DRUG THERAPY OF PSEUDODEMENTIA
AS MODULATION OF STRESS REACTIONS:
THREE CASES
Renato
COCCHI, MD, neurologist and medical psychologist
Abstract
Stress reactions play
a major role in intellectual impairments of old people. When it happens so,
they can get out pseudodementia. Stress reactions can come out from external
stressors, or internal stressors or both. The internal stressor most likely is
an illness itself, but this one could also be true dementia (eg. DAT). These
facts can account for some consequences: i. We can found a share of
pseudodementia in true dementia too; ii. When pseudodementia is a share of true
dementia the only therapeutical success we can obtain now comes from the cut
down of the pseudodementia share; iii. We can modulate stress reactions by
drugs, by this way reducing pseudodementia; iv. Modulation of stress reactions
affects even the course of true dementia.
Drug modulation of
stress responses mainly acts on GABA and related brain mechanisms and its
results have a direct effect on the EEG. EEG power analysis seems a tool to
point the time course out.
Three cases are
presented according to these premises: A female aged 53, with DAT; A 62 old
male, with depressive pseudodementia, without significant EEG findings; A male
aged 52 with severe EEG alterations and pseudodementia. Therapies lasted more
than two years each.
Key works: Dementia; pseudodementia;
stress; drug therapy.
Dementias
Wold Congresses on
Stress and other congresses.
Drug modulation of
stress reactions
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Before pointing up the relationship
between stress reactions in old people and pseudodementia, I need defining stress
itself. Although I do not fully agree with it, this is the more authoritative
definition of stress. " .... it generally refers to physical or
psychological alterations capable of disrupting homeostasis." (Cullinan et
al., 1995).
Waiting for a more precise one, I should
propose this as a operational definition. We can term stress a set of relations
linking external or internal stressors of physical, chemical, biological /
metabolic 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, and act as a common final pathway.
Stress reactions can come out from external
stressors, or internal stressors or both. The internal stressor most likely is
an illness itself, but this one could also be true dementia (eg. DAT).
Stress
and pseudodementia
In every illness we have to consider the sum
of three factors:
- the causal agent;
- the organism's specific response;
- the organism's nonspecific response,
which is a stress response to the condition of the current illness. (Loo and
Loo, 1986).
Now, in every illness too the organism
immediately sets off stress reactions, which seems first to go along the
neurochemical pathway glutamate-GABA (Horger and Roth, 1996)
It is easy to add that stress reactions
differ from individual to individual and depend on constitutional, inherited
and acquired characteristics. Among which the particular time of the biological
cycle of a living organism could greatly affect stress reactions.
As we are interested in, stress reactions in
old people affect more intellectual performances, and can get out
pseudodementia (Savoldi, Zerbi and Cocchi, 1985)
These facts can account for some
consequences:
i. We can found a share of pseudodementia in
true dementia too;
ii. When pseudodementia is a share of
true dementia the only therapeutical success we can obtain now comes from the
cut down of the pseudodementia share (we cannot revive dead neurons);
iii. We can modulate stress reactions by
drugs, by this way reducing pseudodementia;iv. Modulation of stress reactions
also affects the course of true dementia.
Modulation
of stress reactions by drugs: A temptative rationale.
To make of drug therapies, we need to have a
very short and rough sum up of some neurochemical mechanisms involved in
reactions to chronic stress of a human body:
1. Direct acting on type A gabaergic
receptors; these modify their conformation and by this way reduce type A
gabaergic inhibition (Horger and Roth, 1995);
2. Reduced need of GABA for type A gabaergic
inhibition and more GABA into the synaptic cleft (Cocchi, Patrucco, Zerbi,
1987);
3. Increased type B gabaergic inhibition
that, in its turn, inhibits brain acetylcholine (Scatton and Bartholini, 1980),
serotonin (Scatton et al., 1986);
As for acetylcholine, its reduced turnover
seems to drive to a reduced brain synthesis, lowering blood-brain barrier
transport of choline by reduced high-affinity uptake (Hope, 1979). Although a
low-affinity uptake starts working (Hope, 1979) there is more choline supply
for the synthesis of peripheral acetylcholine.
This could account, at least in part, for
increased strength of parasympathetic / vagal responses, elicited by direct
stimulation of type B gabaergic receptors (Williford et al, 1981; Goto et al.,
1985).
4. Compensatory incretion of peripheral
adrenalin (Zigmond, Finlay and Sved, 1995), and glucocorticoids (Sorg and
Kalivas, 1995), the latter affecting also hippocampal memory sites (McEwen,
1995).
5. More GABA into the synaptic cleft
backwards reduces GAD activities (Baxter, 1976, Loescher 1980) with reduced
transformation of glutamate into GABA.
6. Excess of glutamate, besides being
excitatory and eventually neurotoxic (Rothman and Olney, 1986), seems to
increase mesoprefrontal dopamine (Horger and Roth, 1995). Although
controversial, the same appears to happen for noradrenalin activity in Locus
Coeruleus, the main brain site for this neurotransmitter Zigmond, Finlay and
Sved, 1995).
Of course, this is only a very simplistic
general frame, but it is a good point to start.
Modulation
of stress responses by drugs and EEG changes.
Drug modulation of stress responses mainly
acts on GABA and related brain mechanisms and its results have a direct effect
on the EEG. EEG mapping seems a tool to point the time course out.
According to what I have just said, the main
focal points to act by drugs are:
- increase type A gabaergic inhibition;
- decrease type B gabaergic inhibition;
- increase brain acetylcholine
synthesis;
- Increase the GAD action;
- decrease cortisol incretion;
- decrease both vagal outflow and
increased strength of vagal responses.
Being a cascade events having its starting
point on reduced type A gabaergic inhibition, from a theoretical point of view
one could use only one drug, a benzodiazepine (Schoch et al., 1985). This is
not the best way to afford it, because we shall need high dosages, which in
turns produce side effects (eg.: drowsiness). They could also induce a new
share of stress reactions (chemical stress due to the foreign nature of drugs,
according to Antelman, 1988).
As I did, mainly in Down children and in
autistic children (Cocchi, 1996), we can do better using:
- A low dose benzodiazepine, to act on type A
gabaergic receptor (eg.: clobazam 10-20 mg; diazepam 3-12 mg: daily doses);
- carbamazepine, a Ca-antagonist in the
brain (Crowder and Bradford, 1987) and so the best antagonist of type B
gabaergic inhibition (200-400 mg/daily);
- pyritinol (100 mg/daily), a good
increaser of brain ACh synthesis (Blusztajn and Martin, 1988; Greiner, Haase
and Seifried, 1988; Toledano and Bentura, 1994);
- pyridoxine (150 mg daily), acting as
cofactor of all decarboxylases, and of GAD too;
- if the case, a low dosis antidepressant
drug has to be added.
Benzodiazepines reduce the incretion of
cortisol (Bruni et al. 1980; Viukari, 1983), and the lowering of type B
gabaergic inhibition cuts down the vagal outflow. Increased synthesis of brain
Ach drives the synthesis of peripheral Ach to normal, by reducing the
peripheral choline supply. Nearly always serotoninergic mechanisms need to be
balanced too. In this case use antidepressant drugs, from tricyclics to SSRIs.
This is a very short introduction, but it is
enough for a more comprehensive therapeutic approach.
Casuistry
Now I shall present three cases according to
these premises: A female aged 53, with DAT and significant EEG findings; A 62
old male, with depressive pseudodementia, without significant EEG findings; A male
aged 52 with severe EEG alterations and pseudodementia.
If drug therapies involve the pathways
glutamate-GABA, we can expect changes in EEG-mapping, mainly Delta and Theta
waves. EEg mapping has been made by the same professional using
Electroencephalograph ERA 18, by Esaote Biomedica of Florence with Brain
Surveyor Mapping Device by ŠBasis of Arbizzano di Valpolicella, Verona.
Only maps made by 8 seconds epochs were used
for this study.
Because color printing is not allowed by
this Journal, brain maps were converted into % power's presence of delta or
theta waves (sure pathological bands) at each EEG reference point of the scalp.
Average power's presences permitted to follow the time course of variations
induced by drug therapies.
Case 1: female aged 53 at first consultation
in 1992; my first diagnosis was wrong because I highlighted the depressive
symptoms instead of the cognitive ones. She had soon after a diagnosis of
Alzheimer type dementia, made by an extensive neuropsychological evaluation and
NMR.
Starting therapy (daily dosis, if not
otherwise specified): carbamazapine 200; pyritinol 100; pyridoxine 150;
bromazepam 1.5.
Current therapy (April '96): lamotrigyne 50,
carbamazepine 200, clobazam 10, diazepam 10; viloxazine 100, a polyvitaminic
and mineral salts compound (DIAGRAN MINERALE RAFFORZATO Hoffman LaRoche) 3
tablets x one week , nimodipine 70.
Maps from July 92 to Nov. 95. Keys: Black
bar = Delta waves; Open bar = Theta waves
She did not tolerate a higher dose of
carbamazepine, so carbamazepine has been reduced and nimodipine has been added
to act more on type B gabaergic receptors.
A recent neuropsychological evaluation shows
a declining of intellectual performances, but slower than one can expected.
Currently she is autonomous, self-conscious
about her difficulties, depressed, with mild apraxias, but a fluent language.
Sleep, eating and bowel functions are regular. She can well swim, but no more
biking, because she tended to run in the middle of the way.
Case 2: man, 62 years old at first
admittance on our clinic in 1993, but he was an inpatient about 20 years
before, suffering from a syndrome of anxiety-depression. He always took mild
doses of tricyclic antidepressants and benzodiazepines with fairly good results
until six months before that entry.
The new severe depressive episode did not
respond to drugs therapies he got as inpatient in another clinic. Laboratory
findings were normal, but CAT showed an atrophic increase of intraventricular
and peri-cerebral liquoral spaces.
At his entry he presented loss of short term
memory, time and space disorientation, night-day inversion for sleep, loss of
autonomy, some apraxias and agnosias, repetitive speech without any reference
to the current environment, visual hallucinations.
He was unable to perform WAIS, Raven's
Coloured Matrices, but he scored 15 in Mini Mental State. EEGmapping did not
show any anomalies.
First treated with oxazepam 60 mg,
l-glutamine 250 mg, pyridoxine 150 mg, amineptine 100, flunitrazepam 2 mg, few
days later had l-glutamine substituted by pyritinol 100, oxazepam by bromazepam
3 mg, amineptine by viloxazine 100, and carbamazepine 200 was added. (Daily
doses)
After 4 weeks he fully recovered. Raven's coloured
Matrices scored 20/36.
EEG Mapping did not show any presence of
Delta or Theta waves higher than 12.5 % in every EEG scalp points.
Three years later when he was again an
inpatient to adjust antidepressant therapy, MMS scored 20 and WAIS IQ scored 83.
Last therapy prescribed: chlomipramine 10 mg, amitriptyline 10, l-glutamine
250, bromazepam 4.5, pyridoxine 150, trazodone 100, 5-hydroxytriptophan 100.
Case 3: Man, 53 years old when he had first
admittance in our clinic, after 15 years of antidepressant therapies and 4
admittances in psychiatric sections of local general hospitals. Clinical
diagnosis at last discharge was "Dementia syndrome".
At his first entry he was agitated,
restless, apathetic, with space and time disorientation, with reduction and
slowing down of the speech, and jargon aphasia. No neuropsychological tests
could have done, because he did not understand the orders.
Therapy started with pyritinol 100,
pyridoxine 150, carbamazepine 400, amantadine 100, viloxazine 100, clonidine 75
gamma, bromazepam 3. Later on he had carbamazepine 600, bromazepam 4.5,
clonidine 150 gamma. CAT showed no abnormalities.
Discharged after 6 weeks, without any
symptoms but some anxiety and depression, and some mild sleep troubles.
From January 94 to March 96 he had 5 other
entries in our clinic, usually because overanxious, depressed with suicidal
thoughts, and recurrent gastrointestinal pain.
EEG mapping from December 93 to April 94
showed a decrease in delta and theta waves. In August 95 he got valproate
instead of carbamazepine, following the prescription of a consulted neurologist
and a clear worsening of his symptoms followed. During this new entry in our
clinic, EEG mapping showed a large increase of Theta waves. A December 95 EEGmapping
showed a good reduction of such Theta waves.
Maps from December 93 to December 95. Keys:
Black bar = Delta waves; Open bar = Theta waves
Last therapy: carbamazepine 400;
pyridoxine 150, viloxazine 100, citalopram 20, Bromazepam + propanteline 3
tablets /day, dihydroergochristine 6 mg.
Neuropsychological tests (MMS, WAIS, RCM)
made during last staying in our clinic, scored normal. The patient has a severe
trouble of inhibitory brain neurotrasmitters as showed by mapping and confirmed
by clinical and EEGmapping worsening after valproate.
Conclusion
This short and perhaps confused report aims
only to inform about a different approach to pseudodementia. Stated that we
cannot revive dead neurons, but dysfunctional neurons are our therapeutic
target, the modulation of stress responses can be an interesting approach, as
the 3 cases here presented show. Of course this approach does not use
monotherapy, because absurd per se, and especially when we are dealing with
stress. This condition is a sure paradigm that our brain works according to a
multivariate system of cause and effect's relationships.
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Presented at the 10th World Congress of IASSID, Helsinki, 1996
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Author’s address : Renato COCCHI, via Rabbeno, 3
42100 Reggio Emilia (Italy)
renatococchi@libero.it
Dementias
Wold Congresses on Stress and other congresses.
Drug modulation of stress reactions
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