increase by 50%. Down's syndrome is also known as trisomy 21.
Its genetical characteristic is to have three chromosome 21's instead of two and therefore for the aforementioned dosage effect, to increase by 50% all the metabolisms whose control genes are found in chromosome 21.
In other words, if in a normal individual the same two genes, one for each of the two chromosome 21's, control a particular metabolism 100%, each of them controls half, that is to say 50% .
If a chromosome 21 increases, as in the case of Down's syndrome, all the genes which depend on chromosome 21 also increase by one.
That particular metabolism is no longer controlled by two genes, as in normal individuals, but by three genes, and therefore is increased by 50% .
This is a fact and has been verified for many metabolisms.
I had finally found the origin of the Down individual's stress.
The 50% increase of a whole series of metabolisms sets off a homeostatic alteration which produces an endogenous biological stress. A stress which starts from within the organism itself.
This stress begins at conception in the free trisomy 21 and translocation forms, or some hours later in the mosaic forms.
In Down individuals, the endogenous biological stress is continuous, affecting all the cells.
As for stress, in Down subjects:

the causal agent is the extra chromosome 21
the organism's specific response will produce similar symptoms in all subjects because the cause is the same

The first two have been asserted by Lejeune and his team, and consist of the increased consumption of tetridofolate and of l-methionine [31];

finally, all the symptoms which present themselves differently from individual to individual or which can even be missing completely, will be symptoms derived from the aspecific stress response, also different in every Down

As regards the two symptoms discovered by Lejeune et al. 1986, [31] luckily for us, these two substances consumed in excess are freely available in Italy and are easily administered orally, as I did even before Lejeune's findings.
The matter of stress response symptoms and their treatment is a very different, and much more complicated area to tackle.
Other symptoms on which a pharmacological therapy can work to improve the organism's aspecific stress responses are those more well known typical of Down's syndrome subjects. These are the so-called 'mongoloid' face; the motor abilities [35-36], attention concentration and memory, and through these the intellective and social aspects [38]; the weight-height ratio [39]; penis size and erection [40] and eyes movement [41], to mention some of the areas which I have been investigated.
As you all will have clearly understood, we are talking about symptoms or capabilities which differ from child to child but which have the same chromosomic anomaly; in 92-94% of cases this is standard trisomy 21.
To state, as some specialists do, that a child showing these symptoms is afflicted by a slighter form is correct only from this point of view and not from that concerning chromosomic anomalies.
Referring to the latter, the lesser forms should only be the mosaic ones. In clinical practice however, Down children suffering from mosaic forms are encountered who show stronger symptoms than children of the free trisomy 21 type. It should be evident, or at least it is to me, that the difference lies in the resistance to stress factor. Less resistance means stronger stress symptoms.
A mosaic form carrier with little resistance to stress will show stronger symptoms than a free trisomy 21 sufferer with a high level of resistance. (See: Cocchi R.: Mosaic forms in Down's syndrome. A Survey on sixteen cases. It. J. Intellect. Impair. 1996, 9: 45-54)
Moreover, these symptoms are modified following a therapy which changes the aspecific stress response.
According to the criteria which in medicine is stated as ex-juvantibus, and which connects a symptom or illness to a disorder which can be cured, if an intervention on stress improves certain symptoms, then these symptoms could be connected, or be dependant on the stress.
If we want to stick to what are now well accepted facts, it is known that stress lowers immunity responses, and this is something found in a large number of Downs [42-45].
Teeth grinding, also known as bruxism, is a well known stress symptom [46]. It is present in over 40% of Down cases and it too enjoys favorable results given this type of therapy [47].
Increased corticosteroid action, which to exist does not require an increase of corticosteroids in the bloodstream [48], inhibits the hormone controlling upward growth [49]., and the Down individual tends to be shorter than average height.
Stress, in animals too, is the cause of hyponeofagia, which is the aversion to trying new foods.
This limited alimentary choice disappears in animals given anti-stress therapy [49]. The majority of Down subjects are hyponeofagic, and following the therapies I use, start to expand their dietary choices.
Perhaps the most interesting aspect however is something different. A number of Down children suffer from congenital cardiopathy and need to undergo surgery.
This open heart surgery constitutes an enormous stress, the consequences of which can be gauged, for example, on the basis of the time the child needs to spend in intensive care after the operation.
If, prior to the operation, the child has been undergoing pharmacological therapy to improve the aspecific response to stress, it should follow that the heart operation is tolerated more successfully.
If this is the case, children in therapy for a number of months before the operation should need to spend less time in intensive care compared to those not having been treated.
How is the pharmacological therapy planned out for each individual child ?
This is the most difficult problem as there exists no standard therapy as it varies from child to child depending on their age and symptoms.
As for other drugs, the specialist needs to hypothesize the individual's probable neurochemical imbalance and start to correct it gradually.
To do this I use 30-50 symptoms which I trace back to the functionality of the most well known cerebral neurotransmitters.
Addressing GABA, for example, it has two means of synthesis which derive respectively from glucose and glutamine of an alimentary origin [52].
Glucose is plentifully found in sweet foods; glutamine in meat broth, or can be formed in the bloodstream from the glutamate present in broth made from meat stock cubes.
When I ask whether the child enjoys sweets and cakes, meat broth or stock broth, I can obtain one of the following four answers:

he likes sweets and broth
he does not like sweets but likes broth
he likes sweets but refuses broth
he refuses both sweets and broth [13].

Since the two means of GABA production seem to have a different value for the organism (the way in which it utilizes glutamine seems to act as a reserve) already in this way I have to start hypothesizing 4 different neurochemical imbalances.
My therapeutic intervention would have to take account of 4 variations, given that everything else is the same, which is never the case.
But I think that l-gutamine, pyridoxine and a benzodiazepine could be a common point of departure.
When I then look into the symptoms related to serotonin, I can find evidence of deficiency, excess or normality. One of the symptoms which I can examine is the individual's ease in falling asleep.
This is all to show that, on average, I take a year to understand a child's neurochemical imbalance because often some symptoms are hidden by other, more evident ones. It is not always an easy job.
To arrive at this point I therefore need to see the child every three months for the first year of therapy which goes ahead on the basis of successive approximations. The starting point is an attempt to correct, by means of low medicinal dosages, the most obvious imbalances.
The drugs I mostly use are listed in table following table.

Table 1:drug used (mg/day if not otherwise indicated)
alphaketoglutarate of pyridoxine	300-600
alphatokopherol	50-100
arginini pidolas	250
amitryptiline	3-10
baclofen	2.5-5
biotin	2.5-5
bromazepam	1-2.5
carbamazepin	50-200
carnitine	500-1000
clonidine	0.05-0.15
chlordesmethyldiazepam	0.2-0.5
chlotiapine	3.3-9.9
deanol emisuccinate	1000-2000
diazepam	1-3
phosfatidilserine	50-100
gammaidroxybutirate	500
5-hydroxytriptophan	25-100
l-glutamine	125-500
methyltetrahydrofolate	7.5
nicotinamide	50-100
oxazepam	5-10
oxiracetam	800
pantotenate	150-300
piracetam	800
pyridoxine	75-150
pyridoxol dimaleate	150-300
pyritinol	50-100
s-adenosil-l-methionine	100-200
thiamine	75-150
viloxazine	25-100
glutamine + pemoline	(5+5)-(90+10)
thiamine + pyridoxine + cyanocobalamine gamma	125mg+125mg+250

Three final problems.
The extra chromosome exists in every cell, will stay there for life, and will give problems for life.
It therefore follows that my therapy is substitutive and not curative,and will need to carry on throughout the subject's life but undergoing modification to account for age.
This is a balanced therapy which can be interrupted at any time without consequence, as indeed the parents do often when other treatment is necessary, usually for respiratory infection.
After a certain period of time, as the subject ages, some symptoms which had improved or were eradicated by the therapy start to reappear again or other new symptoms arise.
Finally the big fear: the toxicity of the medicines used. I use mainly physiological substances, and in any case, the medicines are prescribed are all at low dosages.
To parents who nevertheless have doubts, I always recommend laboratory analysis, even more than once a year.
I know that these have been undertaken in many cases and as yet no report of toxicity has been made to me.
We have however found some allergy to one drug, carbamazepine, which can in fact cause this, as well as some cases of excitement caused by glutamine + pemoline.
I prefer to repeat myself to emphasize the point that the pharmacological therapies which I prescribe are completely compatible with any intervention programme of a senso-, psycho-, and neuro-motor, orthophonic, logopedic, psycho-pedagogic, behavioral, occupational etc. They can indeed constitute an aid, at times an indispensible necessity, so that such programmes produce maximum results.
There would be so many more points to clarify, especially for my fellow specialists.
In any case I will continue to publish research on particular aspects and results, both in Italy and abroad, as we gradually move forwards one step at a time. I do not intend to use any double-blind investigation for this, which I consider to be questionable from an ethical point of view, but where possible only the control group. However longer and more insecure it may be, I have chosen not to interfere in any way with the primary objective of the goal, that is to bring relief to the patients and their families.

Reference

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