POSSIBILITIES AND LIMITS
OF DRUG THERAPIES IN DEMENTIAS
Renato
COCCHI. neurologist and medical psychologist
Abstract
There is not drug therapy of dementias, because we cannot revive dead
neurons. We can instead act on the share of pseudodementia due to the
dysfunction of alive but sick neurons, which always escort any type of
dementia. According to this perspective too, the best approach is not the one
drug therapy because it acts on only one of many altered neurochemical
mechanisms. Moreover it obliges to high doses to which the body will answer
with stress reactions and consequent neurochemical resetting leading to lower
efficiency of the drug used. Multiple drug therapy let acting in a synergical
way on many neurochemical altered circuits, by allowing low doses. The paper
presents the guidelines to face more common forms of dementias, from MID to
ATD. Key words: Dementia,
pseudodementia, drug therapy.
Key words: Dementia,stress,GABA,glutamate,drug
therapy,acetylcholine,serotonin,noradrenaline.
Dementias
Drug therapy
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I think the topic I was charged to develop be the
harder one, among the others this meeting presents. Perhaps it is so, because
it is the sole that is going into an uncharted territory, when we come out from
the aim to give the disease a diagnosis.
If we want to propose even drug therapy
in dementias, we should clarify some basic ideas. In the same time we have
immediately to reduce any excessive trust in a drug able to act alone, like
somebody should assert.
We need starting from a trivial but
often forgotten statement: We cannot revive dead neurons. So, to find a target
in our therapeutic action, we have to reconsider the idea of pseudodementia.
Dementia, pseudodementia and depression
The elaboration of the term
"pseudodementia" as opposed to "dementia" comes out by the
crossing of two conceptual axes. The first axis relates to depression in a
broad sense as the causal factor, and the second derives from reversibility, as
a clinical-therapeutic result (Savoldi, Zerbi, Cocchi 1986).
A pure depressive pseudodementia usually
shows an acute beginning and a quick progression to a steady state. On the
contrary, true dementias have a sly starting, and slow and progressive
development that lasts many years (Zerbi and Cocchi, 1986; Haggerty et al.,
1988). In that pseudodementia the case history often reports episodes of
affective troubles, especially when the age was in depression prone time, a
fact rarer in dementias.
Besides that, other criteria but less
sure can help suggesting a diagnosis of pure pseudodementia, the therapy of
which needs mainly antidepressant and anxiolytic drugs (Axelopoulos et al.,
1993). Pure pseudodementia, also called "depressive dementia," can
also be seen as a transitional state towards a clear and true dementia (Emery
and Oxman, 1997).
The psychopathological history of the
case does not always give enough correct directions.
Neuropsychological tests can hardly
distinguish current cognitive performances, reduced in whole or in part, as
demential or pseudodemential (Caltagirone et al., 1985). Clinical forms of pure
pseudodementia, so defined because fully reversed by suitable drug therapy,
first did not show any specific symptoms driving to a functional origin
(Cocchi, 1996).
No doubts that to find frank depressive
aspects can direct both diagnosis and therapy, but these are not always so
evident. Eventually indeed, is the ex juvantibus criterion what until
now remains as the surer way to differentiate these two frames.
Only by that we can distinguish dementia
as organic irreversible disease, from pseudodementia as functional reversible
disease (Fisman, 1985; Bulbena and Berrios, 1986; Savoldi, Zerbi and Cocchi,
1986).
But in this perspective too we are
facing further difficulties. Dementia and pseudodementia seem belonging to
opposite fields not only in a prognostic sense, as they are, but also in a
spatial sense. So, where the first stands there is no room for the other. We
have to remember such conditions self-showing as dementias and so diagnosed by
instrumental investigations, but in which some partial restore can be obtained
following suitable drug therapy. They risk becoming a paradox or a no-man land,
at least from a theoretical point of view.
Somebody may object that this partial
improvement could simply follow a wrong treatment, either for ignorance or
because we cannot do anything else, at the present state of art. Even though
this objection is close to the target, it is not a sufficient explanation.
Anyhow, it is an objection vitiated by the same oversimplified conceptual
scheme that opposes dementia to pseudodementia even in a spatial sense, without
any middle way.
In facts, if we account the
therapeutical success as the final goal of medicine, and of geriatrics, on our
case, we need exactly to start again from that. On the other hand, even if a
whole reversibility ought to be a medical hope, we cannot think we are in
search for the long-life elixir for intellectual abilities. Perhaps we can
postpone the cognitive impairment but we cannot avoid it forever.
Senile decay is a datum we have always
to take into account, and clinical and therapeutical research cannot do other
than moving the age of that decay.
Reversibility as a distinctive criterion
To distinguish dementia from pseudodementia,
the reversibility of the latter opposes non reversibility of the first one
(Reifler and Sherril, 1990). But we can value this reversibility as distinctive
criterion, only after therapy. If cognitive impairment comes back after
suitable therapy, we have faced a form of pseudodementia.
We propose to go over this entanglement
of contradictions by using functional inhibition instead of depression.
Functional inhibition does not imply any specific causal factor. Depression is
a term too strictly defined in psychiatry and only one possible causal factor
(Savoldi, Zerbi and Cocchi, 1986).
It is well known that CNS can show
reversible situations of reduced or abolished functionality. Pseudopalsies
following convulsive seizures or a brain ictus, which regress in a short time,
come out from a state of temporary functional inhibition. Areas, or structures
or neuronal circuits related to voluntary movement's brain programming do not
work for a certain while.
From this we can infer that not all the
cells of an ictal brain area are, for example, or damaged or healthy. Between a
share surely damaged and a share surely healthy there are even cells that ware
less hit by the vascular trauma, but now they are ill functioning.
We maintain the same should happen in
dementias where a share of pseudodementia is constantly present, and able to
make worse the whole cognitive performance elicited by neuropsychological
tests. It does that throughout the impairment of cognitive mechanisms such as
attention, concentration, memory, thinking mobility, ability to use second and
third order integrative mechanisms, etc.
This pseudodementia that escorts the
dementia will be the target of any partly successful drug therapy because only
pseudodementia is reversible.
When we have refined our therapeutical
means, we shall better verify its extent, surely larger in initial forms.
However, our successful therapies do not overcome the share of true and non
reversible dementia due to neuronal death.
Monotherapy as a deceptive choice
I hope what I have just written could be
accepted as a fair approximation to a fundamental, and I am going to develop
the second basic problem. Since many years research on dementias have pointed
out that there are many brain neurotransmitters involved in the same time. In
1983 Constantinidis reported 14 neuromediators, among them all brain
monoamines, GABA, GLU, ASP and GLY. In 1984 Gottfries et al. outlined ACH, DA,
NA, 5-HT, GABA, Somatostatin, Substance P.
I think that among all these
neurotransmitters should exist if not hierarchies, at least some priorities as
for the role of neuromodulators like GABA. Anyhow, ACH could occupy one of the
last places of what seems a cascade reaction.
The use of a unique drug as monotherapy
in dementia is already debatable for this reason. What is more, because it
assumes the brain as working by linear and independent relationships of cause
and effect.
As a rough metaphor, to use a
cholinergic drug in dementia as monotherapy is alike to favour Mississippi's
downflow by digging only one arm of its delta. It is little use because in a
short time the slime the water drags will raise the dug bottom.
Brain mainly works as a multivariate
system of dependent relationships, a fact that always implies the polytherapy
with synergical drugs. This approach allows low doses, with increased results
and reduced side-effects.
Guidelines to drug
therapy of pseudodementia in dementias
I will let out cognitive impairments
after brain trauma because they are too particular events, and often matched to
impressive motor deficits. The same happens for internal haemorrhages by the
breaking of a brain vascular malformation, mainly when the subject is less than
50.
Multi-infarct dementia. To detail, as for multi-infarct dementia, part
of its therapy is the control of causal agents like blood tension, platelet
aggregability, and the rate of free fatty acids. We can reach this control by
drugs and, in part, by an oriented diet. Drugs and surgical interventions can
raise brain blood flow. Health education or risk representation can reduce or
abolish smoking as a worsening factor (Mayer et al., 1986; Savoldi, Zerbi and
Cocchi, 1986).
The always present depression can be
treated by using viloxazine, a drug less lowering the epileptic threshold
(Cocchi and Occhialini, 1982). Nootropic drugs did unsatisfying results
(Gottfries, 1987). Cholinergic drugs are not "the therapy" of
dementias, but a class of possible therapeutical compounds. Among them I prefer
pyritinol, an old drug the action of which however has got also recent and
significant literature. (Blusztajn and Martin, 1988; Geiner, Haase and
Seyfried, 1988; Toledano and Ventura, 1994).
Dementia in Binswanger's disease. About one fourth of the people suffering from
subcortical arteriosclerosis leucoencephlopathy, or Binswanger's disease, has a
dementia outcome. Medical and diet control of blood hypertension and diabetes,
the two main risks factors of the illness, can give benefit also on cognitive
impairment. (Kindel et al., 1985; Savoldi, Zerbi and Cocchi, 1986).
Dementia in Parkinson's disease. Dementia is not always the fate of Parkinson's
disease, nor it comes out together when the symptoms of the illness begin
(Huber et al. 1986b). Although it is a subcortical form, with cognitive aspects
less involved
than affective aspects (Huber et al.,
1986a), Gottfries et al., 1980 suggested a major link with Alzheimer's disease.
A careful therapeutic conduct of Parkinson itself with the control of the
frequent depression can act on the demential symptoms. As for the choice
antidepressant drug, the DA agonist amineptine seems the more suitable
according to the basic disease.
Senile dementia. The age at which senile dementia - also called
Alzheimer's type -, comes out, is strongly conditioning any therapeutical result.
The control of functional parameters (Eg. blood nitrogen), the care on diet,
often non proper, with integration of vitamins and mineral salts, a better
regulation of sleeping, and a low dose antidepressant drug are the pillars the
therapy can be built on. A brain Ca+ antagonist and a cholinergic drug always
produce some positive results.
Pre-senile dementia. I left as the last the bogey among all
dementias, the presenile one when identified as the Alzheimer's disease. Even
if it was the more dramatic as for the age of the onset, luckily it is not the
easier to happen. As for my experience, I ought to say that there is always a
depressive component needing treatment. Depression is often its starting
symptom. In middle age the choice of the antidepressant drug does not ask so
much cautions as it happens in old age.
Normally I use a low dose tricyclic
antidepressant (Cocchi, 1996), but recent trials with SSRIs drugs appear very
promising (Tsiouris, 1996). Besides this antidepressant drug, a benzodiazepine
anxiolytic does never fail (Cocchi, 1996), but this association is an old habit
of Italian psychiatrists. Vit. B6 is another useful drug, because in form of
pyridoxal-phosphate, it enters about 60 brain mechanisms, among which all
decarboxylases (Ebadi, 1981). To act on brain ACh I prefer here too pyritinol.
Other drugs could be added according to symptoms related to brain
neurotransmitters or to the EEG. In all the cases, the only result we can
obtain is the slowing of the neurons' death as an irreversible process at the
moment.
Conclusion
This is only a short prelude to a
complex problem, which is giving theoretical and practical clarification. To
believe drugs fully useless in dementias means to condemn us to nihilism that
does not match the current knowledge. To believe in miracles, according to
doped and promotional information coming from non specialised press, is a
legitimate hope but professional. Often the family of a demented individual
should be satisfied with a specialist's "little" answer. It should be
enough that the patient was sleeping in the night and let sleeping the
relatives.
As I experienced, we can always help to
reach it but that task is not easy nor simple. In must cases we need to do it
by following approximations made in a hospital setting.
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Author's address: Renato COCCHI MD, via Mercalli 10
42100 Reggio Emilia
renatococchi@libero.it
Dementias
Drug therapy
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