Drug Therapy in Downs's Syndrome: A Theoretical Context

Renato Cocchi M.D., Ph.D. (Sociology) Italian Journal of Intellective Impairment 6 (2): 143-154 (1993 Dec)

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

My encounter with drug therapy in Down subjects came about roughly 15 years ago and was completely by chance.

Since 1970 I have been dealing with developmental age problems and their relative pharmacological therapies. My first article on the subject came out in 1974 [1].

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].

News spread around, or perhaps I had spoken of this in lectures in Urbino where I taught at the Scuola Superiore Magistrale Ortofrenica as it was then known. This college prepared, as it still does today but under a different name, support teachers for handicapped children.

Anyway, whatever the reason, one day a mother arrived with her Down child in my outpatients' 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 all 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 a particular cerebral neurotransmitter, GABA. 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. A paper of mine dealing with this can be found in the acts of a national psychiatric congress which took place in 1975 [5].

GABA, as is beginning to be understood now, is what becomes primarily involved in every stress response. I had been aware of this and wrote about the fact as far back as 1978 [6].

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. Having published, the first of its kind in the world, in Belgium in 1978 the outline of a syndrome resulting from possible GABA deficiency [9], later confirmed and better justified [10], I had a line of research to work on. As happens in such cases, that line has always two sides to it: positive and negative.

I will explain what I mean better.

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 childrens' 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-rational non-conscious autome-medication.

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. A psychological origin is the easiest conclusion to make because it is always justified: if no obvious conflict exists then we just say that it is unconscious.

Unfortunately this tidy little explanation does not convince me in the least, especially in the case of babies who have not yet reached an awareness of their own difficulties and diversity.

To blame the parents - another technique frequently used - stating that, sub-consciously, they were rejecting the child, would have meant ignoring the evidence before me: Almost all the parents I saw were genuinely concerned for their child, maintaining a well balanced affective relationship. 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 metabolisms activated by the enzymes superoxide-dismutase-1, indolo-phenol-oxidase, phosphorybosil-amino-imidazole synthetase, which all have their control genes in chromosome 21 (17-27). I had finally found the origin of the Down individual's stress. The 50% increase of a whole series of metabolisms produces 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.

Bearing in mind that stress can be of a physical, chemical, biological or psychological origin, raises the question 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 phenomena, it cannot be too unimportant given that it is also considered a factor which helps to bring on fits in epileptic women.

In Down individuals, the endogenous biological stress is not cyclic but continuous, affecting all the cells.

This concept of stress, which I have had clear and written about for some time now (28), has recently 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:

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

This response will differ from individual to individual and depends on constitutional, hereditary and acquired characteristics.

In Down subjects:

1. the causal agent is the extra chromosome 21;
2. the organism's specific response will produce similar symptoms in all subjects because the cause is the same;
3. I had already foreseen that certain symptoms, depending directly on the metabolisms' acceleration, would be in common (30).

The first two have been asserted by Lejeune and his team, and consist of the increased consumption of tetraidofolate and of s-adenosine-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.

I was already prescribing folates, having arrived at this usage through studying the child's dietary habits.

I was unaware of the need for S-adenosyl-l-methionine, but for 7 years now I have been gradually prescribing both these physiological substances for all the children undergoing therapy.

The control checks I am carrying out, especially on the addition of SAMe, seem very encouraging.

The matter of stress response symptoms and their treatment is a very different, and much more complicated area to tackle.

I should first of all state that, as with all stress, this too can induce depression.

On the whole I treat depression with viloxazine, because this drug, unlike the other anti-depressants, does not lower the epileptic threshold, while if anything increasing it (32-33), that is, lessening the risk of eventual epileptic disturbances (34).

There is nothing particularly alarming about this, it just requires a certain amount of cautiousness on the part of the specialist. However important it may be, the depressive consequence is not one of the most frequent aspects.

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), the linguistic ones (37); attention concentration and memory, and through these the intellective and social aspects (38); the weight-height ratio (39); penis size and erection (40) and ocular-global 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 free 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. 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 immunitary 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 favourable 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 (50).

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.

Not only is this actually proving to be the cases (51), often to the wonder of the heart surgeons, but I had always reassured the parents that this would come about.

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. 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:

1. he likes sweets and broth;
2. he does not like sweets but likes broth;
3. he likes sweets but refuses broth;
4. 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 which utilises glutamine seems to act as a reserve) already in this way I have to start hypothesizing 4 different neurochemical imbalances. My therapeutic intervention will have to take account of 4 variations, given that everything else is the same, which is never the case. 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.

Considering only GABA and serotonin, the possible imbalances have already increased to 4 times 3, making 12.

Seven years ago I examined for the first time an autistic Down child, who had a keen liking for sweet foods. I told his parents that the cure would be easier. This fact was confirmed (53), unlike my experience with psychotic Down children who violently refused sweets and broth.

Evidently, in the latter cases there exists a neurochemical imbalance which I have not yet completely understood and which I am not able to treat successfully given my present level of knowledge.

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 medicines I use are listed in table 1.

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.

I have been concerned with the toxicity of psychotropic drugs since 1972 when I was working in a psychiatric hospital.

At that time we found data which excluded the possibility; we found it again 8 years later and it was confirmed by other researchers (54-57). Those were therapeutic situations in which the quality, and above all the quantity, of drugs administered to the patients were far different from the ones I prescribe for Down subjects today.

Moreover, evidence is continually being found about the fact that psychotropic drugs give protection against the onset of some cancers (58). 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.

If it helps to debunk this idea of toxicity, I should add that I have, for over 11 years, been a consultant at the AIAS centre in Castelfranco Veneto, responsible for the neuropharmacological therapies of a group of seriously ill cerebropaths.

There, laboratory analysis of blood, liver and urine have always been carried out very frequently.

Not only have no signs of toxicity been found, but quite the contrary, results to confirm the opposite (59).

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.

This is the stance I have taken since 1984, (60), regarding the habilitation or rehabilitation of handicapped subjects in general, and in particular those suffering from Down's syndrome.

There would be so many more points to clarify, especially for my fellow specialists. I hope soon to be able to make an expert system available which will help colleagues to repeat my findings.

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 exercise, that is to bring relief to the patients and their families.

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