Workshop on Drug
Therapy in Mental Retardation
Renato
Cocchi MD, PhD. (Sociology)
Paper presented at the X World Congress on the International Association for
the Scientific Study of Intellectual Disabilities (IASSID), July 1996,
Helsinki, Finland.
Keywords: mental retardation, pseudo mental retardation, stress, drug, therapy, Down syndrome, rationale.
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:
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 first two have been asserted by Lejeune
and his team, and consist of the increased consumption of tetridofolate and of
l-methionine [31];
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:
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.
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Posted on Internet on 01.09.2007, without any Italian translation.
Dr Renato Cocchi
Via Rabbeno 3, I-42100
Reggio Emilia
renatococchi@libero.it