Vol. 2, Nr.

3, 4
2002






JURNALUL ROMN DE
PSIHOFARMACOLOGIE

ROMANIAN JOURNAL OF
PSYCHOPHARMACOLOGY
















Editura Medical Universitar Craiova
2002


CUPRINS / CONTENTS


M. Bourin
Editorial: De la psihofarmacologia noului nscut la cercetarea comportamental
Editorial: From psychopharmacology in newborn babies to behavioural research .......................... 1

M. Bourin
Receptorii nicotinici
Nicotinic receptors ............................................................................................................................. 7

D. Marinescu, T. Udritoiu, A. Miloescu, I. Udritoiu
Actualiti neurobiologice i psihofarmacologice n demene
Neurobiological and psychopharmacological updates in dementias ............................................... 22

C. tefnescu, Roxana Chiri, V. Chiri
Intervenia farmacologic n depresia la vrsta a III-a
Pharmacological intervention in depressive disorders in the elderly .............................................. 30

M. Weiser, H. Knobler, I. Grotto, M. Davidson
ntrzierea debutului schizofreniei prin administrare de medicaie antipsihotic:
o ncercare ipotetic de definire a numrului pacienilor de tratat
Delaying the onset of schizophrenia by administering anti-psychotic medications:
a hypothetical attempt to define the number needed to treat ............................................................ 38

Rodica Mihaela Enache, P. Boiteanu
Schizofrenia la femeie - particulariti terapeutice
Treatment of schizophrenia in women particular aspects .................................................................. 43

A.I. Grigoriu, Adina Coman, Hania Hapczinski
Rolul olanzapinei n influenarea calitii vieii la pacienii cu schizofrenie cronic
The role of olanzapine in influencing the quality of life in patients with chronic schizophrenia ..... 49

Victoria Burtea
Noi ipoteze asupra bazelor moleculare ale atipicitii antipsihoticelor
Molecular basis of atypical antipsychotics new hypothesis........................................................... 59

C. Friedmann
Noi reconsiderri i perspective n boala bipolar
Updates and perspectives in bipolar disorder .................................................................................. 65

M. A. Bir
Tratamentul cu buspiron n tulburrile anxioase asociate alcoolismului
Therapy with buspirone in anxious disorders associated to alcoholism ......................................... 75

Veronica Sfredel, G. Bdescu, I. Udritoiu, A. Tril
Unele efecte neurofiziologice i farmacologice ale digitalei
Some neurophysiological and pharmacological effects of digitalis ................................................ 86

Romanian Journal of Psychopharmacology



BOARD

T. Udritoiu Editor fondator / FOUNDING EDITOR
M. D. Gheorghe Redactor ef / EDITOR
D. Marinescu Redactor ef Adjunct / DEPUTY EDITOR




EDITORIAL BOARD




CONSULTANI TIINIFICI / ADVISORY BOARD

M. Bourin
M. Davidson
S. Kasper
H.J. Mller
J. Zohar






A R
P F
CONSILIU TIINIFIC
(SCIENTIFIC BOARD)

M. D. Gheorghe
T. Udritoiu
D. Marinescu
P. Boiteanu
V. Chiri
M. Dehelean
A. Grigoriu
G. Ionescu
M. Lzrescu
R. Mihilescu
D. Prelipceanu
V. Voicu
COMITET DE REDACIE
(REDACTION)

L. Alexandrescu
Victoria Burtea
Roxana Chiri
Doina Cosman
Pompilia Dehelean
V. Entescu
C. Friedmann
C. Fulga
Marieta Grecu-Gabo
A. Niretean
Gh. Talu
R. Vrati















































Asociaia Romn de Psihofarmacologie
Romanian Association for Psychopharmacology

Clinica de Psihiatrie
Str. Nicolae Romanescu, 41, Craiova
Tel: 0251 426161; Fax: 0251 428584
E-mail: psy@umfcv.ro

M. D. Gheorghe preedinte / president
T. Udritoiu vicepreedinte / vice-president
D. Marinescu secretar / secretary

Partener Principal ELI LILLY S.A.
A R
P F
1


FROM PSYCHOPHARMACOLOGY IN NEWBORN BABIES
TO BEHAVIOURAL RESEARCH
M. Bourin
France


I began my academic life taking my studies at the Faculty of Pharmacy at the University of
Tours, where I was born. After a few years, it became clear to me that I did not want to become a
pharmacist working in a shop. Consequently, I entered a lab in my faculty and began to conduct
some research studies in the field of growth factors in plants and inhibiting factors in the mistletoe.
I spent many months in different research labs whilst studying at the Faculty of Pharmacy. I
took some chemistry exams and I was put forward as an Assistant Professor of analytical chemistry
in my own Faculty, but had to spend one year in the Army performing my national service.
Upon returning to the Faculty of Pharmacy, I began to teach mainly in the field of
chromatography (gas and liquid). But during my period in the army I had met two medical doctors
who convinced me to begin my medical studies. Then, I was teaching chemistry as well as learning
medicine. A few years later, I was helping some of my friends, residents in medicine, to assay some
special metals (copper, zinc) in blood and I met the professor of pharmacology of the school of
medicine. He asked me to join him to study drug monitoring as well as emergency toxicology at the
hospital.
So I entered psychopharmacology by assessing psychotropics in stomach juices, blood and
urine (1). I understood at that moment that I had to take special studies in pharmacology and this
was the beginning of my Parisian life. For two years I was completing my medical studies as well
as my pharmacology education. I met Professor Pierre Simon at La Piti Hospital in Paris and I
joined his lab to begin behavioural psychopharmacology. I was quite naive in that field when I
chose as my thesis project research on depression using animal models as predictive tools (2). I
used six models and thirteen drugs. At that time, there was no personal computer and my memory
was not adequate to retain my results to make comparisons. Thus, when I had to write up my
results, it was difficult to comprehend to have dose-effect relationships.
After a few years I moved to Nantes where I began to manage a psychopharmacology lab. I
started from nothing because previous research there had been essentially in the field of
antitubercular drugs. I taught psychiatry residents neurobiology and psychopharmacology and
completed my studies to become a psychiatrist. My early research involved some screening for
small pharmaceutical companies. This activity allowed me to teach technicians and a few students
2
behavioural tests. I tried to have in parallel some research in humans mainly in the area of
psychometry of benzodiazepines. While doing that I met Brian Leonard and Ian Hindmarch who
helped me by advising me. Benzodiazepines were widely used in Europe, however no French text
was available at this time. So I wrote a book in 1981 mainly on the Pharmacokinetics of
Benzodiazepines (I recently published a second edition including dependence, 1989). Subsequently
I was sollicited to join a Committee in the World Psychiatric Association then part of the World
Health Organization to publish (with colleagues) a WHO document on the Rational use of
Benzodiazepines chaired by Jorge Costa et Silva (3). The first CINP meetings I attented (Paris and
Goeteborg) were very important for advancing my knowledge since I met so many people, like
Arvid Carlson in the field of dopamine, Herman Van Praag and Alec Coppen in the field of
serotonin, whose papers I had read previously.
I followed with some work on phenobarbital in newborn babies, trying to understand its
pharmacokinetic parameters in that very specific population. When I published that the half-life of
phenobarbital in newborn babies was up to 300 h, it was difficult to convince the reviewers that it
was so long (4).
My lab was now growing thanks to some grants from pharmaceutical firms, and the forced
swimming test model became, in our hands, a tool for a better understanding of the mechanisms of
action of antidepressants. Several researchers came from Canada, China, Ireland and Israel and the
model, aided by the discovery of specific agonists and antagonists of 5-HT receptors, gave us some
interesting results which lead to the idea that 5-HT
1A
and 5-HT
1B
receptors play a key role in the
mechanism of action of antidepressants (5,6).
In 1986, I met at a meeting in Stockholm Yvon Lapierre who had just been appointed as
Chairman of the Department of Psychiatry of Ottawa. Each of us was presenting a poster that lead to
the same idea, i.e. that antidepressants where decreasing retardation whether working though 5-HT or
NA. In fact, it was the beginning of a strong friendship and of my Canadian connection. A few
months afterward, Yvon and I met again at a CINP meeting in Puerto Rico and Yvon invited me to
become visiting professor in his department. When I took the position in 1990, one of my students,
Jean-Michel Le Melldo, was in Ottawa and between two tennis matches he spoke to me about
Jacques Bradwejn who was at this time at St-Mary's Hospital in Montral. When I met Jacques we
realized in few minutes that we would have a good relationship and a good scientific collaboration.
It was almost the beginning of the CCK story where we showed that CCK4 was able to induce
panic attacks and that it was possible to have a safe human model (7,8,9). The idea that CCK4 could
induce panic attacks so quickly (20 seconds) was somewhat in contrast with the previous experience
with lactate; however, even if Donald Klein was sceptical, it was for me the beginning of a good
friendship with him and Rachel (10).
3
Jacques and I were disappointed that CCK2 antagonists were not efficient enough to be used in
psychiatry in panic disorder patients, but they could appear soon. The CCK story gave us the
opportunity to meet Eero Vasar from Estonia; he is still a collaborator in preclinical research as well as a
friend (11,12). This is a very strong illustration of the key role of science in linking people together.
Another story relates to my teaching in Canada following my visiting professor experience. I
had been teaching every year at Mc Gill University. It was an opportunity for me to meet young
psychiatry residents to work with them on research in the field of psychopharmacology. I was
primarily teaching about benzodiazepines and the general pharmacokinetics of psychotropics. At
this period I was attending meetings of the Canadian College of Neuropsychopharmacology
(CCNP) and I met Glen Baker, first in Banff then in Quebec City. He decided to send me a
postdoctoral fellow in Nantes; she began to learn behavioural tests with me, mainly in the field of
depression. After a few months, the young lady had not markedly improved her French and was
concerned about the fact than there was very little neurochemistry. She finally wants back to
Edmonton via a postdoctoral followship in Montral and we became friends with her boss Glen
Baker. The collaboration between Glen and I is still alive and well and we have published
extensively on the mechanisms of action of antidepressants (13,14). Glen is a very quiet man and
the first to become Chair of a Department of Psychiatry in Canada without being a psychiatrist. He
improved many of my manuscripts, always saying that he had made only a few amendments even
when he edited extensively. I am now sure that when one of my papers is rejected or has major
modifications to be done it is not only because of my poor English.
The story is moving along quickly. Two years ago now, Jacques Bradwejn replaced Yvon
Lapierre in Ottawa as Chairman of the Department. My love story with Canada is still alive, and
every year I send medical or pharmaceutical students to Halifax, Montreal, Ottawa, Edmonton and
Vancouver. Some of them get married there and I am a grandfather of some young French-Canadian
children. On a more serious note, European-American collaboration is easy through Canada even where
people not fluent in French respect the bilinguism and are very tolerant with the language problems; that
as a case in point, I am an Adjunct Professor in the Department of Psychiatry in Edmonton.
Another part of my Academic life began when I joined the European College of
Neuropsychopharmacology as a member of the Executive Committee and Treasurer.
From 1995 until the present I am pleased to work in preparing annual meetings, regional
meetings and the future of the College, but as well as my work for the CINP I am on the Education
Committee of ECNP giving me the opportunity to teach in several countries (Vietnam, Turkey,
Poland, etc.). These ECNP tasks gave me the opportunity to work with several friends including
Stuart Montgomery.
4
I met Stuart at the 25
th
ACNP meeting in Washington D.C. where there were no more than half
a dozen Europeans. Stuart and I discovered that we had a summer house in the South of France close to
Beziers and Narbonne. We had the opportunity to discuss our fields of interest. Stuart was well known
as the originator of the MADRS scale and coordinated numerous clinical trials in Europe. I started
working with him by starting with my own network of 25 psychiatrists and 60 general practitioners in
the Nantes area. Our personal links have grown when meeting in the South, and recently Stuart and
Deirdre bought a house in our village of Capestang on the bank of Le Canal du Midi.
Returning to science, I was surprised when patients referred to me, told me that small doses
of benzodiazepines taken as an hypnotic did not help them to sleep but rather to feeling better in the
morning. I got the idea after checking several of these patients, mainly intellectual people, that there
was something behind it. Afterwards I successively performed studies in healthy volunteers
showing first that even with only a few volunteers it was possible to see differences between drug
and placebo. In two other studies, I clearly showed that lorazepam, 0.25 mg twice a day, and
alprazolam, 0.125mg, twice a day, improved the performance in these healthy volunteers (15,16).
One reviewer claimed that it was not a huge increase after one week, but to be able to increase the
performance of well-trained medical students between 5 to 12 % is not so bad. The world record for
the 100 m run is never improved 5 % in any one attempt!
So, from behavioural psychopharmacology in rodents to psychometry in humans as well as
through drug evaluations in patients, I still try to improve the understanding of psychiatric
pathology using drugs as tools.
Psychopharmacology was for me a real chance to meet many excellent people who
impressed me often by their modesty and generosity.
My last collaboration is now closer to Nantes than the previous one. I have extended my
way of thinking by working with a young French researcher, Alain Gardier, in the field of
microdialysis to improve our knowledge using knockout mice (difficult to work with in the field of
behaviour) (17). Thus the beginning of the new century I have begun as well to work on
behavioural disorders in Alzheimer disease not only because of my own ageing but because I think
that there is so much exciting progress to be made in the field of neurodegenerative disorders.
I have now been for the last sixteen years head of research of Psychopharmacology (EA
3256 Neurobiology of Anxiety and Depression) as well as Professor of Pharmacology at the
University of Nantes where I teach medical students. The objective of my hospital is to join under
the same roof behavioural psychopharmacology and clinical pharmacology including
pharmacovigilance. It will be my greatest achievement to give my colleague and probable successor
Professor Pascale Jolliet, the means to develop psychopharmacology. Another goal involves Gilles
Fillion, who retired in 1999 from the Pasteur Institute in Paris, and who now joins me, to develop
5
antagonists of 5-HT modulin as psychotropic drugs in the field of depression and anxiety disorder
(18). This new story will be part of the last years of my academic career but occur perhaps outside
University, in a socalled start up. It would allow one the possibility to contribute in developing
my own drugs and to involve myself in what is the huge gap between preclinical and clinical
pharmacology.


References
1. Bourin M, Breteau M., 1979 Acute overdosage with benzodiazepine derivatives. Toxicol.
Eur. Res., 2, 163-167.
2. Bourin M., 1979 Peut-on, l'aide de tests pharmacologiques simples, prvoir l'activit
d'un antidpresseur ? Thse de Doctorat en Mdecine, Tours.
3. Rational Use of Benzodiazepine. WHO document, PSA, 96-11.
4. Bourin M, Gold F, Breteau M, Laugier J., 1980 Concentrations du phnobarbital dans le
cerveau, le liquide cphalorachidien et le sang de nouveau-ns. Nouv. Presse Md., 9, 386.
5. Redrobe JP, MacSweeney CP, Bourin M., 1996 The role of 5-HT
1A
and 5-HT
1B
receptors
antidepressant drug actions in the mouse forced swimming test. Eur J. Pharmacol., 368,
213-220.
6. Redrobe JP, Bourin M., 1997 Partial role of 5-HT
2
and 5-HT
3
receptors in the activity of
antidepressants in the mouse forced swimming test. Eur. J. Pharmacol., 325, 129-135.
7. Bourin M, Bradwejn J, Vasar E, Palmour R., 1993 CCK provocation as a research tool in
panic disorder. Eur. Neuropsychopharmacol., 3, 253-256.
8. Bradwejn J, Koszycki D, Payeur R, Bourin M, Borthwick H., 1992 Replication of action
of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings. Am. J.
Psychiat., 149, 962-964.
9. Bradwejn J, Koszycki D, Bourin M., 1991 Dose ranging study of the effects of
cholecystokinin in healthy volunteers. J. Psychiatr. Neurosc., 16, 91-95.
10. Bradwejn J, Legrand JM, Koszycki D, Bates J, Bourin M., 1998 Effects of
cholecystokinin tetrapeptide on respiratory function in healthy volunteers. Am. J. Psychiat.,
155, 280-282.
11. Vasar E, Lang A, Harro J, Kks S, Volke V, Sihver S, Mnnist PT, Bourin M, Bradwejn J.,
1994 Subdiaphragmatic vagotomy does not prevent the antiexploratory effect of coerulein
in the elevated plus maze. Neuropeptides, 26, 39-45.
12. Volke V, Koks S, Vasar E, Bourin M, Bradwejn J, Mnnist P., 1995 Inhibition of nitric
oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze. Neuroreport, 6,
1413-1416.
6
13. Bourin M, Redrobe JP, Baker G., 1998 Pindolol does not act only on 5-HT
1A
receptors in
augmenting antidepressant activity in mouse forced swimming test. Psychopharmacology,
136, 226-234.
14. Bourin M, Hascot M, Colombel MC, Redrobe JP, Baker GB., 1996 Differential effects
of clonidine, lithium and quinine in the forced swimming test in mice for antidepressants:
possible roles of serotoninergic systems. Eur. Neuropsychopharmacol., 6, 231-236.
15. Bourin M, Colombel MC, Malinge M., 1995 Lorazepam 0.25 mg twice a day improves
aspects of psychometric performance in healthy volunteers. J. Psychopharmacol., 9, 251-257.
16. Bourin M, Colombel MC, Guitton B., 1998 Alprazolam 0.125 mg twice a day improves
aspects of psychometric performance in healthy volunteers. J. Clin. Psychopharmacol., 18,
364-372.
17. Malagie I, Trillat AC, Bourin M, Jacquot C, Hen R, Gardier AM., 2001 5-HT
1B

autoreceptors limit the effects of selective serotonin reuptake inhibitors in mouse
hippocampus and frontal cortex. J. Neurochemistry, 76, 865-871.
18. Bentue-Ferrer D, Rousselle JC, Massot O, Bourin M, Allain H, Fillion G., 1998 5-HT
moduline, a 4-HT
1B/1D
receptor endogenous modulator, interacts with dopamine release
measured in vivo by microdialysis. Eur. J. Pharmacol., 358, 129-137.

















7


NICOTINIC RECEPTORS
M. Bourin
Group of Research Neurobiology of Anxiety and Depression
Faculty of Medicine, Nantes, France



Introduction
Nicotinic receptors were the first receptors to be isolated and purified, well before other
receptor types. In fact, the electricity-producing organ of the electric eel is composed of a mass of
electrical cells that originate from embryonic tissue identical to that of skeletal muscle, which is rich
in nicotinic receptors.
The characterization of cholinergic receptor subtypes was initially based on the
pharmacologic activity of two alkaloids, nicotine and muscarine. The receptors were classified well
before the chemical structures of these natural agonists were determined. The great differences in
antagonist activity (atropine on muscarinic receptors and d-tubocurarine on nicotinic receptors)
made it possible to deduce the existence of many receptors. Subsequently it was proven that not all
nicotinic receptors are identical. Thus, we distinguish between the nicotinic receptors of
neuroneuronal synapses, the nicotinic receptors found at the myoneural junction, and the receptors
of the central nervous system (CNS).

Structure of the nicotinic receptor
Nicotinic receptors are composed of 5 subunits, arranged around a pseudo-axis of symmetry.
They belong to the group of polymeric receptors of the cell membrane that have an ion channel
(transmembrane glycoprotein hetero-oligomer). In addition to nicotinic receptors, this group
includes type A -aminobutyric acid (GABA-A) receptors, 5-HT
3
serotonin receptors, the glycine
receptor, and excitatory amino acid receptors. Nicotinic receptors are key elements in cholinergic
transmission, which includes the myoneural junction of striated muscles, the ganglionic synapses of
the peripheral autonomic system, or the different regions of the brain.
The 5 subunits of the nicotinic receptor include 2 subunits and 1 , , and subunits (see
Figure 1). The genes of the various subunits are carried on different chromosomes. Thus, the
receptor is a pentamer with a molecular weight of approximately 280,000. Under an electron
microscope, it is visible as a rosette-shaped transmembrane protein 11 nm in length and 8 nm in
diameter. The central cavity is an ion channel that is permeable to ions when at rest. Its diameter is
approximately 6.5 angstroms.
8

Figure 1. Sagittal section of a nicotinic receptor
A wide variety of nicotinic receptor subtypes exists, owing to the diversity of the genes that
encode the receptor subunits. Sixteen genes encoding the subunits (
1
to
9
,
1
to
9
, , and ) are
derived from a common ancestor that has been cloned in vertebrates. Only the subunits have a
cystine bridge between the cysteine residues of the extracellular N-terminal domain. However, the
subunits have several common structural traits. For example, a large N-terminal domain, 4 putative
transmembrane sequences (M1-M4), an intracellular loop of variable length depending on the subunit,
connecting to the third and fourth transmembrane domain (which is very important for receptor
regulation), and a short extracellular C-terminal sequence comprise each subunit (Figure 2).

Figure 2. Transmembrane organization of a nicotinic receptor subunit

Analysis of subunit amino acid sequences indicates that the nicotinic receptors may be divided
into 3 subfamilies. The first group is composed of the skeletal muscles and the electricity-producing
organ of the electric eel, which consists of
1
,
1,

1,
and
1
in the fetal form and
1
,
1,
, and
1
in
9
the mature form. These nicotinic receptors are selectively recognized and blocked by the -
bungarotoxin isolated from cobra venom. The neuronal nicotinic receptors also have a pentameric
structure formed from the combination of
2,

3,

4,
and

6
with
2
or
4
subunits and occasionally

5
or
3
subunits. The third subfamily is composed of nicotinic receptors that bind to -
bungarotoxin and are formed by the
7
,
8
, or
3
subunits. The acetylcholine binding site is located
in the extracellular N-terminal domain of the interface between the subunits and the other types of
subunits. Currently, receptor classification is based on the pharmacologic properties of the various
subunits, depending on the structural characteristics of each complex (essentially and ).
Of the numerous subtypes of nicotinic receptors that are expressed in mammalian brains,
types
4
-
2
and
7
are encountered most often. They are both pre- and postsynaptic (Albuquerque
et al., 1996; Alkondon et al., 1999). The
7
receptor subtype has different properties from the
4
-
2

receptor (ie, greater sensitivity to Ca
++
ions as well as very rapid desensitization, and activation by
choline and blocking by -bungarotoxin) (Figure 3). Due to its sensitivity to choline, the
7

receptor can be chemically excited, even after acetylcholine has been split by cholinesterases. The

7
receptor can thus also respond not only to synaptic events, but also to the volume change in
concentration ratios between acetylcholine and choline. Rapid desensitization of the
7
receptor
and an appropriate refractory period may be prerequisites to a delayed response. Due to is
permeability, the
7
receptor may produce metabotropic responses (compare with glutamatergic
receptors) in the excited cell, which include control of transmitter release by Ca
++
as well as
stimulation of gene transcription and protein biosynthesis.

Figure 3. Distribution of subunits in nicotinic receptors according to their location
The initial electrophysiologic studies on the interneurons of the human cerebral cortex have
recently been published (Alkondon et al., 1999). These studies showed that
4
-
2
and
7
nicotinic
receptors are located in the somatodendritic regions of human interneurons and thus demonstrated
10
their capacity to modulate GABA release. This tends to prove that nicotinic receptors might be
involved in the inhibitory and disinhibitory mechanisms of the cortex (Figures 47). In short, the
7

receptor subtypes are essentially presynaptic, generate fast Ca
++
currents, and participate in the
release of glutamate, 5-HT, and acetylcholine. The
4
-
2
receptor subtypes are pre- and
postsynaptic, and participate in the neuronal stimulation induced by acetylcholine.

Figure 4. Diagram of the , , and subtype nicotinic receptor.


Figure 5. Schematic of X Y Z type nicotinic receptor where XY and Z are
1

1


Figure 6. Schematic of the
4
-
2
subtype nicotinic receptor

11

Figure 7. Schematic of the
7
nicotinic receptor

Location of nicotinic receptors
Cerebral cholinergic innervation stems from 5 major regions:
The basal prosencephalon, which innervates the cortex and hippocampus;
The diencephalon, which gives rise to local circuits and innervates the cortex;
The striatum, which also gives rise to local circuits;
The brainstem, which innervates the thalamus, the basal prosencephalon, and the
cerebellar cortex;
The spinal cord, which innervates the cranial muscles and the somatic muscles as well as
the secretory glands;
The system is largely interconnected, leading to the coordination of neuronal excitability
and to different cholinergic subsystems (Mesulam and Geula, 1988; Mesulam et al., 1989; Gotti et
al., 1997). Nicotinic receptors are essentially located in several cortical areas, ie, the periaqueductal
gray matter, the basal ganglia, the thalamus, the hippocampus, the cerebellum, and the retina (Gotti
et al., 1997).
Table 1 lists the nicotinic receptor subunits of several cortical areas.
Table 1. Nicotinic receptor subunits of various cortical areas*
Cortical area Subunit (s)
Cortex o
3
, o
4
, |
2
, and |
4
subunits, which are unequally
distributed among various layers
Hippocampus o
3
, o
4
, o
5
, o
7
, |
2
, |
3
, and |
4
subunits
Auditory cortex o
7
subunits
Retina o
2
, o
5
, o
6
, o
7
, and |
2
subunits
Occipital cortex o
2
, o
3
,

o
4
, o
6
, o
7
, o
8
, |
3
, |
4,
and |
2
subunits
*All of this work was done by Jones et al. (1999) and Vailati et al. (1999).

The subtypes are located pre- and postsynaptically in the nervous system (Gotti et al., 1997;
Wonnacott, 1997). It is possible that nicotinic receptors in the same cerebral regions may be located in
different neuronal domains. Current knowledge about the regional distribution of neuronal subtypes,
12
which is essentially based on in situ hybridization studies, is still insufficient to define the neuronal
circuits in which the nicotinic receptors are involved; more accurate immunolocation of the various
subunits is required. The location of the subunits should also be studied more critically, because it is
becoming evident that this varies in the brains of different animal species. For example, there is no
8

in the human brain, and the
3
and
5
subunits are expressed differently and located in rodent as well
as human brains (Rubboli et al., 1994). Another source of perplexity is the non-neuronal distribution
of the nicotinic receptors that have been found in keratinocytes, muscle cells, lymphoid tissue, and
neurosecretory cells. Their role in these tissues has not been elucidated, but a great number of
hypotheses have been advanced relative to their involvement in disease conditions.

Interactions of nicotinic receptors with other neurotransmitter systems
The brain is an organ of connections; therefore, no one receptor system acts
in isolation from the others, including the nicotinic receptor system. In fact, they provide the
opportunity to demonstrate interactions with other neurotransmitter systems, particularly with
respect to their activity on cognitive functions. Nicotine induces the release of a variety of
neurotransmitters, including acetylcholine, dopamine, noradrenaline, serotonin, and glutamate.

Muscarinic Receptors
Because nicotine stimulates the release of acetylcholine, it can produce effects through
muscarinic receptors. It has been shown that nicotine induces improvement in working memory
performance, which is antagonized by the injection of scopolamine, a specific muscarinic receptor
antagonist (Levin and Rose, 1991).

Dopaminergic Receptors
Very large quantities of nicotinic receptors are found in the dopaminergic nuclei of the
mesencephalon. The administration of nicotine results in an increase in the flow of dopamine in the
striatum and the nucleus accumbens septi (Lichteristeiger et al., 1982); it also increases extracellular
concentrations of dopamine in the cortex (Summers and Giacobini, 1995). Furthermore, the
blocking of D
1
dopaminergic receptors can inhibit the release of acetylcholine, whereas their
stimulation increases cholinergic transmission. The stimulation or the blocking of D
2
dopaminergic
receptors decreases the release of acetylcholine (DiChiara et al., 1994).
The importance of the interactions between nicotinic and dopaminergic receptors with
respect to cognitive functions has been widely documented. For example, dopaminergic substances
can antagonize working memory deficits induced by a surgical lesion in the medial cholinergic
pathway (McGurk et al., 1992). Moreover, agonistic and antagonistic effects on mnemonic
performance have significant interactions with D
1
and D
2
receptors. Injection of a nicotinic receptor
13
antagonist, mecamylamine, into the dopaminergic nuclei of the mesencephalon significantly
decreases working memory in the radial maze test done by rats (Levin et al., 1994). Many other
rodent studies have confirmed the importance of nicotinic receptors in cognitive deficits that
traditionally were thought to be linked to dopaminergic mechanisms. These include attention deficit
disorders in hyperkinetic children and in cases of schizophrenia.

Serotoninergic Receptors
A wide variety of studies using anatomic or pharmacologic lesions in serotoninergic neurons
(5-HT) have revealed interactions with the cholinergic system (Riekkinen et al., 1991). It has also
been shown that a specific 5-HT
3
receptor antagonist, ondansetron, stimulates cortical release of
acetylcholine and thereby improves cognitive performance in rodents and primates (Barnes et al.,
1990). Furthermore, the depletion of serotoninergic neurons by administering
parachlorophenylalanine (PCPA) did not modify the performance of treated animals with respect to
their working memory or their passive avoidance behavior. However, the 5-HT depletion induced
by PCPA worsened the decrease in working memory induced by mecamylamine (a nicotine
receptor antagonist) and decreased nicotine-induced performance in a standard memory test in rats
(the Morris test, a water maze test). However, injecting PCPA does not exacerbate the cognitive
deficit caused by scopolamine in elderly subjects (Little et al., 1995), but administering
m-CPP, a 5-HT
1B
receptor agonist/antagonist, exaggerates the mnemic deficit induced by
scopolamine in elderly subjects. Thus, an interaction between the 5-HT system and the central
cholinergic system exists, with no absolute proof that the nicotinic system is involved.

Noradrenergic Receptors
Intracerebroventricular administration of nicotine increases the concentration of
noradrenaline in gray matter, the cingulate cortex, and the pontine nuclei (Toth et al., 1992). High
doses (0.4 and 1.2 mg/kg) of nicotine injected subcutaneously increase the release of noradrenaline
in the cortex (Summers and Giacobini, 1995) and the hippocampus (Brazell et al., 1991). The
increased release of hippocampal noradrenaline is apparently linked to the cell bodies of
noradrenergic neurons located in the locus ceruleus (Mitchell et al., 1990). In addition to nicotine
itself, nicotinic agonists such as epibatidine and lobeline increase the concentration of noradrenaline
in the hippocampus (Sershen et al., 1997). However, no interaction between nicotine and
noradrenaline has been demonstrated in memory tests.

14
Glutamate Receptors
Electrophysiologic studies have shown that glutamate release is stimulated by the
administration of nicotine (McGehee et al., 1995).
In contrast, administering a glutamatergic antagonist, kynurenic acid, blocks glutamate release
induced by nicotine (Toth et al., 1992). This antagonist is also capable of blocking dopamine release
induced by nicotine, thereby suggesting that dopamine release is probably a consequence of glutamate
release. Furthermore, behavioral studies have shown that nicotine attenuates the amnestic effects of
dizocilpine, an NMDA-type glutamatergic receptor antagonist, which causes mnemic deficits in both
working memory and reference memory in behavioral tests in animals (Levin and Bettegowda, 1997).

Other Neurotransmitters and Hormonal Systems
Other neurotransmitter systems, such as those of GABA, opioids, and histamine, may also be
involved in nicotinic effects on cognitive function. Nicotine may cause a transient increase in the
release of GABA in gray matter and the globus pallidus (Kayadjamian et al., 1994), as well as amino
acids such as glycine and taurine. Furthermore, nicotine significantly decreases cerebral
concentrations of substance P. It has been shown that the mnemonic improvements that occur with
administration of lysinevasopressin can be blocked by pretreatment with a central nicotinic receptor
antagonist, mecamylamine, but not by a peripheral receptor antagonist such as hexamethonium
(Faiman et al, 1988). These results suggest a correlation between nicotinic effects and brain
neuropeptides (Sershen et al, 1987). Nicotine also stimulates the release of cortisol (Pauly et al, 1992).

Functions of the nicotinic receptor
It has been known for decades that nicotinic receptors play an important role in ganglionic
transmission and control autonomic nervous system functions (Asher et al., 1979); however, their
role in the brain is still poorly understood. We know that nicotinic receptors are involved in
complex and varied cognitive functions such as attention, learning, memory consolidation, arousal,
and sensory perception, but also in the control of locomotor activity, pain perception, and body
temperature (Gotti et al., 1997). Most of these data originate from behavioral studies using nicotine
and nicotinic receptor antagonists in humans, animals, and disease models that include nicotinic
denervation (ie, degenerative diseases). It is generally thought that the majority of these effects
are due to presynaptic nicotinic receptors, which modulate the release of numerous
neurotransmitters (see above). However, postsynaptic receptors also play important roles, as
demonstrated by their control of ganglionic transmission and fast cholinergic transmission in the
hippocampus and sensory cortex (Jones et al., 1999).

15
Experimental data indicate that different subtypes of nicotinic receptors are involved in the
different functions described above. Ganglionic transmission is essentially regulated by the
3
(
5
)
4

subtype, and gene deletion of
3
and
2
induces a phenotype correlated with a decrease in ganglionic
transmission (Xu et al., 1999). Pain control is essentially exerted by
4
and
2
subtypes (Marubio et
al., 1999). The release of dopamine by dopaminergic neurons is partially controlled by a subtype that
contains the
4
subunit (but also possibly the
6
subunit) (Wonnacott et al., 1997), whereas glutamate
release is dependent on the
7
subtype (Radcliffe et al., 1999). The
2
subtype in mice is important
with respect to control of presynaptic GABA release (Lu et al., 1998) and the response to nicotine of
mesencephalic dopaminergic neurons. The
3
subtype may control motor activity through the
intermediary of dopamine release in the striatum and other areas of the CNS where receptors
containing the
3
subunit are expressed at the presynaptic or preterminal levels of the neurons.
Nicotinic receptors also appear to be involved in neuronal survival. For example, elderly
mice whose
2
subunits have been eliminated by genetic selection (
2
knocked-out mice)
demonstrate hypotrophy of the neocortex, loss of hippocampal neurons, and astrogliosis and
microgliosis (resembling a neurodegenerative disease). The functional correlate of these
histopathologic changes is the fact that the animals lose spatial learning abilities (Xu et al., 1999).
These observations appear to correlate well with epidemiologic data showing that chronic
stimulation of nicotinic receptors by the use of tobacco provides protection from the development of
Parkinson's disease (Baron, 1996). Furthermore, in vitro studies have shown that exposure to
nicotine protects cultured neurons from neurotoxicity induced by various agents. It is possible that
nicotinic receptors participate more generally in brain development, as they are expressed very early
in fetal life (Court et al., 1997), and their involvement in axonal growth (Pugh and Berg, 1994)
suggests that they may be involved in forming and maintaining the integrity of the neuronal circuit.
The central role of nicotinic receptors in the physiology of the brain is confirmed by the fact that the
expression of the various subunits is regulated during development.

Nicotinic receptors and disease
Many autoradiographic and histochemical proofs from autopsy tissue (Perry et al., 1995), as
well as radiographic images from patients, now show that the loss of nicotinic receptors is
correlated with the severity of Alzheimer's disease (AD) (Nordberg et al., 1995). However, other
recent studies indicate that nicotinic receptor subtypes may be involved in certain other diseases.
For example, nocturnal frontal lobe epilepsy is due to a mutation of the subunit that decreases the
function of
4

2
receptor subtypes (Kuryatov et al., 1997). The decrease in the sensation threshold
in schizophrenics appears to be correlated with abnormal expression of the
7
subunit (Freedman et
al., 1997). In patients with AD, it is the
4
subunits that appear to be the most affected. Although
16
the number of receptors containing the
3
subunit remain unchanged, it is not clear whether or not
there is a decrease in the number of receptors with a
7
subunit (Wevers et al., 1999).
A recent study gives another dimension to the importance of nicotinic receptors. In fact, it
shows that the -amyloid peptide (1-42) in rats directly modulates nicotinic receptors (Pettit et al.,
2001). Researchers found that this -amyloid peptide inhibits the entire cell as well as the nicotinic
currents of hippocampal interneurons by blocking the ion channels of the nicotinic receptors
at extremely low concentrations (100 nm). This inhibition appears to be specific to the peptide
sequence, and its amplitude depends on the receptor subtype expressed. Therefore, chronic
inhibition of these receptors by the -amyloid peptide could explain the cognitive deficits of AD.
Another important aspect from the physiopathologic perspective is the dependence induced by
nicotine, knowing that there are nicotinic receptors at the level of the presynaptic terminals of
dopaminergic neurons in the nucleus accumbens septi. As with other addictive substances, there
may be a very strong relationship with the pleasure neurotransmitter, dopamine.

Modulation of o
7
receptor subtype activity by allosteric ligands
The activity of many channel receptors, such as nicotinic receptors, is subject to modulation
by ligands other than the natural agonist. There are two well-known examples: the modulation of
the NMDA glutamatergic receptor by glycine (Scatton, 1993) and of the GABA-A receptor by
benzodiazepines and steroids (McDonald and Twyman, 1992). The existence of such an allosteric
modulation site on
7
nicotinic receptors has recently been demonstrated (see Figure 8).


Figure 8. Schematic of the nicotinic ACh (acetylcholine), LA (local anesthetic),
steroid, and arachidonic acid (ARA) receptors.

17
Molecules such as galantamine, physostigmine, and codeine can facilitate the action of
acetylcholine on nicotinic receptors. This modulation allows each acetylcholine molecule to better
bind to the subunits of the nicotinic receptor and also facilitates the release of acetylcholine (when
the stimulated receptor is presynaptic). Because nicotinic receptors are also present on the
presynaptic terminals of several other neurotransmitters, this modulating action induced by
galantamine (or other modulators) causes the release of other neurotransmitters.
As previously discussed, one of the most important cholinergic deficits in AD consists of the
decrease in the number of nicotinic receptors in the hippocampus and the cortex. This deficit is the
result of a decrease in the sensitivity of these receptors to acetylcholine, which therefore alters not
only postsynaptic depolarization but also the presynaptic release of acetylcholine as well as entry of
Na
+
into the cells. At present, the most common approach to treating cholinergic deficit in AD is
the use of cholinesterase inhibitors, which decrease the metabolism of acetylcholine in synapses.
Consequently, a greater number of muscarinic and nicotinic receptors can be activated. One of the
allosteric modulators of nicotinic receptors is galantamine. Nicotinic allosteric modulation of
galantamine is similar to the allosteric modulation of benzodiazepines on GABA-A receptors.
Furthermore, the action of galantamine on human nicotinic receptors has been demonstrated in
electrophysiologic studies using thin layers of human brain (Alkondon et al., 2000). All 3 subtypes
of human nicotinic receptors are sensitive to galantamine activity, but especially the
7
and
4

subtypes.
Of the allosteric modulators of nicotinic receptors, only galantamine is also a cholinesterase
inhibitor. This effect has been demonstrated in both rat and human studies (Maelike and
Albuquerque, 2000). These 2 pharmacologic properties of galantamine are interesting with respect
to treating AD, inasmuch as there are 2 potential targets (ie, decrease in the sensitivity of nicotinic
receptors and cerebral cholinergic deficit). Therefore, it is conceivable that galantamine activity
could result in an increase in the number of expressed receptors (Perry et al., 1995) and a decrease
in the speed of neurodegeneration due to the protection of nicotinic receptors against the -amyloid
protein, which also induces neuronal death (Pettit et al., 2001; Wang et al., 2000). In conclusion,
there is an important potential for therapeutic applications linked to nicotinic receptors in the near
future, not only in the particular areas of cognition and attention, but also in antineurodegenerative
activity (Rusted et al., 2000).

Brief summary
Nicotinic receptors, one of the first receptor types to be isolated and purified, belong to the
group of polymeric receptors of the cell membrane and are key elements of cholinergic
transmission. Numerous subtypes of nicotinic receptors exist, with the
4
-
2
and
7
types
18
encountered most frequently. The nicotinic receptor system interacts with other neurotransmitter
systems and induces the release of a variety of neurotransmitters, including acetylcholine,
dopamine, noradrenaline, serotonin, and glutamate. Deficiencies in nicotinic receptors play a role in
many diseases, including Alzheimer's disease. Allosteric modulators of nicotinic receptors, such as
the cholinesterase inhibitor galantamine, can facilitate the action of acetylcholine on nicotinic
receptors and may provide therapeutic benefits in the areas of cognition, attention, and
antineurodegenerative activity.


References
1. Albuquerque EX, Alkondon M, Pereira EF, et al, 1996 Properties of neuronal nicotinic
acetylcholine receptors, pharmacological characterization and modulation of synaptic
function. J Pharmacol Exp Ther 280, 1117-1136.
2. Alkondon M, Pereira EFR, Cortes WS, et al, 1997 Choline is a selective agonist
of o
7
nicotinic acetylcholine receptors. Eur J Neurosci 9, 2734-2742.
3. Alkondon M, Pereira EFR, Eisenberg HM, et al, 1999 Choline and selective antagonists
identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release
from CA1 interneurons in rat hippocampal slices. J Neurosci 19, 2693-2705.
4. Alkondon M, Pereira EFR, Eisenberg H, et al, 2000 Nicotinic receptor activation
in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of
neuronal networks. J Neurosci 20, 66-75.
5. Asher P, Large WA, Rang HP, 1979 Studies on the mechanism of action of acetylcholine
antagonists on rat aparasympathetic ganglion cells. J Physiol 155, 372-384.
6. Barnes JMC, Coughlan J, Domeney AM, et al, 1990 The effects of ondansetron, a
5-HT
3
receptor antagonist, on cognition in rodents and primates. Pharmacol Biochem
Behav 35, 955-962.
7. Baron JA, 1996 Cigarette smoking and Parkinson's disease. Neurology 36, 1490-1496.
8. Brazell MP, Mitchell SN, Gray JA, 1991 Effects of acute administration of nicotine on in
vivo release of noradrenaline in the hippocampus of freely moving rats: a dose-response
and antagonist study. Neuropharmarmacology 30, 823-833.
9. Court JA, Llyod S, Johnson M, et al, 1997 Nicotinic and muscarinic cholinergic receptor
binding in the human hippocampal formation during development and aging. Dev Brain
Res 101, 93-105.
10. DiChiara B, Morelli M, Consolo S, 1994 Modulatory functions of neurotransmitters in
the striatum: Ach/dopamine/NMDA interactions. Trends Neurosci 17, 228-233.
19
11. Faiman CP, de Erausquin GA, Baratti CM, 1988 Vasopressin modulates the activity of
nicotinic cholinergic mechanisms during memory retrieval in mice. Behav Neural Biol 50,
112-119.
12. Freedman R, Coon H, Myles-Worsley M, et al, 1997 Linkage of a neurophysiological
deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94, 587-592.
13. Gotti C, Fornasari D, Clementi F, 1997 Human neuronal nicotinic receptors. Prog
Neurobiol 53, 199-237.
14. Jones S, Sudweels S, Yakel JL, 1999 Nicotinic receptors in the brain: correlating
physiology with function. Trend Neurol Sci 22, 555-561.
15. Kayadjanian N, Retaux S, Menetrey A, et al, 1994 Stimulation by nicotine of the
spontaneous release of [
3
H]-aminobutyric acid in the substantia nigra and in the globus
pallidus of the rat. Brain Res 649, 129-135.
16. Kuryatov A, Gerzanich V, Nelson M, et al, 1997 Mutation causing autosomal dominant
nocturnal frontal lobe epilepsy alters Ca
2+
permeability, conductance, and gating of human

4

2
nicotinic acetylcholine receptors. J Neurosci 17, 9035-9047.
17. Le Novre N, Changeux JP, 1995 Molecular evolution of the nicotinic acetylcholine
receptor: an example of multigene family in excitable cells. J Mol Evol 40, 155-172.
18. Levin ED, Bettegowda C, 1997 Nicotinic-NMDA interactions with working and
reference memory. Soc Neurosci Abstr 23, 216.
19. Levin ED, Briggs SJ, Christopher NC, et al, 1994 Working memory performance and
cholinergic effects in the ventral tegmental area and substantia nigra. Brain Res 657, 165-170.
20. Levin ED, Rose JE, 1991 Nicotinic and muscarinic interactions and choice accuracy in
the radial-arm maze. Brain Res Bull 27, 125-128.
21. Lichtensteiger W, Hefti F, Felix D, et al, 1982 Stimulation of nigrostriatal dopamine
neurons by nicotine. Neuropharmacology 21, 963.
22. Little JB, Martin A, Hill JL, et al, 1995 Serotonergic modulation of anticholinergic effects
on cognition and behavior in elderly humans. Psychopharmacology 120, 280-288.
23. Lu Y, Grady S, Marks MJ, Picciotto M, et al, 1998 Pharmacological characterization of
nicotinic receptor-stimulated GABA release from mouse brain synaptosomes. J Pharmacol
Exp Ther 8, 648-657.
24. Maelicke A, Alburquerque EX, 2000 Allosteric modulation of nicotinic acetylcholine
receptors as a treatment strategy for Alzheimer's disease. Eur J Pharmacol 393, 165-170.
25. Marubio LM, del Mar Arroyo-Jimenez M, Cordero-Erausquin M, et al, 1999 Reduced
antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398, 805-810.
20
26. McDonald RL, Twyman RE, 1992 Kinetic properties and regulation of GABA
A
receptor
channels. Ion Channels 3, 315-343.
27. McGehee DS, Heath MJS, Gelber S, et al, 1995 Nicotine enhancement of fast excitatory
synaptic transmission in CNS by presynaptic receptors. Science 269, 1692-1696.
28. McGurk SR, Levin ED, Butcher LL, 1992 Dopaminergic drugs reverse the impairment of
radial-arm maze performance caused by lesions involving the cholinergic medial pathway.
Neuroscience 50, 129-135.
29. Mesulam MM, Geula C, 1988 Nucleus basalis (Ch4) and cortical cholinergic innervation
in the human brain, observation based on the distribution of acetylcholinesterase and
choline acetyltransferase. J Comp Neurol 275, 216-240.
30. Mesulam MM, Geula C, Botwell MA, et al, 1989 Human reticular formation: cholinergic
neurons of the peduncolopontine and laterodorsal tegmental nuclei and some cytochemical
comparison to forebrain cholinergic neurons. J Comp Neurol 281, 611-633.
31. Mitchell SN, Brazell MP, Schugens MM, et al, 1990 Nicotine-induced catecholamine
synthesis after lesions to the dorsal or ventral noradrenergic bundle. Eur J Pharmacol 179,
383-391.
32. Nordberg A, Lundqvist A, Hartvig P, et al, 1995 Kinetic analysis of regional
(S)(-)
11
C-nicotine binding in normal and Alzheimer brains: in vivo assessment using
positron emission tomography. Alzheimer Dis Assoc Disord 9, 21-27.
33. Pauly JR, Grun EU, Collins AC, 1992 Glucocorticoid regulation of sensitivity to nicotine.
In Lippiello PM, Collins AC, Gray JA, Robinson JH (eds): The Biology of Nicotine:
Current Research Issues. New York, Raven Press, 121-137.
34. Perry E, Morris C, Court J, et al, 1995 Alteration in nicotine binding sites in Parkinson's
disease, Lewy body dementia and Alzheimer's disease, possible index of early
neuropathology. Neuroscience 64, 385-395.
35. Pettit DL, Shao Z, Yakel JL, 2001 Beta-amyloid (1-42) peptide directly modulates
nicotinic receptors in the rat hippocampal slice. J Neurosci 21, RC 120.
36. Pugh PC, Berg DK, 1994 Neuronal acetylcholine receptors that bind -bungarotoxin
mediated neurite retraction in a calcium-dependent manner. J Neurosci 14, 889-895.
37. Radcliffe KA, Fisher JL, Gray R, et al, 1999 Nicotinic modulation of glutamate and
GABA synaptic transmission of hippocampal neurons. Ann NY Acad Sci 868, 591-610.
38. Riekkinen PJS, Valjakka A, Miettinen R, et al, 1991 Pharmacological consequences of
cholinergic plus serotonergic manipulations. Brain Res 552, 23-26.
39. Rubboli F, Court JA, Sala C, et al, 1994 Distribution of nicotinic receptors in the human
hippocampus and thalamus. Eur J Neurosci 6, 1596-1604.
21
40. Rusted JM, Newhouse PA, Levin ED, 2000 Nicotinic treatment for degenerative
neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease. Behav
Brain Res 113, 121-129.
41. Scatton B, 1993 The NDMA receptor complex. Fundam Clin Pharmacol 7, 389-400.
42. Sershen H, Balla A, Lajtha A, Vizi ES, 1997 Characterization of nicotinic receptors
involved in the release of noradrenaline from the hippocampus. Neuroscience. 77, 121-130.
43. Sershen H, Hashim A, Lajtha A, 1987 Behavioral and biochemical effects of nicotine in
an MPTP-induced mouse model of Parkinson's disease. Pharmacol Biochem Behav 28,
299-303.

44. Summers KL, Giacobini E, 1995 Effects of local and repeated systemic administration of
(-) nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and
serotonin in rat cortex. Neurochem Res 20, 753-759.
45. Toth E, Sershen H, Hashim A, et al, 1992 Effect of nicotine on extracellular levels of
neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid.
Neurochem Res 17, 265-271.
46. Vailati S, Hanke W, Bejan A, et al, 1999 Functional
6
-containing nicotinic receptors are
present in chick retina. Mol Pharmacol 56, 11-19.
47. Wang HY, Lee DSH, D'Andrea MR, et al, 2000 Amyloid 1-42 binds to
7
nicotinic
acetylcholine receptor with high affinity. J Biol Chem 275, 5626-5632.
48. Wevers A, Monteggia L, Nowacki S, et al, 1999 Expression of nicotinic acetylcholine
receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical
correlation with amyloid plaques and hyperphosphorylated-tau protein. Eur J Neurosci 11,
2551-2565.
49. Wonnacott S, 1997 Presynaptic nicotinic Ach receptors. Trends Neurosci 20, 92-98.
50. Xu W, Orr-Urtreger A, Nigro F, et al, 1999 Multiorgan autonomic dysfunction in mice
lacking the B2 and the B4 subunits of neuronal nicotinic acetylcholine receptors. J Neurosci
19, 9298-9305.






22


ACTUALITI NEUROBIOLOGICE I
PSIHOFARMACOLOGICE N DEMENE
D. Marinescu, T. Udritoiu, A. Miloescu, I. Udritoiu
Clinica de Psihiatrie Craiova


Rezumat
Boala Alzheimer (AD) rmne cea mai frecvent form de demen, dar s-au mai
conturat dou entiti: demena fronto-temporal (FTD) i demena cu corpusculi
Lewy (LBD).
Pentru majoritatea cazurilor de AD se recunoate o transmitere genetic
multifactorial; au fost totui descrise mutaii genetice pe C21 (proteina
precursoare a amiloidului), C14 (presenilina 1) i C1 (presenilina 2). Nu se pot
corela aceste mutaii cu viteza declinului cognitiv, dar exist argumente clinice
pentru implicarea balanei 5-HT/DA.
Sunt discutate principalele direcii terapeutice n AD, de la inhibitorii
acetilcolinesterazei (IACE) i blocarea NMDA, la vaccinul anti-amiloid, blocarea
fosforilrii proteinei tau i inhibiia secretazelor care scindeaz APP n |-amiloid.
n demena fronto-temporal (FTD) nu s-au evideniat anomalii colinergice, deci nu
beneficiaz de tratament cu IACE; SSRI pot ameliora tulburrile comportamentale.
Demena cu corpusculi Lewy asociaz simptome de Alzheimer i boal Parkinson, cu
frecvente manifestri psihotice; rspunde foarte bine la tratament cu IACE i
clonazepam.
Autorii ncearc o clasificare psihofarmacologic a principalelor demene
presenile, cu consecine terapeutice prezente i viitoare, i susin posibilitatea
utilizrii agonitilor D
1
i D
5
.
Cuvinte cheie: demen, neurobiologie, tratament.


NEUROBIOLOGICAL AND PSYCHOPHARMACOLOGICAL
UPDATES IN DEMENTIAS

Abstract
Although Alzheimers disease (AD) remains the most frequent form of dementias, two
more entities have been recently described: the fronto-temporal dementia (FTD) and
the Lewy body dementia (LBD).
Most cases of AD are known to have a plurifactorial genetic transmission: mutations
on C21 (the precursor protein of amyloid), on C14 (presenilin-1 gene) and on C1
(presenilin-2 gene) were found. It is impossible to correlate these mutations with the
rate of cognitive decline, but there are clinical reasons to believe that the 5-HT/DA
balance may be implicated.
We discuss the main therapeutic directions in AD, from the acetylcholinesterase
inhibitors (ACEI) and NMDA blockade to the anti-amyloid vaccine, the blocking of
tau protein phosphorylation and the inhibition of the secretases that cleave APP in
|-amyloid.
In the fronto-temporal dementia (FTD), no cholinergic abnormalities have been
found; thus, ACEI are not effective; SSRI may ameliorate the behavior disturbances.
23
The Lewy body dementia (LBD) expresses symptoms of the Alzheimers disease and
Parkinsons disease and, frequently, psychotic symptoms; it responds very well to the
treatment with ACEI and clonazepam.
We are trying to define a psychopharmacological profile of the main pre-senile
dementias, which may lead to present and future therapeutic benefits and sustain the
possibility of using D
1
and D
5
agonists.
Key words: dementia, neurobiology, therapy.


Demena este o tulburare caracterizat prin deficite cognitive multiple, afectnd memoria,
inteligena, limbajul, rezolvarea problemelor, nvarea, orientarea, percepia, atenia, judecata,
concentrarea i abilitile sociale. Dup DSM-IV-TR, defectul trebuie s reprezinte o schimbare
semnificativ fa de situaia iniial i s interfere funcionarea social.
Demena constituie n primul rnd o boal a vrstnicilor, prevalena fiind estimat de
majoritatea studiilor la 5 % pentru grupa de vrst 65-80 ani i 20-25 % pentru vrsta peste 80 ani.
Odat cu creterea speranei de via, ea devine o problem major de sntate public. Cea mai
frecvent form de demen este, fr ndoial, boala Alzheimer cca. 60 % (Cummings, 1992),
dar noi entiti nosologice s-au clarificat n ultimii ani (demena fronto-temporal, demena cu
corpusculi Lewy), n timp ce alte concepte, ca demena subcortical i demena vascular, ncep s-
i piard din relevan.
Elementul patogenic central n demene este considerat deficitul colinergic i, prin urmare,
orientrile terapeutice au urmat aceast direcie. Cum ns, pe de o parte, speranele n eficacitatea
inhibitorilor acetil-colin-esterazei s-au dovedit exagerate, iar, pe de alt parte, cercetrile recente au
artat i alte mecanisme implicate n demene, aceast atitudine tinde s fie abandonat. Ne
propunem ca pe baza cercetrilor recente de genetic, psihofarmacologie i neuroimagistic, s
stabilim principalele tendine n abordarea problematicii demenelor.

Mutaiile genetice factor de risc n Boala Alzheimer (AD)
Se susine c cel puin 10 % din cazurile cu debut precoce se bazeaz pe o transmitere genetic
autosomal dominant, dup o mutaie punctiform a genei ce codific proteina precursor al amiloidului
(APP) aflat pe C21. Krasuski 2002, evideniaz o asemnare ntre Boala Down (DD) i AD.
Sindromul deficitar din DD este similar fenotipic cu cel din AD, caracterizndu-se iniial prin dificulti
mnezice. n ambele boli, principala disfuncie neurobiologic se afl la nivelul lobului temporal median,
confirmndu-se atrofii la nivelul hipocampului, amigdalei i girului parahipocampic. n ultimul an, au
fost incriminate nc dou defecte genetice: mutaii pe genele ce codific presenilina 1 (PS1) de pe C14
i presenilina 2 (PS2) de pe C1. Aceste trei defecte genetice ar avea ca rezultat o cretere a fragmentului
peptidic | A4 al APP, acesta formnd nucleul plcii amiloide (Holmes, 2002).
24
Majoritatea cazurilor de AD cu debut precoce i practic totalitatea celor cu debut tardiv, au
ns o manier de transmitere poligenic multifactorial, mult mai dificil de investigat dect
paternul simplu mendellian. Studiile de tip linkage constnd n screening genomic complet n
familiile afectate de AD cu debut tardiv au ajuns la rezultate de multe ori contradictorii. Cea mai
puin controversat alel ca factor de risc pentru AD este cea pentru APOE4, ce codific varianta c4
a apolipoproteinei E. Aceast alel modific riscul pentru AD prin dou mecanisme:
1. modificarea proprietilor funcionale ale APOE;
2. diferene cantitative n expresia APOE (Artiga, 1998).

Genotip i fenotip n boala Alzheimer
Mutaiile genetice implicate n transmiterea AD influeneaz n primul rnd vrsta de debut.
Astfel, purttorii mutaiei genei pentru APP de pe C21 au vrsta de instalare a BA ntre 40 i 65 ani.
Cele care transmit mutaia pentru PS1 (C14) au vrsta de debut cea mai mic (35-55 ani, cu un caz
descris la 24 ani) Wisniewski, 1998.
Dei s-a suspectat mult vreme faptul c mutaiile n genele pentru APP, PS1, PS2 i alela
APOE4 ar fi asociate cu o frecven crescut a simptomelor non-cognitive n AD, nu s-a putut
demonstra acest lucru. S-au descoperit n schimb alte corelaii clinice dependente probabil de
mutaiile ce survin la nivelul C14, care implic balana 5-HT/DA:
- frecvena mai mare a simptomelor depresive aprute pentru prima dat n cursul AD la
pacienii din familii cu istoric de tulburare depresiv (Tunstall, 2000);
- prezena halucinaiilor auditive i vizuale asociat mutaiilor genelor pentru receptorii
5-HT
2A
i 5-HT
2C
la pacienii cu AD (Tunstall, 2000);
- agresivitatea n AD asociat cu mutaii ale genelor codoare ale receptorilor D
1
i D
3

(Sweet, 1998).
Nu s-a reuit corelarea ntre viteza declinului cognitiv i vreo mutaie a genelor mai sus
menionate. S-a dovedit ns c purttorii alelei APOE4 au o durat de boal mai lung dect purttorii
mutaiei la gena pentru PS1, la care decesul survine rapid dup debutul bolii (Holmes, 2002).

Noi orientri terapeutice n demene
Nu se poate nega rolul de plac turnant al acetilcolinei n patogenia demenelor. Sintetizat
intraneuronal din colin i acetil-CoA, acetilcolina este degradat n fanta sinaptic, dup ce a
acionat pe receptori, sub aciunea acetil-colin-esterazei la colin i acetat. Neurotransmitorul
acioneaz pe dou tipuri de receptori:
- nicotinici (N1 i N2), localizai cu precdere n locus coeruleus, habenul i nucleul
interpeduncular;
25
- muscarinici (M1, M2, M3, M4, M5), localizai mai ales n cortexul prefrontal, corpii
striai, amigdal, hipocamp, talamus.
Acetilcolina are un rol excitator direct, obiectivabil prin creterea frecvenei descrcrilor
neuronale. Principalele ci de aciune a acetilcolinei sunt:
- calea septo-hipocampic cu nucleul bazal Meynert, unde se descrie jonciunea
multifuncional Ach/DA/NA/5-HT;
- calea habenulo-interpeduncular;
- aferene cerebeloase i amigdaliene;
- structuri interneuronale din striatum.
Rolul excitator al acetilcolinei se exercit mai pregnant n condiiile n care DA, NA i 5-HT
sunt sczute.
Suplinirea neuronilor colinergici insuficieni (distrui cu precdere de ctre depozitele
amiloide ale plcilor neuritice i de ctre aglomerrile neurofibrilare principalele dou mecanisme
patogene n AD) se poate face, fie prin agoniti muscarinici sau nicotinici, fie prin inhibarea acetil-
colin-esterazei. Cum agonitii muscarinici i nicotinici s-au dovedit a avea o fereastr terapeutic
mic, toate speranele s-au pus n inhibitorii acetil-colin-esterazei (IACE).
n prezent, sunt utilizate n tratamentul demenelor trei produse: donepezilul, rivastigmina i
galantamina (ultimul neomologat nc n ara noastr). Analog cu utilizarea levo-dopa n boala
Parkinson, IACE nu ofer dect un tratament simptomatic, cu combaterea unui proces complex ce
duce la scderea acetilcolinei; efectul lor const n scderea ratei de declin cognitiv. Oricum, ele nu
pot fi administrate dect n formele uoare i medii (scor MMSE > 10) i exist o rat mare de
neresponsivitate (cca. 60 %), n prezent necunoscndu-se markerii acesteia.
Implicarea glutamatului n etiopatogenia demenelor a condus la o nou opiune terapeutic:
blocarea N Metil D Aspartatului cu memantin. Rezultatele sunt promitoare i n prezent se fac
ultimele demersuri de omologare (Bullock, 2002).
Descifrarea proceselor patologice implicate n etiologia AD a condus la noi premize pentru
strategii terapeutice. Astfel, descoperirea complexului de atac al complementului n titruri mari
perilezional (McGeer, 1998) a determinat introducerea n tratament a antiinflamatoarelor
nesteriodiene (AINS), inhibitori selectivi ai COX2, cu rezultate promitoare n studiile pe animale.
Observaia c femeile sub terapie hormonal de susinere postmenopauz au o inciden mai
mic a bolii a condus la omologarea tratamentului cu estrogeni ca profilaxie a AD n S.U.A.
(Mullnard, 2000).
S-a demonstrat, de asemenea, c tratamentul cu vitamina E n doze mari (2.000 UI/zi),
singur sau n asociere cu gingko-biloba, nicergolin sau piracetam, scade rata instituionalizrii
bolnavilor cu AD (Sano, 1997).
26
O nou arie de cercetare este ncercarea de blocare a activrii celulelor gliale cu preparate de
genul propentofilinei i de stimularea factorului de cretere neuronal cu derivai xantinici.
Pornind de la baza patogenic a AD se dezvolt n prezent dou alternative terapeutice:
- producerea unui vaccin pe baz de amiloid, care s acioneze ca antigen pentru
anticorpii ce vor distruge plcile amiloide nc de la formare;
- blocarea procesului de fosforilare n exces a proteinei tau.
Proteina tau cuprinde un grup de 6 subtipuri peptidice ce stabilizeaz microtubulii neuronali,
asigurnd astfel supravieuirea neuronului, prin susinerea structurilor vitale de transport. Gena ce
codific proteina tau se afl pe C17 i mutaii ale ei au fost implicate n aa-zisele tauopatii
(demena fronto-temporal, degenerarea cortico-bazal, paralizia supranuclear progresiv, scleroza
lateral amiotrofic). Fosforilarea sa n exces este implicat n patogenia demenelor.
Nobuyuki 2002, susine c nivelul proteinei tau n LCR este direct proporional cu
numrul neuronilor distrui. Combinnd msurtorile nivelului proteinelor tau din LCR i a fluxului
sanguin cerebral (CBF) regional se poate determina un indicator de predicie al evoluiei spre AD a
deficitului cognitiv uor la pacienii n vrst. Cea mai evident diminuare a CBF este la nivelul
cortexului cingulat posterior.
Se cunoate, de asemenea, c producerea aberant de APP, ce stimuleaz sinteza i
agregarea amiloidului n creier, este factorul cheie n patogenia AD. Scindarea APP n amiloid
se face sub aciunea a dou enzime: secretaza i secretaza. Activitatea acesteia din urm este
reglat de PS1 i PS2. Mutaia situsurilor active ale PS1 (obinut experimental la oareci) a generat
o scdere de 5 ori a produciei de amiloid. n prezent, se ncearc descoperirea unor medicamente
care s inhibe activitatea secretazei i a secretazei (Lyons, 2002).

Demena fronto-temporal (FTD)
Reprezint 20 % din totalul demenelor presenile, fiind a doua form de demen la pacienii
de vrst mijlocie. Durata de evoluie este similar AD (2-20 ani, cu o medie de 8 ani). Dei att n
ICD-10 ct i n DSM-IV-TR, este categorie nosologic separat, boala Pick a fost recent inclus n
grupul demenelor fronto-temporale (FTD), n cadrul cruia formeaz o minoritate.
Trstura clinic definitorie a FTD const ntr-o profund alterare a personalitii i
comportamentului social, cu tocire afectiv i pierderea precoce a insight-ului (Snowden, 2002).
Macroscopic, se descrie o atrofie bilateral frontal i temporal anterioar, nsoit de
degenerarea striatului. Histologic, se descriu trei tipuri de modificri:
- degenerare spongiform n urma pierderii neuronilor mari (leziuni microvacuolare), fr
glioz 60 %;
27
- modificri de tip Pick (pierderi neuronale masive, nsoite de glioz) predomin n
sistemul limbic i striat 25 %;
- leziuni microvacuolare, coexistnd cu leziuni de scleroz lateral amiotrofic (SLA) 15 %.
n toate cele trei tipuri de modificri, neuronii afectai sunt pozitivi pentru protein tau
anormal fosforilat i ubiquitina (Snowden, 2002).
Au fost descrise trei forme clinice:
- dezinhibat dezinhibiie, hiperactivitate, distractibilitate, inadecvan social;
- cu apatie apatie, inerie, hipobulie, fatigabilitate mental;
- cu stereotipii comportamentale de la manierisme pn la ritualuri superstiioase
complexe; este frapant lipsa de preocupare i de reacie emoional fa de aceste
comportamente.
Cum n acest grup de demene nu s-au evideniat anomalii n sistemul colinergic, singurul
afectat fiind cel serotoninergic, FTD nu beneficiaz de tratament cu IACE. SSRI amelioreaz n
msur variabil tulburrile comportamentale.

Demena cu corpusculi Lewy (LBD)
Este o form frecvent de demen (15-20 % din btrnii instituionalizai), mult
subdiagnosticat n prezent, care asociaz ca trstur definitorie simptomele bolii Alzheimer i ale
bolii Parkinson.
Corpii Lewy sunt inclutiuni neuronale formate din proteine neurofilamentare anormal
fosforilate, agregate cu ubiquitin i sinucleina. Se ntlnesc n substantia nigra din trunchi cu
deficit dopaminergic, n nucleul bazal Meynert cu deficit colinergic, n regiunile hipocampice CA2
i CA3, n nucleul dorsal al vagului i n cortexul transentorinal. Plcile amiloide sunt similar
reprezentate ca n boala Alzheimer, dar aglomerrile neurofibrilare lipsesc. Neuroimagistic, se
observ o cruare a lobilor temporali mijlocii, ceea ce poate constitui un element de diagnostic
diferenial cu AD.
Pacienii prezint frecvent simptome psihotice (halucinaii vizuale complexe sau deliruri
sistematizate), dar datorit unei sensibiliti neuroleptice generate de deficitul dopaminergic important,
nu este posibil tratarea lor cu antipsihotice (nici mcar risperidon sau olanzapin). Pe de alt parte,
datorit faptului c neuronii muscarinici corticali sunt intaci, pacienii cu LBD rspund remarcabil la
IACE. Se observ att ameliorri ale performanelor cognitive, ct i regresia simptomelor psihotice.
Unii autori au sugerat chiar c, dac un pacient diagnosticat cu AD rspunde foarte bine la IACE, este
mai probabil diagnosticul de LBD. Tulburrile de somn rspund bine la clonazepam.


28
Corelaii ntre psihofarmacologia demenelor i tratamentul difereniat
O posibil clasificare psihofarmacologic a principalelor tipuri de demen primar ar putea fi:
- demen prin deficit colinergic demena Alzheimer (deficitul noradrenergic raportat n AD
nu pare a avea rezonan clinic); n schimb, se poate susine i o alterare a echilibrului
Ach/DA, deficitul cognitiv putnd fi ameliorat de agoniti ai receptorilor D
1
i D
5
;
- demene prin deficit serotoninergic demenele fronto-temporale; studiile recente
(Sheline, 2002), evideniaz o diminuare semnificativ a numrului receptorilor 5-HT
2A

odat cu naintarea n vrst, cu scderea dramatic a funciei serotoninice, n special la
nivelul hipocampului i cortexului prefrontal;
- demen prin deficit mixt (colinergic i dopaminergic) demena cu corpi Lewy.
Principala variant terapeutic n momentul actual, att pentru AD ct i pentru LBD, o
reprezint IACE, cu un rspuns net mai bun n cazul LBD. n plus, LBD i AD ar putea beneficia i
de o alt alternativ terapeutic, puin explorat n prezent, i anume agonitii dopaminergici. n
ceea ce privete FTD, acest grup nu beneficiaz de IACE, sistemul colinergic fiind practic intact.
Deficitul de serotonin rspunde n msur variabil la SSRI.
Cum demenele devin o problem de sntate tot mai important odat cu creterea speranei
de via, iar cercetrile sunt abia la nceput, se poate spera c aceast problem i va gsi, n anii ce
vin, o rezolvare ct mai satisfctoare prin abordare terapeutic difereniat.


Bibliografie selectiv
1. Artiga, M.J., Bulido, M.J., Frank, A., 1998 Risk for Alzheimers disease correlates with
transcriptional activity of the APOE gene. Human Molecular Genetics, 7, 1887-1892.
2. Bullock, R., 2002 New drugs for Alzheimers disease and other dementias. Brit. J.
Psychiat., 180, 135-139.
3. Cummings, J.L., Benson, D.F., 1992 Dementia: a clinical approach. 2
nd
Edition, Butter
Worths, London.
4. Holmes, C., 2002 Genotype and phenotype in Alzheimers disease. Brit. J. Psychiat., 180,
131-133.
5. Krasuski, J.S., Alexander, G.E., 2002 Relation of medial temporal lobe volumes to age
and memory function in nondemented adults with Downs syndrome: implications for the
prodromal phase of Alzheimers disease. Am. J. Psychiat., 159, 74-81.
6. Lyons, D., McLoughlin, D.M., 2002 Identificarea secretazei i a secretazei n boala
Alzheimer. BMJ, ediia n limba romn, vol. 9, 1, 32-33.
7. McGeer, P.L., McGeer, E.G., 1998 Mechanisms of cell death in Alzheimers disease
inumopathology. J. Neuronal Transmission, 54 suppl., 159-166.
29
8. Meyer, M.R., Tschanz, J.T., 1998 APOE genotype predicts when not whether one is
predisposed to develop Alzheimers disease. Nature Genetics, 19, 321-322.
9. Mullnard, R.A., Gotman, C.W., Kawes, C., 2000 Estrogen replacement therapy for
treatment of mild to moderate Alzheimers disease. JAMA, 283, 1007-1015.
10. Okamura, N., Aray, H., 2002 Combined analysis of CSF tau levels and iodamphetamine
SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimers
disease. Am. J. Psychiat., 159, 3, 474-476.
11. Sano, M., Ernesto, C., 1997 A controlled trial of selegiline, alpha tocopherol, or both, as
treatment for Alzheimers disease. New England J. of Medicine, 336, 1216-1222.
12. Sheline, Y.I., Mintum, M.A., 2002 Greater loss of 5-HT
2A
receptors in midlife than in
latelife. Am. J. Psychiat., 159, 3, 430-435.
13. Snowden, J.S., Neary, D., Mann, D.M.A., 2002 Frontotemporal dementia. Brit. J.
Psychiat., 180, 140-143.
14. Sweet, R.A., Nimgaonkar, V.L., Kanboh, M.I., 1998 Dopamin receptor genetic variation,
psychosis and aggression in Alzheimers disease. Arch. Neurol., 55, 1335-1340.
15. Tunstall, N., Owen, M.J., Williams, J., 2000 Familial influence on variation in age of
onset and behavioral phenotype in Alzheimers disease. Brit. J. Psychiat., 176, 156-159.
16. Wisniewski, T., Dowjat, W.K., Buxbaum, J.D., 1998 A novel polish presenilin 2 mutation
is associated with familial Alzheimers disease and leads to death as early as the age 28
years. Neuroreport, 9, 217-221.











30


INTERVENIA FARMACOLOGIC N DEPRESIA
LA VRSTA A III-A
C. tefnescu, Roxana Chiri, V. Chiri
Universitatea de Medicin i Farmacie Gr. T. Popa Iai


Rezumat
Scopul articolului este de a atrage atenia cititorilor asupra unor probleme
importante legate de tratamentul depresiei la vrsta a III-a. Medicii practicieni au
recunoscut de o lung perioad de timp c, datorit particularitilor biologice,
psihologice i sociale ale mbtrnirii, pacienii depresivi n vrst necesit
modificri ale protocolului terapeutic. Aceste modificri n tratament sunt mai mult
rezultatul observaiilor clinice acumulate n timp, datorit lipsei datelor studiilor
controlate, care de obicei nu nroleaz subieci n vrst.
Meta-analiza studiilor clinice asupra SSRIs i antidepresivelor triciclice au
demonstrat o eficacitate similar a celor dou clase, dar o tolerabilitate superioar
a antidepresivelor moderne. Aceast tolerabilitate este un avantaj important n cazul
asocierii depresiei cu boli somatice sau cu demena.
Exist o serie de dovezi consistente care ar putea s ne sprijine conduita terapeutic
n depresia la vrsta a III-a, dar sunt n continuare domenii largi care necesit a fi
cercetate.
Cuvinte cheie: depresie, vrst naintat, antidepresive.


PHARMACOLOGICAL INTERVENTION IN
DEPRESSIVE DISORDERS IN THE ELDERLY

Abstract
The aim of the paper is to draw the attention of the readers to some important issues
related to the treatment in depression in later life. Clinicians have long recognized
that, due to the biological, psychological and social effects of ageing, older people
with depression require adjustments to treatment protocols. These adjustments have
primarily relied on accumulated clinical wisdom, due to the lack of data from
controlled studies, which often excluded the elderly.
Meta-analyses of clinical trials of SSRIs and tricyclic antidepressants showed a similar
efficacy, but a better tolerability of the modern antidepressants. These advantages are
more important in depressive patients with somatic comorbidity or dementia.
There are some consistent evidences that could guide us in treating depression in
elderly, but a lot of areas are still open to research.
Key words: depression, elderly, antidepressants.


Depresia la persoanele n vrst este o tulburare diagnosticat insuficient i tratat inadecvat.
Dac includem toate formele de depresie, se constat o prevalen de 15 % peste vrsta de 65 ani.
Exist o heterogenitate att n ceea ce privete etiologia ct i rspunsul terapeutic, n comparaie cu
adultul tnr. Datorit simptomatologiei atipice i a insuficientei informaii despre aceast
31
afeciune, pacienii i aparintorii acestora nu contientizeaz prezena tulburrii i, prin urmare, nu
solicit asisten medical. Nu rareori, chiar medicii de familie sau serviciile sociale care se ocup
de vrstnici ignor simptomele depresive, pe care le consider fenomene psihologice normale,
datorat mbtrnirii fiziologice.
n prezent, tratamentul depresiei la pacienii n vrst cunoate o dezvoltare deosebit,
afeciunea este cercetat, iar noile date tiinifice permit alegerea unor metode curative,
chimioterapice i/sau psihoterapice eficace.

Tratamentul depresiei la vrsta a III-a
Pacienii n vrst, care sufer de o tulburare depresiv, trebuie abordai terapeutic de o
manier particular deoarece efectele biologice, psihologice i sociale caracteristice procesului de
mbtrnire necesit o adaptare individualizat a protocolului terapeutic. Aceste constatri s-au
delimitat de-a lungul timpului, pe baza observaiilor empirice ale clinicienilor ntruct studiile
psihofarmacologice au exclus, de regul, populaia la vrsta a III-a.
Chiar i n prezent exist puine date susinute de studii credibile, iar aceste date pot fi puse
sub semnul ntrebrii deoarece rezultatele studiilor controlate nu pot fi ntotdeauna generalizate. De
exemplu, ntr-un studiu de faz III cu un antidepresiv au fost inclui numai 4,2 % din totalul
pacienilor vrstnici desemnai. Motivul principal a fost aplicarea criteriilor de excludere privind
medicaia concomitent permis precum i a comorbiditilor somatice i psihiatrice acceptate.
Studiile i focalizeaz obiectivele, de cele mai multe ori, asupra episoadelor acute. Exist foarte
puine studii, i acestea necontrolate, privind rezistena la tratamentul antidepresiv sau prevenirea
recderilor. Dar tocmai aceste ultime dou aspecte sunt particulare depresiei la vrsta a III-a.
Se consider c pacienii n vrst, cu comorbiditi somatice i instituionalizai, practic nu
se regsesc n studiile de psihofarmacologie efectuate pe o scar larg, dei aceti pacieni
reprezint segmentul cu rata cea mai mare de depresie din populaie.
Eficacitatea unui tratament antidepresiv depinde foarte mult de abilitile clinicianului.
Exist dovezi, rezultate din studii tiinifice, care atest faptul c medicii psihiatri obin remisiuni
ale sindroamelor depresive n timp mai scurt i stabile pe o lung perioad de timp n comparaie cu
medicii de familie, dei au utilizat aceleai preparate medicamentoase i s-au adresat aceleiai
populaii de bolnavi. n cazul pacienilor la vrsta a III-a, rata beneficiilor terapeutice se apropie de
60 % n cazul specialitilor n gerontopsihiatrie fa de aproximativ 25 % la lotul asistat de medicul
de familie. Un argument n plus pentru asistena depresiei vrstnicului numai de ctre un personal
specializat l constituie ratele mai mari de recuperare obinute n clinica de psihiatrie fa de
asistarea depresiei n spitalul de medicin general.
32
n acelai timp trebuie s inem seama de importana actual a unei relaii de colaborare ntre
medicul specialist i medicul de familie, ntr-o direcie complementar. Aceast relaie a fost obiect
de studiu aprofundat, dar rezultatele trebuie evaluate atent. Colaborarea ntre medicul de familie i
specialistul n gerontopsihiatrie a avut un efect semnificativ n detecia depresiei i alegerea
strategiei terapeutice, dar n ceea ce privete asistena ulterioar, exist preri diferite. Primeaz
opinia c depresia diagnosticat trebuie asistat de specialistul psihiatru, iar rezultatele majoritii
studiilor susin aceast atitudine.
O alt problem legat de particularitile depresiei la vrsta a III a este frecvena mare a
depresiei minore i absena unor date verificate tiinifice asupra tratamentului depresiei minore,
distimiei i a depresiei secundare unei boli somatice.
Cele mai multe studii se focalizeaz asupra ameliorrii unor simptomatologii particulare,
care definesc sindromul depresiv. Modificrile n intensitatea simptomatologiei depresive sunt
considerate puin relevante la ora actual, dac nu sunt coroborate cu evalurile privind integrarea
social, disabilitatea, calitatea vieii i disabilitatea la serviciile de sntate public.

Tratamentul farmacologic
n psihiatria contemporan, arsenalul terapeutic adresat depresiei este suficient de larg, ceea
ce ofer clinicianului posibilitatea individualizrii terapiei, dar n acelai timp ne pune n dificultate,
n absena unor criterii clare i unanim acceptate n alegerea substanei antidepresive.
Preparatele medicamentoase cel mai des utilizate sunt:
1. Antidepresive triciclice (TC): desipramina, maprotilina, mianserina, nortriptilina,
amitriptilina, clomipramina, doxepina, imipramina.
2. Inhibitorii selectivi ai recaptrii serotoninei (SSRIs): citalopram, fluoxetina,
fluvoxamina, paroxetina, sertralina.
3. Altele: nefazodona, trazodona, moclobemide, venlafaxina, srurile de litiu.
ncepnd cu anul 1964, au fost publicate o serie de studii pe populaii de pacieni n vrst.
Marea majoritate a subiecilor prezentau o stare de sntate somatic bun, erau independeni din
punct de vedere social, sufereau de o depresie fr simptome psihotice, necomplicat de
comorbiditi. Aceste studii au fost revzute i reanalizate, concluzia fiind c tratamentul
antidepresiv a fost eficace n 60 % de cazuri (n comparaie cu 30 % placebo). Aceste procente
sugereaz c eficacitatea antidepresivelor n cazul depresiei majore nu depinde de vrsta subiecilor.
Studiile care au evaluat i parametrii sociali i de cantitate a vieii au relevat c SSRIs
mbuntesc semnificativ funcionarea social i senzaia de satisfacie fizic i psihic a
pacienilor. Mai mult dect att, exist date care demonstreaz o evoluie bun a parametrilor
cognitivi, alturi de cei ai calitii vieii, n cazul administrrii SSRIS, dei ameliorrile constatate
33
prin aplicarea scalelor pentru depresie au fost similare. Un alt aspect interesant a fost ideea c
activitatea antidepresiv a diferitelor medicaii administrate au un debut ntrziat la pacientul n
vrst, fa de adultul tnr. Aceste aspecte nu sunt nc demonstrate, se bazeaz pe aplicarea
scalelor de autoevaluare.
Rezultatele tratamentului episodului acut sunt influenate de o serie de factori. Pacienii n
vrst a cror prin episod depresiv a debutat nainte de 60 ani par a necesita cu 5-6 sptmni mai
mult pentru a obine remisiunea terapeutic n comparaie cu depresii a cror debut este situat dup
60 de ani. Un rspuns tardiv s-a constat i la pacienii care prezint anxietate marcat i la cei
asistai n ambulator. Ali cercettori afirm c rezistena la tratamentul psihofarmacologic se
coreleaz semnificativ cu zone de hiperintensitate localizate n substana alb frontal profund,
ganglionii bazali i formaiunea reticulat pontin la explorarea RMN.
S-au ncercat i strategii de augmentare a tratamentului cu antidepresive, ca de exemplu o
noapte de deprivare de somn la nceputul curei sau terapiei de substituie cu estrogeni.
Cel mai important semn de ntrebare este asupra eficacitii i eficienei unei substane
antidepresive, sau, cu alte cuvinte, care este cel mai indicat preparat n asistena episodului depresiv
la vrstnic. n prezent majoritatea clinicienilor sunt de acord c, din grupul antidepresivelor
triciclice aminele secundare au profilul efectelor adverse cel mai redus (nortriptilina, desipramina),
dar antidepresivele de ultim generaie (SSRIs, inhibitori reversibili ai MAO tip A RIMA,
inhibitorii selectivi ai receptorii noradrenalinei i serotoninei, antagonitii receptorilor SHT2 i
antagonitii adrenoreceptorilor) sunt comparate cu aminele teriare cum ar fi amitriptilina sau
imipramina. Rezultatele acestor studii nu pot fi interpretate n cazul vrstnicilor.
Metaanaliza studiilor care compar antidepresivelor triciclice cu SSRIs pe diferite grupuri
de vrst au artat c ambele clase posed relativ aceeai eficacitate, dar tolerabilitatea este n
favoarea SSRIs. Unii autori consider c semnificaiile globale n cazul SSRIs sunt rezultatul
anselor mai mari de meninere a tratamentului timp ndelungat la o doz adecvat.
n pofida rezultatelor diferitelor studii, sunt voci care infirm superioritatea SSRIs n cazul
pacienilor la vrsta a III-a. Argumentele invocate sunt: vrstnicii nu tolereaz SSRIs la fel de bine
ca pacienii tineri, sunt mai expui la efectele extrapiramidale i scderea n greutate. Cercettorii
specializai n farmacologie afirm c alegerea unui SSRIs trebuie s fie n funcie de capacitatea
substanei de a determina efecte adverse prin interaciunea farmacokinetic cu alte substane. Cu
alte cuvinte vom alege acea substan care inhib n cea mai mic msur citocromul hepatic P450.
Studiile demonstreaz c sertralina i citalopramul au efectul inhibitor cel mai redus asupra
sistemului metabolic al citocromului hepatic P450, deci teoretic cel puin aceste dou substane sunt
n prima linie a curei antidepresive la vrstnic. Ecourile din practica clinic nu verific n ntregime
aceste postulate.
34
Depresia asociat cu o afeciune somatic
Evoluia unui episod depresiv depinde ntr-o mare msur de terenul somatic al pacientului.
Orice dezechilibru somatic are un efect negativ, deci stabilitatea unei boli somatice este o condiie
important n eficacitatea tratamentului antidepresiv. n aceste condiii, evoluia depresiei depinde
mai mult de modalitatea n care este controlat boala somatic dect de alegerea substanei
antidepresive, sau, mai bine spus, nu putem afirma eficacitatea unui agent antidepresiv n condiiile
existenei unor variabile importante care in de terenul somatic. Studiile de psihofarmacologie pe
loturi comparate au avut de suferit din aceste motive. Numeroi pacieni nu au fost nrolai datorit
criteriilor de excludere severe, ali subieci au fost exclui pe parcurs, motivele principale fiind
exprimarea clinic a bolii somatice sau efecte adverse ale medicaiei.
Studiile controlate placebo nu au demonstrat o eficacitate semnificativ a medicaiei
antidepresive n episoadele depresive asociate cu boli somatice acute severe. Aceste rezultate
bulverseaz clinicianul. Este necesar administrarea unui antidepresiv? Evident, orice studiu este
criticabil i n orice caz, rezultatele nu sunt axiomatice (trebuie totui luate n considerare i
interpretate). Spre deosebire de bolile somatice acute, afeciunile cronice cu evoluie controlat care
se nsoesc de o depresie, sunt studiate i evaluate tiinific, concluzia fiind eficacitatea
tratamentului antidepresiv. i n aceste situaii exist comentarii, unii specialiti susinnd c nu este
efectul medicaiei antidepresive, ci echilibrarea bolii somatice i confortul pacientului care rezult
din aceasta.
Principala preocupare asupra antidepresivelor triciclice este datorat profilului de efecte
secundare, n special anticolinergice, hipotensiunea ortostatic i toxicitatea cardiac, efecte care
limiteaz utilizarea acestor substane la pacienii n vrst. Prin urmare, noua generaie de
antidepresive, cu un profil de siguran i tolerabilitate sporit este prima opiune pentru pacienii n
vrst, cu comorbiditi somatice. Aceast afirmaie nu este nc susinut de suficiente studii
adresate grupului de pacieni cu vrsta peste 60 de ani, ceea ce justific rezervele exprimate de unii
clinicieni.
Un studiu recent cu paroxetin i nortriptilin la pacieni cu cardiopatie ischemic cronic a
demonstrat avantajul SSRIs; la pacienii tratai cu nortriptilin s-a ntlnit mai frecvent tahicardie,
hipotensiune ortostatic i aritmii cardiace.
O alt propunere n ceea ce privete tratamentul farmacologic al depresiei de vrstnici
suferinzi de boli somatice este administrarea psihostimulantelor de tipul metilfenidat, care i
instaleaz efectul rapid i are un profil lipsit de cardiotoxicitate. Este aceeai problem, absena
datelor suficiente din studii.


35
Depresia asociat cu demena
Studiile controlate placebo au constatat un rspuns la administrarea de placebo extrem de
larg. n literatur exist studii publicate care afirm eficacitatea citalopramului, a maprotilinei, dar
exist i studii publicate n care antidepresivele nu i-au demonstrat eficacitatea de exemplu,
compararea trazodonei cu acidul folic. De exemplu, n acest ultim studiu, simptomatologia
depresiv a sczut n comparaie cu evaluarea de pornire, conform scalei HAMD, dar scorul s-a
meninut peste 18 dup 8 sptmni de tratament.
Un alt aspect care trebuie luat n considerare este efectul agenilor antidepresivi asupra
funciilor cognitive i a comportamentului la pacienii cu demen. Exist preri care susin c
maclobemide mbuntete funcia cognitiv, citalopramul are un impact benefic asupra
tulburrilor de comportament (cum sunt agitaia, iritabilitatea i nelinitea), sertralina reduce la
normal refuzul alimentar. n contrast, imipramina afecteaz funcia cognitiv.

Concluzii
n concluzie, se pare c eficacitatea medicaiei antidepresive nu este modificat n cazul
pacineilor n vrst care sufer de boli somatice cronice stabile. n pofida informaiile insuficiente,
SSRIs sunt agenii de prim linie recomandai n depresia vrstnicului, indiferent de intensitatea
episodului. Riscul mai mare de efecte secundare i adverse limiteaz utilizarea triciclicelor, dar
aminele secundare de tipul nortriptilinei trebuie pstrate n arsenalul terapeutic mai ales n depresia
major rezistent. n cazul asocierii demenei cu depresia, SSRIs i maclobemide sunt preparatele
de elecie. O problem rmne asocierea depresiei cu boala somatic acut, n care antidepresivele
se pare c nu sunt eficace.

Recomandri
Trecerea n revist a datelor din literatura de specialitate privind depresia la vrsta a III-a
conduc la o concluzie general dezamgitoare: metodele de cercetare sunt neadecvate i nu pot
prefigura factorii de prognostic i protocolul terapeutic. Depresia este cea mai frecvent tulburare
psihiatric la vrstnic i dac nu reuim s identificm i s modificm factorii de prognostic
inadecvat, atunci ntreaga activitate de cercetare n acest domeniu este pus sub semnul ntrebrii.
Sunt necesare studii pe loturi extinse care s urmreasc evoluia pacienilor timp de cel puin un
an, iar alturi de evalurile i scalele adecvate simptomatologiei psihiatrice, s cuantificm calitatea
vieii, integrarea social i starea de sntate general. Aceste studii este bine s se desfoare n
condiii de ambulator, cel mai bine n colaborare cu medicii de familie, pentru a mbunti detecia
i urmrirea evoluiei pacienilor. Se poate astfel interveni prompt n situaii de criz sau n cazul
agravrii simptomatologiei prin diverse afectri somatice (boal acut sau cronic neechilibrat).
36
Depresia la persoanele n vrst este frecvent, simptomatologia poate fi mascat, evoluia
unui episod este mai lung, iar comorbiditile somatice agraveaz prognosticul. Dei nu poate fi
exprimat n cifre, riscul decesului este n mod sigur crescut la aceti pacieni. Este un motiv n plus
s identificm prompt i s tratm energic depresia la vrsta a-III-a.
1. Tabloul clinic al depresiei la persoanele n vrst este similar cu cel constatat la tineri,
diferenele fiind existena mai rar a dispoziiei disforic i mai frecvent prezena
simptomelor somatice.
2. Antidepresivele sunt eficiente n tratamentul depresiei la btrni; triciclicele se
recomand mai rar datorit efectelor adverse mai frecvente; se prefer antidepresivele
moderne (SSRIs) sau nortriptilina.
3. Terapia electroconvulsivant i-a demonstrat eficacitatea n cazurile severe, rezistente,
care necesit un rspuns terapeutic rapid.
4. Rata suicidului este mare.
5. Se are n vedere posibilitatea existenei unor subtipuri diferite ale depresiei; depresia
delirant i depresia vascular par a avea validitate clinic.
6. Evoluia i prognosticul difer la btrni; prognostic rezervat l au cazurile cu suferin
somatic asociat, afectare cognitiv, simptome depresive severe. La btrni, depresia se
asociaz cu disabilitate fizic i mortalitate crescut.
7. Interveniile psihosociale sunt utile, dar exist un dezacord n ceea ce privete
modalitatea aleas.
8. Studiile neuroendocrine i neurobiologice prezint o serie de date, dar cu specificitate
modest pentru depresie.

Domenii deschise cercetrii
1. Caracterizarea subtipurilor depresive.
2. Relaia depresie-afectare cognitiv.
3. Patologia cardio-vascular (n special HTA) factor de risc pentru depresia vascular i
demena vascular; relaia dintre cele dou tulburri.
4. Factorii psihosociali n dezvoltarea depresiei.
5. Terapia antidepresiv.
6. Evoluia i prognosticul tulburrii.
7. Depresia rezistent la tratament.
8. Tratamentul de ntreinere i prevenirea recderilor.
9. Asistena depresiei n instituiile cu pacieni internai pe termen lung.

37
Bibliografie selectiv
1. Andersen G., Vestergaard K., Lauritzen L., (1994) Effective treatment of post-stroke
depression with the selective serotonin reuptake inhibitor citalopram. Stroke, 25,1099-1104.
2. Maj M., Sartorius N. (edited by), 1999 Depressive Disorders. Edit. Wiley, New York.
3. Schneider L.S., Olin J.T., 1995 Efficacy of acute treatment for geriatric depression. Int.
Psychogeriatr., 7 (Suppl.), 7-25.
4. Simpson S.W., Jackson A., Baldwin R.C., Burns A., 1997 Subcortical hyperintensities in
late-life depression: acute response to treatment and neuropsychological impairment. Int.
Psychogeriatr., 9, 257-275.
























38


DELAYING THE ONSET OF SCHIZOPHRENIA BY ADMINISTERING
ANTI-PSYCHOTIC MEDICATIONS: A HYPOTHETICAL ATTEMPT
TO DEFINE THE NUMBER NEEDED TO TREAT
M. Weiser, H. Knobler, I. Grotto, M. Davidson
Sheba Medical Center, Tel Hashomer, affiliated with the Sackler School of Medicine, Tel-Aviv
University, Tel-Aviv, Israel
The Divisions of Mental Health and Public Health, Israeli Army Medical Corps, IDF, Israel and the
Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel



Abstract
Previous data indicate that in male adolescents, having a schizophrenia-spectrum
personality disorder (paranoid or schizotypal personality disorder) increases the risk
of subsequent schizophrenia by approximately 20-fold. This paper is a theoretical,
hypothetical attempt to examine the possibility of administering low-dose
antipsychotic medications to these adolescents, in an attempt to delay the onset of
schizophrenia. Assuming that anti-psychotic treatment will be effective in delaying
the onset of schizophrenia in 60 % of the cases, the number of adolescents who need
to receive treatment in order to delay the onset of one case of schizophrenia was
approximately thirty-five. Although used here theoretically in order to make this
point, the relatively small numbers of patients with schizotypal or paranoid
personality disorder followed for later schizophrenia make it impossible to apply
these calculations practically. As all known anti-psychotic medications cause
significant side effects, we conclude that preventive treatment of adolescents with
schizophrenia-spectrum personality disorders using low-dose anti-psychotics is
premature at this time.
Key words: personality disorders, antipsychotics, schizophrenia.


Secondary prevention detects a disease early, with the intention of preventing it or
attenuating its progression. In schizophrenia, several researchers have attempted to administer low-
dose anti-psychotics to prevent, or at least to delay, the onset of the illness in patients at high risk for
becoming schizophrenic. In the largest, best described study on the topic, high risk patients, defined
either as having attenuated psychotic symptoms, or persons with genetic risk for schizophrenia who
have a decrease in their functioning, are administered low doses of Risperidone. Their results
(McGorry et al, 2002) indicate that Risperidone at a mean dose of 1.3 mg/day significantly reduced
the risk of conversion to schizophrenia, p=0.03. Another study (Tsuang et al 2002) administered
open-label Risperidone at doses of 0.25 to 2 mg/day to six patients on patients with schizotaxia,
(defined as having negative symptoms and neuropsychological deficits in the absence of psychosis
or prodromal symptoms) and found increased cognitive abilities and social interest.
Theoretically, the issue of secondary prevention of schizophrenia can be addressed based on
data from a population-based cohort study. In that study adolescents diagnosed with having a
39
schizophrenia-spectrum personality disorder (schizotypal or paranoid personality disorder) at the
Israeli Army Draft Board assessment were followed for subsequent schizophrenia using a national
psychiatric hospitalization registry. Seven out of 147 of these male adolescents were later
hospitalized for schizophrenia, representing an approximately 20-fold increased risk of
hospitalization relative to the risk for schizophrenia in the general population. Hypothetically, one
could conjecture that by administering low-doses of anti-psychotic medications to these adolescents
at high risk, the onset of the illness might be delayed, or perhaps the amplitude of the symptoms
could be attenuated. Assuming that the same anti-psychotic drugs that ameliorate psychotic
symptoms in patients already manifesting psychosis will also delay the appearance of psychotic
symptoms, a possible strategy might be to administer preventive treatment with a low dose atypical
neuroleptic to all 147 adolescents with schizophrenia-spectrum personality disorder. Response
would constitute delay of first hospitalization for one half to one year for those 7/147 of patients
who eventually convert to schizophrenia. If among those future patients, 60% respond to preventive
treatment with low dose atypical anti-psychotics, (a response rate similar to rate that first episode
patients respond to anti-psychotic treatment (Emsley 1999; Lieberman et al 1996), it can be
hypothesised that among those 7/147 of patients expected to convert to schizophrenia, in
approximately 60% of them, or 4/7, the first hospitalization might be delayed by one half to one
year. As the peak incidence of the first hospitalization for psychosis corresponds with a critical
period of intellectual and vocational development in the young adult, even modest gains such as
continuing life outside of hospital for an additional one half to one year should be considered a
valid form of secondary prevention.
A term used to illustrate the effectiveness of an intervention is the number needed to treat
(NNT), which is the number of individuals who need to receive treatment in order to prevent one
bad outcome (Sackett et al 1997). Although used here theoretically in order to illustrate this issue,
the relatively small numbers of patients with schizophrenia-spectrum personality disorder followed
for later schizophrenia make it impossible to apply these calculations practically. The Number
Needed to Treat (NNT) is the number of patients who need to be treated for a given period to
achieve an event (treatment) or to prevent an event (prophylaxis) (McQuay and Moore 1997). The
NNT is treatment specific and describes the difference between treatment and control in achieving a
particular clinical outcome. The NNT is the reciprocal of the change in absolute risk brought about
by an intervention. For example, a drug is given to 100 people with a certain disorder and 70 of
them experienced a clearly defined clinical outcome e.g. improvement in the symptoms. If a
placebo is given to a similar population of 100 people, only 20 of them experienced an
improvement of the symptoms. So, the drug is responsible for 50 of the 100 people obtaining
improvement in symptoms under treatment. This is 50 % or an absolute risk reduction of 0.5. The
reciprocal of this absolute risk reduction is 1/0.5 and the NNT is therefore 2. This means that 2
40
people have to be given this drug for one of them to obtain the defined outcome of improvement.
There is no absolute value for an NNT to be considered clinically effective, but it is generally
accepted that the lower the NNT the better. The NNT is reported rounded up to the nearest whole
number and accompanied by its 95 % CIs. Any NNT is just a point estimate. All point estimates
have some uncertainty around them, usually reflected in the 95% CI. The CI becomes narrower as
the amount of data increases (McQuay and Moore 1997).
The NNT in this hypothetical case is determined by first calculating the frequency of
conversions to schizophrenia in the adolescents with schizophrenia-spectrum personality disorder
with no intervention, here 7/147=0.048. This is considered the Control Event Rate, or CER. The
Experimental Event Rate (EER) is the rate of conversions to schizophrenia in the population of
adolescents with schizotypal or paranoid personality disorder receiving treatment with low dose
atypical anti-psychotics. As we are assuming that treatment with preventive low dose atypical anti-
psychotics might delay hospitalization for one half to one year for 60 % of these adolescents, the
frequency of conversion to schizophrenia in this treatment group would be 100 %-60 %=40 %, or
0.4 X 0.048 (the frequency of conversion in the untreated population)=0.0192. The absolute risk
reduction (ARR) is the difference in risk between the control condition and the experimental
condition, (ARR=CER-EER)=(0.048-0.0192)=0.0288. The number needed to treat (NNT) is the
inverse of the ARR: NNT=1/ARR=1/0.0288=34.7. This means that, hypothetically, one must
administer preventive low dose atypical anti-psychotics to 35 adolescents with paranoid or
schizotypal personality disorder in order to delay hospitalization for schizophrenia by one half to
one year, for one patient. Again, it is emphasized that because of the relatively small numbers of
patients with schizotypal or paranoid personality disorder available for follow-up for later
schizophrenia, it is impossible to apply these calculations practically.
These NNTs must be contemplated in comparison with other interventions in psychiatry or
medicine. For example, intensive intervention with 7 families of schizophrenic patients must be
conducted for one year to prevent relapse in one patient (Pharoah et al 2000), approximately 70
elderly patients with moderate hypertension must be treated with anti-hypertensive drugs for five
years to save one life, and 100 men with no evidence of coronary heart disease must be treated with
aspirin for five years in order to prevent one heart attack (Sackett et al 1997).

Discussion
To summarize this hypothetical scenario, as the peak incidence of the first hospitalization for
psychosis corresponds with a critical period of intellectual and vocational development in the young
adult, even modest gains such as continuing life outside of hospital for an additional one half to year
should be considered a valid treatment target. However, the relatively low specificity of the markers
currently used for identifying persons at high risk for future schizophrenia dictates that a large number
41
of individuals who will not later convert from schizophrenia-spectrum personality disorder to
schizophrenia must be unnecessarily exposed to preventive treatments. Practically speaking, this
hypothetical prevention plan would entail telling 35 adolescents and their parents that they are at
significant risk of later hospitalization for schizophrenia. This would certainly be upsetting for these
patients and their familys, in some cases might have damaging consequences, and might even act as a
self-fulfilling prophecy. In addition, the adverse effects of medication must be considered. For
example, as the mean weight gains of persons treated with atypicals at standard doses for 10 weeks is
4 kg and above (Allison et al 1999), even low doses of atypical anti-psychotics might be expected to
cause significant weight gain when administered over a significant period of time. If the preventive
treatment was less toxic, preventive treatment might be more conceivable. For example, in the
prevention of coronary heart disease, the number of persons who need to receive low dose aspirin to
cause one significant adverse event is 500, making this much safer intervention.
In summary, despite the potential benefits of preventive treatment, due to the relatively low
specificity of the currently available markers for schizophrenia, the relatively high rates of significant
adverse events expected, and the lack of certainty that these medications would, in fact, prevent or
delay the onset of psychosis, the application of preventive treatment in daily clinical today practice is
premature. In the future, when our understanding of the illness will enable the utilization of
biological markers with better predictive abilities, and/or when medications that are less toxic are
available, then, and only then, might this hypothetical conjecture be clinically relevant.


References
1. Allison DB, Mentore JL, Heo M, et al, 1999 Antipsychotic-induced weight gain: a
comprehensive research synthesis. Am J Psychiatry 156, 1686-96.
2. Andreasson S, Allebeck P, Engstrom A, Rydberg U, 1987 Cannabis and schizophrenia. A
longitudinal study of Swedish conscripts. Lancet 2, 1483-6.
3. Cannon M, Jones PB, Murray RM, 2002 Obstetric complications and schizophrenia:
historical and meta-analytic review. Am J Psychiatry 159, 1080-92.
4. Emsley RA, 1999 Risperidone in the treatment of first-episode psychotic patients: a
double-blind multicenter study. Risperidone Working Group. Schizophr Bull 25, 721-9.
5. Lieberman JA, Alvir JM, Koreen A, et al, 1996 Psychobiologic correlates of treatment
response in schizophrenia. Neuropsychopharmacology 14, 13S-21S.
6. Malaspina D, Goetz RR, Friedman JH, et al, 2001 Traumatic brain injury and
schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am J
Psychiatry 158, 440-6.
42
7. McGorry PD, Yung AR, Phillips LJ, et al, 2002 Randomized controlled trial of
interventions designed to reduce the risk of progression to first-episode psychosis in a
clinical sample with subthreshold symptoms. Arch Gen Psychiatry 59, 921-8.
8. McQuay HJ, Moore RA, 1997 Using numerical results from systematic reviews in
clinical practice. Ann Intern Med 126, 712-20.
9. Pharoah FM, Mari JJ, Streiner D, 2000 Family intervention for schizophrenia. Cochrane
Database Syst Rev 2.
10. Sackett DL, Richardson S, Rosenberg W, 1997 Evidence Based Medicine. How to
Practise and Teach EBM. London: Churchhill-Livingstone.
11. Tsuang MT, Stone WS, Tarbox SI, Faraone SV, 2002 An integration of schizophrenia
with schizotypy: identification of schizotaxia and implications for research on treatment
and prevention. Schizophr Res 54, 169-75.
12. Weiser M, Reichenberg A, Rabinowitz J, et al. 2001 Association between nonpsychotic
psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia. Arch Gen
Psychiatry 58, 959-64.


















43


SCHIZOFRENIA LA FEMEIE - PARTICULARITI TERAPEUTICE
Rodica Mihaela Enache, P. Boiteanu
Spitalul Universitar de Psihiatrie Socola Iai



Rezumat
Schizofrenia este o boal cu etiologie necunoscut care debuteaz n tineree, dar la
femeie se poate manifesta pentru prima dat i n perimenopauza (estrogenii par s
aib un rol protectiv). Exist un numr important de particulariti prin care
algoritmul de diagnostic i tratament difer de la brbat la femeie. Dei femeile se
angajeaz mult mai uor n tratament, ele vor suferi mai mult de pe urma reaciilor
adverse ale medicaiei. Importana unui bun tratament la femeie este minimalizat
dei este clar c posibilitatea de a preveni schizofrenia la copil este parial
influenat de eficiena managementului acestei boli. Tratamentul femeii schizofrene
trebuie s in cont de perioada menstrual, sarcin, menopauz i de condiiile
socio-economice cu care pacienta se confrunt.
Cuvinte cheie: schizofrenia la femei, terapie.


TREATMENT OF SCHIZOPHRENIA IN WOMEN PARTICULAR
ASPECTS

Abstract
Schizophrenia is often harder to diagnose in women than in men and may manifest
as late as perimenopausal years. Women tend to be more open to treatment but are
more likely to suffer adverse reactions to antipsychotic drugs. Comprehensive
treatment is crucial as is suicide prevention. Hormone fluctuations can worsen the
condition. Early intervention for mothers may help and protect children who face a
1:10 risk of disease themselves.
Key words: schizophrenia in women, therapy.


Schizofrenia este, adesea, mai greu de diagnosticat la femeie dect la brbat i poate s se
manifeste la fel de bine i n perimenopauz. Simptomele includ idei delirante, halucinaii, vorbire
incomprehensibil, comportament dezorganizat, izolare social, apatie i pierderea treptat a
tonusului emoional. Pentru ca diagnosticul s fie cert, aceste simptome trebuie s fie nsoite de
disfuncie social sau ocupaional sau ambele.
Se pare ca femeile sunt mai deschise la tratament, dar frecvent sufer din cauza reaciilor
adverse la medicamentele antipsihotice. Terapia complex, incluznd o bun cooperare ntre
psihiatru, psiholog, medic de familie, este crucial i are rol esenial n prevenia suicidului.
Fluctuaiile hormonale pot nruti situaia. Intervenia precoce la mamele bolnave poate ajuta i
proteja copilul care el nsui are un risc de a face boala de 1:10.
44
De aceea, tratamentul schizofreniei la femeie trebuie croit astfel nct s in cont de
perioadele menstruale, sarcin i menopauz, ca i de condiiile socio-economice cu care aceasta i
copiii ei se pot confrunta.

Cum este tratat schizofrenia?
Convingerea pacientului c nu este bolnav i c tratamentul medical nu poate s l ajute n a
depi problema este cel dinti obstacol n managementul schizofreniei. Pacientul i
experimenteaz simptomele ca i cum acestea ar avea sursa n afara sa; de aceea, pare ilogic s ia
vreo medicaie pentru a le micora amploarea.
Doar o alian terapeutic bine constituit ar putea convinge pacientul c are nevoie de
tratament.
Un nou obstacol poate s apar n momentul n care pacientul refuz orice tip de relaie ntre
terapeut i familia sa, tiut fiind c suportul familial este esenial n tratament. Medicul de familie
care are deja o relaie stabil cu pacientul poate fi de mare ajutor n depirea acestui neajuns. n
cazul n care eueaz, asistentul social are un rol important n a obine i transmite psihiatrului
informaiile eseniale legate de relaiile familiei cu pacientul.
Odat ce pacientul a fost lmurit c are nevoie de tratament, urmtorul pas const n
alegerea celui mai potrivit antipsihotic la o doz eficient, care nu cauzeaz disconfort. Tratamentul
va fi iniiat numai de psihiatru, dar medicul de familie l va urmri.
Dintre antipsihoticele noi, uor se poate ncepe cu olanzapina 10 mg seara care va
mbunti i somnul (fcnd pacientul s se simt subiectiv mai bine) i care va cauza puine reacii
adverse. Deoarece marja terapeutic a olanzapinei este restrns, doza eficient poate fi atins
relativ repede. Pe termen lung, nsa, olanzapina prezint dezavantaje legate de creterea n greutate,
hiperlipidemie i, eventual, diabet.
Risperidona determin o cretere n greutate mai redus dect olanzapina, iar riscul de diabet
este neglijabil. Aceste aspecte i confer sigurana pe termen lung. Totui, tinde s nruteasc
insomnia i poate avea efecte intolerabile asupra vieii sexuale. Chiar dac are un interval mic de titrare
a dozei (1 pn la 8 mg), pacienii se pot confrunta adesea cu efecte adverse de tip parkinsonian.
Aceste medicamente, dar n special risperidona, sunt asociate cu un risc crescut de hiperprolactinemie.
Quetiapina se pare c are cele mai puine efecte adverse, dar este dificil de utilizat deoarece
necesita o perioad lung de ajustare a dozei. Titrarea ncepe cu 25-50 mg, apoi se crete treptat.
Uneori, doza eficient este situat n jurul a 1000 mg pe zi. Aceast cretere lent a dozei este dificil
de realizat, mai ales n ambulatoriu, deoarece pacienii au tendina de a se opune schimbrilor n
regimul de medicaie.
45
Antipsihoticele clasice pot induce efecte extrapiramidale n afara cazului n care sunt
asociate cu medicaie anticolinergic. Unii pacieni pot tolera ns i rspund bine la doze mici din
antipsihoticele clasice. Dei creterea n greutate este un loc comun, ea este mai redus dect la
antipsihoticele noi. n cazul n care pacientul nu rspunde la nici unul din aceste medicamente,
psihiatrul ar trebui s sugereze o nou variant: clozapina.

Diferente legate de sex
Dup cei mai muli autori, este mai lesne de stabilit o relaie terapeutic cu femeia dect cu
brbatul schizofren. Este relativ mai uor s convingi o femeie s urmeze un tratament pentru c
mai frecvent femeia experimenteaz simptome somatice (cefalee, insomnie) i afective (depresie,
anxietate).
Pe de alt parte, femeile sunt mai susceptibile la reaciile adverse dect brbaii deoarece:
- femeile vor primi n cele mai multe cazuri doze calibrate dup greutatea corporal a
brbatului (doza medie din literatur); aceasta va fi frecvent prea mare pentru femeie.
- antipsihoticele sunt lipofile i au remanen crescut n esutul gras, iar femeile dispun
de o cantitate mai mare de esut gras dect brbaii. Astfel, antipsihoticele rmn un timp
mai lung i se pot acumula n corpul femeii. Acumularea reprezint o mare problema
mai ales n cazul medicaiei depot.
- femeile adesea vor primi i o alta medicaie: anticoncepionale orale sau depot,
ortotimizante, antidepresive, sedative, anxiolitice, analgezice, antiinflamatorii sau
antihistaminice. Antipsihoticele interacioneaz cu toate aceste medicamente.
Efectele secundare la femeie pot avea consecine serioase. De ex: o scdere a tensiunii
arteriale la o femeie n vrst ar putea cauza cdere, fractur de col femural i, ulterior, moarte. Alte
efecte induse de medicaie care ar pute fi periculoase la femeie sunt:
- pasivitatea care crete tolerana la abuzul domestic
- sedarea care poate reprezenta un mare neajuns la mamele care i ngrijesc copiii
- creterea n greutate.

Reducerea efectelor adverse
De cate ori este posibil, medicaia trebuie s fie foarte simpl; pentru muli pacieni, o
singura doz seara este cea mai buna alegere. Adesea, efectele adverse pot fi sczute dac
tratamentul este nceput cu o doz mic i apoi aceasta este crescut treptat pn este atins efectul
terapeutic. Dac efectele adverse se nrutesc, dozele pot fi spaiate; medicaia administrat de 2-3
ori pe zi este suficient pentru a menine ameliorarea.
46
Toi clinicienii care trateaz schizofreni ar trebui s-i pun problema funcionarii lor pe
parcursul ntregii zile. Somnolena diurn poate fi evitat prin administrarea medicaiei seara la
culcare. ncurajarea unei diete sntoase i a exerciiilor regulate ajut la prevenirea creterii n
greutate. Este la fel de important s se ofere instruciuni privitoare la modul cum poate fi evitat
hipotensiunea postural.

Dincolo de medicaie
Dei antipsihoticele sunt foarte importante n managementul schizofreniei, tratamentul
complex este crucial. n plus, fa de recomandrile generale de meninere a sntii, clinicienii
trebuie s se adreseze i situaiilor legate de scderea stimei de sine, siguran, activiti domestice,
venituri, familie i relaii sociale, educaie, ocupaie. Prevenirea recderii este la fel de important
ca i cea a suicidului. O echip multidisciplinar, incluznd psihiatru, psiholog, medic de familie, ar
trebui s lucreze pentru a acoperi toate zonele crora li se adreseaz tratamentul.

Aspecte deosebite la femeia cu schizofrenie
Femeile cu schizofrenie au nevoi speciale:
- fluctuaia simptomelor trebuie monitorizat de-a lungul ciclurilor menstruale.
Simptomele sunt mai severe n momentele n care se produce o scdere a nivelului de
hormoni estrogeni, astfel c este indicat ajustarea dozei n faza menstrual.
- medicaia nu trebuie s interfere cu menstruaia. Din cauza hiperprolectinemiei induse de
medicaie se poate instala amenoreea. Pentru a rezolva acest neajuns, este preferat
scderea dozei sau schimbarea cu o alt medicaie.
- educaia sexuala i importana contracepiei trebuie ntotdeauna subliniate i repetate.
Este recomandat psihoeducaia prin care femeia va fi informat asupra bolii sale i
urmrilor ei.
- femeilor care vor s devin mame trebuie s li se furnizeze informaii asupra viabilitii
fetale. Ele vor fi sftuite s nu fumeze, s nu consume alcool, s pstreze regularitatea i
continuitatea tratamentului, s ia suplimente vitaminice i folai, s mearg regulat la
controale ginecologice/obstetricale.
- alegerea medicaiei i dozajul sunt foarte importante pe durata sarcinii i n perioada
postpartum. Neurolepticele sunt n general sigure pe durata sarcinii. Exista o experien
redus cu antipsihoticele noi. Dac este posibil, trebuie s meninem o doz sczut n
primul trimestru de sarcin, dar poate fi necesar ca n al treilea trimestru s se creasc
doza corespunztor cu creterea volumului sanguin. O scdere a dozei cu 50 % este
recomandat cu o sptmn nainte de data ateptat a naterii pentru a preveni
interferena cu travaliul i a ne asigura c nou-nscutul nu este suprasedat sau n sevraj.
47
Exacerbrile post-partum ale bolii sunt frecvente; medicaia trebuie s fie administrat n
doze mari n aceast perioad, pacienta necesitnd o monitorizare foarte atent.
- selecia i dozajul antipsihoticului trebuie urmrite atent dac pacienta alpteaz.
Antipsihoticele clasice sunt n general considerate sigure n aceasta perioada. Aceste
medicamente interfer ns cu secreia lactat ntr-un foarte mare grad. n trecut, femeile
erau sftuite din acest motiv sa nu alpteze, dar nu este sigur c este cea mai bun
soluie. Noile antipsihotice (olanzapina, risperidona, quetiapina) sunt gndite astfel nct
s fie potrivite n perioada alptrii, dar experiena este limitat. Clozapina nu este cea
mai bun alegere n perioada sarcinii sau alptrii.
- beneficiile continurii tratamentului sunt totui mai mari dect riscurile, de aceea,
medicaia antipsihotic nu trebuie retras pe parcursul alptrii. Anumite strategii pot fi
aplicate pentru a reduce cantitatea de medicament din laptele matern. De ex: mamele vor
fi instruite s alpteze mai puin pentru a evita suprasedarea copilului. Este recomandat
monitorizarea atent a nou-nscutului pentru a asigura un ciclu somn/veghe fiziologic i
o cretere n greutate potrivit. Riscurile pentru nou-nscut sunt mari n prima sptmn
deoarece metabolismul este nc imatur, dar scad dup prima lun. Copiii prematuri pot
avea un risc crescut.
- nivelul hormonilor estrogeni trebuie monitorizat i la menopauz cnd scderea acestuia
va determina nrutirea simptomelor. Vor trebui evaluate regulat densitatea mineral a
osului, dieta; se vor realiza anual testul Papanicolau i mamografii. Dac este necesar,
clinicianul trebuie s pun la dispoziia pacientei terapia de nlocuire hormonal, care
poate determina ameliorarea simptomatologiei schizofrene.

Cum putem preveni sechelele?
La femeile care vor s devin mame, pot fi de ajutor cteva intervenii: ncurajarea ngrijirii
fetale, evitarea pe ct posibil a complicaiilor obstetricale, creterea dozajului n perioada post-
partum, asigurarea de suport psihologic i material mamei, consilierea acesteia, prevenirea abuzului
de substane la mam i la copil, socializarea mamei i asigurarea unui mediu ct mai puin stresant
pentru copil.
Copiii a cror mam sufer de schizofrenie prezint un risc statistic de a face boala de 1:10.
Exista sperana ca acest risc s poat fi redus prin intervenia precoce asupra mamei
Adeseori, mamele cu schizofrenie nu sunt cstorite, au un nivel de trai mizer i un standard
de via sczut. Ele pot fi izolate, fr un sistem de suport, cele mai multe abuzeaz de substane i
sunt implicate n relaii abuzive. Ageniile de protecie a copilului pot sau nu s fie informate n
acest sens.
48
Clinicianul trebuie s asigure suport mamei ori de cte ori aceasta se afl n dificultate. Dac
pacienta i permite, acesta trebuie s menin legtura cu cei de la protecia copilului, cu familia, s
interacioneze pozitiv cu asistenii sociali care au n grij familia.
Copiilor mamelor schizofrene trebuie s li se asigure constant suport psihologic i consiliere
pentru a evita abuzul de substane mai ales n momentul schimbrilor hormonale ce survin la vrsta
adolescenei. Aceste msuri trebuie s fie cu att mai ferme cu ct copilul se afl la vrsta debutului
unei eventuale psihopatologii.


Bibliografie
1. Fitzgerald, P.B., Seeman, M.V., 2000 Women and schizophrenia: treatment implications.
Cambridge Universitz Press, Cambridge, 95-110.
2. Grigoriadis, S., Seeman, M.V., 2002 The role of estrogens in schizophrenia: implications
for schizophreniapractice guidelines for women. Can. J. Psychiat., 47, 437-442.
3. Seeman, M.V., 1996 The mother with schizophrenia, Cambridge Univ. Press, 190-200.
4. Seeman, M.V., 1999 Improving outcomes for patients with schizophrenia: new hope for
an old illness. CMAJ, 160, 826-828.
5. Seeman, M.V., 2001 Current issues in the psychopharmacology of schizophrenia.
Lippincott Williams &Wilkins, 489-496.












49


ROLUL OLANZAPINEI N INFLUENAREA CALITII VIEII
LA PACIENII CU SCHIZOFRENIE CRONIC
A.I. Grigoriu, Adina Coman, Hania Hapczinski
Spitalul de Psihiatrie i Neurologie Braov



Rezumat
Tratamentul antipsihotic influeneaz calitatea vieii pacienilor cu schizofrenie
dac: reduce eficient simptomele pozitive i negative, mai ales simptomele negative,
primare, responsabile de declinul progresiv al pacientului, dac are efecte
secundare ct mai reduse pentru a asigura compliana la tratamentul pe termen lung
prevenind astfel recidivele i spitalizrile repetate. Antipsihoticele convenionale au
eficien limitat asupra simptomelor negative i sunt asociate cu efecte secundare
importante, potenial invalidante, fapt ce scade compliana terapeutic i crete
riscul recidivei. Antipsihoticele novel ofer o eficien mai bun asupra simptomelor
negative controlnd n acelai timp i simptomele pozitive, se asociaz cu efecte
secundare semnificativ mai reduse, o toleran superioar i o complian mai bun
la tratamentul pe termen lung.
Metod: este un studiu prospectiv, noncomparativ, pe un lot de 32 de pacieni aflai
n evidena Spitalului de Psihiatrie i Neurologie Braov, cu dg. de schizofrenie
cronic, diagnosticai conform criteriilor ICD10 i DSM-IV, n tratament de
ntreinere cu fluanxol depot n ritm de 20 mg la 2-4 sptmni i care au fost trecui
pe olanzapina 10mg/zi cel puin 3 luni (media 6,7luni). Evaluarea s-a fcut cu
scalele PANSS, CGI, GAFF i QOL-OMS. Rezultatele arat o ameliorare
semnificativ a urmtoarelor domenii din cadrul calitii vieii: sntate somatic,
psihologic, nivel de independen, relaii sociale. De asemenea a sczut rata
recidivelor i a spitalizrilor.
Cuvinte cheie: schizofrenie, calitatea vieii, olanzapin.


THE ROLE OF OLANZAPINE IN INFLUENCING THE QUALITY OF LIFE
IN PATIENTS WITH CHRONIC SCHIZOPHRENIA

Abstract
Antipsychotic treatment influences the quality of life in patients with schizophrenia if it
is effective on the positive and negative symptoms, especially on the primary negative
symptoms considered to be the core of the illness, if it has a low incidence of side-
effects and a good tolerability, a good compliance with long-term treatment which
decreases the risk of relapses and hospitalizations. Conventional antipsychotics have
limited efficacy on the negative symptoms, are associated with a high incidence of side-
effects (some of them severe and incapacitating), with poor compliance in the long-term
treatment, raising the risk of relapses. Novel antipsychotics are more effective on
negative symptoms, are associated with fewer side effects and a better tolerability and
improved compliance with the long-term treatment.
Method: it is a prospective and noncomparative study on 32 patients with chronic
schizophrenia treated with fluanxol depot 20mg at 2 to 4 weeks who were switched to
olanzapine 10mg/day, at least 3months (mean time 6,7months). For diagnosis we
used ICD-10 and DSM-IV criteria and for assessing the patients before initiating the
50
new treatment and after the considered time we used PANSS, CGI, GAFF, QOL-
OMS. Results: there was a significant improvement of the following domains of the
quality of life: somatic health, psychological level, level of independence, social
relationships. The rate of relapses and hospitalizations decreased.
Key words: schizophrenia, olanzapine, quality of life.


Calitatea vieii este definita de OMS ca percepia pe care oamenii o au asupra poziiei lor n
via, n relaie cu scopurile lor i cu sistemul de valori pe care ei l-au acceptat i nsuit n
perspectiva lurii deciziilor corecte.
Definiia plaseaz centrul problematicii calitii vieii n zona voinei i capacitii persoanei
de a comunica, de a fi independent i de a participa la realizarea destinului propriu. Aceste aspecte
ale personalitii sunt semnificativ afectate n bolile psihice.
Preocuparea fa de calitatea vieii a nceput s se manifeste n psihiatrie ncepnd din anii
70, o dat cu procesul de dezinstituionalizare al bolnavilor psihici cronici (permis de era
neurolepticelor) i de dezvoltare a psihiatriei comunitare. Psihiatria comunitar are n vedere
ngrijirea pacientului pe ct posibil n comunitate, n condiii cat mai fireti de existen, evitarea
spitalizrilor prelungite, creterea toleranei populaiei la prezena n mijlocul ei a persoanelor cu
boli psihice etc.
Calitatea vieii pacienilor suferind de schizofrenie este influenat de numeroi factori ce in
de complexitatea bolii care afecteaz pacientul pentru ntreaga lui via, perturbndu-i existena att
n timpul puseului, prin simptomele psihotice pozitive, ct i n perioadele de remisiune, prin
simptomele negative, defectuale. Boala debuteaz ades n adolescen sau n perioada adultului
tnr, interfernd cu formarea personalitii, cu desvrirea pregtirii colare i profesionale, cu
integrarea social i profesional, cu formarea familiei, a relaiilor de grup social etc. Boala are n
marea majoritate a cazurilor o evoluie cronic, marcat de recidive, pe un fond de deteriorare
funcional gradual. Dintre factorii care influeneaz mai pregnant calitatea vieii, civa pot fi
cuantificai pentru a se putea face o comparaie intre efectele produse de diferitele medicamente
antipsihotice asupra evoluiei pacientului, cei mai importani fiind:
Sntatea somatic perceput de pacient ca nivel de funcionare n familie i societate;
aceasta este afectat mai ales de declinul funcional determinat n principal de simptomele negative
(primare i secundare) care rspund slab la medicaia antipsihotic i care pot fi determinate n parte
de aceast medicaie;
Confortul psihologic perceput de pacient ca o cretere a interesului pentru activiti i
relaionare; acesta este afectat de efectele adverse ale medicaiei, dintre care cele extrapiramidale
sunt cele mai importante n declinul funcional al pacientului;
51
Nivelul de independen este determinat n primul rnd de cogniie i mobilitate, afectate
cel mai pregnant de medicaia antipsihotic clasic prin efectele adverse de ncetinire a asociaiilor,
de slbire a ateniei, de asimilare a informaiilor noi i cele de hipotonie muscular;
n plus, la aceti pacieni, mortalitatea este crescut fa de populaia general mai ales
prin comiterea suicidului, 10 % dintre pacienii cu schizofrenie decednd n acest fel.
n ciuda progreselor terapeutice, 20-30 % din pacienii cu schizofrenie au beneficii pariale
la tratamentul de faza acuta, 20-30 % recad n primul sau al doilea an de la episodul acut dei
urmeaz tratamentul de ntreinere (procentul crescnd semnificativ n caz de noncomplian), iar
15 % nu au ameliorri semnificative chiar de la primul episod (Barnes i Kane, 1996).
Aceasta tulburare afecteaz viaa familiei pacientului, fiind i o boal costisitoare pentru
pacient, pentru familia sa, pentru sistemul de asigurare al sntii. Costurile directe cresc prin
spitalizrile frecvente i prelungite datorate recidivelor. Costurile indirecte includ scderea sau
pierderea capacitii de munc, utilizarea resurselor comunitare etc.
Spitalizrile prelungite au rol nefavorabil asupra evoluiei bolii: pacientul pierde progresiv
capacitatea de a exista independent, de a lua decizii i de a aciona, de a rezolva problemele practice
de zi cu zi, de a stabili i ntreine relaii sociale.
Managementul ideal al pacientului cu schizofrenie presupune, n vederea mbuntirii
calitii vieii:
controlul eficient al simptomelor pozitive i negative
prevenirea recidivelor
evitarea spitalizrilor i mai ales a celor prelungite
programe de reabilitare psiho-social, care s permit reintegrarea n
comunitate
programe de educare a familiei (care s devin un aliat n procesul terapeutic),
programe de informare i de educare a populaiei (care trebuie s accepte
pacientul n comunitate).
Tratamentul medicamentos antipsihotic deine un rol important n managementul bolii i n
influenarea calitii vieii pacientului. Obiectivele lui sunt:
reducerea simptomelor pozitive i a simptomelor negative, mai ales a celor
primare responsabile de declinul progresiv al pacientului
toleran bun, fr efecte secundare notabile, pentru a asigura compliana la
tratamentul de lung durat
prevenirea recidivelor prin tratament de ntreinere
reducerea costurilor directe i indirecte.
52
Conform unui model conceptual pentru calitatea vieii la pacienii cu schizofrenie n
tratament cu neuroleptice propus de Awad 1995, determinanii majori ai calitii vieii sunt:
simptomele bolii, efectele adverse ale medicaiei i performana psihosocial. Exist studii clinice
care susin acest model artnd corelaii ntre calitatea vieii apreciat prin autoevaluare, akatisie i
rspunsul subiectiv la neuroleptice (Awad, 1995; Voruganti, 1994).
Antipsihoticele tradiionale au eficien limitat n general (30-40 % dintre pacieni rspund
slab la tratament Kane, 1996) i n special asupra simptomelor negative i sunt asociate cu efecte
adverse importante, potenial invalidante (sindroame extrapiramidale, diskinezia tardiv etc), fapt ce
reduce compliana i crete riscul recidivei. De asemenea, efectele adverse sunt n parte
responsabile de simptomele negative secundare. Antipsihoticele novel ofer o eficien mai bun
asupra simptomelor negative controlnd n acelai timp i simptomele pozitive, se asociaz cu
efecte adverse semnificativ mai sczute, tolerana este superioar i compliana mai buna.
Dintre antipsihoticele novel am ales pentru studiul nostru olanzapina datorit profilului ei de
aciune ei pe receptori: are afinitate mai mare pe receptorii 5HT
2A
dect pe receptorii D
2
(mai puin
de 70-80 % dintre receptorii D
2
sunt ocupai n studii PET), cu o ocupare mai mare a receptorilor
D
2
mesolimbici dect a celor nigrostriatali (Stahl, 1999). De asemenea are o afinitate mai mare pe
receptorii D
1
i D
4
dect haloperidolul (Tollefson, 1997). Testri comportamentale n vivo cu
olanzapin au artat c comportamentele mediate de 5-HT apar la doze mai mici dect cele necesare
pentru manifestarea comportamentelor mediate de D (Moore, 1993). Studiile clinice arat
ameliorri semnificative ale simptomelor negative.

Material i metod
Este un studiu longitudinal, prospectiv, noncomparativ, pe un lot de 32 de pacieni aflai n
evidena Spitalului de Psihiatrie i Neurologie Braov, cu schizofrenie cronic, diagnosticai
conform ICD-10 i DSM-IV, n tratament de ntreinere cu antipsihotice depot, i.e. fluanxol depot
n ritm de 20mg la 2-4 sptmni i care au fost trecui pe olanzapin 10mg/zi. Urmrirea a durat
cel puin 3 luni. Evaluarea clinic s-a efectuat la iniierea tratamentului i dup 3 luni cu scalele
PANSS (cu scoruri 1-7 ale itemilor) i CGI, iar evaluarea calitii vieii, cu scalele GAFF i QOL-
OMS. Pentru a obine informaii relevante din aplicarea scalelor calitii vieii, care sunt scale de
autoevaluare, pacienii au fost instruii s colaboreze cu un membru al familiei la completarea
chestionarelor. Este cunoscut faptul c msurarea calitii vieii la pacienii cu schizofrenie implic
dificulti metodologice (McKenna, 1997)

Rezultate
Lotul a cuprins 32 de pacieni cu vrste ntre 21 i 56 de ani, vrsta medie actual fiind de
35,67 ani, vrsta medie la debutul bolii fiind 25,18 ani, cu o medie de evoluie a bolii de 9,22 ani.
53
Sex: raportul femei/brbai a fost de 21/11.
Vrst
Grupa de vrst Nr. pacieni actual Nr. pacieni la debut
18-20 ani 0 7(21,87 %)
21-30 ani 12 (37,50 %) 15 (46,87 %)
31-40 ani 11 (34,37 %) 9 (28,12 %)
41-50 ani 8 (25,00 %) 1 (3,25 %)
Peste 50 ani 1 (3,25 %) 0

Studii
Superioare 11 pacieni (34,37 %)
Liceale 14 pacieni (43,75 %)
Gimnaziale 6 pacieni (18,75 %)
coal ajuttoare 1 pacient (3,25 %)
Statut profesional
Angajai 9 pacieni (28,12 %)
n program de nvmnt 3 pacieni (9,37 %)
omeri 2 pacieni (6,25 %)
Pensionai de boal 14 pacieni (43,75 %)
Fr ocupaie 4 pacieni (12,50 %)
Statut marital
Cstorii 7pacieni (21,87%), dintre care 3 cu copii
Divorai 9 pacieni (28,12%) dintre care 4 cu copii n
ngrijire
Necstorii 16 pacieni (50,00%)
Toi pacienii beneficiaz de suport familial.
Diagnostic
Schizofrenie paranoid 23 pacieni (71,87 %)
Schizofrenie nedifereniat 4 pacieni (12,50 %)
Schizofrenie afectiv 5 pacieni (15,65 %)
Schimbarea tratamentului de la antipsihoticul clasic depot la antipsihoticul novel a fost
determinat de :
prezena a numeroase efecte adverse, semnificative din punct de vedere clinic
i intolerabile subiectiv, conducnd la non-complian la tratamentul de
ntreinere i anume: simptome extrapiramidale intense (mai ales akatisie i
tremor parkinsonian) la doze terapeutice de antipsihotic clasic, prezente la 9
pacieni (28,12 %) i tulburri cognitive (mai ales prosexice i mnezice de
54
nvare de informaii noi), anxietate i/sau agitaie, depresie la 5
pacieni(15,65 %).
controlul insuficient al simptomatologiei n ansamblu, cu recderi frecvente la
18 pacieni (56,25 %).
Durata tratamentului a fost de minimum 3 luni.
Numr de luni de tratament Numr de pacieni
3 luni 5 (15,65 %)
4 luni 2 (6,25 %)
5 luni 6 (18,75 %)
6 luni 4 (12,50 %)
9 luni 8 (25,00 %)
9 luni 3 (9,37 %)
Peste 12 luni 4 (12,50 %)

Evoluia scorurilor medii PANSS
SCALA La iniierea tratamentului Dup 3 luni
P pozitiv 23,33 12,22 scdere cu 47,62 %
N negativ 30,05 16,24 scdere cu 45,62 %
G general 62,07 31,75 scdere cu 48,84 %

Se observ o scdere a scorurilor pozitive, negative i generale cu peste 20 %, ceea ce indic
eficiena tratamentului; foarte important este scderea scorurilor negative.
Dintre dimensiunile scalei N, ameliorri marcate au nregistrat tocirea afectiv, retragerea
emoional, apatia, gndirea stereotip i mai puin gndirea abstract i spontaneitatea (scorul
fiecrui item a sczut de la 6-5-4 la 3-2). De asemenea, la nivelul scalei G scderi semnificative ale
scorurilor au nregistrat anxietatea, tensiunea, depresia, inhibiia psihomotorie, atenia, insight-ul,
tulburarea voinei i evitarea social. Ameliorarea tuturor acestor dimensiuni determin modificri
pozitive la nivelul funcionrii pacientului i la nivelul perspectivei pe care pacientul o are asupra sa
i asupra posibilitilor sale de a face fa solicitrilor mediului n care triete i de a se relaiona.
Evoluia scorurilor CGI

Scor de severitate CGI La iniierea tratamentului Dup 3 luni
6 sever 4 (12,50 %) 0
5 marcat 20 (62,50 %) 0
4 moderat 8 (25,00 %) 2 (6,25 %)
3 uor 0 24 (75,00 %)
2 la limit 0 6 (18,75 %)
1 normal 0 0

Scoruri CGI de ameliorare Numr de pacieni
3 puin ameliorat 2 (6,25 %)
2 mult ameliorat 24 (75,00 %)
1 foarte mult ameliorat 6 (18,75 %)
55
Evoluia scorurilor QOL-OMS
Dintre cele 6 domenii distincte ale scalei, i anume, sntate somatic, domeniul psihologic,
nivelul de independen, relaiile sociale, mediul, spiritualitatea, variaii semnificative n sensul
creterii scorurilor au nregistrat:
domeniul sntate somatic A de la 28, 11 la 33,41
domeniul psihologic B de la 41,63 la 56,72
domeniul nivel de independen C de la 38,28 la 46,67
domeniul relaii sociale D de la 34,52 la 40,42
De asemenea aprecierea global G a nregistrat o uoar cretere de la 10,97 la 12,17.
Evoluia scorurilor GAFF

Nivelul scorurilor Numr de pacieni Numr de pacieni
90-81 0 3 (9,37 %)
80-71 0 3 (9,37 %)
70-61 0 21(65,62 %)
60-51 0 5 (15,65 %)
50-41 8 (25,00 %) 0
40-31 20 (62,50 %) 0
30-21 4 (12,50 %) 0
20-10 0 0

Media scorurilor GAFF nainte de tratamentul cu olanzapin a fost de 34,44 iar dup 3 luni
de urmrire a crescut la 63,55.
Recidive: din lotul studiat 5 pacieni au prezentat cte o recidiv, la 4 pacieni nu a fost
necesar spitalizarea, ci doar creterea dozei de olanzapin la 15mg/zi timp de 2-3 sptmni. Un
pacient a fost internat pentru 2 sptmni.
Efecte adverse
Olanzapina a fost bine tolerat de toi pacienii, fr apariia unor efecte adverse cu excepia
creterii n greutate ntre 5 i 10 kg la 6 dintre pacieni

Discuii
Scderea semnificativ sub tratament a scorurilor PANSS pozitive, negative i generale, n
concordan cu ameliorarea clinic subiectiv, s-a asociat cu o cretere a scorurilor domeniilor
sntate somatic, psihologic, nivel de independen i relaii sociale din cadrul calitii vieii. Prin
urmare, controlul medicamentos eficient al simptomelor pozitive i negative ale schizofreniei
exercit o influen important asupra percepiei pe care pacientul o are despre calitatea vieii sale.
Aceast influen este cu att mai mare cu ct medicamentul este bine tolerat subiectiv i are un risc
sczut pentru efecte adverse, asigurndu-se astfel compliana la tratamentul pe termen lung i
consecutiv scderea riscului de recidiv.
56
Din punctul de vedere fenomenologic se face o distincie ntre simptomele negative
secundare (generate de simptomele pozitive, efectele adverse ale antipsihoticelor, mai ales clasice i
simptomele depresive postpsihotice sau corelate cu psihoza) i simptomele negative primare legate
direct de patofiziologia schizofreniei (Carpenter, 1985; Koreen, 1993). Simptomele negative
primare, cunoscute i ca simptome deficitare, sunt persistente, puin influenate de medicaia
antipsihotic i ele sunt responsabile de declinul progresiv n funcionarea social a pacientului i de
diminuarea substanial a calitii vieii sale. Studiile clinice cu antipsihotice novel aduc date
ncurajatoare n legtur cu eficiena acestor medicamente asupra simptomelor negative: fie
indirect, prin controlul simptomelor pozitive, efecte adverse reduse, controlul depresiei, ct i
direct, ceea ce nseamn influenarea simptomelor negative primare. n acest sens, Tollefson et al
ntr-un studiu din 1997 olanzapin vs. haloperidol arat c olanzapina a ameliorat semnificativ toate
dimensiunile SANSS i.e. aplatizarea afectiv, abulia, alogia, apatia, tulburrile prosexice, mai puin
anhedonia i asocialitatea.
Autorii consider c aceste efecte ale olanzapinei se datoreaz profilului ei farmacologic
pleotropic (activitate dopaminergic, serotonergic, muscarinic, adrenergic) i susin ipoteza c
simptomele negative se afl sub influena a mai multor neurotransmitori n cadrul unuia sau mai
multor circuite neuroanatomice.
Prezena efectelor adverse la un medicament scade acceptabilitatea lui de ctre pacient
compromind rezultatele tratamentului. n cazul antipsihoticelor efectele adverse cntresc pentru
pacient adeseori mai mult dect beneficiile pe termen lung i pacientul ntrerupe tratamentul; pe
termen scurt are impresia unei ameliorri a calitii vieii sale (M. Lzrescu).
Dei s-a artat c antipsihoticele clasice au fost eficiente n scderea riscului recidivei de la
65 % la 30 %, (Davis, 1975), non-compliana apare la cca. 30-40 % dintre pacienii tratai cu
preparate standard sau depot (Casey, 1998; Kane, 1985). Dintre efectele adverse, simptomele
extrapiramidale i cu deosebire akatisia se constituie n principale cauze de non-complian (Van
Putten, 1984). Akatisia pare a se corela i cu un rspuns slab la tratamentul antipsihotic (Marder,
1996). Instalarea acut a simptomelor extrapiramidale se coreleaz cu un risc crescut pentru
diskinezia tardiv, efect advers ce apare trziu n tratamentul cu antipsihotice clasice, dar este
invalidant i poate fi ireversibil, perturbnd i mai mult viaa pacientului. Medicamentele
anticholinergice destinate s corecteze simptomele extrapiramidale aduc efecte secundare
suplimentare i nu n ultimul rnd, accentueaz tulburrile cognitive.
Alte efecte adverse cu rsunet subiectiv important pentru pacient sunt: tulburrile cognitive,
anxietatea, simptomele depresive. Aceste efecte sunt reclamate mai ales de pacienii care i
continu activitatea profesional. Antipsihoticele novel par a avea o influen favorabil asupra
tulburrilor cognitive, fie prin lipsa efectelor anticholinergice (sau prezena lor redus), fie prin
57
efect specific (Barnes i Kane, 1996; Goldberg, 1995; Green, 1997) mediat probabil serotonergic.
Analog simptomelor negative, tulburrile cognitive sunt secundare, generate i/sau accentuate de
medicaia antipsihotic, dar i primare, adic deficite neurocognitive intrinseci bolii, prezente n
faza prodromal a bolii i persistente dup remisia simptomelor. Deficitele neurocognitive se
asociaz cu deteriorare funcional: scade capacitatea de achiziie a deprinderilor sociale, de
rezolvare a problemelor sociale, de integrare social. Actualmente ele au devenit inta unor
intervenii terapeutice precoce, eventual n prodrom sau la apariia primelor semne de boal, prin
programe de reabilitare cognitiv aflate n cercetare (Radomsky i Keshaven, 1999). De asemenea
exist date preliminarii care indic influenarea lor n sens pozitiv cu antipsihotice novel.

Concluzii
1. Olanzapina i-a dovedit capacitatea de a controla eficient simptomele pozitive i n
special negative ale pacienilor cu schizofrenie cronic, tratai anterior cu fluanxol depot
cu rezultate pariale.
2. Efectele adverse aprute au fost neimportante clinic i nu au cauzat disconfort
pacienilor. Pacienii au acceptat i tolerat medicaia foarte bine. La aceasta a contribuit
i uurina administrrii (1 tablet de 10mg seara).
bun acceptabilitate a medicaiei asigur compliana la tratamentul pe termen
lung, reducand astfel riscul recidivei.
3. Eficacitatea clinic s-a asociat cu o cretere a scorurilor domeniilor: sntate somatic,
psihologic, nivel de independen i relaii sociale din chestionarul de calitate a vieii QOL
OMS. Pacienii i-au mbuntit percepia asupra strii de sntate somatic i a
nivelului de confort psihologic; a crescut interesul pentru activitate i pentru relaionare, a
crescut mobilitatea, a reaprut sau a crescut dorina i posibilitatea de a exista autonom; s-
au ameliorat funciile cognitive (atenia i capacitatea de a asimila informaii noi).
4. Prin urmare, tratamentul eficient al schizofreniei are un rol major n influenarea calitii
vieii pacienilor i face posibil aplicarea programelor de reabilitare psihosocial.
Olanzapina ndeplinete aceste deziderate de eficien.


Bibliografie
1. Awad, A.G., Vorungati, L.N., 1996 Assessment of the patients subjective experience in
acute neuroleptic treatment: implications for compliance and outcome. International
Clinical Psyhopharmacology, vol 11, supll 2, 55-59.
2. Barnes, T., Kane, J.M., 1996 Choosing between old and new antipsychotics. Current
Opinion in Psychiatry, 9, 41-44.
58
3. Buchanan, R.W., Gold, J.M., 1996 Negative symptoms: diagnosis, treatment and
prognosis. International Clinical Psychopharmacology, vol 11, supll 2, 3-12
4. Casey, D., 1998 Schizophrenia: the whole patient. Synthelabo Groupe, July.
5. Lazarescu, M., 1999 Calitatea vieii n Psihiatrie. Ed. InfoMedica Bucuresti.
6. Perry, P.J., 1995 Clinical use of the newer antipshychotics drugs. Am. J. Health-Syst.
Pharm., 52(suppl.), S9-S14.
7. Radomsky, E., Keshavan, M.S., 1999 Early intervention may improve the overall
outcome in schizophrenia. International Psychiatry Today, vol. 9, nr. 4.
8. Stahl, H.S., 1999 Psychopharmacology of antipsychotics. Martin Duniz Ltd, London.
9. Tollefson, G.D., Todd, M.S., 1997 Negative symptoms: a path analytic approach to a
double-blind, placebo-and haloperidol controlled clinical trial with olanzapine. Am. J.
Psychiat., 154, 466-474.





















59


NOI IPOTEZE ASUPRA BAZELOR MOLECULARE ALE
ATIPICITII ANTIPSIHOTICELOR
Victoria Burtea
Universitatea Transilvania Braov


Rezumat
Utilizate tot mai adesea n practica clinica, antipsihoticele atipice au un mecanism
farmacologic de aciune nc neclar i cel mai probabil neunitar.
Articolul reprezint o trecere n revist a studiilor referitoare la aspecte moleculare,
modelul animal, neuroimagistic i aspecte clinice ale antipsihoticelor tipice i
atipice, n baza crora s-au formulat ipotezele mecanismului de aciune ale
antipsihoticelor atipice. Cele mai noi ipoteze accentueaz rolul constantei de
disociere (Koff) care este mai sczut dect a dopaminei n cazul antipsihoticelor
tipice i mai rapid dect a dopaminei n cazul majoritii antipsihoticelor atipice. A
devenit de asemenea clar c blocada 5-HT2 nu este necesar pentru ca un
medicament s se comporte ca un atipic. Pragul antipsihotic de ocupare a D
2
este
aproximativ 65 %, iar pragul de evitare al EPS este de aproximativ 80 %, indiferent
de gradul de ocupare al 5-HT
2
. Negnd ipotezele multireceptoriale, noile ipoteze
consider c efectul antipsihotic atipic poate fi produs printr-o modulare adecvat
numai a receptorului D
2
, blocada altor receptori nefiind nici necesar, nici
suficient.
Cuvinte cheie: schizofrenie, psihofarmacologie, antipsihotice atipice.


MOLECULAR BASIS OF ATYPICAL ANTIPSYCHOTICS
NEW HYPOTHESIS

Abstract
More and more used in clinical practice, the atypical antipsychotics have a
pharmacological action mechanism still unclear and most probably not unitary.
The article represents a review of the studies referring to the molecular aspects,
animal model, neuroimagistic and clinical aspects of typical and atypical
antipsychotics, based on which the hypothesis on the action mechanism of the
atypical antipsychotics was issued. The most recent hypothesis emphasize the role of
the dissociation constant (Koff), which is lower than the dopamine in the typical
antipsychotics and faster than the dopamine one in the typical antipsychotics and
faster than the dopamine one in most atypical antipsychotics. It also became clear
that the 5-HT
2
blockade is not necessary for a medicine to act as an atypical. The
antipsychotic threshold for D
2
occupation is approximately 65 %, and the EPS
avoidance threshold is approximately 80 %, disregarding the 5-HT
2
occupation
level. Denying the multireceptor model, the new hypothesis considers that the
antipsychotic effect can be induced through an adequate modulation of the D
2

receptor only; the blockade of other receptors is neither necessary, nor sufficient.
Key words: schizophrenia, psychopharmacology, atypical antipsychotics.

60
Exist un consens universal n a utiliza termenul de atipic pentru a descrie noile
antipsihotice (clozapina-Novartis, risperidona-Janssen, olanzapina-Lilly, quetiapina-AstraZeneca,
sertindolul-Lundbeck, ziprasidona-Pfizer, zotepina-Orion, amisulpridul-Sanofi-Synthelabo ).
Definiia atipicitii rmne ns nc neclar, dei n mod general este acceptat faptul ca
dou criterii sunt fundamentale pentru aceasta: absena sau reducerea capacitii de a induce efecte
secundare extrapiramidale (EPS) i reducerea capacitii de a crete nivelul plasmatic al prolactinei.
Nu exista un consens al definirii atipicitii n afara acestor dou criterii dei s-a ncercat extinderea
ei i asupra capacitii de a influena simptomele negative primare sau psihozele rezistente la
tratamentul cu antipsihotice tipice.
La nivel molecular, gradul de ocupare al receptorilor D
2
sau 5-HT
2A
a fost considerat drept o
condiie necesar a atipicitii unui antipsihotic. Fundamentarea ipotezei serotonin-dopamin a
atipicitii i aparine lui Meltzer (Meltzer Hy, Matsubara, Lee J.C, 1989) care a artat c
antipsihoticele atipice au o mai mare diferen ntre afinitile lor pentru 5-HT
2
i D
2
dect au
antipsihoticele tipice. In fapt, studiul efectuat pe 37 antipsihotice demonstra faptul c antipshoticele
atipice se difereniau de cele tipice prin afinitatea sczut pentru receptorii D
2
i prin afinitatea
nalt pentru receptorii 5-HT
2
.
Studiile PET asupra ocuprii receptorului D
2
(Farde & colab. 1992, Nordstron & colab.
1993, Kapur & colab. 2000) la pacieni care au luat diferite antipsihotice au sugerat faptul c pragul
rspunsului clinic i de apariie al efectelor secundare extrapiramidale ar putea fi strns corelat cu
gradul de ocupare al receptorilor D
2
. Astfel, o ocupare a receptorilor D
2
de 65 % pare s fie aceea care
asigur un rspuns clinic semnificativ (n sensul unei aciuni antipsihotice certe), att n cazul
antipsihoticelor tipice (ex. Haloperidolul, Kapur & colab. 2000) ct i n cazul antipsihoticelor
atipice (olanzapina, risperidona, Kapur, 1998; Kapur & colab. 2000, Knable & colab. 1997; Scherer
& colab. 1994; Tauscher & colab. 1999). Astfel, toate antipsihoticele, tipice sau atipice, blocheaz
un important numr de receptori D
2
, dei ele difer n cinetica ocuprii i a legturii dintre gradul de
ocupare i vrful atins. S-a observat de asemenea c pacienii cu un grad de ocupare al receptorilor
D
2
sub 72 % au exprimat efecte minime aspra nivelului prolactinei, n timp ce nivele ale ocuprii de
peste 72 % s-au caracterizat prin creteri semnificative ale prolactinei. Totodat s-a mai observat c
sub 78 % grad de ocupare nu apar efecte secundare extrapiramidale n timp ce peste acest prag ele
sunt prezente la majoritatea pacienilor. O posibil concluzie a acestor studii (teoretic, ntruct
clinic ea nu este fezabil) este aceea ca optimizarea ocuprii D
2
, n spe meninerea gradului de
ocupare a D
2
sub 72 % ar putea genera efecte atipice (n sensul absenei EPS i a creterii
nivelului prolactinei) chiar i n cazul unui antipsihotic tipic cum este haloperidolul.
Un alt argument al atipicitii, acela al ocuprii receptorilor 5-HT
2A
ntr-o proporie mai
mare dect a receptorilor D
2
(fenomen ntlnit n cazul risperidonei, olanzapinei, clozapinei,
61
quetiapinei i ziprasidonei), a fost demontat de studiile ce au artat c i antipsihoticele tipice, cum
ar fi clorpromazina (Trichard & colab. 1998), pot avea un grad nalt de ocupare al receptorilor
5-HT
2A
. Pe de alt parte, antipsihoticele atipice produc un grad nalt de ocupare a receptorilor
5-HT
2A
la doze care nu sunt antipsihotice (ex. <2mg/zi risperidona, <5mg/zi olanzapina, <50mg/zi
clozapina), n timp ce se tie faptul c ele devin eficiente antipsihotic numai la doze la care gradul
lor de ocupare al receptorilor D
2
trece de 65 %. S-ar prea c blocarea 5-HT
2A
nu este suficient
pentru rspunsul antipsihotic (Kapur, 1998; Kapur & colab 2000). S-a observat de asemenea c EPS
sunt n mod ferm corelate cu un grad al ocuprii receptorilor D
2
de peste 78 %, indiferent de tipul de
antipsihotic, tipic sau atipic, iar blocarea concomitent a receptorilor 5-HT
2A
nu confer imunitate
pentru acestea (Kapur & colab. 1997; Kapur & colab. 2000).
Un alt posibil argument susinut ca baz a atipicitii, i anume antagonizarea receptorilor D
4

a fost i el abandonat n urma studiilor lui Seeman, 1994, Seeman & colab. 1997, Scatton & colab.
1997, ce au relevat c afinitatea unor medicamente tipice cum ar fi haloperidolul, clorpromazina,
pentru receptorii D
4
este chiar mai mare dect aceea a unor medicamente atipice cum ar fi clozapina
sau olanzapina, precum i c medicamente care practic nu au nici o afinitate pentru receptorii D
4

cum sunt quetiapina i amisulpridul sunt antipsihotice atipice.
Regndind bazele moleculare ale atipicitii, Kapur i Seeman 2001, consider c o
afinitate sczut pentru receptorii D
2
, prin ea nsi este suficient pentru a produce activitate
antipsihotic atipic, indiferent de oricare alt profil receptorial. Cu ale cuvinte generaia actual de
antipsihotice atipice este atipic nu pentru c antipsihoticele au nivele nalte de ocupare 5-HT
2
sau
D
4
, ci pentru ca ele au o afinitate sczut pentru receptorii D
2
. Afinitatea unui medicament dat
pentru un receptor dat constituie cel mai comun parametru utilizat n caracterizarea aciunii unui
medicament. Afinitatea sau mai corect Kd este n mod obinuit msurat prin mixarea ntr-o
eprubet a unui esut purttor de receptor cu concentraii variate ale unui antipsihotic. Dup dou
ore, cnd reacia a atins echilibrul, afinitatea este msurat ca fiind concentraia de medicament
cerut pentru ocuparea a 50 % dintre receptori. ntruct in vivo dinamica neurotransmitorilor
umani nu se menine constant pentru dou ore pentru a permite interaciunilor medicament-
receptor s ating echilibrul, procesul dinamic al interaciunii medicament-receptor este mai bine
exprimat prin parametrii mai rudimentari, i anume ratele de asociere (Kon) i disociere (Koff).
Legarea unui antipsihotic de un receptor este un proces dinamic cu o continu asociere i disociere.
Afinitatea prin definiie este raportul dintre Koff i Kon (proporia n care medicamentul se mic de
pe i pe receptor. Experimentele (Kapur & Seeman, 2000) au demonstrat c toate antipsihoticele
(tipice sau atipice) se ataeaz de receptorii D
2
cu o rat constant, similar; ele difer numai prin
ct de repede se desprind de receptor. n experimentele de laborator disocierea unui antipsihotic de
receptor este determinat n principal de proprietile moleculare ale medicamentului. n creierul
62
viu, disocierea unui medicament de receptor este determinat att de fenomenele aprute la nivel
molecular n sinaps, ct i de fenomenele la nivel de sistem. In vivo, antipsihoticele intr n
competiie cu dopamina endogen. Se estimeaz c o proporie de 25 40 % a receptorilor D
2
sunt
ocupai de dopamina endogen (Laruelle & colab. 1997 i Ginovart & colab. 1997). Antipsihoticele
i exercit efectul modulnd transmisia dopaminergic. Astfel, dac n experimentele de laborator
antipsihoticele se leag de receptori fr competiie, n creier, antipsihoticele sunt mereu n
competiie cu dopamina endogen. Rata cu care un medicament se disociaz de un receptor sau
Koff-ul lui, este caracteristica cea mai importat ce determin competiia dintre medicament i
dopamin. Cu ct Koff-ul este mai rapid, cu att mai repede medicamentul rspunde la schimbrile
dopaminei endogene. Un fapt observat la pacienii tratai a fost acela c antipsihoticele cu afinitate
joas pentru D
2
sunt date n doze proporional mai nalte. De exemplu, o doz clinic de 2-4 mg/zi
de haloperidol, comparativ cu 200-400 mg/zi de clozapin, care are o afinitate de 100 de ori mai
joas dect haloperidolul. Cu alte cuvinte clozapina, merge pe i de pe receptor de 100 de ori n
timpul n care haloperidolul face aceasta o singur dat. Este de presupus c antipsihoticele cu o
joas afinitate pentru D
2
i o constant de disociere rapid permit o transmitere dopaminic
fiziologic mai bun. Totodat datorit capacitilor sczute de a genera EPS ele ar putea influena
mai mult simptomele negative primare.
Fr a susine c mecanismul de aciune atipic nu ar putea fi generat de rspunsul
agonist/antagonist sau de raportul preferenial presinaptic-postsinaptic, Kapur & Seeman, (2001)
accentueaz rolul receptorilor D
2
considernd c o afinitate joas de blocare a D
2

i o constant
rapid de disociere constituie cheia a ceea ce n mod curent este denumit efectul antipsihotic atipic.
O constant rapid de disociere de receptorii D
2
face ca un antipsihotic s fie mai adecvat
transmiterii dopaminei fiziologice, permind un efect antipsihotic fr EPS, creteri ale prolactinei
i simptome negative secundare.


Bibliografie
1. Farde, L, Nordstrom, AL, Wiesel, FA, Pauli, S, Halldin, C, Sedvall, G, 1992 Positron
emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in
patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side
effects. Arch Gen Psychiatry; 49:538-544.
2. Ginovart, N, Farde, L, Helldin, C, Swahn, CG, 1997 Effect of reserpine-induced
depletion of synaptic dopamine on [11C] raclopride binding to D2-dopamine receptors in te
monkey brain. Synapse; 25:321-325.
63
3. Kapur, S, Zipursky, R, Remington, G, Jones, C, McKay, G, Houle, S, 1997 PET evidence
that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the
treatment of schizophrenia. Am. J. Psychiat., 154, 1525-1529.
4. Kapur, S. A new framework for investigating antipsychotic actions in humans: lessons
from PET imaging. Mol Psychiatry 3,135-140
5. Kapur, S, Zipursky, R, Jones, C, Remington, G, Houle, S, 2000 Relationship between
dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of
first-episode achizophrenia. Am J Psychiat., 157, 514-520.
6. Kapur, S, Zipursky, R, Jones, C, Shammi, CS, Remington, G, Seeman, P, 2000 A
positron emission tomography study of quetiapine in schizophrenia; a preliminary finding
of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy.
Arch. Gen. Psychiat., 57, 553-559.
7. Kapur, S, Seeman, P, 2000 Antipsychotic agents differ in how fast they come off th
dopamine D2 receptors: implications for atypical antipsychotic action. J. Psychiat.
Neurosci., 25, 161-166.
8. Kapur, S, Seeman, P, 2001 Does fast dissociation from the dopamine D2 receptor explain
the action of atypical antipsychotics?: a new hypothesis. Am. J. Psychiat., 158, 360-369.
9. Knable, MB, Heinz, A, Raedler, T, Weinberger, DR, 1997 Extrapyramidal side effects
with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiat.
Res. Neuroimaging, 75, 91-101.
10. Laruelle, M, DSouza, CD, Baldwin, RM, Abi-Dargham, A, Kanes, SJ, Fingado, CL,
Seibyl, JP, Zoghbi, SS, Bowers, MB, Jatlow, P, Charney, DS, Innis, RB, 1997 Imaging
D2 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology,
17, 162-174.
11. Meltzer, HY, Matsubara, S, Lee, JC, 1989 The ratios of serotonin-2 and affinities
differentiate atypical and typical antipsychotic drugs. Psychopharmacol. Bull., 25, 390-392.
12. Nordstrom, AL, Farde, L, Wiesel, FA, Forslund, K, Pauli, S, Halldin, C, Uppfeldt, G, 1993
Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a
double-blind PET study of schizophrenic patients. Biol. Psyhiat., 33, 227-235.
13. Scatton, B, Claustre, Y, Cudennec, A, Oblin, A, Perrault, G, Sanger, DJ, Schoemaker, H,
1997 Amisulpride: from animal pharmacolgy to therapeutic action. Int. Clin.
Psychopharmacol., 12 (suppl 2), S29-S36.
14. Scherer, J, Tatsch, K, Schwartz, J, Oertel, W, Kirsch, MC, Albus, M, 1994 Striatal D2-
dopamine receptor occupancy during treatment with typical and atypical neurolrptics. Biol
Psychiat., 36, 627-629.
64
15. Seeman, P, Van Tol, HHM, 1994 Dopamine receptor pharmacology. Trends Pharmacol.
Sci., 15, 264-270.
16. Seemap, P, Corbett, R, Van Tol, HHM, 1997 Atypical neuroleptics have low affinity for
dopamine D2 receptors or are selective for D4 receptores(reply).
Neuropsychopharmacology; 16, 127-135.
17. Tauscher, J, Kupfferie, B, Asenbaum, S, Fischer, P, Pezawas, I, Barnas, C, Tauscher-
Wisniewski, S, Brucke, T, Kasper, S, 1999 In vivo 1231 IBZM SPECT imaging of
striatal dopamine-2 receptor occupancy in schizophrenic patients trated with olanzapine in
comparison to clozapine and haloperidol. Psychpharmacology (Berl); 141, 175-181.
18. Trichard, C, Palliere-Martinot, ML, Attar-Levy, D, Recassens, C, Monnet, F, Martinot, JL,
1998 Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of
chlorpromazine, clozapine and amisulpride in schizophrenic patients. Am. J. Psychiat., 155,
303-508.




















65


NOI RECONSIDERRI I PERSPECTIVE N BOALA BIPOLAR
C. Friedmann
Clinica de Psihiatrie Constana



Rezumat
n ciuda unei nete diferenieri ntre formele unipolare i bipolare ale tulburrii
afective pe criterii clinico genetice, exist o multitudine de forme i condiii afective
mixte i intermediare cu variate rspunsuri terapeutice derutante pentru clinicianul
practician.
De exemplu, monoterapia antidepresiv eficient i fr riscuri n depresiile unipolare
devine dezastruos de auto-distructiv la pacienii bipolari (risc de agravare a evoluiei
bolii cu viraje manice brute i reciclare rapid).
Strategia asocierii medicaiei stabilizatoare a dispoziiei (sruri de litiu i derivaii de
ac. valproic i mai ales substituirea triciclicelor cu medicaie antidepresiv ISRS a
ameliorat evoluia i prognosticul depresiei bipolare, a formelor mixte i mai ales a
tulburrilor de spectru bipolar de tip soft(soft bipolar disorders-bipolar II i III).
Cuvinte cheie: spectru bipolar, forme afective mixte, manie disforic.


UPDATES AND PERSPECTIVES IN BIPOLAR DISORDER

Abstract
In spite of a clear-cut distinction between unipolar and bipolar forms of affective
disorders on clinico-genetical grounds, there are lots of multiresponsive therapeutic
mixed and intermediate forms that are rather confusing for the clinical practitioner.
For the instance, the antidepressant monotherapy that is efficient and safe in
unipolar patients becomes self-defeating and even disastrous in bipolar patients (risk
of worsening the clinical outcome and manic switching or rapid cycling).
The strategy of augmentation the mood-stabilizing medication (lithium salts and ac.
Valproic derivatives especially) and substitution of the tryciclics with SSRIs) has
improved the outcome of bipolar depression, mixed affective forms and above all the
so-called soft bipolar conditions.
The paper is dealing with this topic with a special impetus on this latter category of
affective pathology (soft bipolar conditions).
Key words: bipolar spectrum, mixed affective forms, dysforic mania.


Dac o condiie sine qua non esenial a bipolaritii este existena unor fenomene sau i mai
clar a unui unic episod de hipomanie sau manie (criteriologia Robert Spitzer RDC), prezena
depresiei n cursul unui episod manic n desfurare schimb evoluia i prognosticul bolii n
totalitate (1).
Existena acestor foarte controversate i difereniate forme de combinare a simptomelor
manice cu simptomele depresive ne conduc la concluzia unor interpoziii i interaciuni ntre cele
dou categorii de manifestri afective, care se cer elucidate i ordonate dup noi criterii
66
epistemologice, din raiuni foarte pragmatice difereniate n primul rnd de responsivitatea
terapeutic, ceea ce ne-a i motivat n a aborda aceast tem insuficient dezbtut de psihiatrii notri
preocupai att de aspectele tematice, ct i de premizele practice ale opiunilor de abordare a
acestui capitol de patologie.
O multitudine de forme clinice aspir spre poziia unor entiti cu o mai bun delimitare
nozologic, apte s fac fa tendinelor de dispersare a granielor de delimitare, nc supuse unor
remanieri nozologice, de la Kraepelin i n prezent, din cauza provocrilor, mai ales de ordin
prognostic i terapeutic.
Asistm la naterea unor noi subforme de boal afectiv sau dimpotriv ne rentoarcem la
vechile structurri nozologice ale nceputului psihiatriei moderne?

1. Depresia major i pstreaz constant uniformitatea fie c aparine formelor unipolar-
recureniale, fie c intr n circuitul bipolar I sau II.
Impactul terapiei antidepresive este ns total diferit, dar pentru pacienii unipolari
(depresivi, firete) i plin de surprize, complicaii i agravri, n cazul pacienilor bipolari.

2. n cazul pacienilor cu boal bipolar tip II, nedelimitarea net a episoadelor
hipomanice poate duce la confuzii ale temperamentelor hipertimice i/sau ciclotimice ale cror
variaii i modulri n rezonan cu evenimentele de via, pot ridica serioase probleme de
difereniere cu instabilitatea afectiv a personalitii borderline ntr-un sens sau altul, asociat cu
accidente afective majore (episoade depresive majore i tentative de suicid,etc.).

3. Riscul de bipolarizare a depresiei la primele episoade nu poate fi subestimat, fapt ce l-a
determinat pe Akiskal s defineasc o suit de variabile predictive a bipolarizrii unei depresii de
acest fel, creia i-a i sugerat denumirea de depresie pseudounipolar (hipomania indus
terapeutic, antecedentele familiale de boal bipolar, semnificativ ncrctur genetic, depresia cu
hipermanie, depresia psihotic, transmisie familial multigeneraional, debut postpartum, debut
timpuriu sub 25 ani, etc.).
Criteriile predictive ale lui Hagop Akiskal (2) au fost confirmate de markerii clinico-
biologici ai lui Bourgeois (9) i de cele 3 grupri de studiu iniiate de grupul elveian a lui Jules
Angst, grupul American al lui Quitkin i grupul lui Winokur i Clayton (Iowa), care au gsit un
consens final i asupra a dou forme diferite de boal bipolar I: 1. una cu predominena depresiei i
2. una cu predominena maniei, cu puncte de plecare diferite, cel puin pentru prima form de boal
bipolar I (aparent, la primele episoade cu evoluia unei forme de depresie pur-unipolar).
Pseudounipolarii convertii ulterior n bipolari I nu se difereniau de pacienii cu tulburare
depresiv major, cu excepia unei simptomatologii mai acute, mai severe i cu elmente psihotice
67
intense, n timp ce pseudounipolarii convertii la tulburarea bipolar tip II, prezentau un profil de
patologie afectiv cu debut mai precoce, intersectri comorbide cu abuzul de droguri i alcool,
severe i recidivante, comportamente disruptive n plan educaional, marital, ocupaional i chiar
delictual, precednd apariia episoadelor hipomanice, deseori discrete ca intensitate, iar episoadele
depresive avnd un potenial suicidar mult mai sever i grevat de o mortalitate mult mai mare.
Diagnosticul acestei subtipologii poate trece subevaluat (criteriologia DSM IV impunnd o
durat de doar minimum 4 zile de manifestri hipomanice), ceea ce dup W. Coryell (12) ar fi un
argument suficient motivat clinic de a-i considera pe probanzii bipolari II cu aceste simptome, ca
fiind clasificai eronat n acest mod, cnd de fapt sunt probanzi bipolari tip I, diagnosticul fiind
deseori retrospectiv.
Depresivii bipolari I prezint un risc suplimentar, dup Coryell, n a face episoade manice
foarte severe i disruptive, cu consecine greu de anticipat. Litiul ar fi agentul cu efect profilactic
asupra riscului de recdere n manie i cu bune efecte antidepresive fa de depresia bipolar I,
comparativ cu antidepresivele triciclice relativ mai puin eficiente fa de acest tip de depresie
bipolar I.

4. Strile mixte i mania disforic: prezint mult mai multe dificulti de diagnostic i
tratament, prin prezena simptomelor depresive n nsi textura strilor maniacale ale acestor
pacieni, deseori etichetai ca prezentnd depresii refractare
Cunoscute nc din edia a 6-a (1899) a Lehrbuch-ului lui Kraepelin aceste forme i
subforme mai greu de diagnosticat i de difereniat de depresiile i maniile pure, cunoscute i sub
denumirea generic de Grundstrungen (tulburri fundamentale) sunt n marea lor majoritate ( 6
din 8 tipologii Kraepeliene), n fond forme mixte cu mari dificulti de tratament din cauza
riscului de switchuri hipomano-manice de scurt durat sau chiar reciclare rapid.
Pentru importana lor istoric i clinic, dar i pentru actualitatea aspectelor diagnostice,
prognostice i terapeutice ce le ridic strile disforice, le reamintim n cele ce urmeaz, ca o
confirmare a observaiilor lui Cassidy i colab. (10,11) (frecvena mare a dispoziiei depresive la
pacienii manici i o semnificativ diminuare a productivitii ideatorii constatare fcut de nsui
Kraepelin n ediiile succesive ale tratatului su (1899, 1913) sub denumirea de Gendankenharm):
mania depresiv sau forme anxioase de manie;
depresia agitat nevoia de comunicare, verbozitate accentuat, dar monoton tematic;
mania neproductiv fr fug de idei, productivitate ideativ sczut
Gendankenharm;
mania stupuroas cu disforie verbal (heitere verstimmung) poate prezenta raptusuri
violente i conduite imprevizibile (importan medico-legal);
68
depresie fr ideaie cu coninut depresiv;
mania inhibat inhibiie psihomotorie ca n mania stupuroas
Aceast paradigm clinic anticipat, confirmat i reconfirmat ulterior de mai muli autori
sub diferite forme de acolare, subsumare i manifestare evolutiv-prognostic a unor aparent
paradoxale forme mixte, de ctre autori ca Clonninger, Svrakic, dar mai ales Hagop Akiskal ar fi de
fapt o reactualizare a conceptului fundamentat nozologic de ctre Kraepelin sub denumirea de
psihoz maniaco-depresiv n forma ei definitiv, n 1921 (Akiskal, 3,4,5) argument determinant n
favoarea conceptualizrii caracterului unitar al tulburrilor afective.
Astfel, boala afectiv conceput ca un continuum cuprindea melacolia recurent, mania cu
toate formele ei clinice inclusiv disforice, cu reciclare rapid, etc., precum i fluctuaiile
subsindromale de activitate, dispoziie i cogniie, n terminologia Kraepelian echivalate cu
termenul de temperamente afective, postulate ca fiind forme ale unui acelai proces morbid. Cele
6 forme de stri mixte descrise de Kraepelin, ar fi, prin urmare, combinaii i asocieri de stri
depresive i manice, care apar simultan, constituind elementele unei tulburri afective unitare,
concept care a prevalat n psihiatrie pn la descoperirea bipolaritii ca factor de departajare a bolii
afective n unipolare i bipolare (Leonhard, 1965; Angst, 1966; Perris, 1966; Winokur,1966).
DSM-III-R a preluat aceast dihotomie conceptualiznd dou forme autonome de boal
afectiv cu evoluie, terapie i prognostic diferit.
Studiile ulterioare ale lui Akiskal au reluat propriile cercetri i altele de sorginte familial
genetic (Taylor, Abrams, 1980 20), pentru a argumenta n favoarea unui continuum ntre formele
unipolare i cele bipolare, cu readucerea n discuie a multor forme de depresie ciclic, care dup
opinia mai sus citatului autor ar aparine mai degrab spectrului bipolar de boli afective, despre care
vom aminti n cele ce urmeaz, n chiar cuprinsul acestui articol (6).

5. Corelaiile temperamentale cu boala bipolar
Exist o multitudine de raporturi corelative ntre structurile de personalitate premorbid
concepute ca structuri temperamentale, chiar dac cele dou noiuni nu costituie identiti
superpozabile, temperamentul fiind n opinia lui Allport (8) dup cum este cunoscut materia prim
constituional genetic ce formeaz personalitatea sau n termeni metaforici atmosfera intern
n care este zmislit i se dezvolt personalitatea uman.
n spirit neo-Kraepelian, perturbrile temperamentale sunt considerate de Akiskal
prerogative predispoziionale pentru tulburri afective din gama tulburrilor de spectru bipolar, ceea
ce ar putea deveni efecte distale, dar evident patoplastice, n nlnuirea patogenic dintre factorii
endogenetici la care s-ar asocia i factori aparent exogeni (evenimente adverse de via i diverse
stiluri afective, de ex.), concepui ei nii indirect ca elaborri temperamentale n accepiunea
unor studii psihogenetice foarte recente (Kenneth Kendler, 1999, 18).
69
Astfel structurile de temperament ciclotimic, hipertimic, distimic i instabil sunt n
fond fenotipic vorbind manifestrile comportamentale proximale a tulburrilor afective n faza
premorbid a bolii (Akiskal, 1996, 7).
n viziunea unor cercettori de dat mai recent (Cloninger et al. 1998, 13) acest tip de
abordare este mai degrab o configurare multidimensional care include att componenta
temperamental, ct i pe cea caracterial.
Chestionarul tridimensional de personalitate care pune n eviden i cuantific dimensiunile
temperamentale i caracteriale, imaginat de Cloninger, aduce n actualitate asocieri dimensionale
foarte interesante i concludente, cu caracter predictiv n acelai timp. Astfel indivizii cu distimie ar
produce o combinaie de ratinguri crescute pe dimensiunea de evitare a situaiilor nociv-periclitante
(Harm avoidance) i a explorrii i cutrii noutii (Novelty seeking), n timp ce comportamentul
agresiv-impulsiv s-ar asocia cu scoruri nalte pe dimensiunea NS i scoruri joase pe HA (evitarea
situaiilor nociv-periclitante).
n acelai studiu Cloninger, Bayon i Svrakic (1998, 13) au identificat 8 tipuri concepute pe
modelul explorrii dimensiunilor caracteriale (melacolic, hipertimic creativ, dependent,
ciclotimic, schizotipal dezorganizat, autocratic, organizat i fanatic) i le-au corelat cu cele 4 stri
fundamentale descrise de Kraepelin i reconfirmate de Akiskal n studiile ulterioare (manic,
ciclotimic, iritabil i depresiv-melancolic). Toate studiile au demonstrat c dimensiunile
temperamentale sunt repere mult mai solide i concludente n definirea i explicarea
polimorfismului clinic, dect variabilele psihopatologiei, traduse n diverse structurri nozologice
ale patologiei afective.

6. Spectrul bipolar versus tulburarea bipolar
Aparent cadrul tulburrii bipolare pare mult mai bine conturat i implicit acceptat, dect
noiunea de spectru bipolar pentru cei ce n-au nc uzana i documentarea necesare nelegerii
acestei sintagme n cuprinsul semantic al orientrilor actuale. Ca s simplificm lucrurile, noiunea
de spectru bipolar ar terge graniele dihotomiei dintre unipolar i bipolar rentronnd conceptul de
boal n viziune monist, prin care Kraepelin aborda diferitele entiti de boal afectiv ca un
continuum de pri i elemente componente ale unui acelai proces patologic.
Tulburarea bipolar I forma manicdepresiv nu ridic probleme deosebite de diagnostic
n formele clasice de manifestare. Episoadele maniacale n schimb pot cuprinde un repertoriu
simptomatologic necaracteristic pentru boala afectiv (perturbri de ordin sexual, conduite bizare,
acte antisociale, psihoz paranoid, manifestri psihotice explozive, episoade psihotice
confuzionale) ce expun clinicianul la erori de diagnostic cu schizofrenia.
Pacienii cu stri de excitaie psihotic i evoluie bifazic i aspecte schizofreniforme,
etichetai ca schizoafectivi dup criteriologia DSM-IV, sunt n fond subtipologii bipolare I cu
70
ncrctur genetic i risc genetic de transmitere a tulburrilor afective la membrii ai familiilor
acestora (Gershon, 16).
Mult mai multe provocri diagnostice i terapeutice ridic n practica clinic curent
spectrul tulburrilor bipolare tip soft. DSM-IV le-a acordat un statut nozologic sub denumirea
de bipolar II, dar ele sunt mai complexe, mai frecvente, mai polimorfe i puin cunoscute de
psihiatrii, n sensul unei nelegeri consensuale a acestui tip de patologie afectiv (Akiskal, 4, 5).
Aceti bipolari , tip soft sunt bipolari tip II cu depresie recurent i episoade hipomanice
sau hipertimice, descrii ca atare de Dunner i colab. (1976, 15).
Strile mixte disforice de tipul maniei depresive sunt deseori caracterizate prin intruziunea
unor fenomene depresive genernd un tablou psihotic cu agitaie, dispoziie disforic hipertimic,
insomnie sever, ideaie suicidar, hipersexualitate, delir persecutor, halucinaii auditive, stri
confuzionale.
Un asemenea caz descris pentru prima dat de Himmelhoch i colab. (1976. 17) a
demonstrat nocivitatea folosirii neurolepticelor n strile mixte cnd sunt prescrise pentru atenuarea
agitaiei, deoarece prin efectul de aplatizare afectiv pot genera falsa impresie a existenei unor
simptome Bleuleriene de prim rang, asemntoare celor ntlnite n schizofrenie.
Akiskal a acordat o considerabil importan tipurilor bipolare II i III, care prin frecvena
foarte ridicat i complicaiile grave, severe ce le pot antrena, necesit abiliti clinice speciale i o
bun informare a psihiatrului pentru diagnostic corect i terapie adecvat. Cnd vorbim de terapie
la aceti pacieni se impune din capul locului evitarea cu desvrire a folosirii triciclicelor i
pruden chiar i la uzitarea ISRS, oricum recurgerea la protecia ortotimizantelor ca msur de
protecie pentru evitarea virajelor hipomanice sau manice i a reciclrilor rapide sau ultrarapide.
Pacienii depresivi cu aparen de unipolaritate pot aparine categoriei de pre-bipolari ce
vor dezvolta rapid switch-uri hipomanice la provocarea farmacologic, adevrat test de
departajare diagnostic a formelor bipolare de formele non-bipolare. Acetia aparin categoriei de
bipolar III.
Studiul colaborativ Pisa Memphis (Cassano-1992, 14) a dovedit din punct de vedere
genetic c ntre formele de tip bipolar I i cele soft (bipolarii II i III) nu exist nici o diferen.
Mai mult, pacienii cu simptome distimice, mai cu seam n formele cu minidepresie
intermitent, deseori trecnd nediagnosticate i ele fiind forme de boli de spectru bipolar, au
dezvoltat n 1 din 3 cazuri, viraje hipomanice dup farmacoterapie cu antidepresive, n toate studiile
prospective efectuate de psihiatrii diligeni, de ambele pri ale Atlanticului. Copii cu tulburri
distimice monitorizai prospectiv au progresat spre forme de manie mixt-disforic. Copii cu
tulburri distimice fac viraje hipomanice, mai ales dup un episod depresiv major suprapus peste
71
background-ul distimic aducnd dovada faptului c o proporie nsemnat de cazuri de depresie
dubl aparin i ele spectrului de bipolari soft.
n plan genetic pacienii cu depresii unipolare au un numr mai sczut de rude cu boal
bipolar n timp ce probanzii bipolari prezint un numr semnificativ mai mare de rude cu depresie
unipolar, despre care Akiskal prin studii de agregare familial i monitorizare clinic longitudinal
afirm c ar fi n fapt pseudounipolari, adic pacieni predispui la decompensri hipomanice
spontane sau viraje hipomane, hipertimice la medicaia antidepresiv.
Studiile efectuate n centrele specializate ale Spitalului Johns Hopkins (Simpson et al., 1993,
19) au demonstrat fr nici un dubiu prevalena n pedigree-ul spectrului bipolar a tulburrii
bipolare de tip II.
Variabilitatea formelor mixte este demonstrat de existena unor forme de depresie agitat
(de fapt forme mixte) care va impune folosirea unor strategii mai aparte, precum este evitarea
antidepresivelor i n schimb folosirea preferenial a astabilizatorilor de dispoziie i a
antipsihoticelor atipice, dar mai ales a terapiei electroconvulsivante foarte eficace n acest tip de
depresie mixt.
Starea depresiv mixt este o entitate a formelor mixte i nu o simpl nuan deiagnostic,
constituind o bun parte a cohortei de pacieni depresivi cu fenomene de refractaritate terapeutic i
n care temperamentul extrovert este un echivalent predispoziional de bipolaritate ce i manifest
fora destabilizatoare a intruziunii acestuia, n plin afect depresiv.
Akiskal vorbete despre 8 forme de boal bipolar, ceea ce constituie doar un preambul
pentru o mult mai larg ncrengtur de boli avnd acelai numitor comun = spectrul bipolar, mult
mai ncptor i cuprinztor, pentru variabilitatea formelor de boal afectiv ce rspund criteriilor
de bipolaritate ca diagnostic, evoluie, prognostic i terapie.

Concluzii
1. Aceste formulri i reformulri nozologice vin n sprijinul existenei unei cohorte
reprezentative de pacieni cu depresii rezistente, print-o nerecunoatere i nediagnosticare
corect a formelor de apartenen real a unor stri de boal afectiv aparent ireductibile
i refractare la tratament.
2. O problem ce se cere imperios elucidat este raportul abordrii dimensional versus
categorial i implicit a raporturilor corelative ntre personalitate pe deoparte i profilul de
psihopatologie pe de alt parte. De exemplu, rspunsul la ntrebarea este personalitatea
depresiv o entitate distinct de temperamentul distimic? ar da rspuns i la dilema nc
nesoluionat, evocat n enunul de la punctul 2.
72
3. Care este raportul exact n ecuaia de complementaritate dintre trsturile de personalitate
i cea de stare (condiie sau simptom), care ar putea deveni o chestiune de semantic sau
o dilem ontologic, cu toate consecinele clinico-empirice ce decurg din dificultatea de
exemlpu de definire a unor constructe de genul tulburare schizoafectivi /sau
personalitate premorbid?
4. Prin consecinele de ordin evolutiv, minidepresiile cu switch-uri hipomane i dispoziie
ciclotimic i hipertimic, chiar episodic, intermitent au un potenial recidivant mare,
cu invaliditate major i perturbri adaptative majore, dac nu sunt diagnosticate i tratate
corespunztor, fiind deseori etichetate eronat ca tulburri de personalitate (narcisice,
histrionice, borderline), tulburare exploziv intermitent, tulburare hiperactiv cu deficit
de atenie la persoane adulte, politoxicomanii, alcoolism episodic, etc.
5. Strile mixte sunt eronat etichetate ca forme de depresie refractar, deseori incurabile,
necesitnd doar schimbarea abordrii terapeutice (de exemplu tratate cu TEC).
6. Depistarea din timp cu efect predictiv a bipolaritii poate evita virajele hipomanice sau
hipertimice, foarte frecvente n practica clinic.
7. Diagnosticarea corect a microdepresiilor i a strilor hipomane cu durat scurt (1 3
zile sau chiar i mai puin) pot evita complicaii de severitate (suicid, acte licenioase cu
dezinhibiie sexual sau comiterea unor acte antisociale, etc.).
8. Diagnosticarea precoce i corect a formelor mixte foarte frecvente i simulnd
refractaritatea terapeutic ca i evitarea virajelor terapeutice manice sau a reciclrilor
rapide i ultrarapide.
9. Asortarea profilului de temperament cu rspunsul terapeutic (la terapia farmacologic i
la terapia cognitiv-comportamental) ar avea caracter predictiv asupra eficienei
terapeutice.
10. Introducerea unor noi algoritmi terapeutici. Litiul rmne terapia de elecie a bipolarilor
la concentraie plasmatic optimizat de pn la 1mmol/l cu adaosul de ISRS i
stabilizatori de dispoziie conform Algoritmului Consensual European.
Ghidul Expert Consensual American stipuleaz n managementul depresiei bipolare
asigurarea unei asocieri de stabilizatori de dispoziie (SD), antidepresant de tip ISRS plus
medicaie antipsihotic atipic. Antidepresivul de elecie n SUA rmne bupropionul
(Wellbutrin) i preferenial ISRS fa de triciclice din cauza riscului de reciclare rapid i
ultrarapid. Celelalte terapii farmacologice propuse n managementul depresiei bipolare
(lamotrigina, topiramatul, ritalina i inozitolul) rmn s fie abordate ntr-o proxim
lucrare ce va vedea lumina tiparului n aceeai publicaie.

73
Bibliografie
1. American Psyhiatric Association, 1995 Practice guideline for treatment of patients with
bipolar disorder. American Psychiatric Press, 74.
2. Akiskal, H.S., 1981 Subaffective disorders: dysthymic, cyclothymic and bipoar II
disorders in the borderline realm. Psychiatr. Clin. North Am., 4,1.
3. Akiskal, H.S., 1994 Dysthymic and cyclothymic depressions: therapeutic considerations.
J. Clin. Psychiat., 55 (suppl 4), 4, 51.
4. Akiskal, H.S., 1995 Mood Disorders: clinical features. In Kaplan H, Sadock BI, eds.
Comprehensive textbook of Psychiatry. VI. Baltimore. Wilkins & Williams, 1123-1152.
5. Akiskal, H.S., 1981 Subaffective disorders: dysthymic, cyclothymic and bipolar II
disorders in the borderline realm. Psychiatr. Clin. North. Am., 4, 25-46.
6. Akiskal, H.S., Walker, P.W., Puzantian, W.R. et al, 1983 Bipolar outcome in the course
of depressive illness: phenomenologic familial and pharmacologic predictors. J. Affect.
Disord., 5. 115-128.
7. Akiskal, H.S., 1996 Temperamental foundation of affective disorders. In Mundt C,
Goldstein MI, Hahlweg K., Fieller R. (Eds): Interpersonal factors in the origin and course
of affective disorders. London. The Royal College of Psychiatrists.
8. Allport, G.W., 1961 Pattern and Growth in Personality. New York. Holt, Rinehart and
Winston.
9. Bourgeois, M.L., Martinez, R., Degeilh, B., Peyre, F., 1988 Les facteurs prdictifs de
bipolarisation des troubles dpressifs. L'encphale; XIV 353-357.
10. Cassidy, F., Forest, K., Murry, E. et al, 1998 A factor analysis of the signs and symptoms
of mania. Arch. Gen. Psychiat., 55, 27-32.
11. Cassidy, F., Murry, E., Forest, K., et al, 1997 The performance of DSM III-R major
depression criteria in the diagnosis of bipolar mixed states. J. Affect. Disord., 46, 79-81.
12. Coryell, W., 1996 Invited Editorial: Bipolar II Disorder: A progress report. J. Affect.
Dis.; VI, 159-162.
13. Cloninger, C.R., Bayon, C., Svrakic, D.M., 1998 Measurement of temperament and
character in mood disorders: a model of fundamental states as personality types. J. Affect.
Disord., 51, 21-32.
14. Cassano, G.B., Akiskal, H.S., Savino, M., Mussetti, L., Perugi, G., 1992 Proposed
subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymic) and
with hyperthymic temperament J. Affect. Disord., 26, 127-140.
15. Dunner, D.L., Kai Tay, L., 1993 Diagnostic reliability of the history of hypomania in
bipolar II patients with major depression. Compr. Psychiat., 34, 303-307.
74
16. Gershon, S., Hamovit, I., Goroff, I.I. et al, 1982 A family study of schizoaffective, bipolar
I, bipolar II, unipolar and control probands. Arch. Gen. Psychiat., 39, 1157-1167.
17. Himmelhoch, I.M., Mulla, D., Neil, J.F., Detre, T.P., Kupfer, D.J., 1976 Incidence and
significance of mixed affective states in a bipolar population. Arch. Gen. Psychiat., 33,
1062-1066.
18. Kendler, K.S., 1997 Social support: A genetic epidemiological analysis Am. J.
Psychiat., 154, 1398.
19. Simpson, S.G., Folstein, S.E., Meyers, D.A. et al, 1993 Bipolar I: the most common
bipolar phenotype? Am. J. Psychiat., 150, 901-903.
20. Taylor, M.A., Abrams, R., 1980 Reassessing the bipolarunipolar dichotomy. J. Affect.
Disord., 2, 195-217.






















75


TRATAMENTUL CU BUSPIRON N
TULBURRILE ANXIOASE ASOCIATE ALCOOLISMULUI
M. A. Bir
Spitalului Clinic de Aduli Cluj Napoca Secia de Psihiatrie



Rezumat
Obiectiv. Evaluarea eficacitii terapeutice a Buspironei la alcoolicii cu o tulburare
anxioas generalizat (TAG) s-a realizat prin aprecierile clinice i psihometrice ale
anxietii, calitii vieii i evoluia recderilor clinice.
Metod. Buspirona a fost administrat sub form de monoterapie n doze de 15-45
mg/zi la 25 de bolnavi (18 B, 7 F) pe o perioad de 12 luni. Rezultatele au fost
comparate cu loturi de pacieni alcoolici cu o TAG, tratai cu Clomipramin +
Clordiazepoxid i respectiv, numai cu Carbamazepin. n acest sens s-au utilizat:
Scala pentru anxietate Hamilton, Chestionarul obiceiurilor consumului de buturi
alcoolizate - Pelc i Profilul Lancashire de calitate a vieii. Selecionarea cazurilor
s-a fcut conform criteriilor clinice DSM IV.
Rezultate. Pe o perioad de 6 luni s-au nregistrat 32 % de remisiuni totale, 48 %
ameliorri evidente, 20 % din cazuri nefiind influenate terapeutic. Dup 12 luni s-
au consemnat: 40 % remisiuni totale, 48 % ameliorri evidente i numai 12 % din
cazuri nu au rspuns terapeutic. Buspirona a influenat evident att valorile
anxietii psihice i a celei somatice, precum i nivelul calitii vieii. Numrul
recderilor clinice a fost cu 16% mai mic n comparaie cu cel al pacienilor tratai
cu Clomipramin + Clordiazepoxid.
Concluzii. Buspirona este un anxiolitic eficient n tratamentul alcoolismului cu TAG.
Dei, anxioliza se instaleaz lent, Buspirona influeneaz semnificativ anxietatea
psihic i cea somatic, comparativ cu grupurile martor. Efectele secundare reduse
ale preparatului, absena dependenei, o recomand ca un preparat de perspectiv
n tratamentul i prevenirea recderilor clinice cu o comorbiditate psihiatric la
alcoolici.
Cuvinte cheie: buspirona, anxietate, alcoolism.


THERAPY WITH BUSPIRONE IN ANXIOUS DISORDERS
ASSOCIATED TO ALCOHOLISM

Abstract
Objective. The evaluation of the therapeutic efficiency of buspirone in alcoholic
patients with Generalized Anxiety Disorder (GAD) was performed by clinical and
psychometric assessments of anxiety, quality of life and evolution of clinical relapses.
Method. Buspirone was administered as monotherapy in doses of 15-45 mg/day to 25
patients (18 M, 7 F), over a period of 12 months. The results were compared to those
of alcoholic patients with anxious GAD, treated with clomipramine +
clordiazepoxide and carbamazepine alone, respectively.
The following were used: the Hamilton Anxiety Scale, the Drinking Behavior
Questionnaire - Pelc and the Lancashire Quality of Life Profile. The cases were
selected according to DSM IV clinical criteria.
76
Results. Over a period of 6 months, 32 % total remissions and 48 % obvious
improvements were found, while 20% of the cases were not influenced by therapy.
After 12 months, the following results were obtained: 40 % total remissions, 48 %
obvious improvements, and 12 % of cases with no therapeutic response. Buspirone
clearly influenced the values of both psychic and somatic anxiety, as well as of the
quality of life. The number of clinical relapses was 16 % lower compared to that of
the patients treated with clomipramine + clordiazepoxide.
Conclusions. Buspirone is an efficient anxiolytic agent in the treatment of alcoholism
with GAD. Although anxiolysis occurs slowly, buspirone significantly influences
psychic and somatic anxiety compared to control groups. The reduced side effects of
the preparation and the absence of dependence recommend it as a promising
preparation in the treatment and prevention of clinical relapses with psychiatric
comorbidity in alcoholic patients.
Key words: buspirone, anxiety, alcoholism.


Anxietatea la alcoolici se poate manifesta sub form de tulburri de panic, anxietate
generalizat, fobii i entiti clinice, sau sub form de simptome izolate i tranzitorii intricate n
conduita alcoolic. Manifestrile somatice ale anxietii, transpiraiile, palpitaiile, tremurturile,
perturbrile cognitive sunt mult mai frecvente la alcoolici (7).
Schuckit (20-21), consider c anxietatea este indus de alcoolism n proporie de 90 % i
numai 10 % din pacieni ar prezenta o tulburare anxioas primar susceptibil de a persista n
perioada sevrajului alcoolic.
Riscul relativ de asociere ntre alcoolism i anxietate este de 1,4 % (12). Prevalena anxietii
asupra ntregii viei la pacienii prezentnd un abuz sau o dependen alcoolic este de 2,1 % pentru
anxietatea general, 12,6 % pentru fobii (5,2 % pentru agorafobie 2,8 % pentru fobie social, 10 %
pentru fobii simple) (7).
Anxioii ar avea un risc relativ de apariie a dependenei de 1,7, nregistrndu-se 25 % de
alcoolici i toxicomani, conform studiilor efectuate n cadrul populaiei generale (1). Subiecii cu o
anxietate generalizat nu consum mai mult alcool fa de grupul martor. Factorii de stres la anxioi
nu ar accentua riscul consumului abuziv de alcool (2).
Tratamentul anxietii la alcoolici const n utilizarea preparatelor de tip benzodiazepinic, a
SSRI, etc. Riscul instalrii dependenei n urma folosirii benzodiazepinelor este crescut n aceste cazuri.
Buspirona, compus nonbenzodiazepinic din clasa azapironelor, a fost testat iniial ca
antipsihotic, inhibnd discret transmisia dopaminergic, receptorii D
2
. Efectele antipsihotice ale
Buspironei s-au artat foarte modeste n comparaie cu efectele sale anxiolitice (3, 6, 10).
Buspirona este un agonist al receptorilor 5HT
1A
, autoreceptori somato-dendritici. La nivelul
rafeului i hipocampului are o aciune serotoninolitic, acionnd asupra receptorilor 5HT
1A
, iar n
alte regiuni ale creierului o aciune serotoninomimetic datorit aciunii asupra receptorilor
postsinaptici (9).
77
Buspirona amplific activitatea electric a neuronilor dopaminergici din substana neagr i
crete cantitatea de metabolii ai dopaminei n striat. n tratamentele cronice nu produce
hipersensibilitatea receptorilor dopaminergici (10, 23).
Totodat, prezint o blocare a receptorilor alfa 2 noradrenegici stimulnd discret transmisia
noradrenergic i influeneaz activitatea acetilcolinei prin scderea concentraiei de acetilcolin n
striatum (6, 10).
Spre deosebire de benzodiazepine, Buspirona nu are proprieti anticonvulsivante i
miorelaxante i nu provoac modificri performaelor testelor psihomotorii. De asemenea, afecteaz
ntr-o proporie redus continuitatea i arhitectura somnului, crescnd somnul lent paradoxal i
diminund elementele fazice ale somnului. Pe durat ndelungat nu provoac dependen (18, 23).
Buspirona interacioneaz puin cu etanolul. Se consider c este bine tolerat i nu produce
tulburri acute sau cronice de sevraj. Absena efectelor colaterale cardiovasculare de tip depresiv i
mnestic, l recomand ca un tranchilizant de zi. Frecvent se nregistreaz efecte secundare
gastrointestinale, ameeli i uneori insomnii. Eficiena terapeutic a fost confirmat n tulburrile de
anxietate generalizat, att sub form de monoterapie, ct i de coterapie, fobii, tulburri obsesiv
compulsive, alcoolism, sindrom premenstrual, etc. (3, 5, 8, 16, 24, 26). Totui, spectrul terapeutic
oarecum limitat al Buspironei, o recomand ca un preparat de linia a doua (11).

Designul lucrrii
Obiectiv
Acest studiu i propune s prezinte rezultatele terapeutice prin administrarea Buspironei la
alcoolicii cu tulburare generalizat de anxietate (TAG) prin: evaluri clinice i psihometrice ale
anxietii, a calitii vieii pacienilor i a dinamicii recderilor clinice.

Material i metod
Eficacitatea terapeutic a Busparului a fost apreciat la bolnavii alcoolici cu TAG. n acest
sens s-au luat n studiu 25 de pacieni alcoolici cu TAG internai n Secia de Psihiatrie a Spitalului
Clinic de Aduli Cluj-Napoca, care au fost observai clinic att n cadrul seciei ct i al
Ambulatorului de psihiatrie, pe perioade de 6 luni i 12 luni.
Diagnosticul clinic s-a efectuat conform criteriilor elaborate de DSM IV.
Dozele terapeutice s-au situat ntre 15-45 mg/zi pe perioada investigaiei. Rezultatele au fost
evaluate nainte i n perioada tratamentului prin aplicarea Scalei pentru anxietate Hamilton,
Chestionarului obiceiurilor consumului de buturi alcoolizate Pelc (7).
Bunstarea pacienilor a fost evideniat prin Profilul Lancashire de calitate a vieii
(seciunea 2, seciunea 12, seciunea 13) (14).
78
S-a urmrit att evoluia anxietii psihice ct i a celei somatice, cu precdere a itemului 11
i 14 Scala Hamilton i a grilei pentru rezolvarea dificultilor psihologice, n special itemii care
reflect anxietatea 2, 10, 11, 14, 15, 18, 21, 24, 26, 28, 36, 40, 41, 42, 44, 45 - Chestionarul
obiceiurilor consumului de buturi alcoolice Pelc.
Rezultatele au fost comparate statistic cu cele ale unui lot de 25 de alcoolici cu TAG tratai
prin asocierea medicamentoas Clomipramin 75 mg/zi + Clordiazepoxid 20 mg/zi, precum i cu
ale unui alt lot similar aflat sub monoterapie de Carbamazepin, 400 mg/zi.

Rezultate
Repartiia pacienilor pe criterii de vrst, sex, profesii, studii, este prezentat n tabelul
sinoptic nr. 1:

Tabel 1 - Utilizarea Buspironei la alcoolici cu TAG
Nr. total
bolnavi
Sex Grupe vrst Studii Profesii
Doze zilnice
Buspar
25
Femei 7
21-30 ani 5 Elementare 6 Agricultori 4 15 mg 12 bolnavi
31-40 ani 8 Medii 9 Muncitori 7 30 mg 8 bolnavi
Brbai 18
41-50 ani 9
Superioare 10
Tehnice 6
45 mg 5 bolnavi
51-60 ani 3 Liberale 8

Aprecierea global a rezultatelor pe o perioad de 6 luni arat c n urma administrrii
Busparului s-au nregistrat remisiuni clinice totale la un numr de 8 cazuri (32 %), ameliorri clinice
pariale la 12 cazuri (48 %), n timp ce 5 cazuri (20 %) nu au fost influenate terapeutic (Fig. 1).

Fig. 1 - Evoluia tratamentului cu Buspiron n alcoolism cu TAG la 6 luni
48 %
32 %
20 %
cazuri remisiuni clinice totale
cazuri ameliorari
cazuri neinfluentate terapeutic


Dup 12 luni s-au constatat: remisiuni totale la 10 cazuri (40 %), ameliorri clinice la 12
cazuri (48 %), fr nici o ameliorare 3 cazuri (12 %) (Fig. 2).
Evoluia anxietii globale dup administrarea cu Buspar la 6 luni i 12 luni arat
urmtoarele rezultate, comparativ cu lotul de pacieni tratai cu Clomipramin + Clordiazepoxid i
numai cu Carbamazepin (Fig. 3). Att Buspirona ct i asocierea Clomipramin + Clordiazepoxid
reduc semnificativ valorile anxietii totale fa de Carbamazepin.
79
Fig. 2 - Evoluia tratamentului cu Buspiron n alcoolism cu TAG la 12 luni
48 %
40 %
12 %
cazuri remisiuni totale
cazuri ameliorari clinice
cazuri neinfluentate
t ti


Fig. 3 - Evoluia valorilor anxietii globale - Scala de anxietate Hamilton
0
10
20
30
40
50
6 luni 12 luni
p
u
n
c
t
a
j

t
o
t
a
l

H
a
m
i
l
t
o
n
carbamazepin
buspar
clomipramina+clordiazepoxid


Valorile anxietii psihice apreciate prin Chestionarul de anxietate Hamilton arat
urmtoarele rezultate n perioada de 6 luni i 12 luni (Fig. 4). Combinaia Clomipramina +
Clordiazepoxid influeneaz, n mai mare msur, itemii anxietii psihice fa de Buspar, att la 6
luni ct i la 12 luni.

Fig. 4 - Valorile anxietii psihice - Scala de anxietate Hamilton
0
5
10
15
20
25
6 luni 12 luni
carbamazepin
buspar
clomipramina+clordiazepoxid


Nivelurile anxietii somatice la aceeai bolnavi, n aceleai perioade de timp, prezint valori
similare (Fig. 5).
80
Fig. 5 - Valorile anxietii somatice - Scala de anxietate Hamilton
0
5
10
15
20
25
30
6 luni 12 luni
carbamazepin
buspar
clomipramina+clordiazepoxid


Rezultatele obinute prin aplicarea Chestionarului obiceiurilor consumului de buturi
alcoolice - Pelc, pe durata tratamentului cu Buspar, sunt prezentate n Fig. 6.

Fig. 6 - Valoarea scorului - Chestionarul consumului de buturi alcoolice - Pelc
0
20
40
60
80
100
6 luni 12 luni
v
a
l
o
r
i

a
n
x
i
e
t
a
t
e
buspar


Buspirona i valideaz efectele terapeutice, aa cum rezult din modificarea itemilor
2,10,11,14, 15, 18, 21, 24, 26, 28, 36, 40, 41, 42, 44, 45, ai acestui chestionar.
Calitatea vieii apreciat prin Profilul Lancashire a fost mbuntit, evident, n urma
administrrii de Buspar, aa cum se constat din dinamica seciunii a 2 Scala satisfaciei n via
(LSS), (Fig. 7).

Fig. 7 - Evoluia calitii vieii Profilul Lancashire - Scala satisfaciei de via (LSS)
1
2
3
4
5
6
7
buspar 2 5,5 6,2
6 luni 12 luni

Cum nu se poate mai bine
Mulumit
n cea mai mare parte satisfcut
Amestecat (cam la fel de satisfcut i nesatisfcut)
n cea mai mare parte nesatisfcut
Nemulumit
Cum nu se poate mai ru
81
Evoluia numrului de recidive clinice dup administrarea Buspironei pe o perioad de 12
luni, confirm eficacitatea terapeutic a preparatului, nregistrndu-se numrul cel mai mic de
recderi clinice: 16 % dup Buspiron, 32 % dup Clomipramin + Clordiazepoxid i 61 % dup
Carbamazepin (Fig. 8).

0
10
20
30
40
50
60
70
%
Fig. 8 - Evoluia numrului de recidive dup tratamentele efectuate la 12 luni
carbamazepin
buspar
clomipramina+clordiazepoxid


Buspirona a fost bine tolerat de ctre toi pacienii pe ntreaga durat a tratamentului. Efectele
laterale au fost sporadice, de mic intensitate, sub form de cefalee, uscciunea gurii, paloare,
astenie, epigastralgii.

Discuii
Cercetarea confirm informaiile din literatur referitoare la efectul terapeutic al Buspironei
n tratamentul comorbiditii anxioase la alcoolici. ntr-un studiu anterior (4), am artat c
Buspirona este ineficace n atacurile de panic i n perioada de sevraj al alcoolicilor, datorit
absenei proprietilor anticonvulsivante i miorelaxante.
n ceea ce privete Scala de anxietate Hamilton, Buspirona a influenat, n special, starea de
iritabilitate, de team, de anticipare cu team i mai puin itemii: 2 starea de tensiune,
imposibilitatea de a se destinde; 4 senzaia de somn, de ntrerupere a somnului.
Ameliorarea anxietii somatice s-a reflectat, mai ales, la nivelul itemilor: 10 - simptome
respiratorii, 12 - simptome genito-urinare, 8 simptome somatice generale.
Chestionarul privind obieciurile consumului de alcool comportamentul alcoolic a
nregistrat ameliorri substaniale la nivelul itemilor: 10 cnd m simt singur; 11 pentru a-mi
ridica moralul, 14 cnd m simt abandonat, 15 cnd am neplceri pe care nu le suport, 18
pentru a m simi mai bine, 26 cnd m plictisesc, 28 cnd sunt anxios, tensionat, 36 cnd
trebuie s fac un lucru neobinuit, 40 dorina de evaziune, de a fugi de realitate, 42 pentru a fi
mai indiferent pentru ceea ce se petrece n jur, 45 pentru a dormi mai bine seara.
82
Din corelarea rezultatelor nregistrate prin Scala de anxietate Hamilton i a Chestionarului
privind obiceiurile consumului de alcool comportamentul alcoolic, reiese evident c Buspirona
amelioreaz manifestrile anxioase, att pe cele din registrul psihic ct i pe cele din registrul somatic.
Evaluarea calitii vieii prin Profilul Lancashire seciunea 12 relev ameliorri evidente
referitoare la concepia despre sine, mbuntirea valorizrii personale, a atitudinii pozitive fa de
sine nsui, rectigarea respectului i redobndirea sentimentului utilitii. Seciunea 13 a aceluiai
Profil, reflectnd starea general de bunstare, nregistreaz de asemenea, o acceptare a vieii n
ansamblu: pacienii i accept situaia social, se declar mulumii de starea sntii lor. Pe
primul loc n cadrul evenimentelor care le-a mbuntit viaa se consemneaz dispariia anxietii,
urmat de autocontrolul semnificativ exercitat asupra consumului de alcool i ameliorarea
climatului familial.
Rezultatele obinute prin Profilul Lancashire de apreciere a calitii vieii confirm efectul
terapeutic al Buspironei asupra anxietii alcoolicului.
Dei, n literatur exist unele studii n care se menioneaz c Buspirona ar reduce apetitul
fa de butur al alcoolicilor (19), din datele prezente, se pare c, aciunea terapeutic a Buspironei
se exercit asupra tulburrii de anxietate generalizat al alcoolicului, indiferent c aceasta este
primar sau secundar.
Efectul terapeutic al Buspironei, comparativ cu al Clomipraminei + Clordiazepoxid arat
rezultate asemntoare, dei pacienii care au urmat tratamentul cu Clomipramin + Clordiazepoxid
l-au ntrerupt de mai multe ori, att n primele 6 luni, ct mai ales n perioada urmtoare. Astfel, s-ar
explica i numrul de recidive clinice nregistrate la aceti pacieni. Printre motivele care au dus la
ntreruperea tratamentului s-au enumerat greutile evocate de ctre pacieni referitoare la asocierea
a dou preparate pe perioade ndelungate.
Spre deosebire de aciunea Clomipraminei + Clordiazepoxid, care este manifest nc din
primele zile ale tratamentului, efectul anxiolitic al Buspironei este mult mai lent dup 7-10 zile,
ceea ce ar putea explica diferenele terapeutice nregistrate n primele 6 luni.
Modul de aciune al Buspironei se reflect, n special, prin normalizarea funciilor
serotoninergice prezente la alcoolici cu o comorbiditate anxioas (15). Cloninger (citat 7) consider
c activitatea hiposerotoninergic s-ar asocia cu alcoolicii de tip 2 (debut precoce, sex masculin,
personalitate sociopat). Pacienii din lotul nostru se ncadreaz, mai ales, n clasificarea alcoolicilor
de tip 1 dup Cloninger, astfel c nu se poate absolutiza activitatea hiposerotoninergic a
alcoolicilor anxioi n funcie de o anumit tipologie clinic. Acest mecanism nu este unic, fiind
posibil ca Buspirona s acioneze i asupra receptorilor D
2
avnd aciuni similare cu Bromocriptina.
De altfel, Lawford i col. (1995) a avansat ipoteza conform creia alcoolicii prezentnd alele A
1
a
genei D
2
s-ar caracteriza printr-o hipofuncie dopaminergic (13).
83
Rspunsul terapeutic nregistrat, la doze diferite zilnice (15 45 mg.) s-ar putea datora
rolului transmisiei dopaminergice n apariia alcoolismului i a anxietii. n plus, este bine cunoscut
c Buspirona n doze ridicate ar aciona asupra receptorilor dopaminergici postsinaptici, iar n doze
terapeutice ar bloca mai curnd receptorii dopaminergici presinaptici (10).

Concluzii
1. Buspirona este un anxiolitic eficient n tratamentul alcoolismului cu TAG;
2. Dei anxioliza se instaleaz lent dup 7-10 zile de la administrare, Buspirona
influeneaz semnificativ activitatea psihic i cea somatic i mbuntete evident
calitatea vieii pacienilor;
3. Efectele secundare reduse ale Busparului, precum i absena dependenei, l recomand
ca un preparat de perspectiv n tratamentul i prevenirea recderilor clinice cu o
comorbiditate psihiatric la alcoolici.


Bibliografie
1. Ads J., Rouillon F., Leon Elisabeth, 1995 Troubles anxieux in Therapeutique
Psychatrique, Ed. Hermann, Paris, 635-646.
2. Allan C.A., 1995 Alcohol problems and anxiety disorders a critical review. Alc
Alcoholism, MASSON 30/2, 145-151.
3. Argyropoulos S.V., Nutt D.J., 1999 The use of benzodiazepines in anxiety and other
disord, Eur., Neuropsychophat., 9 (Supl 6), S 407-S 412.
4. Bir M.A., andor V., 2002 Tratamentul cu Buspar n psihiatria ambulatorie, Buletin de
Psih. Integrat, An VIII, vol II, 2, Iai, 78-84.
5. Bougerol Th., Dufour H., 1998 Pharmacotherapie du trouble panique in Le
troublepanique, Th. Lemperiere, MAPS, MASSON-Paris, 145 157.
6. Olga Brawman-Mintzer, Lydiard B.R., Ballenger C.J., 2000 Buspirone in Kaplan &
Sadocks, Comprehensive Textbook of Psychiatry, vol. Lippincott Williams& Wilkins,
Philadelphia, II, 2324-2333,
7. Cardot H., Lejoyeux J., Ads J., 1997 Anxit et alcoolismne, in Alcoolisme et
psychiatrie, J. Ads, M. Lejoyeux, MASSON, Paris, 103-120.
8. Hollander E., Bienstock C.A., Coram M.L., Palanti S., Marazziti O., Rashussen A.S., Ravizza
L., Benkelfat C., Saxena S., Greenberg B., Sasson Y., Zohar J., 2002 Refractory obsessive-
compulsive disorder: State of the art treatment. J. Clin Psychiatry, 63, Supl. 6, 20-29.
9. Hutt D.J., Cowen P.J., 1987 Benzodiazepine - Serotonin interactions in Man.
Psychopharmacol. Ser., 3, 72-76.
84
10. Jann M.N., 1988 Buspirone: An Update on a unique anxiolytic agent. Pharmacotherapy, 8
(2), 100-116.
11. Kaplan, Sadock, 2001 Manual de buzunar de Psihiatrie clinic, Ed. a treia, Lippincott,
Williams & Wilkins, Ed. Medical, 450.
12. Kessler R.C., 1995 Epidemiology of psychiatric comorbidity. In Textbook in psychiatric
epidemiology. Tsuang, Tohen, Zahner eds.Wiley and Sons, INC 200P, 1995.
13. Lawford B.R., Young R. Mc D., Rowell J.A., Qualichefski J., Fletcher B. H., Syndulko K.,
Ritchie T., Noble E.P., 1995 Bromocriptine in the treatment of alcholics of alcoholics
with the D2 dopamine receptor A1 allele, Nat Med., 1/4: 337-341.
14. Lzrescu M., 1999 Profilul Lancashire de calitate a vieii, n Calitatea Vieii n psihiatrie.
Ed. INFO Medica, Timioara, 45.
15. Obrien C.P., Eckardit M.J., Linnoila Vmi., 1995 Pharmacotherapy of alcoholism. In
Psychopharmacology: The fourth generation of progress, FE Bloom, DJ Kupfer, ed. Raven
Press, New York, 1745-1755.
16. Pato N.T., Pigott T.A., Hiu J.L., 1991 Controlles comparison of Buspirone and Clomipramine
in Patients with obsessive-compulsive disorder, Am. J. Psychiat., 184, 127-129.
17. Pelc I., 1986 Contribution ltude de la psychopathologie de lalcoolisme chronique.
Thse pour lagrgation de lenseignement suprieur.Universit libre de Bruxelles, in
M.Bouvard, J. Cottraux Protocoles et chelles dvaluation en psychiatrie et en
psychologie, MASSON, Paris.
18. Pelissolo A., Bisserbe J.C., 1994 Dependance aux Benzodiazepines: Aspects cliniques et
biologiques, LEncphale XX, 147-157.
19. Pettinati M., Helen, 2001 The Use of Selective Serotonin Reptake Inhibitors, in Treating
Alcholic Subtypes, J. Clin. Psychiatry, 62, supl.20,26.
20. Schuckit M.A., Hesselbrock V.M., 1994 Dependence and the anxiety disorders. What is
the relationship ? Am J Psych, 1994; 151, 1728-1734.
21. Schuckit M.A., Hesselbrock V.M., Tipp J., Nurnberger J.I., Anthenelli R.M., Crowe R.R.,
1995 The prevalence of major anxiety disorders in relatives of alcohol dependent men
and women, J. Stud Alc, 56, 309-317.
22. Pollack, M.H., 2001 Comorbidity, Neurobiology, and Pharamacotherapy of Social
Anxiety Disorder, J. Clin. Psychiatry, 62, supl. 12, 24.
23. Senon J.L., Richard D., 1995 Anxiolitiques in Therapeutique Psychiatrique, Ed.
Hermann, Paris, 227-270.
85
24. Sheehan D.V., Raj A.B., Harnett S.K., 1993 The relative efficacy of high dose Buspirone
and Alprazolam in the treatment of panic disorder: a double- blind placebo- controlled
Study. Acta. Psychiatr. Scand., 88, 1-11.
25. Thase E.,M., Salloum M.,I., Cornelius D.J., 2001 Comorbid Alcoholism and Depression:
Treatment Issues, J. Clin. Psychiatry, 62, supl. 20, 32.
26. Tollesfson G.D., Monagu-Clouse J., Lancaster S.P., 1990 Buspirone in comorbid alcohol
dependency and generalized anxiety disorders. The Bull, suppl. aot 35-50.

























86


UNELE EFECTE NEUROFIZIOLOGICE
I FARMACOLOGICE ALE DIGITALEI
Veronica Sfredel, G. Bdescu, I. Udritoiu, A. Tril
U.M.F. Craiova



Rezumat
Exist numeroase date care atest folosirea n trecut a glicozidelor digitalice n
terapia neuropsihiatric. Justificat sau nu aceast metod a fost folosit, de
exemplu n tratarea formelor de epilepsie. Datele actuale privind efectele digitalei
asupra funciei celulare n general, a miocardului i structurilor nervoase, n
particular arat ntr-adevr efectele semnificative ale acestor droguri pe structurile
amintite. Se tie c digitalicele inhib reversibil funcia Na
+
/ K
+
ATPazei. Ca
urmare sunt blocate procesele de repolarizare, cu acumulare de Na
+
in citosol i
secundar de Ca
2+
. In creier, transportul Na
+
i al K
+
este cuplat i cu transportul
unor neurotransmitori. Daca admitem c geneza undelor o are loc la nivelul
stratului al V-lea cortical, sub influena pacemakerilor talamici i dac undele
nregistrate sunt expresia diferenelor de potenial aprute prin sumarea temporo-
spaial a potenialelor postsinaptice, trebuie s concluzionm ca digitalicele pot
avea efecte semnificative asupra acestor fenomene electrice cerebrale. Aceasta este
ipoteza care a stat la baza studiului nostru: msurarea modificrilor de amplitudine,
frecven, morfologie a ritmurilor EEG nainte i postterapie cu digitalice. Am lucrat
pe un lot format din 28 de pacieni, 13 femei i 15 brbai. Prelucrarea statistic cu
indici de cuantificare EEG a subliniat diferene semnificative intre cele dou stri.
Cuvinte cheie: EEG, digital, Na
+
/ K
+
ATPaz.


SOME NEUROPHYSIOLOGICAL AND PHARMACOLOGICAL
EFFECTS OF DIGITALIS

Abstract
There are many references concerning the former use of digitalis in neuropsychiatry.
Justified or not, it was used in the treatment of epilepsy. Recent researches about the
digitalis effects on cell function in general and on myocardial and nervous structures
in particular showed significant behavioral changes as a response to this drug. It is
known that digitalis reversibly inhibits the function of Na
+
/ K
+
ATPase.
Consequently, the repolarization is blocked, followed by the accumulation of Na
+
,
then Ca
2+
in citosol. In the brain, the activity of the Na
+
/ K
+
ATPase is linked with
the transport of some neurotransmitters. The owaves are generated in the fifth
cortical layer, under the influence of thalamic pacemakers. These waves are the
expression of the values obtained by temporo-spatial summation of the post-synaptic
potentials. Should we consider these facts, we should conclude that digitalis may
have significant effects on these electrical phenomena of the brain. This hypothesis is
what our study is based on: measuring the modifications in amplitude, frequency and
waves morphology before and after the administration of digitalis. We studied a
group of 28 patients (13 females, 15 males). The statistical analysis showed
significant differences between the two conditions.
Key words: EEG, digitalis, Na
+
/ K
+
ATPase.
87
Introducere
Teoretic, un mesager prim are aceleai efecte moleculare, funcie de receptorul specific,
indiferent de structura celular care l recepioneaz. n realitate, modificarea unor funcii celulare,
prin aciunea ligandului (mesagerului) cu receptorul prezint particulariti legate de funciile
specifice celulei.
O asemenea situaie o avem n cazul efectelor digitalicelor, care prin blocarea Na
+
,
K
+
ATPazei va produce modificri, att n activitatea cardiac i studiile efectuate de-a lungul
timpului sunt detaliate n acest sens, ct i la nivelul altor structuri cu funcii complexe, cum ar fi
SNC, n acest caz cercetrile fiind marcate de o notabil indigen.
Studiile noastre asupra efectelor digitalei pe SNC au plecat de la observaia c parametri
primari ai ritmurilor electroencefalografice fiziologice prezint modificri accentuate la pacienii
digitalizai.
Se tie c, digitalicele au o structur glicozidic, fiind constituite dintr-un aglicon steroidic
(genin), legat n poziia 3 de un rest glucidic. Componenta care confer acunile farmacologice este
agliconul, n timp ce, restul glucidic adaug doar unele particulariti legate de eficien i solubilitate.
O parte din poriunea glucidic iniial (aa cum o gsim n planta proaspt) se pierde n procesul de
prelucrare, rezultnd glucide mai simple, ca digitoxina sau digoxina (V. Stroescu, 1998). Cea mai
bine studiat aciune farmacologic a glicozidelor cardiace este inhibarea Na
+
-K
+
ATPazei (cunoscut
i ca pompa de Na
+
-K
+
), o enzim care catalizeaz hidroliza ATP-ului n ADP i folosete energia
rezultat pentru schimburi ionice: expulzeaz 3Na
+
din celul i introduce 2K
+
, pentru fiecare mol de
ATP hidrolizat, n acest fel meninnd gradientul electrochimic al celor doi cationi (Skou, J.C, 1957).
Enzima are n structura sa dou subuniti, alfa i beta, care strbat membrana celular, avnd site-uri
active att la captul extracelular, ct i la cel citozolic. Separarea celor dou subuniti are ca rezultat
pierderea activitii, dei transportul celor 2 ioni se realizeaz numai prin subunitatea alfa.
Legarea Na
+
la site-ul citoplasmatic al subunitii alfa se face n paralel cu legarea ATP-ului,
care se degradeaz i transfer fosfat pe site-ul de fosforilare. Fosforilarea induce modificri
conformaionale ale proteinei, care favorizeaz expulzia Na
+
din celul. Legarea K
+
de site-ul
extracelular iniiaz defosforilarea subunitii alfa i revenirea la structura anterioar, care permite
intrarea K
+
n celul (Horisberger J.D et al, 1991) Site-ul pentru legarea glicozidelor digitalice se
afl pe extremitatea extarcelular a subunitii alfa. Legarea moleculelor de glicozid blocheaz
funia de enzim i de transport a pompei. Consecina acestei blocri este creterea concentraiei
intracelulare a Na
+
i deficit de K
+
n celul. Creterea concentraiei intracelulare a sodiului va
determina preluarea lui de un alt sistem transportor, sistemul antiport Na
+
-Ca
2+
, care expulzeaz din
celul 3Na
+
, n schimbul ptrunderii 1Ca
2+
n interior. n acest fel, digitalicele stimuleaz
ptrunderea Ca
2+
n celule, secundar blocrii Na
+
-K
+
ATPazei i creterii concentraiei intracelulare
88
a Na
+
, aciune care explic efectul inotrop pozitiv (Vasilets, L.A., Schwarz,W, 1994). Dei,
probabil, Na
+
-K
+
ATPaza are aceeai funcie la nivelul oricrei structuri, pentru cteva dintre
acestea, activitatea enzimei prezint particulariti. De exemplu, n creier se gsesc numai
izoformele
2
,
3
i
3
ale enzimei, iar activitatea ei este cuplat cu transportul unor
neurotransmitori cum este glutamatul (Molnar, L.R., et al,1999), iar la nivel cardiac cu acel sistem
antiport, care transport calciul n celul, n schimbul ionilor de sodiu.

Ipoteza de lucru. Motivaia cercetrii.
Exist puine date despre inhibarea ATP-azei de la nivel cerebral de ctre glicozidele
digitalice dei folosirea acestora n patologia neuropsihiatric a fost, n anii trecui relativ frecvent.
Cercetrile noastre, din pcate doar n domeniul explorrilor funcionale de tip neurofiziologic par
s confirme c efectele centrale ale digitalicelor in dac nu n exclusivitate, oricum n mare parte de
blocarea ATP-azei. Ne-am propus s urmrim efectele induse de digital asupra fenomenelor
electrice cerebrale. Pentru aceasta am msurat modificrile de amplitudine, frecven, morfologie a
ritmurilor EEG, ante i postterapie cu glicozide digitalice.
ntr-o prim faz ne-am rezumat la a msura modificrile parametrilor primari EEG sub
efectul digitalicelor. Chiar dup analiza datelor brute, aceste modificri au fost att de consistente
nct am extins investigaiile noastre pe o suprafa mai mare, incluznd activiti psiho-senzoriale,
cum ar fi studiul modificrilor timpului de reacie la excitaii luminoase i auditive. Cu toat
consistena acestor modificri am considerat oportun cuantificarea lor prin aplicarea unor indici de
cuantificare EEG derivai din indicele Hchel.

Material i metod
Lotul de studiu a fost format dintr-un numr de 28 de subieci, 15 brbai i 13 femei, cu
vrsta cuprins ntre 42 i 65 de ani, vrsta medie fiind de 65,2 ani. Subiecii au fost recrutai dintre
pacienii care s-au prezentat la Cabinetul de Cardiologie din Policlinica nr. 1, Craiova cu o
patologie care a necesitat introducerea digitalei. Tratamentul (digoxin) s-a administrat ambulator,
dup schema standard, ncrcare lent, timp de 5 zile i apoi trecerea la doze de ntreinere.
n lot nu am inclus pacieni cu antecedente de epilepsie, cu accidente vasculare cerebrale, cu
spasmofilie, diabet zaharat sau come de diferite etiologii, toate aceste circumstane patolologice
putnd s influeneze a priori electrogeneza cerebral. Nu a fost nevoie s lucrm cu un lot martor,
deoarece am considerat prima nregistrare EEG, efectuat naintea nceperii tratamentului, ca
unitate de referin pentru eventualele modificri aprute dup digitalizare.
nregistrrile EEG s-au realizat n Cabinetul de Explorri Neurofiziologice din Policlinica
nr. 1, cu un electroencefalograf Bioscript cu 8 canale. Electrozii au fost plasai dup schema
89
standard, iar montajele utilizate au fost M, Tp i L
1
. Deoarece afeciunile cardiace pentru care au
fost digitalizai pacienii din lot au constituit contraindicaii pentru proba de activare prin hiperpnee,
aceasta nu s-a efectuat. Durata fiecrei nregistrri a fost de 15 minute, iar condiiile de nregistrare
au fost cele standard, repaus psiho-senzorial i ochii nchii.
S-au efectuat 2 nregistrri, prima nainte de nceperea digitalizrii i a doua la o sptmn
de tratament. n afar de nregistrarea EEG, pacienilor studiai li s-au aplicat i 2 teste psiho-
fiziologice: timpul de reacie la excitaii optice i timpul de reacie la excitaii acustice, probe care
determin timpul minim necesar unui subiect ca s apese pe un buton imediat ce vede c s-a aprins
un bec, sau aude c s-a emis un sunet.
Parametri EEG studiai: pe fiecare nregistrare au fost analizai parametri primari: indexul,
amplitudinea, frecvena, morfologia undelor pentru ritmurile i i s-a calculat un indice
energetic, indicele N-T
1
, a crui formul pentru traseele monomorfe (normale) este A
2
x F, n care
A = amplitudinea, iar F = frecvena.

Rezultate
Valorile medii ale parametrilor EEG analizai pentru cele 2 nregistrri sunt redate n tab. 1.

Tabel 1 Valorile medii ale parametrilor primari EEG index, amplitudine, frecven,
nainte i n timpul tratamentului cu digital.

Nr.
nreg.
Alfa Beta
Grafoelemente de tip iritativ Index
%
A
(V)
Variaie
%
F (Hz)
Index
%
A
(V)
Variaie
%
F (Hz)
I 60 45 10,8 35 25 17,2 -
II 62 65 |44% 11 35 35 |40% 17
La 27 % dintre nregistrri
apare alfa ascuit cu tendina
de a genera spickes-uri

Analiza statistic a acestor date impune cteva constatri.
Amplitudinea ritmurilor EEG a crescut la a doua nregistrare (efectuat dup digitalizare),
cu 44,4 % pentru ritmul (p<0,01) i cu 40 % (p = 0,02) pentru ritmul (Fig. 1). Frecvena acestor
ritmuri nu s-a modificat semnificativ statistic.
Un procent de 27 % dintre subieci au prezentat la a doua nregistrare un ascuit i amplu,
cu tendina de a genera spickes-uri.
Indicele energetic (Tabel 2) N-T
1
pentru ritmul , cu o valoare medie, la prima nregistrare
de 21870, va deveni la a doua nregistrare 46475, creterea procentual (de 120 %) fiind consistent
i bine susinut statistic (p < 0,01). i pentru ritmul acest indice crete n mod evident la a doua
nregistrare, cu 81 %.

90
Fig. 1 - Variaia amplitudinii medii a ritmurilor alfa i beta, nainte
i n timpul tratamentului cu digital
25
45
35
65
0
10
20
30
40
50
60
70
alfa beta
Ritmul
A

(

V
)


Tabel 2 Valorile medii ale indicelui energetic N-T
1
, nainte i n timpul tratamentului cu digital.

Ritmul EEG I EEG II Cretere % P
alfa 21.870 46.475 120 < 0,01
beta 10.750 20.825 81 0,01

Timpul de reacie la excitaii optice i auditive (tabel nr.3), dei nregistreaz scderi uoare
la a doua determinare, acestea nu au semnificaie statistic.

Tabel 3 Valorile medii ale timpilor de reacie nainte i n timpul tratamentului cu digital.

Proba Determinarea I Determinarea II Variaie % P
Timpul de reacie la excitani
optici (ms)
300 290
Scade cu
3,33%
> 0,05
Timpul de reacie la excitani
acustici (ms)
280 260
Scade cu
7,14%
> 0,05

Comentarii. Discuii.
Elementul cel mai evident al rezultatelor cercetrii noastre este reprezentat de creterea
semnificativ a amplitudinii ritmurilor cerebrale, n special a ritmului , n timp ce modificrile de
frecven sunt practic nesemnificative. Se admite astzi c sursa ritmului este localizat la nivelul
somei i dendritelor marilor neuroni piramidali din stratul V, dispui perpendicular pe suprafaa
cortexului, unde prin nsumarea potenialelor postsinaptice excitatorii sau inhibitorii a milioane de
neuroni iau natere cureni, reprezentai fizic ca un dipol, care se propag ctre scalp, de unde pot fi
preluai cu ajutorul electrozilor. Acest activitate este sincronizat i ritmic, admindu-se n prezent
prezena unor sincronizori profunzi, subtalamici (Misulis, E.K, 1997). Schimburile ionice au loc n
permanen n neuroni via pompa Na
+
, K
+
, ceea ce permite meninerea unui echilibru n compoziia
ionic a celulei i deci, implicit a potenialului de membran. Apariia unei diferene de potenial
transmembranar superioar potenialului de repaus provoac deschiderea canalelor ionice care vin s
restabileasc o repartiie omogen a ionilor de o parte i de alta a membranei. Pompele de Na
+
-K
+
vor
91
intra n aciune pentru a restabili potenialul de repaus i membrana se va hiperpolariza pentru a
scdea excitabilitatea celulei. Augmentarea amplitudinii ritmului n studiul nostru pare a fi explicat
prin efectul direct de blocare al pompei de Na
+
,K
+
de ctre digital, acumularea de K
+
extracelular
mrind valoarea dipolului. Din pcate nu putem corecta-corela aceste valori augmentate, dei ar fi
foarte necesar cu modificarea, n sensul ameliorrii perfuziei cerebrale, secundar ameliorrii funciei
inotrope.
n schimb, uoara cretere a frecvenei ritmurilor cerebrale, dei nesemnificativ ar putea fi n
relaie direct cu blocarea pompei de ctre digital. Putem presupune c tendina de depolarizare a
membranei neuronale, secundar acumulrii intracelulare a Na
+
poate duce la atingerea mai facil a
pragului critic pentru declanarea unor poteniale de aciune la acest nivel. Conform acestei ipoteze
digitala ar trebui s induc la nivel cortical creterea nivelului de excitabilitate, cu creterea implicit a
acuitii senzoriale. Pe de alt parte, se tie c, dac ritmul este doar o succesiune de poteniale
postsinaptice sumate de la nivelul dendritelor i somei marilor neuroni piramidali, n schimb
elementele iritative corticale propriu zise (spickes-urile) reprezint sumaia temporo-spaial a unor
populaii neuronale cu patibilitate iritativ. Teoretic ar fi posibil deci, ca digitala s augmenteze aceste
tendine iritative, iar procentul de grafoelemente de tip iritativ (27%) gsit de noi la a doua
nregistrare pare s confirme aceast ipotez. Activarea mecanismelor iritative corticale prin blocarea
pompei de Na
+
,K
+
ar putea fi n relaie cu acumularea extracelular a glutamatului, al crui transport
la nivel neuronal este cuplat printr-un sistem de cotransport cu aceast pomp, mai exact cu
transportul Na
+
. S-a demonstrat c excesul de glutamat are efect de trigger al morii neuronale, putnd
s determine serioase injurii cerebrale, cu consecine motorii i mentale (Attwel, 2000)
Aplicarea unui indice de cuantificare, n cazul de fa are efectul unei lupe, traducnd
obiectiv creterea amplitudinii ritmurilor EEG. n acelai timp se constat o cretere masiv a
nivelului energetic cerebral, n acest caz, pe lng efectul digitalei asupra pompei de Na
+
, K
+

existnd probabil i o influen a creterii perfuziei cerebrale.
Efectele psiho-senzoriale ale digitalei asupra subiecilor cercetai, la ncrcarea realizat pe
lotul nostru nu sunt semnificative. Se tie ns, c intoxicaia digitalic are efecte semnificative de
tip psiho-senzorial, mai ales asupra analizatorului optic i auditiv de aceea putem presupune c
modificrile modice gsite de noi in de doza de drog folosit.
Notm totui, uoara cretere a excitabilitii cerebrale i ne punem n continuare ntrebarea
dac aceast cretere nu are o valoare relativ, la modul absolut fiind vorba de fapt despre o
nomalizare a unor funcii n mod logic perturbate anterior. Un rspuns la aceast ntrebare ar putea
veni doar din cercetarea efectelor drogului asupra unor loturi comparative, sntoase, performante i
nu numai pe loturi de pacieni cardiaci, a cror deficien de perfuzie ar putea induce, cel puin
funcional anomalii cerebrale sau senzoriale.
92
Concluzii
1. Digitala modific semnificativ amplitudinea grafoelementelor nscrise electro-
encefalografic, n special a ritmului . Aceast constatare ar putea servi ca marker pentru
impregnarea digitalic.
2. La dozele uzuale de digital, efectele psihofiziologice i senzoriale sunt de intensitate
moderat i fr acoperire statistic.


Bibliografie
1. Attwel, D, 2000 Brain Uptake of Glutamate: Food for Thought. J. Nutr. 130, 1023S-
1025S
2. Horisberger J.D et al, 1991 Structure-function relationship of Na
+
, K
+
ATPase. Ann. Rev
Physiol. 12, 71.
3. Misulis, E. K, 1997 Essentials of Clinical Neurophysiology. Ed. Butter Worth.Heinemann
Boston. 13, 11-120.
4. Molnar, L.R., et al, 1999 The role of the sodium pump in the developmental regulation of
membrane electrical properties of cerebellar Purkinje neurons of the rat. Brain Res Dev
Brain Res., 112(2), 287-291.
5. Skou, J,C. The Nobel Prize in 1997, for the first dicovery (in 1957) of an ion transporting
enzyme, sodium-and potassium-stimulated adenosine triphosphatase (Na
+
, K
+
-ATPase).
6. Stroescu, V., 1998 Bazele farmacologice ale practicii medicale. Ediia VI, Editura
Medical. 8, 252-268.













93


Instruciuni pentru autori



Textul trebuie s fie redactat n MS Word, la 1,5 rnduri, cu margini de 2 cm. Se vor folosi
obligatoriu caracterele romneti (, , , , ). Se va utiliza fontul Times New Roman din
Windows. Fiierul text va purta numele autorului i un element definitor din titlu (Ex.
Popescu_Schizofrenie.doc). Este obligatorie expedierea materialului pe diskete 3,5 i a dou
exemplare listate; v rugm a verifica integritatea disketelor i efectuarea mai multor copii ale
fiierului (fiierelor). Putei folosi un program obinuit de comprimare (RAR, ZIP, ARJ).
Utilizai ct mai puine comenzi de formatare posibil:
- numai tasta Enter pentru a indica sfritul paragrafelor, titlurilor, listelor etc;
- numai tasta Tab pentru a indica paragrafele;
- evideniere numai Bold sau Italic, fr alte tipuri de caractere.
Tabelele i figurile vor fi redactate n MS Word i vor fi numerotate n ordine, cu cifre
arabe, fiind nsoite de un text explicativ minim. V rugm s inserai tabelele i figurile la sfritul
fiierului sau n fiier separat. Fotografiile scanate vor fi salvate n format .tif sau .jpg.
Articolele vor avea maxim 15 pagini (exclusiv bibliografia i rezumatele). Se accept numai
abrevierile unanim recunoscute (ex. SNC); celelalte abrevieri vor fi precedate de termenul ntreg la
prima apariie n text. Indicai n text locul tabelelor i figurilor, specificnd numrul acestora.
Prima pagin va cuprinde: titlul articolului (maximum 80 caractere), numele autorului
(autorilor), denumirea i adresa locului unde i desfoar activitatea, adresa complet (telefon /
fax / E-mail) a unuia dintre autori.
A doua pagin va cuprinde: rezumatul n limba romn (maximum 150 cuvinte) + cuvinte
cheie (minimum 3 i maximum 5); titlul i rezumatul n limba englez + cuvinte cheie (minimum 3
i maximum 5).
Bibliografia va fi grupat n ordine alfabetic.
Exemplu de articol citat
Dubovsky, S.L., Christiano, J., Daniell, L.C. et al, 1989 Increased platelet intracellular
calcium concentration in patients with bipolar affective disorder. Arch. Gen. Psychiat., 46, 632-638.
Exemplu de carte citat
Torrey, E.F., 1995 Surviving schizophrenia: a manual for families, consumers and
providers. New York, Harper Collins, 409.
Exemplu de capitol dintr-o carte
File, S.E., Baldwin, H.A., 1989 Changes in anxiety in rats tolerant to, and withdrawns
from, benzodiazepines: behavioural and biochemical studies. In: Tyrer P, eds. The
psychopharmacology of anxiety. Oxford University Press, 28-51.

Lucrrile i corespondena pentru revist vor fi trimise pe adresa: Asociaia Romn de
Psihofarmacologie Clinica de Psihiatrie Craiova, Str. Nicolae Romanescu, 41 1100 Craiova.





94


Instructions to authors



The text must be edited in MS Word, at 1,5 lines spacing and 2 cm margins. The font used
will be Times New Roman from Windows. The text file will have the name of the author and a key
element from the title. (ex. Smith_Schizophrenia.doc). It is compulsory to send the materials on 3,5
floppy disks and two printed copies; please check the integrity of your disks and make more copies
of the file (files). You can use any usual compressing software (RAR, ZIP, ARJ).
Use as little as possible of the formatting commands:
- Enter to indicate the end of paragraphs, titles, lists etc.
- Use only Tab key to indicate paragraph.
- for highlighting use only Bold and Italic.
Tables and figures will be edited in MS Word and will be numbered in the right order with
arabic numbers, followed by a minimum explanatory text. Please insert the tables and figures at the
end of the file or in a separate file. The scanned images will be saved as *.tif or *.jpg.
The articles will have maximum 15 pages (not including the bibliography and the abstracts).
Only the recognised abbreviations will be used (ex. CNS); other abbreviations will be fully written
at their first appearance in the text. Indicate in the text the location of the tables and figures,
mentioning their numbers.
The first page must include: the title of the article (maximum 80 characters), the name and
affiliation of the author (authors), the full address (phone/fax/e-mail) of one of the authors.
The second page will include: title and abstract in English + keywords.
The bibliography will be organised alphabetically.
Example of quoted article
Dubovsky, S.L., Christiano, J., Daniell, L.C. et al, 1989 Increased platelet intracellular
calcium concentration in patients with bipolar affective disorders. Arch. Gen. Psychiat., 46, 632-638.
Example of quoted book
Torrey, E.F., 1995 - Surviving schizophrenia: a manual for families, consumers and
providers. New York, Harper Collins, 409.
Example of chapter quoted from a book
File, S.E., Baldwin, H.A., 1989 - Changes in anxiety in rats tolerant to, and withdrawns
from, benzodiazepines: behavioural and biochemical studies. In: Tyrer P, eds. The
psychopharmacology of anxiety. Oxford University Press, 28-51.

The articles and correspondence for the Journal will be send to the following address:
Romanian Association for Psychopharmacology Clinica de Psihiatrie Craiova, Str. Nicolae
Romanescu, 41 1100 Craiova.