DRUG THERAPY IN DOWN'S
SYNDROME:
A THEORETICAL CONTEXT
Renato Cocchi, a neurologist and a medical
psychologist
Summary
The guidelines justifying drug therapies
in Down's syndrome children are roughly reported. The starting point is the
double series of symptoms in these subjects, one series directly related to the
dosage effect of the extrachromosome 21, and the second series as symptoms of
stress due to homeostatic inbalance the dosage effect of the extrachromosome 21
produces.
Since stress responses are peculiar to
each individual, for genetic and acquired factors, related symptoms in Down
subjects can be more or less present, quite indipendently from the type of
chromosomal anomaly. A mosaic subject can show more evident symptoms than a
pure trisomy 21 one, although only a share of the cells of his/her body is
trisomic. Stress responses of one Down subject can be modulated by drugs, but
the choice of the drugs needs to be tailored to the peculiar expression of
stress symptoms this individual displays.
Key words: Down’s sydrome; metabolic
stress; stress responses; modulation; drug therapy; individualized therapy.
Home Page / / / Pagina iniziale
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
resistent 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 realise 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:
In Down subjects:
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);
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:
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.
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 0.5-0.15
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
pantotenate 150-300
pyridoxine 75-150
pyridoxol dimaleate 150-300
pyritinol 50-100
s-adenosil-l-methionine 100-200
thiamine 75-150
viloxazine 25-100
glutamine + pemoline (45+5)-(90+10)
thiamine + pyridoxine + cyanocobalamine
125mg+125mg+250 gamma
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 I.
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.
References
[1] Cocchi R., Terribili F.: Prime
esperienze sull’uso della dibenzotiazepina (clotiapina) come farmaco anticaratteriale.
Note Riv. Psichiat. (Pesaro) 1971, 64, 23-41.
[2] Cocchi R.: Susceptibility to infective
respiratory diseases in depressed children. Epidemiological survey of 126
subjects, clinical-theraputical report of 61 cases. Acta Psychiat. Belg. 1981,
81: 350-365. [3] Cocchi R.: Facilita’ alle malattie infettive respiratorie nei
down:
Indagine epidemiologica su 450 casi. Riv.
Ital. Disturbo Intellet. 1990, 3: 131-136.
[4] Cocchi R.: Reduction of susceptibility
to upper respiratory tract infections in Down Syndrome children following
treatment with GABAergic drugs: Report of 70 cases. Int. J. Psychosom.
(Philadelphia) 1987, 34/2: 3-7.
[5] Cocchi R.: Sulle caratteristiche
antidepressive della l-glutammina. Atti del XXXII congreso nazionale della SIP,
Vol. II. AGE, Reggio Emilia, 1977: 495-502.
[6] Cocchi R., Ghiglione Rocca R., Mastruzzo
A.: L-glutammina in aggiunta alle usuali terapie in pazienti psichiatrici.
Saggio a doppio cieco incrociato. Rass. Studi Psichiat. 1978, 67: 292-300.
[7] Lake C.R., Ziegler M.G., Coleman N.,
Kopin I.J.: Evaluation of the sympathetic nervous system in Trisomy-21 (Down’s
syndrome). J. Psychiat. Res. 1979, 15: 1-6.
[8] Udeschini G., Casati G., Bassani F.,
Picotti G.B., Culotta P.: Plasma cathecolamines in Down’s Syndrome, at rest and
during sympathetic stimulation. J. Neurol. Neurosurg. Psychiat. 1985, 48:
1060-1061.
[9] Cocchi R.: A syndrome from a possible
GABA deficiency. Clinical-therapeutic report on 15 cases. Acta Psychiat. Belg.
1978, 78: 407-424.
[10] Cocchi R.: Hypo-A-GABA-erge Depression
bei Kindern. Klinisches Bild und mit neurochemischen Mechanismen verbundene
Symptome. In: Friese H.-J., Trott G.-E.: Depression in Kindheit und Jegend.
Huber, Bern, 1988: 126-333.
[11] Cocchi R.: L’intolleranza al caldo nel
soggetto Down. Una indagine epidemiologica su 432 casi. Riv. Ital. Disturbo
Intellet. 1989, 2: 195-199.
[12] Cocchi R.: Greediness for sweet things
in children as a symptom of antidepressive homeostatic compensation: 41 cases.
Acta Paedipsychiat. 1980, 45: 293-300.
[13] Cocchi R.: Precursori diretti dell’ac.
glutammico e del GABA e abitudini alimentari nei Down: Indagine epidemiologica
su 460 soggetti. Riv. Ital. Disturbo Intellet. 1990, 3: 307-312.
[14] Cocchi R., Lorini G.: Disturbi di parto
e depressione infantile come antecedenti psicopatologici nella storia di
tossicomani cronici. Rass. Studi Psichiat. 1980, 69: 49-62.
[15] Cocchi R., Felici M., Tonni L., Venanzi
G.: Behavior troubles in nursery school children and their possible
relationship to pregnancy or delivery difficulties. Acta Psychiat. Belg. 1984,
84: 173-179.
[16] Cocchi R., Branchesi R.: Strabismo e
disturbi pre-, peri- e neonatali in soggetti affetti da sindrome di Down.
Indagine epidemiologica su 215 casi. Rass. Studi Psichiat. 1986, 75: 504-512.
[17] Sichitiu S., Sinet P.M., Lejeune J.,
Frezal J.: Surdosage de la forme dimerique de l’indophenoxidase dans la
trisomie 21, secondaire au surdosage genetique. Humangenetik 1974, 23: 65.
[18] Sinet P.M., Allard D., Lejeune J., Jerome
H.: Augmentation de l’activite’ de la superoxyde dismutase erithrocytaire dans
la trisomie pour le chromosome 21. CR Acad. Sci. [D] (Paris) 1974, 278:
3267-3270.
[19] Sinet P.M., Couturier J., Dutriallaux
B., et al.: Trisomie 21 et superoxyde dismutase (I.P.O.A.). Localisation sur la
bande 21q221. Exp. Cell. Res. 1976, 97: 47-55.
[20] Crosti N., Serra A., Rigo A., Viglino
P.: Dosage effect of SOD-A gene in 21-trisomic cells. Hum. Genet. 1976, 31:
197-202.
[21] Feaster W., Kwok L., Epstein C.: Dosage
effect for superoxyde dismutase-1 in nucleated cells aneuploid for chromosome
21. Am. J. Human Genet. 1977, 29: 563-570.
[22] Jezorowska A., Jacubowski L., Armatys
A., Kaluzewski B.: Copper/zinc superoxyde dismutase (SOD-1) activity in regular
trisomy 21, trisomy by translocation and mosaic trisomy 21. Clin. Genet. 1982,
22: 160-164.
[23] Neve J., Sinet P.M., Molle L., Nicole
A.: Selenium, zinc and copper in Down’s syndrome (trisomy 21): blood levels and
relations with glutathione peroxidase and superoxyde dismutase. Clin. Chim.
Acta 1983, 133: 209-214.
[24] Moore E.E., Jones C., Kao F.T., Gates
D.C.: Synteny between glycinamide ribonucleotide synthetase and superoxyde
dismutase (soluble). Am. J. Hum. Genet. 1977, 29: 389-396.
[25] Patterson D., Graws S., Jones C.:
Demonstration, by somatic cell genetics of coordination of genes for two enzyme
of purine synthesis assigned to human chromosome 21. Proc. Natl. Acad. Sci. USA
1981, 78: 405-409.
[26] Chadefaux B., Rethore’ M.O., Raoul O.
et al.: Cystathionine beta synthetase: gene dosage effect in trisomy 21. Bioch.
Biophys. Res. Comm. 1985, # 1: 128.
[27] Skovby F., Krassikoff N., Francke V.:
Assignement of the gene for cystathionine beta synthetase to human chromosome
21 in somatic cell hybrids. Hum. Genet. 1984, 39: 291-294.
[28] Cocchi R.: Psychopharmacotherapy of
anxiety in the first years of life. Agressology 1981, 22,"D": 5-8.
[29] Loo P., Loo H.: Le stress permanent.
Masson, Paris, 1986. [30] Cocchi R.: La sindrome di Down. In: Strutture e
dinamiche psicopatologiche in eta’ evolutiva. Montefeltro, Urbino, 1986.
[31] Lejeune J., Rethore’ M.O., DeBlois
M.C., Mannoury-Burolla C. et al.: Metabolisme des monocarbones et trisomie 21:
sensibilite’ au MTX. Ann. Genet. 1986, 29: 16-19.
[32] Cocchi R., Occhialini O.: La viloxazina
come farmaco di scelta nella depressione degli epilettici e dei cerebropatici:
13 osservazioni. Rass. Studi psichiat. 1981, 70: 1-9.
[33] Cocchi R., Occhialini O.: La viloxazina
in bambini cerebropatici con o senza epilessia. In: Antidepressivi atipici.
Alternativa ai triciclici nella terapia della depressione. Flaccovio, Palermo,
1984.
[34] Cocchi R., Somenzini G.: Convulsivita’
specifica e aspecifica nel soggetto Down non istiruzionalizzato. Studio
epidemiologico su 366 casi ambulatoriali. Osp. Psichiat. (Naples) 1986, 54:
1-8.
[35] Cocchi R.: The anticipation of walking
in drug treated Down infants: A controlled study. Ital. J. Intellect. Impair.
1989, 1: 15-19.
[36] Cocchi R., Favuto M.: Miglioramenti
motori dopo 3-8 mesi di trattamento con farmaci, nei Down. Riv. Ital. Disturbo.
Intellet. 1993, 2: 251-258.
[37] Belacchi C.: Evoluzione del Q.I. e del
linguaggio in bambini Down trattati anche con farmacoterapia. Riv. Ital.
Disturbo Intellet. 1993, 6: 53-64. [38] Cocchi R.: School learning in 8 year
old Down children treated or not with drugs. Ital. J. Intellect. Impair. 1992,
5: 143-148.
[39] Cercolani P.: Il rapporto peso/altezza
in soggetti Down trattati con farmaci. Riv. Ital. Disturbo Intellet. 1990, 3:
137-140.
[40] Cocchi R.: Pene piu’ proporzionato ed
erezione in 56 bambini Down trattati con farmaci. Riv. Ital. Disturbo Intellet.
1990. 3: 145-148.
[41] Cocchi R.: Drug therapy of squint in
Down syndrome subjects. Results according to the length of drug taking: Report
on 125 case. Ital. J. Intellect. Impair. 1991, 4: 9-14.
[42] Jacobs P.F., Bourdas N.M., Manos J.P.,
Duncan R.C.: Immunologic parameters in down’s syndrome. Ann. Clin. Lab. Sci.
1978, 8: 17-22. [43] Krzanowska-Dyras M.: Immunoglobulins in Down syndrome.
Folia Med. Cracov. 1980, 22: 49-68.
[44] Cocchi R.: Reduction of susceptibility
to upper respiratory tract infections in Down syndrome children following
treatment with GABAergic drugs: Report of 70 cases. Int. J. Psychosom.
(Philadelphia) 1987, 34/2: 3-7.
[45] Cocchi R.: Facilita’ alle malattie
respiratorie nei Down: Indagine epidemiologica su 450 casi. Riv. Ital. Disturbo
Intellet. 1990, 3: 131-136.
[46] Morse D.R.: Stress and bruxism. J. Hum.
Stress 1982, 8: 43-52.
[47] Lamma A., Cocchi R.: Drug therapy of
bruxism in Down children. Ital. J. Intellect. Impair. 1988, 1: 19-24.
[48] Svec F.: Glucocorticoid receptor
regulation. Life Sci. 1985, 36: 2359-2366.
[49] Wehremberg W.B., Baird A., Ling N.:
Potent interaction between glucocorticoids and growth hormone in vivo. Science
1983, 221: 556-558.
[50] Shephard R.A., Estall L.B.: Anxiolytic
actions of chlordiazepoxide determine its effects on hyponeophagia in rats.
Psychopharmacology 1984, 82: 343-347.
[51] Cocchi R.: The use of drugs to modulate
stress responses reduces the time of intensive care needed by Down children to
recover after open-heart surgery. Ital. J. Intellect. Impair. 1990, 3: 11-16.
[52] Ward H.K., Thank C.M., Bradford H.F.:
Glutamine and glucose as precursors of transmitter amino acidis: Ex vivo
studies. J. Neurochem. 1983, 40: 855-860.
[53] Cocchi R.: Trattamento con farmaci
delle psicosi infantili: Storia di due soggetti usciti dalla psicosi. Riv.
Ital. Disturbo Intellet. 1991, 4: 245-253.
[54] Frassanito L.S., Cocchi R., Colapinto
D.: Studio della funzionalita’ epatica in pazienti in trattamento prolungato
con psicofarmaci. Primo rapporto. Note Riv. Psichiat. 1972, 65: 135-152.
[55] Frassanito L.S., Cocchi R., Colapinto
D.: Studio della funzionalita’ epatica in pazienti in trattamento prolungato
con psicofarmaci. Secondo rapporto. Note Riv. Psichiat. 1972, 65: 283-295.
[56] Cordella L., Lazzari D., Passanisi S.,
Cocchi R.: Analisi delle prove di funzionalita’ epatica, dell’assetto lipidico
e della glicemia in 84 pazienti sottoposti a trattamenti psicofarmacologici
prolungati. Riv. Neurobiol. 1980, 26: 291-302.
[57] Baldessarini R.J.: Farmacoterapia in
psichiatria. Masson, Milano 1978.
[58] Mortensen P.B., Neuroleptic treatment
and other factors modifying cancer risk in schizophrenic patients. Acta
Psychiat. Scand. 1987, 75: 585-590.
[59] Rossato P. Rossato G.: Trends in blood,
liver and kidney functions in severe brain damaged subjects following long term
neuropsychopharmacological treatment. Ital. J. Intellect. Impair. 1988, 1:
119-126.
[60] Cocchi R.: La farmacoterapia come
ulteriore strumento per lo sviluppo motorio nel bambino Down. Il Cinesiologo
(Naples) 1984, # 37: 35-37.
Printed on It. J. Intellect. Impair. 1993, 6: 143-154.
Author’s address: dr
Renato COCCHI, via Mercalli 10
42100 Reggio Emilia
(Italy)
renatococchi@libero.it
Home Page / / / Pagina iniziale