romanian journal of psychopharmacology

Transcription

Vol. 7, Nr. 1, 2
2007
ROMANIAN JOURNAL OF
PSYCHOPHARMACOLOGY
Editura Medicală Universitară Craiova
2007
CONTENTS
Treatment of acute mania in bipolar disorder
Michel Bourin, Corina Prica .............................................................................................................................. 1
Metabolic effects of antipsychotics “in an up-to-date vision”
C. Friedmann ................................................................................................................................................... 14
Neurobiological aspects in the diagnosis and therapy of the Alzheimer’s disease
D. Marinescu, T. Udriştoiu .............................................................................................................................. 26
Interrelations stress, depression, antidepressant treatment in neuronal plasticity
G. Talau, Lavinia Duică, D. Nicoară, R.D. Talau ........................................................................................... 35
Therapeutic strategies in obsessive-compulsive disorder (OCD)
Delia Marina Podea, Ramona Maria Chendereş ............................................................................................. 41
Causes and management of antipsychotic-induced hyperprolactinemia
A. Chimorgiachis, D. Marinescu ..................................................................................................................... 51
Depression in schizophrenia
Maria Toma, A. Chimorgiachis ....................................................................................................................... 63
Clinical and therapeutical aspects in psychiatric pathology associated with the HIV infection
Angela Dumitrescu, D.M. Dumitrescu, Carmen Dumitrescu .......................................................................... 70
Neurobiological implications in cognitive impairment. Parallel study depression-dementia
Emanuela Alina Stoica Spahiu, Elena Albu .................................................................................................... 81
AR
P
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Romanian Journal of Psychopharmacology
BOARD
T. Udriştoiu
M. D. Gheorghe
D. Marinescu
FOUNDING EDITOR
EDITOR
DEPUTY EDITOR
EDITORIAL BOARD
T. Udriştoiu (Craiova)
M. D. Gheorghe (Bucureşti)
D. Marinescu (Craiova)
P. Boişteanu (Iaşi)
V. Chiriţă (Iaşi)
Pompilia Dehelean (Timişoara)
V. Enătescu (Satu Mare)
C. Friedmann (Constanţa)
C. Fulga (Bucureşti)
J. Grecu-Gaboş (Târgu Mureş)
A. Grigoriu (Braşov)
R. Mihăilescu (Bucureşti)
G. Talău (Sibiu)
V. Voicu (Bucureşti)
INTERNATIONAL BOARD
M. Bourin (Nantes, France)
M. Davidson (Tel Aviv, Israel)
S. Kasper (Vienna, Austria)
H.J. Möller (Munich, Germany)
P. Ruiz (Houston, USA)
J. Zohar (Ramat Gan, Israel)
Asociaţia Română de Psihofarmacologie
Romanian Association for Psychopharmacology
AR
P
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Clinica de Psihiatrie
Str. Nicolae Romanescu, 41, Craiova
Tel: 0251 426161; Fax: 0251 428584
E-mail: office@psycv.ro
M. D. Gheorghe – preşedinte / president
T. Udriştoiu – vicepreşedinte / vice-president
D. Marinescu – secretar / secretary
Partener Principal – Fundaţia PRO Craiova
Vol. 7, Nr. 1, 2
TREATMENT OF ACUTE MANIA IN BIPOLAR DISORDER
Michel Bourin1, Corina Prica1,2
1
Faculté de Médecine Nantes, France
2
Faculty of Biology, Bucharest, Romania
Abstract
Bipolar affective disorder is a serious mental illness associated with
significant morbidity and mortality. There continues to be a lack of goodquality research available on which, to base treatment regimens, particularly
with regard to manic or hypomanic episode. Lithium continues to be
advocated as a first-line treatment, particularly in long-term therapy. Over
recent years the anticonvulsant valproate has joined lithium as an alternative
first-line therapy, despite what some would argue as a relative dearth in
conclusive evidence.
The difficulty remains in comparison between antipsychotics, essentially used
in the manic phase and some mood stabilisers, such as lithium (with equal
efficacy in the acute phase and the prevention of the onset of additional
phases) and to propose one or more reference medicines.
Keywords: bipolar disorder, mania, evaluation criteria, anticonvulsants,
atypical antipsychotics.
Introduction
Mania and depression are polar opposites on a continuum between grandiose selfimportance and self-perceived ability on one side, and feelings of self-loathing, incompetence and
apathy on the other. These two opposite states of mood can exist at different times in one individual
forming bipolar disorder.
Mania and depression have been seen as distinct, yet related, phenomena since ancient
Greece (American Psychiatric Association). Only in recent history, mood disorders have been
divided into syndromes of mania and depression. As the father of current psychiatric nosology,
Kraepelin was one of the first to distinguish individuals with mania into those with and without
depression. The purpose of this paper is to discuss the treatment for acute mania
Classical Clinical Descriptions
Manic states are typically characterized by heightened mood, more and faster speech,
quicker thought, brisker physical and mental activity levels, greater energy (with a corresponding
decreased need for sleep), irritability, perceptual acuity, paranoia, heightened sexuality, and
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impulsivity. The degree, type and chronicity of these cognitive, perceptual, and behavioral changes
determine the major sub classification of mania, namely hypomania or mania.
In hypomania, the above changes are generally moderate and may or may not result in
serious problems for the individual experiencing them. In more intense episodes, however, they
profoundly disrupt the lives of patients, their families, and society.
Mood in acute mania is not well described by the classic writers, perhaps because extreme
changes in cognition and behavior are more clearly observable than subjective mood states. Two
thousand years ago, however, Aretaeus of Cappadocia noted that those who are manic, are active,
and expansive. They are naturally joyous, they laugh and they joke: “they show off in public with
crowned heads as if they were returning victorious from the games; sometimes they laugh and
dance all day and night” (Roccatagliata, 1986; Kraepelin, 1921), writing centuries later, agreed, but
stressed the instability path manic mood: “Mood is unrestrained, merry, exultant, occasionally
visionary of pompous, but always subject to frequent variation, easily changing to irritability and
irascibility or even to lamentation an weeping”
Activity and behavior are greatly increased and diversified in mania. Patients appear to be
indefatigable; they are rash, virulently opinionated, and interpersonally aggressive.
For many patients, excessive energy translates directly into pressured writing and an
inordinate production of written declaration, poetry and artwork.
Particularly dramatic and extreme among the clinical features of acute mania are the
frenetic, seemingly aimless, and occasionally violent activities of manic patients. Bizarre, driven,
paranoid, impulsive and grossly inappropriate behavior patterns are typical.
Diagnosis
The history of psychiatric diagnosis has been notable for its confusion, reflected in the
myriad overlapping systems for classifying and subdividing depressive disorders. However,
Kraepelin, (1921), brought order to the diagnosis of depression by grouping all of the recurrent
affective disorders under the rubric of manic-depressive illness, a broad category later divided into
unipolar and bipolar subgroups.
When making a diagnosis, the clinician should assess presenting signs and symptoms, and
weigh them together with the patient’s history and prior response to treatment, as well as the family’s
history. Individual symptoms even clusters of symptoms examined at one point in time often lack
diagnostic specificity, although such cross-sectional views are sometimes the only ones available.
The structure of mania has been examined in recent phenomenological studies using factor
analytic and other methods. These studies have revealed that the most common signs of mania are
motor activation, flight of ideas, pressured speech, and decreased sleep, while elated mood and
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increased sexuality are decidedly less common. These studies have also identified four types of
mania that coincide with Kraepelin’s observations: hypomania, acute mania, delusional mania and
depressive or anxious mania.
The manic episode can occur in the different aspects that accompany bipolar disorder:

In type I the patient presents manic episodes, either major depressive episode (Ahearn et
al., 1996);

In type II, the patient presents recurrent major depressive episodes and at least one or
several hippomanic episodes (Hantouche et al., 1998);

In type III, the patient presents some recurrent major depressive episodes with one or
several pharmacologically induced hippomanic episodes.
Adequate factor analyses of signs and symptoms of mania have been reported. Five clearly
interpretable and clinically relevant factors were identified. The first and strongest factor
represented dysphoria in mania, with strong positive loadings for depressed mood, lability, guilt,
anxiety, and suicidal thoughts and behaviours and a strong negative loading for euphoric mood.
Factors 2 through 5 represented psychomotor acceleration, psychosis, increased hedonic function,
and irritable aggression, respectively. (Cassidy et al 1998)
Treatment
Anti-manic medications tended to be prescribed for the acute treatment of mania or
hypomania, and antidepressant drugs for the treatment of depression. In this section we review the
literature on various medications used to treat acute mania: lithium, and anticonvulsants.
Lithium
Earlier controlled studies of lithium clearly established its superiority to placebo in treating
acute mania. Studies conducted since 1990 were designed to compare newer medications with
lithium as a reference antimanic drug (Bowden et al., 1994).
Early placebo-controlled studies established lithium as an effective, although not rapidly
acting, treatment of choice for mania. Many of these studies varied as to dosage, serum levels, and
rapidity of dosage titration, making it difficult to establish the precise time to onset of lithium’s
antimanic action. Nonetheless, there is little doubt that lithium as effective as other antimanic agents
over a 3-week period, with some studies showing a more rapid onset of action (as little as 10 days).
The largest randomized double-blind study of lithium versus placebo in acutely manic
patients was actually designed to study the benefits of divalproex (valproate) for the treatment of
acute mania, with lithium-and placebo treated groups serving as controls (Bowden et al., 1994;
Swann et al., 2000; Swann et al 1997). In this study 49 percent of the lithium-treated patients
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responded (i.e., had at least a 50 percent reduction in their YMRS scores) during the 3-week trial
period (efficacy comparable to that seen for the valproate group). This result doubled the response
rate of 25 percent in the placebo group. Nearly half of the patients had a history of poor response to
lithium, which predicted the differential response seen in this trial. Thus, among the prior lithium
responder who received lithium in this trial, there was a 15-point mean reduction in YMRS scores
(a 60 percent improvement), compared with only a 1-point mean improvement in the previously
non-responsive group (Bowden et al., 1994). Among the prior lithium responders randomized to
valproate, by contrast, there was only a 27 percent improvement, compared with the 60 percent
improvement with lithium.
Anticonvulsants
The use of anticonvulsant agents for the treatment of bipolar disorder was a watershed event
for the psychiatry in the late twentieth century. The clear effectiveness of some anticonvulsants for
patients who do not respond well to or cannot tolerate lithium has made these drugs a welcome
addition to the armamentarium. Controlled trials have shown both valproate and carbamazepine to
be more effective than placebo, and as noted above, as effective as lithium for the treatment of acute
mania (Bowden et al., 1994; Post et al., 1986; Small et al 1991; Bowden et al., 2006; Weisler et al.,
2004; Weisler et al., 2005)
Carbamazepine
Starting in the 1970s, a number of studies showed carbamazepine to be superior to placebo,
although not necessarily equivalent to lithium, in the short-term treatment of mania. Okuma and
colleagues (1990) conducted a double-blind placebo-controlled study of manic patients who were
undergoing treatment with antipsychotics without substantial benefit. Half of the 105 patients were
given 400-200mg/day of carbamazepine, and the other half were given lithium in amounts sufficient
to establish relatively low mean serum levels of 46 all the patients continued on haloperidol. The
final assessment revealed moderate to mark in both groups of patients. Since no group was assigned
to continue antipsychotic alone, however, it remains unclear how much of the improvement seen
was due to the adjunctive mood stabilizers versus the antipsychotic themselves. Small and
colleagues (1991) conducted an 8-week double-blind comparison of carbamazepine and lithium in
52 hospitalized acutely manic patients. They found that the two drugs were equally effective in
reducing manic symptoms (as judges by YMRS scores), a conclusion supported by later metaanalysis (Emilien et al., 1996).
Valproate
The French psychiatrist Lambert first reported a possible role of valproate in the treatment
of bipolar disorders in the course of its first clinical trials in patients with epilepsy in 1960s
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(Lambert et al 1966) [30]. Many years later, Calabresse and Delucchi (1990) found that the drug,
appear to have marked effect in treating mania. They also noted that most patients (63 percent) with
a good response to the drug had failed to improve on lithium or carbamazepine (or both).
Randomized, placebo-controlled studies have compared valproate with placebo and with
lithium. In the first such study (Pope et al 1991), 17 patients were randomized to divalproex and 19
to placebo. The dilvaproex-treated patients showed a median improvement in YMRS scores of 54
percent, versus only 5 percent for the placebo group. Similar benefit was seen on the Global
Assessment of Social Scale (GAS) and the Brief Psychiatric Rating Scale (BPRS). A significant
problem with this and several other studies of mania is that the compilation rate for the 3-week
study was only 24 percent in the dilvalproex group and 21 percent in the placebo group.
In the largest placebo-controlled study of acute mania conducted to date, 179 patients with
acute mania were treated with either dilvaproex, lithium, or placebo for 21 days (Bowden et al
1994) [20] [as in the Pope et al (1991)], study, a large number of patients failed to complete this
study). About half of the patients in the divalproex-and lithium treated groups but only one-fourth
of the patients in the placebo-treated group showed marked improvement. While the authors
concluded that the efficacy of divalproex appeared to be independent of prior responsiveness to
lithium in fact the drug showed only a 27 percent response rate among prior lithium responder
(compared with a 60 percent response rate lithium) while having greater efficacy among prior
lithium non-responders.
Lamotrigine
Lamotrigine is an anticonvulsant with sodium channel blocking activity to that of
carbamazepine and phenytoin. Case reports and open studies have suggested some efficacy for this
drug in treating mania, but this finding was not confirmed in controlled studies. A small (30
subjects) 4-week randomized controlled trial compared lamotrigine with lithium for the treatment of
hospitalized manic patients (Ichim et al 2000). The lithium and lamotrigine groups shared similarly
reduced YMRS scored, but the absence of the placebo group renders the results of this
underpowered study inconclusive. Other controlled studies in patients presenting with mania found
no significant difference between lamotrigine and placebo (Frye et al 2000).
Antipsychotics
During the past decade the treatment of mania has been significantly altered by the
introduction of atypical antipsychotics.
Among the atypical antipsychotics, olanzapine and risperidone have been studied most
extensively.
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Haloperidol
Haloperidol is an older antipsychotic agent that remains in wide clinical use. In recent
studies, this agent has also demonstrated acute anti-manic efficacy. Prophylactic utility of this agent
in long-term studies has not been adequately examined.
The main objectives in treating mania are to control dangerous behaviour, reduce suicide,
produce appropriate acute sedation and shorten the episode of mood disturbance. Among different
drugs, haloperidol has for many years been used in treating psychotic patients, but it has a
troublesome side effect profile.
To assess the effects of haloperidol for the treatment of mania in comparison with placebo or
other active drugs, either as monotherapy or add-on treatment, Cipriani et al, (Cipriani et al 2006),
realised a randomised trials comparing haloperidol with placebo or other active treatment in the
treatment of acute manic or mixed episodes in patients with bipolar disorder.
Fifteen trials involving 2022 people were included. Compared to placebo, haloperidol was
more effective at reducing manic symptoms, both as monotherapy (Weighted Mean Difference
(WMD) 5.85, 95% Confidence Interval (CI) 7.69 to 4.00) and as adjunctive treatment to lithium or
valproate (WMD 5.20, 95% CI 9.26 to 1.14). There was a statistically significant difference, with
haloperidol being less effective than aripiprazole (Relative Risk (RR) 1.45, 95% CI 1.22 to 1.73). No
significant differences between haloperidol and risperidone, olanzapine, carbamazepine or valproate
were found. Compared with placebo, a statistically significant difference in favour of haloperidol in
failure to complete treatment (RR 0.74, 95% CI 0.57 to 0.96) was reported. Haloperidol was
associated with less weight gain than olanzapine (RR: 0.28, 95% CI 0.12 to 0.67), but with a higher
incidence of tremor (RR: 3.01, 95% CI 1.55 to 5.84) and other movement disorders.
Authors' conclusions: there is some evidence that haloperidol is an effective treatment for
acute mania. From the limited data available, there was no difference in overall efficacy of
treatment between haloperidol and olanzapine or risperidone. Some evidence suggests that
haloperidol could be less effective than aripiprazole. Referring to tolerability, considering the poor
evidence comparing drugs, clinicians and patients should consider different side effect profiles as an
important issue to inform their choice.
There was some evidence that haloperidol was more efficacious than placebo in terms of
reduction of manic and psychotic symptom scores, when used both as monotherapy and as add-on
treatment to lithium or valproate. There is no evidence of difference in efficacy between haloperidol
and risperidone, olanzapine, valproate, carbamazepine, sultopride and zuclopentixol. There was a
statistically significant difference with haloperidol being probably less effective than aripiprazole.
No comparative efficacy data with quetiapine, lithium or chlorpromazine were reported.
Haloperidol caused more extrapyramidal symptoms (EPS) than placebo and more movement
disorders and EPS but less weight gain than olanzapine. Haloperidol caused more EPS than
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valproate but no difference was found between haloperidol and lithium, carbamazepine, and
risperidone in terms of side effects profile.
Olanzapine
This atypical agent has been shown to be superior to placebo in several randomized, double
blind comparisons in acutely manic patients. In the first of these studies, olanzapine at the dose of
5-20 mg/day resulted in substantially greater improvement over that seen in placebo-treated subject
in a 3-week study (Tohen rt al., 1999). The olanzapine treated patients’ response rate (defined as a
reduction in YMRS score) was 48 percent, compared with 24 percent for the placebo-treated group.
The difference favouring olanzapine was not apparent, however, until the third week of the study.
A second randomized, placebo-controlled study yielded similar results, except that the
difference in efficacy between olanzapine and placebo appeared after only 1 week of treatment and
was sustained throughout the remainder of the trial (Tohen et al., 2000). In a 3-week randomized,
double-blind study comparing olanzapine (5-20 mg/day, mean dose 17,4 mg/day) with divalproex
(500-2,500 mg/day, mean dose 1,401 mg/day, achieving a mean blood level of 82 mg/ml) for the
treatment of acute mania, (Tohen et al., 2002) demonstrated a slight but significant advantage for
olanzapine over dilvalproex as measured by the percentage pf patients achieving a greater than 50
percent decrease in YMRS score, by the percentage achieving remission as defined by a YMRS
score of 12 or lower, and by the mean reduction in score among the two groups. A 44-week doubleblind extension of this study found that only after 15 weeks of treatment was the efficacy of
valproate comparable to that of olanzapine (Tohen et al., 2003; Zajecka et al., 2002), by contrast,
found that olanzapine and valproate had comparable efficacy in a 12-wek randomized, double-blind
study involving 120 patients with acute mania. The difference between the results of these two
studies appears to be explained by dose: compared with the Lilly-funded Tohen study, the Abbottfounded Zajeka et al study used a lower dose of olanzapine (mean daily dose were 14, 7 mg) and a
higher dose of valproate (2,115 mg/day). In both studies, patients in the olanzapine group
experienced significantly more side effects, especially somnolence significantly more side effects,
especially somnolence and weight gain, than those in the valproate group.
Risperidone
In open studies of manic patients Tohen and colleagues (1996), (Tohen et al., 1996) found a
50 percent or greater reduction in manic symptoms in 10 of 12 patients when risperidone was added
to lithium. Keck and colleagues (1995), studies a mixed groups of patients treated with risperidone,
noting that all 9 bipolar patients with mania showed moderate to marked improvement when the
drug was added to a mood-stabilizing regime consisting of lithium, valproate, or carbamazepine,
Ghaemi and Sachs (1997), found that 9 of 14 bipolar patients, most with mania or mixed states,
responded well to addition of risperidone in small doses, averaging under 3mg/day.
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Other study was realised by Hirschfeld and colleagues (1999), randomised 134 manic
patients to risperidone (mean modal dose 4, 1 mg/day) and 125 to placebo, also for 3 weeks. An
improvement in mania (YMRS score) was significantly greater in the risperidone group, with
separation from placebo evident as early as 3 days: 43 percentage of those randomized to
risperidone met response criteria at 3 weeks, versus 24 percent in the placebo group. Remission
rates (decline YMRS score ≤ 12) were 38 percent for risperidone versus 24 percent for placebo.
A randomized, double blind study of risperidone in combination with lithium,
carbamazepine, or valproate showed a significantly more rapid decline in YMRS scores for patients
taking risperidone in addition to their other medication. The mean modal dose, in this study was
4mg/day (Yatham et al 2003). In another prospective double blind, placebo-controlled trial of
risperidone as adjunctive treatment for mania (added to lithium or valproate, to which the patients
were not responding adequately), Sachs and colleagues (2002), noted more improvement in YMRS
scores with risperidone than with placebo at the end of weeks 1, 2, 3. Similar findings were
reported by Yatham and colleagues (2004), who randomly added risperidone (n=75) or placebo
(n=75) to lithium or valproate, noting significantly more reduction in mania (YMRS scores) with
the combined treatment.
In a randomized, double blind trial of risperidone monotherapy, 45 manic patients trial of
risperidone took risperidone monotherapy, 45 manic patients took risperidone 6mg/day, haloperidol
10mg/day, or lithium 800-1,200 mg/day in a 3-week trial. (Tohen et al 2003). There were no
differences in treatment outcomes among the three groups, all of which showed a mean improvement
of about 50-60 percent on the YMRS, as well as substantial improvement on general psychopathology
and functioning scale (Segal et al., 1998). The fact that lithium and risperidone showed similar
efficacy in this monotherapy study appears at first glance to be at odds in this results of controlled
studies reviewed above in which adjunctive risperidone was superior to lithium (or valproate).
In a recent randomized double-blind comparison, risperidone and olanzapine had equivalent
antimanic efficacy. (Perlis et al, 2006b).
Quetiapine
Several case reports (Dunayevich and Strakowski, 2000), and retrospective case series suggest a
useful role for the atypical antipsychotic quetiapine when used as adjunctive treatment for mania.
Two large international multicenter randomized, double blind, placebo-controlled trials
evaluated the efficacy of quetiapine monotherapy (400-800mg/day) in hospitalized manic patients.
In one (Bowden et al., 2005), 302 patients were randomized to quetiapine (n=1007), lithium (n=98),
or placebo (n=95). At 3 weeks the decrease in YMRS scores was significantly greater (p<0,001) for
both drugs compared with placebo; the extent of the improvement was virtually identical for the
two drugs. The other study (McIntyre et al., 2005), was of the same size and design, except that the
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active comparator was haloperidol; results were similar as well, except that at 3 weeks, the effect of
haloperidol was slightly more robust than that of quetiapine. In both studies, quetiapine had
significantly greater effect than placebo.
Two large randomized, placebo-controlled trials (Sachs et al., 2004; Yatham et al., 2004)
examined the efficacy of adjunctive quetiapine in 402 hospitalized manic patients who were still
substantially symptomatic (IMRS scores ≥ 20) after a minimum of 7 days of lithium or dilvaproex.
In both studies, the combined treatment was significantly better that the mood stabilizer alone.
Regarding adjunctive olanzepine and risperidone, it is important to note that patients entered these
studies after at best a partial response to a week or more on the mood stabilizers alone; thus the
generalisation of the study findings is limited.
Aripiprazole
This atypical antipsychotic has pharmacodynamic profile that distinguishes it from other
antipsychotic by virtue of its being a partial agonist rather than an antagonist at dopamine D2
receptors. Keck and colleagues, (Keck et al., 2003), conducted a 3-week double blind, placebocontrolled study of aripiprazole for the treatment of mania in 262 hospitalized patients. They found
a 40 percent response rate (defined as a decrease of 50 percent or more in YMRS scores) compared
with 19 percent for placebo. These findings were subsequently replicated in a second multisite 3week study involving 272 manic patients (135 on aripriprazole, 137 on placebo). On the basis of the
results of these two studies, The FDA has approved aripiprazole for the treatment of acute mania.
How does this agent compare with haloperidol? Vieta and colleagues (2005), addressed this
question in a large double-blind comparison in which 347 manic/mixed-state patients were
randomized 1:1. 76, 6 percent of the aripiprazole group but only 55, 2 percent of the haloperidol
group completed the first 3 weeks of treatment; by 12 weeks these percentages were 50, 9 and 29, 1,
respectively. At week 12, significantly more patients in the aripiprazole group met response criteria
of 50 percent or greater improvement (49, 7 versus 28, 4 percent). The high dropout rate in the
haloperidol group was due at least in part to low tolerability, which can be attributed largely to the
protocol’s not allowing anticholinergic medication to deal EPS (extrapyramidal symptoms). The
authors also noted another factor limiting the generalisation of the comparison: the limited dose
range allowed for haloperidol.
Conclusion
There is not a reference drug to study treatments in acute mania. In Europe haloperidol is
still a gold standard even if this drug is not registered in the treatment of acute mania. Clinical
studies suggest that carbamazepine is weaker than lithium and that sodium valproate is superior to
lithium in reducing symptoms of mania. Sodium valproate is used very often in patients resistant to
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lithium treatment. Among the atypical antipsychotics, olanzapine and rispridone have been studied
most extensively.
In our opinion atypical antipsychotics are very important in the treatment of mania because
they are less sedative. Lithium would be the ideal comparator except if mania occurs in patients
treated for maintenance treatment at right dose.
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39. Weisler RH, Keck PE Jr, Swann AC, et al., 2005 – Extended-release carbamazepine
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Clin Psychiat., 63, 1148-55.
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EFECTELE METABOLICE ALE MEDICAŢIEI ANTIPSIHOTICE
„într-o viziune up-to-date”
C. Friedmann
Universitatea „Ovidius” Constanţa
Rezumat
Ca o constatare alarmantă, din datele raportate de literatura de specialitate
şi în conformitate cu propria noastră experienţă, un număr apreciabil de
pacienţi supuşi tratamentului cu SGA prezintă efecte secundare de tipul
„sindromului metabolic” ca o consecinţă directă a obezităţii induse de o
seamă de medicamente din această categorie ce se fac răspunzătoare de
creşterea rezistenţei la insulină, de creşterea concentraţiei glicemiei, de
diabetul de tip 2 şi altor factori de risc cardiovascular.
Există o corelaţie semnificativă între tratamentul cu diferite molecule
antipsihotice cu variate efecte ale sindromului metabolic cum ar fi creşterea
în greutate corporală – înregistrând creşteri discrete (mai puţin de 2 kg) cum
e cazul terapiilor cu aripiprazole, ziprasidone şi amisulpride până la creşteri
ponderale excesive în tratamentele cu agenţi farmacologici de tipul
olanzapinei şi clozapinei (de exmeplu de la 4 la 10 kg şi uneori mult peste).
Argumente clinice şi de markeri biochimici pledează pentru rolul adipozităţii
în scăderea sensibilităţii la insulină, ceea ce implicit conduce la fenomenul
creşterii rezistenţei la insulină, hiperglicemie, diabet zaharat de tip 2 cu şi
fără complicaţii ketoacidozice şi a altor factori de risc cardiovascular.
Cuvinte-cheie: medicaţie antipsihotică, efecte adverse, sindrom metabolic,
obezitate, rezistenţa la insulină, diabet zaharat de tip 2, dislipidemie,
hiperglicemie, ketoacidoză, boală cardiovasculară.
METABOLIC EFFECTS OF ANTIPSYCHOTICS
“in an up-to-date vision”
Abstract
As the psychiatric review literature has been revealing as a black-box warning
confirmed by our own practical experience, an increasing number of patients are
presenting the symptoms of weight gain, hyperglycemia, dyslipidemia and type 2
diabetes mellitus – the so called “metabolic syndrome” – as an aftermath
consequence directly related with the second generation antipsychotic
treatments, in these patients.
There’s a strong corelation between adiposity and the medical risks of
developing the “metabolic syndrome”, but not in equal proportions when
using these antipsychotic molecules (SGAs).
As a real consequence, treatment with a different antipsychotic medication is
associated with variable effects in body weight, ranging from modest
increases (for example less than 2 kg) experienced with aripiprazole,
ziprasidone and amisulpride to larger increases during treatment with agents
such as olanzapine and clozapine (for example 4 to 10 kg and even more).
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Evidence-based arguments indicate that increasis in adiposity are associated
with decreases in insulin sensitivity leading to insulin resistance in
individuals both with and without psychiatric disease.
Key words: antipsychotic medication, adverse effects, metabolic syndrome,
adiposity, insulin resistance, type 2 diabetes mellitus, dyslipidemia,
hyperglycemia, ketoacidosis, cardiovascular disease.
Antipsihoticele de generaţie secundă sunt remedii providenţiale care oferă beneficii
importante pacienţilor suferind de tulburări psihotice cum ar fi schizofrenia şi bolile înrudite, cu o
reducere considerabilă a efectelor de tip extrapiramidal imputabile antipsihoticelor convenţionale de
generaţie mai veche.
Faptul că unele medicamente din această categorie de avangardă produc creşteri
semnificative în greutate, risc pentru stări dislipidemice şi diabet zaharat de tip 2, ne determină să
aprofundăm mecanismele de producere ale acestor efecte adverse şi să studiem măsurile de
contracarare a acestor efecte.
Pacienţii cu boli mentale severe au rate ridicate de mortalitate şi de comorbiditate cu boli severe
în complicaţii şi consecinţe, cum ar fi diabetul zaharat şi bolile coronariene. Pe lângă factorii genetici
cărora le revine evident un rol important, stilul de viaţă, sedentarismul, alimentaţia defectuoasă, precară,
influenţează starea de sănătate a acestor oameni afectaţi de condiţii patologice mentale, ele însele
balasturi greu de contracarat. Măsurile de prevenţie primară şi secundară vizează aceşti factori de risc şi
ne determină să găsim soluţii noi pentru noile ameninţări ce întunecă perspectiva orizontului de
dezvoltare umană şi spirituală a acestor fiinţe ameninţate de aceste noi pericole.
Un factor de risc de importanţă cardinală este adipozitatea excesivă care poate fi cuantificată
cu ajutorul calculării BMI. Indicii crescuţi de BMI sunt asociaţi cu risc major de îmbolnăvire
cardiovasculară şi morbiditate crescută (Calle EE, Thun MJ et al 1999).
Dintre toate formele de adipozitate cea cu depunere viscerală, dar mai ales abdominală de
aspect protuberanţial se asociază cu o descreştere a sensibilităţii insulinei, deci implicit cu o creştere
a rezistenţei la insulină (Banerji MA, Lebowitz J, Chaiken RL, 1997). Rezistenţa la insulină este
asociată cu o dereglare a mecanismelor de control a glicemiei, dislipidemie aterogenetică ceea ce
implică creşterea trigliceridelor plasmatice, creşterea particulelor de LDL saturate prin oxidare,
creşterea tensiunii arteriale, creşterea riscului de coagulare intravasculară, creşterea concentraţiei
markerilor proinflamatori, ceea ce amplifică riscul de afectare coronariană cu consecinţe fatale,
aproape inevitabile.
În conformitate cu stipulările ghidurilor US National Cholesterol Education Program ATP
III, pacientul care întruneşte 3 dintre criteriile menţionate în aceste ghiduri poate fi diagnosticat ca
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prezentând “sindromul metabolic” care-l face candidat de certitudine pentru îmbolnăvirea de tip
diabet zaharat 2 sau boală coronariană cu toată suita de complicaţii caracteristice acestei boli severe:

obezitate – definită ca depăşind măsurarea perimetrului de brâu ombilical peste limita de
102 cm la bărbaţi şi 88 cm la femei;

nivele scăzute de colesterol HDL < 40 mg % la bărbaţi şi < 50 mg % la femei;

nivele crescute de trigliceride plasmatice ( > 150 mg %);

creşteri ale valorilor presiunii arteriale ( ≥ 130 mm Hg pentru presiunea sistolică şi 85
mm Hg pentru presiunea diastolică);

creşterea glucozei „a jeun” ( fasting glucose ) ≥ 110 mg %.
Există riscul pe termen lung de a prezenta valori crescute de glicemie şi dezvoltarea unui
diabet zaharat tip 2, ceea ce echivalează cu predispunerea respectivilor subiecţi la cele două forme
maligne de patologie cardiovasculară sistemică:

boala microvasculară (constând în retinopatie diabetică, nefropatie diabetică şi
neuropatie de origine diabetică) şi

boala macrovasculară (cuprinzând ateromatoza coronariană, boala coronariană
anginoasă, angina instabilă sau forma de boală coronariană indoloră – severă, în
consecinţe cu risc de moarte subită, boala cerebrovasculară, boala vasculară periferică).
Diabetul zaharat de tip 2 nediagnosticat sau neglijat se asociază cu complicaţii severe pe
termen scurt, incluzând în primul rând „diabetul ketoacidozic” şi stările hiperosmolare nonketotice
care, deşi destul de rare, pot fi de o mare severitate (Lorenzo C, Oboloise M, 2003).
Riscul de mortalilate al cazurilor de diabet ketoacidozic este de aproximativ 2% în condiţii
clinice optimale şi creşte până la 20 % la pacienţii vârstnici, acest risc fiind corelat cu creşterea în
vârstă, bolile intercurente, întârzierea instalării tratamentului cu insulină (Von Hayek D et al, 1999).
Asociaţia Americană de Diabet – cosponsorizată de Asociaţia Americană de Psihiatrie,
Asociaţia Americană a Clinicienilor Endocrinologi şi Asociaţia Nord-Americană de Studiu a Obezităţii
a constatat şi a declarat că „din gama de antipsihotice clozapina şi olanzapina sunt asociate într-o
manieră potenţial severă cu cele mai accentuate creşteri de greutate corporală şi cu dovezi constante
asupra riscului crescut de apariţie a diabetului zaharat de tip 2 şi a dislipidemiilor de mare severitate”
(American Diabetes Association Consesus, 2004). Raportul subliniază, cu toată categoricitatea, că
medicilor prescriptori şi terapeuţilor le revine întreaga responsabilitate de evaluare a riscurilor versus
beneficiul terapeutic psihiatric în prescrierea acelor agenţi terapeutici farmacologici specifici la care
potenţialul beneficiu terapeutic poate fi pus în discuţie de riscurile sindromului metabolic, deja cunoscut
prin nocivitatea consecinţelor asupra sănătăţii fizico-somatice a pacienţilor psihici, mai ales a celor
suferind de forme de schizofrenie refractară terapeutic şi la care ghidurile terapeutice cele mai
prestigioase sugerează încă folosirea clozapinei (de exemplu) ca medicaţie de ultim recurs.
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Tratamentul cu medicaţia antipsihotică duce la creşteri semnificative ale greutăţii corporale
– complicaţie cu consecinţe redutabile date fiind cunoştinţele noastre practice şi teoretice ale
efectelor nocive a obezităţii asupra unor importante sectoare a sănătăţii somatofizice a pacienţilor
noştri şi în primul rând rezistenţa insulinică şi diabetul zaharat de tip 2.
Creşterile în greutate induse de medicaţia psihotropă în general, dar mai ales de medicaţia
antipsihotică uzitată actualmente ( SGA ) cu rezultate superioare în plan clinico-terapeutic faţă de
antipshihoticele de primă generaţie, ne obligă să abordăm problema acestor corelaţii
medicamentoase cu toată seriozitatea şi îngrijorarea justificate de urmările acestor fenomene ce se
constituie în factori majori de risc cardiovasculari, cu scăderea dramatică a speranţei de viaţă şi
producerea multor complicaţii letale.
Studiile comparative placebo, trialurile clinice randomizate şi metaanalizele bazelor de date
au relevat diferenţe semnificative de efecte corelative a diferitelor antipsihotice, cu riscul dezvoltării
unui proces diabetic de tip 2 sau chiar direct a unor complicaţii de tip ketoacidozic pe fondul unei
evoluţii latente, subclinice chiar, atât pe termen scurt, cât mai ales pe termen lung.
Şi studiile pe termen scurt (“short-term”) au dovedit că administrarea antipsihoticelor
“SGA” produc creşteri în greutate între 1 şi 4 kg ( Allison DB, Mentore JL, 1999, Am. J. of
Psychiatry ), dar mai ales studiile comparative cu antipsihotice pe termen lung au scos în evidenţă
într-un mod mult mai drastic şi relevant diferenţele în inducerea creşterilor în greutate şi a stărilor
de obezitate, în terapiile cu diverse asemenea medicaţii antipsihotice.
Programele trialurilor clinice de terapie cu aripiprazole (Marder SR, McQuade RD et al,
2003) şi ziprasidonă ( Hirsch SR, Kissling W et al, 2002 ) s-au soldat cu creşteri în greutate
corporală în medie de 1 kg după 1 an, în timp ce la lotul de pacienţi trataţi cu amisulprid creşterea
de greutate a fost de 1,5 kg; la quetiapină şi risperidonă de 2-3 kg la acelaşi interval de timp, în
discrepanţă cu creşteri de greutate de peste 6 kg până la 10 kg şi chiar mai mult ( > 10 KG)
înregistrate în acelaşi interval de timp (Nemeroff CB, 1997).
Cel mai elaborat studiu prospectiv sponsorizat de NIMH ( CATIE ) a avut ca scop evaluarea
eficacităţii principalelor antipsihotice “SGA” (olanzapină, quetiapină, risperidonă şi aripiprazole) şi
a unui agent farmacologic de primă generaţie (perfenazină) asupra unui lot de 1493 pacienţi
schizofrenici din 57 de locaţii din SUA.
Obiectivul direct a fost studiul fenomenului de
discontinuare a tratamentului din varii motive, pentru estimarea eficacităţii, tolerabilităţii şi
siguranţei medicaţiei, inclusiv a situaţiilor de intoleranţă medicamentoasă prin efectele secundare cu
accentul major pe creşterea în greutate corporală şi sindromul metabolic cu toate componentele sale.
Primele rezultate de Fază 1 ale trialului CATIE au fost publicate în septembrie 2005 cu
constatarea îngrijorătoare a unor creşteri semnificative de greutate de 0,9 kg/lună şi în 30 % din
cazurile tratate cu olanzapină chiar de 7% şi peste, ceea ce depăşeşte cu mult efectele dismetabolice
ale tuturor celorlalte antipsihotice.
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Switch-ul terapeutic de la o terapie cu medicaţie antipsihotică cu risc de creştere majoră a
greutăţii la o medicaţie de aceeaşi eficacitate, dar cu un coeficient de risc dismetabolic mult mai
scăzut a dus la scăderi semnificative statistic (şi deci omologabile) a greutăţii corporale la pacienţii
trataţi cu olanzapină şi trecuţi pe aripiprazole (Lieberman JA, Stroup TS, 2005) sau ziprasidonă atît
după intervale de 6-8 săptămâni cât mai ales la intervale de timp mai mari.
Astfel studiul de switch terapeutic eşalonat pe o perioadă de 58 săptămâni la pacienţii pe
olanzapină trecuţi pe terapie cu aripiprazole a demonstrat o reducere a concentraţiei de colesterol
plasmatic total şi de trigliceride, ca şi reducerea dramatică a greutăţii corporale cu o medie de 9,8 kg
şi un BMI sub 25, concomitent cu modificările de profil a lipidogramei şi a glicemiei recoltate “a
jeun” (fasting plasma glucose) (Casey DE, Carson WH, Saho AR, 2003).
Rezultatele studiului CATIE de Fază 1 demonstrează că terapiile randomizate pe termen
lung pot induce scăderi semnificative de greutate corporală, mai ales în tratamentele iniţiate cu
aripiprazole (McQuade RD, Stock E, Marcus R, 2004), ceea ce alături de ziprasidonă aduc un
argument suplimentar în susţinerea argumentată a unui efect dublu ce i-ar conferi acestei medicaţii,
pe lângă o creştere minimă de greutate, capacitatea intrinsecă chiar de scădere a surplusului de
greutate iniţiat de terapiile cu olanzapină sau leponex şi chiar de alte antipsihotice cu efect
dismetabolic mai puţin sever (quetiapină, risperidonă).
O temă de preocupare majoră este asocierea medicaţiei antipsihotice cu riscul crescut pentru
rezistenţa la insulină, hiperglicemie şi apariţia DZ de tip 2 – în comparaţie cu pacienţii încă netrataţi
(“naive patients”) sau trataţi cu antipsihotice alternative (Casey DE, Haupt DW et al, 2004).
Un studiu recent (Ryan MC, Collins P, Newcomer JW, Thakore JH, 2003) de tip “crosssectional” secvenţial (aleatoriu) asupra unui lot de pacienţi schizofrenici spitalizaţi, la primul epizod
psihotic, încă nesupuşi unui tratament antipsihotic medicamentos (“naive patients”) au prezentat
într-o proporţie de 15% modificări semnificative ale glicemiei efectuate dimineaţa, după o noapte
de post alimentar (morning fasting glucose).
Pacienţii schizofrenici din alte studii au prezentat aleatoriu valori mai crescute ale glicemiei
matinale după o perioadă de post alimentar, epizoade de hiperglicemie persistentă mai frecventă ca
subiecţii de control selectiv comparativ după date antropometrice relativ omogene (sex, vârstă, stil
de viaţă etc.) şi cu monitorizarea unor parametri metabolici din sindromul metabolic (glicemia
matinală de tip “fasting”, insulina, nivelele de cortizolemie).
Concentraţiile crescute de cortizol – caracteristice epizoadelor acute psihotice şi perioadelor
de agitaţie psihomotorie şi anxietate generalizată în evoluţia multor cazuri de schizofrenie – pot
explica numărul mare de subiecţi cu rezistenţă crescută la insulină şi perioade frecvente de
hiperglicemie persistentă, ceea ce nu se întâlneşte cu aceeaşi frecvenţă la pacienţii schizofrenici
cronici stabilizaţi, sub efectul unei terapii cu medicaţie antipsihotică care nu se asociază în mod
sistematic cu perioade de hipercortizolemie.
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Mai mult, la un număr destul de mare de pacienţi cu adipozitate intraabdominală crescută
(perimetrul ombilical de peste 102 cm la bărbaţi şi peste 88 cm la femei), nu s-au observat date
concludente de ordin corelativ pentru definirea unei legături de predispoziţie între acest tip de
depunere adipoasă şi apariţia sindromului metabolic, deşi în contextul adipogenezei la pacienţii cu
boli mentale severe, legat şi de stilul de viaţă, tipul de alimentaţie şi sedentarism, adipozitatea
predominant abdominală ar fi un factor important în geneza sindromului metabolic.
Oricum cercetări de notorietate (Haupt şi John Newcomer, 2002) subliniază riscul existent al
pacienţilor suferind de schizofrenie sau alte condiţii mentale severe de a dezvolta o propensiune
spre fenomenele de rezistenţă a insulinei şi de a apariţie a unui diabet zaharat de tip 2, independent
de expunerea acestora la medicaţiile antipsihotice cu risc diabetogen.
John Newcomer sistematizează pe 3 nivele de argumentaţie pledoaria pentru efectul
corelativ diabetogen al diverselor formule de medicaţie antipsihotică în baza unui
1. screening amplu al studiilor observaţionale al analizelor de caz urmărite pe un follow-up
cronologic longitudinal, al unei
2. analize observaţionale a diverselor date clinice furnizate de arhivele bazelor de date ale
unor structuri medicale specializate, precum şi al unor
3. studii experimentale controlate, cum ar fi Trialurile Clinice Randomizate şi analizele
rezultatelor lor.
Din toate aceste trei paliere de date clinico-epideiologice şi de metaanalize din literatura de
specialitate şi din arhivele bazelor de date disponibile şi menţionate într-un amplu studiu de sinteză,
se pot desprinde unele concluzii foarte interesante ce vor fi prezentate şi comentate sintetic după
expunerea argumentelor de care se face menţiune în prezenta lucrare.
Palierul I de argumente cu referire la studiile observaţionale ale analizelor
cazuistice ce face referire la eventualele corelaţii între riscul apariţiei
sindromului metabolic şi folosirea unei anumite medicaţii antipsihotice
Din toate metodele ce au permis culegerea, selectarea şi interpretarea datelor, ne-am orientat
împreună cu autorii deja evocaţi spre evaluarea unei eventuale asociaţii între uzitarea anumitor
medicaţii antipsihotice şi riscul apariţiei evenimentelor metabolice adverse, care ar include
urmărirea următorilor parametrii clinico-metabolici:

hiperglicemiile;

dislipidemiile;

rezistenţei la insulină;

exacerbării unui preexistent diabet zaharat (DZ) de tip 1 sau DZ de tip 2;

al unui debut recent de DZ tip 2;

al unui accident diabetic ketoacidozic.
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Conform unor date furnizate de studii recente (Casey, Haupt, Newcomer, 2004), studii vizând, pe
termen scurt şi termen lung (cel puţin 1 an) modificările de greutate corporală în tratamentele efectuate cu
ziprasidonă, aripiprazole şi chiar şi amisulprid sunt congruente cu lipsa de efecte adverse de ordin
metabolic, mai ales în ceea ce priveşte stările dislipidemice şi dibetul zaharat de tip 2, cu excepţia
pacienţilor trataţi cu olanzapină şi leponex (American Diabetes Association Consensus, 2004).
Studii retrospective a cazurilor noi de diabet zaharat de tip 2 asociate corelativ cu
tratamentele cu clozapină, olanzapină şi chiar risperidonă din baza de date US FDA Med Watch
sugerează că în timp ce o mare parte a cazurilor noi de diabet erau însoţite de substanţiale creşteri în
greutate sau obezitate, un procentaj de circa 25 % nu prezentau asemenea fenomene însoţitoare –
presupuse a avea un rol cauzal. De asemeni, multe dintre aceste cazuri cu debut recent a diabetului
zaharat de tip 2 apăreau la un interval de circa 6 luni după iniţierea tratamentului şi nu aveau, în cel
puţin 50 % din aceste din urmă cazuri, antecedente ereditare familiale de diabet.
Relaţia temporală între iniţierea tratamentului şi discontinuarea tratamentului păstra o
corelaţie paralelă între dezvoltarea, atenuarea sau chiar rezolvarea cu succes a cazurilor
problematice de hiperglicemie, legate evident de administrarea acestor medicaţii.
Multe din cazurile monitorizate au prezentat complicaţii diabetice de tipul cetoacidozei, mai
ales al celor tratate cu clozapină. În conformitate cu datele constatate în arhivele FDA MedWatch
Surveillance System (cuprinse între ianuarie 1990 până în februarie 2001) a fost identificat un
număr de 384 cazuri de hiperglicemie (Kaller, Schneider et al., 2001).
Ketoacidoza a complicat hiperglicemia în 80 de cazuri, dintre care cea mai mare parte (în
număr de 73) erau cazuri de diabet cu debut recent şi foarte recent.
S-au înregistrat 24 de cazuri de deces în decursul acestor epizoade hiperglicemice, în timp ce
fenomene de complicaţie acidozică şi cetozică au fost raportate la 16 din aceste din urmă cazuri.
În grupul de pacienţi trataţi cu olanzapină incluşi în acelaşi eşantion de studiu al FDA
MedWatch Drug Surveillance System (între ianuarie 1994 şi mai 2001) au fost identificaţi un număr
de 237 cazuri de diabet sau de hiperglicemie cu accidente ketoacidozice la 80 de cazuri din totalul de
237, ceea ce reprezintă procentual o proporţie de 33,8 % din totalul cazurilor tratate cu olanzapină.
Fatalităţile ketoacidozice au înregistrat un procentaj de 11,3 % ceea ce raportat la eşantioanele nonpsihiatrice cu asemenea situaţii (de la 3 % la 5 %) ar reprezenta, din totalul de 15 decese al pacienţilor
trataţi cu olanzapină, un număr de 9 cazuri de fatalităţi prin complicaţii ketoacidozice !!
Cazurile tratate cu risperidonă incluse în baza de date a FDA MedWatch Drug Surveillance
System (cronologic cuprinse între 1993 şi februarie 2002) au furnizat un număr de 131 cazuri de
diabet şi hiperglicemii cu statut nozologic încă neprecizat.
Acidoza metabolică şi ketoza a fost raportată la 26 pacienţi trataţi cu risperidonă, din care 22
au prezentat cazuri de diabet cu debut recent şi foarte recent, iar din cle 4 cazuri de deces din rândul
celor trataţi cu risperidonă, 3 cazuri pe monoterapie cu risperidonă au decedat prin ketoacidoză.
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Din rândul pacienţilor trataţi cu quetiapină incluşi în baza de date a FDA MedWatch Drug
Surveillance System (în intervalul ianuarie 1997 – iulie 2002) au fost identificaţi 46 de cazuri de
diabet şi hiperglicemii persistente asociate tratamentului cu acest antipsihotic. Dintre aceştia, 21 de
pacienţi au prezentat acidoză diabetică şi ketoză. Din rândul celor 11 pacienţi decedaţi, 7 au
prezentat o evoluţie soldată cu deces prin ketoacidoză.
Din rândul pacienţilor trataţi cu aripiprazole, ziprasidonă şi amisulprid nu s-a înregistrat nici
un caz de hiperglicemie severă sau ketoacidoză, cu excepţia unui singur caz de rabdomioliză,
hiperglicemie şi pancreatită la un pacient psihotic supus tratamentului cu ziprasidonă (Young SH,
McNeely MJ, 2002).
Palierul II
Analizele observaţionale a datelor furnizate de „bazele de date” ale unor structuri medicale
specializate caută să investigheze existenţa unor corelaţii cazuistice, fie şi predispoziţionale între
medicaţia antipsihotică şi prezenţa unor semne directe sau indirecte de diabet, chiar cu caracter de
surogat argumentativ (de exemplu decelarea unor prescripţii de medicaţie orală hiperglicemiantă).
Acest palier argumentativ face recurs la diverse subterfugii metodologice, reuşind să
constate şi să scoată în evidenţă incapacitatea acestor metodologii de a ameliora modalităţile de
diagnosticare corectă a unui mare număr de subiecţi, ce scapă nediagnosticaţi şi prin urmare suferă
de consecinţele inerente ale subdiagnosticării unei maladii metabolice cu mare risc cardiovascular, a
căror apariţie şi evoluţie sunt influenţate negativ de medicaţia antipsihotică de ultimă generaţie,
folosită pe scală largă – cel mai adesea fără prudenţă şi discernământ clinic.
Cercetarea MEDLINE and Current Contents (efectuată între ianuarie 1990 şi septembrie
2004) şi-a propus să cuprindă toate studiile şi metaanalizele ce se referă la folosirea
„antipsihoticelor atipice” în tratamentul schizofreniei şi a psihozelor înrudite.
Toate datele existente din bazele de date abordate de Newcomer prezintă un caracter
retrospectiv, suferind de mari carenţe
metodologice şi reuşind doar să dovedească în ciuda
însumării unui mare număr de pacienţi (232 871 cazuri) că atât clozapina, cât şi olanzapina sunt în
mod consistent asociate cu o „creştere îngrijorătoare” a riscului pentru diabet în analize comparative
cu antipsihoticele convenţionale.
Palierul III
Palierul III de argumentaţie se referă la studiile experimentale controlate, dar mai ales la
studiile clinice randomizate. Ca un corolar al tuturor acestor studii se degajă o concluzie cu subiect
demonstrabil de tip „evidence-based” şi care rezumativ s-ar putea enunţa ca incriminând
medicamentele antipsihotice cu cel mai mare potenţial de creştere a greutăţii corporale şi implicit a
adipozităţii la pacienţii la care în acest mod creşte proporţional riscul pentru diabet zaharat.
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Mecanismul prin care adipozitatea excesivă produce efectul diabetogen este creşterea
rezistenţei insulinice cu modificările implicite ale creşterii concentraţiei de glucoză plasmatică şi a
lipidelor plasmatice mai ales din gama fracţiunilor lipidice cu rol aterogen (trigliceridele, very low
density lipoprotein, LDL).
Pattern-ul caracteristic al declanşării sindromului metabolic ar fi efectul antipsihoticelor
atipice asupra greutăţii corporale, a cărei creştere excesivă duce la obezitate, care la rândul ei
accelerează şi accentuează rezistenţa insulinică răspunzătoare de producerea unei cascade de
modificări metabolice, cu creşterea nivelului glucozei, dereglarea metabolismului lipidelor şi multe
alte modificări metabolice, cu răsunet pe multe organe şi ţinte viscerale.
Adipozitatea se corelează primordial cu creşterea rezistenţei insulinice, care până la un
anumit moment reuşeşte să tempereze creşterile concentraţiei de glucoză circulantă, hiperglicemia
fiind mult timp compensată printr-un efect secretor al insulinei, ceea ce face ca glicemia să rămână
în limite normale chiar şi după declanşarea diabetului în stadiul preclinic al normalităţii înşelătoare
a valorilor glicemiei.
Multiple studii controlate de terapie antipsihotică şi răsunetul pe diversele componente ale
sindromului metabolic au arătat că de fiecare dată când se trece de la olanzapină la un alt produs
antipsihotic (cum ar fi risperidona, ziprasidona, dar în special aripiprazolul) se înregistrează
modificări în configuraţia sindromului metabolic cu scăderea greutăţii corporale, scăderea BMI,
scăderea nivelelor de glucoză matinală „a jeun”, scăderea insulinei serice, îmbunătăţirea rezistenţei
insulinice, înbunătăţirea testului de toleranţă la glucoză.
Trialuri controlate de aripiprazole în terapia pacienţilor schizofrenici pe termen scurt ( 4-6
săptămâni ) au dovedit modificări ale concentraţiei glucozei serice, în condiţii de post alimentar,
similare cu cele înregistrate sub efect placebo.
Trialurile clinice de terapie a schizofreniei pe termen lung, mai ales în formele cronice de
schizofrenie stabilizată n-au putut înregistra diferenţe de concentraţie a glucozei serice „a jeun”
(fasting glucose) la cei trataţi cu aripiprazole în comparaţie cu pacienţii trataţi cu placebo.
La pacienţii trataţi cu olanzapină – comparativ cu cei trataţi cu aripiprazole – s-au înregistrat
modificări la toate componentele lipidogramei (colesterol total, trigliceride, LDL, HDL) în timp ce
aceleaşi componente au suferit minime modificări sau au rămas identice cu cele înregistrate în
perioadele de terapie cu placebo, la cei aflaţi în terapie cu aripiprazole.
Studiile pe eşantioane populaţionale au demonstrat că orice factor cauzator de creştere a
adipozităţii tinde să fie asociat cu creşteri a rezistenţei la insulină. Rezistenţa la insulină produce o
secreţie compensatorie de insulină la indivizii cu o bună rezervă de celule β-pancreatice din insulele
Langerhans şi dă hiperglicemie la subiecţii cu epuizare funcţională a celulelor β.
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Un studiu revelator a fost efectuat cu subiecţi sănătoşi, primind terapie cu olanzapină timp
de 2 săptămâni şi la care s-a observat o creştere a responsivităţii insulinice şi o descreştere a
senzitivităţii insuliniei, în mod corelativ cu modificările BMI. După ajustarea efectelor greutăţii
corporale responsivitatea şi sensibilitatea insulinică au revenit la normal pentru o anumită perioadă
de timp şi la aceşti din urmă pacienţi.
Un studiu recent (Sowel et al, 2003) examinând sensibilitatea reactivităţii insulinei la
voluntari sănătoşi, indemni de vreo boală metabolică cu răsunet asupra mecanismelor
glucoreglatorii, s-au administrat olanzapină, risperidonă sau placebo pe o durată de 3 săptămâni cu
restrângerea accesului la alimentaţie în perioadele cu tendinţă spre bulimie şi s-a observat absenţa
modificărilor de sensibilitate a insulinei.
În studiul CATIE pacienţii trataţi cu olanzapină au prezentat cele mai semnificative creşteri
ale trigliceridelor, a colesterolului total şi a hemoglobinei glicozilate.
Efecte independente de modificări de adipozitate
În general, riscul relativ de a dezvolta un proces diabetic de tip 2 în condiţiile unui tratament
antipsihotic pare a marca o curbă paralelă cu potenţialul de a induce o creştere proporţională a
greutăţii corporale.
O minoritate semnificativă de subiecţi prezintă dereglări ale metabolismului glucidic – în
mod inependent de creşterile de greutate corporală şi adipozitate, ceea ce ar sugera existenţa unui
mecanism direct de acţiune asupra senzitivităţii insulinei sau a mecanismului secretării acesteia.
Pacienţii suferind de schizofrenie cronică, nediabetici prezintă aceleaşi modificări a
rezistenţei la insulină când sunt trataţi cu clozapină sau olanzapină. Rolul adipozităţii abdominale
nu poate fi exclus sau minimalizat, repartiţia masei adipoase abdominale continuând să influenţeze,
prin mecanisme încă insuficient elucidate, sensibilitatea insulinei, odată cu celelalte mecanisme ce
ţin de efectele adipozităţii generale.
Concluzii
1. Variate surse informative, documentare şi experimentale pledează pentru rolul ce-l au
antipsihoticele atipice în precipitarea riscului pentru creşterile în greutate şi perturbările
metabolismului glucidic şi lipidic.
2. Este totodată evident că îngrăşarea, creşterea în greutate nu este o condiţie „sine qua
non” a dezvoltării rezistenţei insulinice, a afectării toleranţei la glucoză, a dislipidemiei
şi a DZ de tip 2.
3. Se impun noi studii şi descoperiri a celorlalţi factori de adversitate care conduc la cote
crescute de morbiditate şi mortalitate cardiovasculară la pacienţii schizofrenici.
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4. Evident că agenţilor farmacologici cu efect terapeutic în bolile mentale severe le revine
un rol în bună măsură elucidat în producerea sindromului metabolic, dar nu în totalitate
cunoscut şi care necesită noi abordări şi reconsiderări pentru descoperirea şi a altor
mecanisme terapeutice încă neelucidate de cercetările fundamentate până în această
etapă, care s-ar face răspunzătoare de unele efecte adverse cu consecinţe nefaste.
5. Până la apariţia unei noi generaţii de medicamente antipsihotice cu alte mecanisme de
acţiune şi cu alt profil de efecte secundare, suntem constrânşi să facem faţă unei
provocări cu triplă implicare (morală, umană şi clinică) în găsirea celor mai rezonabile
soluţii de apărare a sănătăţii şi intereselor pacienţilor noştri, concomitent cu dorinţa
noastră de a evita, cu judiciozitate, situaţiile de culpă medicală.
Bibliografie
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1999 – Antipsichotic-induced weight gain:a comprehensive researh synthesis. Am. J.
Psychiat., 136, 1686-96.
2. American Diabeties Association, 2004 – Consensus development conference on
antipsychotic drugs and obesity and diabetes. Diabetes Care, 27, 596-601.
3. Banerji MA, Lebowitz J, Chaiken RL, Gordon D, Lebowitz HE, 1997 – Relationship of
visceral adipose-tissue and glucose disposal is independent of sex in black NIDDM
subjects. Am. J. Psychiat., 273, E425-32.
4. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, 1999 – Body-mass index and mortality in
a prospective cohort of US adults. N. Engl. J. Med, 341, 1097-105.
5. Haupt DW, Newcomer JW, 2002 – Abnormalities in glucose regulation associated with
mental illness and treatment. J. Psychosom. Res., 53, 925-33.
6. Hirsh SR, Kissling W, Baum J, Power A, O’Connor R, 2002 – A 28-week comparison
of ziprasidone and haloperidol in outpatients with stable schizophrenia. J. Clin.
Psychiat., 63, 516-23.
7. Koller E, Schneider B, Bennet K, Dubitski G, 2001 – Clozapine-associated diabetes.
Am. J. Med., 111, 716-23.
8. Lorenzo C, Okoloise M, Williams K, Stern MP, Hoffner SM, 2003 – The metabolic
syndrome as predictors of type 2 diabetes. The San Antonio Heart Study Diabetes Care,
26, 3153-9.
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2003 – Aripiprazole in the treatment of schizophrenia:safety and tolerability in shortterm, placebo-controlled trials. Schizophr. Res., 61, 123-36.
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10. Nemeroff CB, 1997 – Dosing the antipsychotic medication olanzapine. J. Clin.
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11. Ryan Mc, Collins P, Thakore JH, 2003 – Impaired fasting glucose tolerance in forstepisode drug naive patients with schizophrenia. Am. J. Psychiat., 160, 284-9.
12. Sowel M, Mukhopadhyan N, carazzoni P, Carlson C, Mudaliar S, Chinnapongse S and
others, 2003 – Evaluation of insulin sensitivity in healthy volunteers treated with
olanzapine, risperidone or placebo: a prospective randomised study using the two step
hyperinsulinemic, euglycemic clamp. J. Clin. Endocrinol. Metab., 88, 5875-80.
13. Von Hayek D, Huhl V, Reiss J, Schweiger HD, Fuesel HS, 1999 – Hyperglycemia and
ketoacidosis associated with olanzapine. Nervenarzt, 70, 836-7.
14. Yang SH, McNeely MJ, 2002 – Rabdomyolysis, pancreatitis and hyperglicemis with
ziprasidone, Am. J. Psychiat., 159, 1435.
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ASPECTE NEUROBIOLOGICE ÎN DIAGNOSTICUL
ŞI TERAPIA BOLII ALZHEIMER
D. Marinescu, T. Udriştoiu
Universitatea de Medicină şi Farmacie Craiova
Rezumat
Autorii trec în revistă o serie de aspecte epidemiologice, genetice şi
neurobiologice ale bolii Alzheimer (BA) şi Mild Cognitive Impairment (MCI).
Se discută spectrul genetic, elementele neurodegenerative, tulburarea
neuromediaţiei, intervenţia modificărilor vasculare şi oportunităţi de
diagnostic precoce şi predicţie pentru MCI şi BA. Autorii pledează pentru
introducerea cât mai precoce, chiar din stadiul de MCI, a activatorilor
colinergici pe baza nivelelor etiopatogenice (degenerativ, tulburarea
neuromediatorilor şi vascular) şi factorilor de risc în BA (antecedente familiale
BA sau Down, evenimente psihotraumatice repetate, depresie, tratament cu
antidepresive sau antipsihotice anticolinergice, alterări vasculare ischemice.
Cuvinte cheie: boala Alzheimer, alterări neurobiologice, tratament precoce.
NEUROBIOLOGICAL ASPECTS IN THE DIAGNOSIS
AND THERAPY OF THE ALZHEIMER’S DISEASE
Abstract
The authors are reviewing certain epidemiological, neurobiological and
genetic aspects of the Alzheimer’s Disease (AD) and the Mild Cognitive
Impairment (MCI). We discuss the genetic spectrum, neurodegenerative
elements, the alterations in neurotransmission, the consequences of vascular
changes and the opportunities for early diagnosis and prediction for AD and
MCI. The authors plead for the early use of cholinergic activators, already in
the stage of MCI, based on etiopathogenic levels (degenerative,
neurotransmitter and vascular) and risk factors in AD (family history of AD
or Down syndrome, repeated psychotraumatic events, treatment with
anticholinergic antidepressants or antipsychotics, ischemia).
Key words: Alzheimer’s disease, neurobiological alterations, early treatment.
Studiul bolii Alzheimer (BA), bazat pe cercetarea fundamentală în corelaţie cu evoluţia,
sugerează incapacitatea modelelor etiopatogenice actuale de a acoperi realitatea clinică. Din acest motiv,
boala este considerată ca fiind subdiagnosticată şi subtratată, intervenţia terapeutică fiind în general
tardivă, cu eficacitate limitată. În această perspectivă, ţinând cont de îmbătrânirea generală a populaţiei
şi de faptul că BA la vârstă înaintată are o prevalenţă estimată de majoritatea autorilor la 5% pentru
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grupa de vârstă 65-80 de ani şi peste 30% peste 80 de ani, se estimează pentru Statele Unite 4,5 milioane
cazuri cu BA, în anul 2000 şi 13,2 milioane cazuri în 2050 de cazuri (Hebert – 2003).
Aceste estimări sugerează că elementele de tip neurodegenerativ intră în acţiune numai în
condiţiile unui teren neurobiologic favorabil, vulnerabilizat prin procesele de îmbătrânire peste care
se
pot
suprapune
alterări
neurobiochimice
(tulburări
depresive,
paranoide,
anxioase),
neurostructurale (apoptoze şi scăderea neuroprotecţiei prin hipoxie sau elemente toxice endo- sau
exogene) şi neurometabolice (alterarea fluxului sanguin şi a suportului energetic).
În acest context, modelul etiopatogenic al BA este unul multifactorial, cu multiple nivele de
vulnerabilitate (genetică, neurobiochimică, neurobiologică, cognitivă şi psihosocială). Studiile
genetice au reconfirmat implicarea majoră a factorului genetic numai în varianta BA cu debut
precoce, prin mecanismele neurodegenerative. Numărul foarte mic de cazuri al acestei variante de
BA (1 % din cazuri) sugerează faptul că vulnerabilitatea genetică poate fi cuantificată diferit, având
un rol predominent permisiv de tip spectral – “spectrul genetic al BA”. Putem sugera că în tipul
majoritar ca frecvenţă – “BA tardiv”, factorii genetici pot fi consideraţi ca fiind factori de risc.
Acest risc este corelat în majoritatea cercetărilor cu elementele neurodegenerative (beta-amiloid,
neurofibrile) şi anomalii ale cromozomilor 21, 14, 9, 4, ce constituie veritabila spectralitate
(vulnerabilitatea genetică primară) a bolii.
Elementul genetic poate fi legat semnificativ şi de modificările enzimatice la nivelul
sistemelor de neuromediaţie (monoaminoxidazele, acetilcolinesteraza, dopaminbetahidroxilaza etc.)
sau la nivelul informaţiei celulare de transducţie pe baza suportului proteic (secretazele),
determinând alterări ale neurotransmisiei şi ale sistemelor de semnalizare secundare şi terţiare,
constituind astfel vulnerabilitatea genetică secundară. Creşterea frecvenţei BA odată cu înaintarea în
vârstă ne sugerează faptul că rolul vulnerabilităţii secundare devine o verigă importantă în
etiopatogenia bolii şi argumentează necesitatea abordării terapeutice precoce.
Factorul neurodegenerativ, care implică apolipoproteine, neurofibrile, beta-amiloid,
presenilina 1 şi 2 şi proteinele Tau, devine cu atât mai agresiv cu cât nivelul de neurotransmisie
acetilcolinică scade (Wong – 1999) – Fig. nr. 1, modelul acetilcolinic fiind confirmat şi validat prin
blocada colinergică.
Vulnerabilitatea sistemului acetilcolinic se află în strânsă relaţie cu conservarea structurii
hipocampice. Numeroase studii au pus în evidenţă faptul că hipoxia sau agresiunea de tip toxic
(endo- sau exogen) poate favoriza dezorganizarea structurală a zonei hipocampale, în special la
nivelul interferenţelor sinaptice între zonele CA1/CA3. Din punct de vedere practic, este cunoscut
faptul că tulburările deteriorative de tip Alzheimer sunt precipitate de expunerea persoanelor
vârstnice la hipoxie prelungită (anestezii şi intervenţii chirurgicale de lungă durată). Asimetria
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hipocampică obiectivată neuroimagistic poate constitui un indicator precoce de risc neurobiologic
pentru boală Alzheimer (Wolf – 2002) – Fig. nr. 2.
Fig. nr. 1. Corelarea agregării plăcilor de betaamiloid cu distrofia dendritelor colinergice (Wong – 1999)
A – plăcile de betaamiloid la nivel hipocampal;
B – alterări grosiere ale fibrelor colinergice de tip distrofie neuritică în jurul plăcilor.
Fig. nr. 2. Asimetrii ale volumului hipocampic corelate cu declinul cognitiv (Wolf – 2002)
(CDR – Clinical Demential Rating)
Sistemul colinergic poate fi fragilizat şi de utilizarea medicamentelor cu efect anticolinergic
central (antidepresive triciclice, antipsihotice din prima generaţie) sau chiar periferic
(parasimpaticolitice).
Se poate susţine că depistarea şi tratamentul precoce al BA şi menţinerea eficienţei
transmisiei acetilcolinice ar trebui să devină o zonă centrală în cadrul strategiilor terapeutice.
Corelaţiile existente între scăderea nivelului de transmisie al tuturor neuromediatorilor în
perioada îmbătrânirii, argumentează modelul biochimic complex al deficitului cognitiv din BA,
intricat cu elementele neurodegenerative şi scăderea neuroprotecţiei (Fig. nr. 3).
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Fig. nr. 3. Modelul etiopatogenic complex al deficitului cognitiv din boala Alzheimer
Elementul vascular perturbă echilibrul unităţii neurofuncţionale cerebrale, binomul neuron
/ celulă glială, aceasta din urmă având un rol important în destructurarea unităţii funcţionale. La
nivelul celulei gliale se sintetizează glutamatul, dar există şi o importantă enzimă de prelucrare a
acetilcolinei, butiril-colinesteraza, a cărei inhibiţie asigură creşterea eficienţei acetilcolinice. Aceste
date sunt concordante cu modelul evolutiv neuroanatomic descris de Braak – 1991, şi sugerează
faptul că în fazele iniţiale ale BA deficitul raportului neuron/astroglie este funcţional şi condiţionat
de neuromediatori, apoi determină apoptoza neuronală, pentru ca. în stadiile tardive să fie
declanşate şi mecanismele de apoptoză la nivelul astrogliei.
Se conturează din ce în ce mai evident existenţa unei faze prodromale a bolii caracterizată
prin prezenţa unei alterări progresive a memoriei definită în literatură ca Mild Cognitive
Impairment (MCI). La examenul RMN se poate obiectiva hipoperfuzia cortexului prefrontal şi
alterări la nivelul hipocampului (Fig. nr. 4).
Fig. nr. 4. Atrofie hipocampică la un pacient cu MCI şi sindrom amnestic (Petersen – 2000)
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Sindromul MCI, descris de Petersen în anul 2000, este caracterizat prin alterarea obiectivă
a memoriei, capacitatea de compensare a disfuncţiei mnezice prin surplus de informare, ceea ce
permite o funcţionare cognitivă aproape normală, cu conservarea funcţionării zilnice, fără a
îndeplini criteriile diagnostice pentru demenţă.
Ritchie – 2001, apreciază că MCI este un indicator pentru instalarea BA în următorii doi,
trei ani. Se discută în prezent despre un MCI amnezic, specific BA şi un MCI non-amnezic, specific
demenţei cu corpusculi Lewis (DLB). Petersen – 2001, apreciază că, în această ultimă formă de
demenţă, conservarea hipocampului este net superioară celei din BA. Rata anuală de trecere a MCI
în BA, pentru pacienţi ce depăşesc 60 de ani, este estimată variabil (6-25 %), iar principalul factor
care poate accelera trecerea pare a fi hipoxia. Indicatorii neuroimagistici de predicţie pentru evoluţia
MCI către BA ar fi atrofiile minore ale cortexului la nivel entorinal, temporal superior şi cingulat
anterior (Fig. nr. 5).
Fig. nr. 5. Modificări neurostructurale progresive în boala Alzheimer (Petersen, 1998)
Studiile SPECT au evidenţiat ca şi indicator precoce al instalării BA hipoperfuzia
complexului hipocampo-amigdalian şi a talamusului anterior. Studiile MRS (Rezonanţă Magnetică
Spectroscopică) au evidenţiat o pozitivare a raportului între NAA (n-acetil aspartat) / MI
(mioinositol) (Kantarci – 2000).
Existenţa datelor neuroimagistice de evaluare şi chiar predicţie argumentează încă o dată
posibilitatea tratamentului precoce al BA (Fig. nr. 6).
Fig. nr. 6. Progresia elementelor neurodegenerative de tip betaamiloid
obiectivate pe studii neuroimagistice (Klunk – 2005)
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Susţinem ideea că tratamentul bazat pe substanţe ce augmentează funcţia acetilcolinică
trebuie administrat precoce, chiar din stadiul care cumulează factori de risc pentru vulnerabilitate
crescută a structurilor hipocampale (hipoxie, agresiune glicocorticoidă, depresie, expunere la
substanţe toxice etc.) sau la cazurile cu diagnostic cert de MCI.
Tulburarea depresivă din faza prodromală a bolii constituie prin frecvenţă şi intensitate un
factor de risc important, cu atât mai mult cu cât este recunoscut faptul că această tulburare asociază
risc pentru boli cardiovasculare (Frasure-Smith – 1999) şi alterări ale elementelor de tip
neuroprotectiv:

scăderea semnificativă a CREB (Mac Queen – 1998) şi BDNF la nivelul hipocampului
şi cortexului frontal (Duman – 2000);

creşterea agresiunii de tip glicocorticoid pentru zona hipocampală.
Implicarea glutamatului în BA prin hiperfuncţionalitatea receptorilor de tip NMDA ar
putea determina o entitate etiopatogenică particulară, în care hiperfuncţia glutamatergică este
asociată cu manifestări de tip epileptic (clinc sau electric) şi simptomatologie noncognitivă de tip
halucinator-delirant. Modularea NMDA poate facilita circuitele mnezice prin mecanisme de tip
potenţare pe termen lung, dar blocarea intensivă a acestui tip de receptori poate activa DA şi NA
prin reacţii de firing. Aceste mecanisme de reglare heterologă pot reactiva comportamentul agresiv,
anxietatea şi fenomenele de tip psihotic. În opinia noastră, glutamatul intervine ca şi activator
secundar în etiopatogenia bolii, atunci când raportul neuron/astroglie este intens perturbat şi
distrucţia neuronală este importantă, tablou neurobiologic al fazelor tardive ale bolii.
Rezultatele limitate ale strategiilor terapeutice, utilizate pe baza criteriilor tradiţionale de
diagnostic al BA sunt datorate nerecunoaşterii fazelor prodromale ale bolii sau a sindromului MCI.
Acest tip de abordare terapeutică poate încetini evoluţia, dar nu influenţează mecanismele
etiopatogenice.
Tratamentul precoce al BA ar putea oferi premisele unei eficacităţi şi eficienţe crescute din
perspectivă neurobiologică, pe baza argumentelor etiopatogenice şi factorilor de risc.
Nivele etiopatogenice:

reducerea
eficienţei
neuromediatorilor,
în special
a
acetilcolinei
(principalul
neuromediator implicat în cogniţie), cu amplificarea activităţii glutamatului în stadiile
moderate şi severe, care creşte lezionalitatea cerebrală. Se va lua în considerare şi
diminuarea semnificativă a dopaminei, noradrenalinei şi serotoninei ce pot fi corelate cu
simptomele noncognitive predominent depresive, activările de tip psihotic fiind un
indicator al hiperactivităţii glutamatergice;
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Vol. 7, Nr. 1, 2

elemente neurodegenerative (betaamiloid, neurofibrile) corelate cu vulnerabilitatea
genetică (anomalii ale cromozomilor 21, 14, 9, 4);

alterările vasculare cerebrale, hipoxia, disfuncţia metabolică (hipercortizolemie indusă
psihotraumatic sau medicamentos).
Evidenţierea factorilor de risc (genetic, psihotraumatic, psihiatric, vascular), evaluarea
complexă clinică, paraclinică şi neuroimagistică a pacienţilor şi utilizarea precoce a substanţelor
activatoare colinergice, pot oferi o perspectivă evolutivă mai bună pentru BA.
Bibliografie selectivă
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transcriptional activity of the APOE gene. Human Molecular Genetics, 7, 1887-1892.
2. Braak, H., Braak, E., 1991 – Neuropathologycal staging of Alzheimer related changes .
Acta Neuropathol (Berl), 82, 239-259.
3. Bullock, R., 2002 – New drugs for Alzheimer’s disease and other dementias. Brit. J.
Psychiat., 180, 135-139.
4. Carter, C., McDonald, A., Ross, L., Stenger, V.A., 2001 – Anterior cingulate cortex
activity and impaired self-monitoring of performance in patients with schizophrenia: an
event-related fMRI study. Am. J. Psychiat., 158, 1423-1428.
5. Chen, B., Dowlatshahi, D., MacQueen, G.M., Wang, J.F., Young, L.T., 2001 –
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant
medication. Biol Psychiat., 50(4), 260-5.
6. Cummings, J.L., Benson, D.F., 1992 – Dementia: a clinical approach. 2nd Edition,
Butter Worths, London.
7. Cummings, J.L., Saloway, S., 1997 – The limbic system: An anatomic phylogenetic and
clinical perspective. Journal Neurology, Psychiatry and Clinical Neurosch., 9, 315-350.
8. Cummings, J.L., 2004 – Alzheimer’s Disease. N Engl J Med, 351, 56-67.
9. Frasure-Smith, N., Lespérance, F., Juneau, M., Talajic, M., Bourassa, M., 1999 –
Gender
Depression,
and
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Prognosis
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Myocardial
Infarction.
Psychosomatic Medicine, 61, 26-37.
10. Hebert, L.E., Scherr, P.A., Bienias J.L., Bennett, D.A., Evans, D.A., 2003 – Alzheimer
disease in the US population: prevalence estimates using the 2000 Census. Arch
Neurol., 60, 1119-22.
11. Holmes, C., 2002 – Genotype and phenotype in Alzheimer’s disease. Brit. J. Psychiat.,
180, 131-133.
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12. Kantarci, K., et al., 2000 – Regional metabolic patterns in mild cognitive impairment
and Alzheimer’s disease. Neurology, 55, 210-217.
13. Klunk, W.E., Price, Julie C., DeKosky, S.T., Mathis, C.A., 2005 – The Application of
Amyloid-imaging to the diagnosis and treatment of Alzheimer’s Disease, Alzheimer's
and Dementia, Volume 1, Issue 1, Pages 5-6.
14. Krasuski, J.S., Alexander, G.E., 2002 – Relation of medial temporal lobe volumes to
age and memory function in nondemented adults with Down’s syndrome: implications
for the prodromal phase of Alzheimer’s disease. Am. J. Psychiat., 159, 74-81.
15. Lyons, D., McLoughlin, D.M., 2002 – Identificarea β secretazei şi a γ secretazei în
boala Alzheimer. BMJ, ediţia în limba română, vol. 9, 1, 32-33.
16. Marinescu, D., Udriştoiu, T., 2004 – Actualităţi neurobiologice; Mecanisme colinergice;
Consideraţii psihofarmacologice şi terapeutice. Ed. Aius, Craiova.
17. McGeer, P.L., McGeer, E.G., 1998 – Mechanisms of cell death in Alzheimer’s disease –
inumopathology. J. Neuronal Transmission, 54 suppl., 159-166.
18. Meyer, M.R., Tschanz, J.T., 1998 – APOE genotype predicts when – not whether – one
is predisposed to develop Alzheimer’s disease. Nature Genetics, 19, 321-322.
19. Morris G.R., Koppelmann M.D., 1986 – The memory deficits in Alzheimer-type
dementia: A review. Quaterly J Experimental Psychology, 38A, 575-602.
20. Mullnard, R.A., Gotman, C.W., Kawes, C., 2000 – Estrogen replacement therapy for
treatment of mild to moderate Alzheimer’s disease. JAMA, 283, 1007-1015.
21. Okamura, N., Aray, H., 2002 – Combined analysis of CSF tau levels and
iodamphetamine SPECT in mild cognitive impairment: implications for a novel
predictor of Alzheimer’s disease. Am. J. Psychiat., 159, 3, 474-476.
22. Perry, E., Lee, M., et al., 2001 – Cholinergic activity in autism: abnormalities in the
cerebral cortex and basal forebrain. Am. J. Psychiat., 158, 1058-1066.
23. Petersen, R.C., 2000 – Aging, mild cognitive impairment and Alzheimer’s Disease.
Neurol. Clin., 18, 789-806.
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Disord, 9 (suppl 3), 16-24.
25. Ritchie, K., et al., 2001 – Classification criteria for mild cognitive impairment: A
population-based validation study. Neurology, 56, 37-42.
26. Sano, M., Ernesto, C., 1997 – A controlled trial of selegiline, alpha tocopherol, or both,
as treatment for Alzheimer’s disease. New England J. of Medicine, 336, 1216-1222.
27. Sheline, Y.I., Mintum, M.A., 2002 – Greater loss of 5-HT2A receptors in midlife than in
latelife. Am. J. Psychiat., 159, 3, 430-435.
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28. Snowden, J.S., Neary, D., Mann, D.M.A., 2002 – Frontotemporal dementia. Brit. J.
Psychiat., 180, 140-143.
29. Sweet, R.A., Nimgaonkar, V.L., Kanboh, M.I., 1998 – Dopamin receptor genetic
variation, psychosis and aggression in Alzheimer’s disease. Arch. Neurol., 55, 1335-1340.
30. Thome, J., Sakai, N., Shin, K.-H., Steffen, C., Zhang, Y.J., Impey, S., Storm, D.,
Duman, R. S., 2000 – cAMP Response Element-Mediated Gene Transcription Is
Upregulated by Chronic Antidepressant Treatment. J. Neurosci., 20, 4030-4036.
31. Tunstall, N., Owen, M.J., Williams, J., 2000 – Familial influence on variation in age of
onset and behavioral phenotype in Alzheimer’s disease. Brit. J. Psychiat., 176, 156-159.
32. Wisniewski, T., Dowjat, W.K., Buxbaum, J.D., 1998 – A novel polish presenilin 2
mutation is associated with familial Alzheimer’s disease and leads to death as early as
the age 28 years. Neuroreport, 9, 217-221.
33. Wolf, H., Kruggel, F., et al, 2002 – Hippocampal volumetry in normal aging
questionable and mild dementia, Alzheimer’s disease. Vol. 6, 75-81.
34. Wong, T.P., Debeir, T.H., et al., 1999 – Reorganisation of cholinergic terminals in the
cerebral cortex and hippocampus in transgenic mice carrzing mutated Presenilin-1 and
Amyloid precursor protein transgenes. J. Neurosci., 19(7), 2706-2716.
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INTERRELAŢII STRESS, DEPRESIE,
TRATAMENT ANTIDEPRESIV ÎN PLASTICITATEA NEURONALĂ
G. Talau1, Lavinia Duică1, D. Nicoară, R.D. Talau
1
Universitatea „Lucian Blaga” Sibiu
Facultatea de Medicină ”Victor Papilian” Sibiu
Rezumat
Elucidarea mecanismelor subiacente plasticităţii neuronale este un obiectiv
major al cercetării în domeniul neuroştiinţelor. Aceste mecanisme includ
reglarea transducţiei semnalului şi expresiei genice şi, de asemenea,
alterările structurale a spinelor neuronale. Plasticitatea alterată contribuie
la apariţia tulburărilor psihiatrice. Lucrarea de faţă face o revizie a
mecanismelor moleculare ce stau la baza alterării plasticităţii neuronale prin
expunerea la stres şi efectul advers al acţiunii tratamentului antidepresiv
cronic care induce răspunsuri asemănătoare plasticităţii neuronale.
Cuvinte cheie: stres, plasticitate neuronală, tratament antidepresiv.
INTERRELATIONS STRESS, DEPRESSION, ANTIDEPRESSANT
TREATMENT IN NEURONAL PLASTICITY
Abstract
Elucidation of the mechanisms underlying neural plasticity is a major goal of
neuroscience research. These mechanisms include regulation of signal
transduction and gene expression and also, structural alteration of neuronal
spines. Altered plasticity intervenes in the psychiatric disorders. This article
make a revision of molecular mechanisms that underlying altered plasticity in
response to chronic stress and the adverse effect of chronic antidepressant
treatment that induces neural plasticity-like responses.
Key words: stress, neuronal plasticity, antidepressant treatment.
Plasticitatea neuronală este un proces fundamental care permite creierului să recepţioneze
informaţii din mediu şi să formeze răspunsuri adaptate la stimuli noi. Răspunsurile adaptative de tip
molecular şi celular ce stau la baza învăţării sunt cele mai bine studiate modele de plasticitate
neuronală. În orice caz, diferiţi stimuli pot activa procesele de plasticitate neuronală în diferite regiuni
ale creierului, stimuli de natură ambientală socială, comportamentală precum şi farmacologică.
Mai mult decât atât, plasticitatea anormală poate să ducă la răspunsuri neuronale
maladaptative şi, prin urmare, comportament anormal. Aceasta poate apărea ca răspuns la unele
anomalii genetice ale elementelor constituente ale mecanismelor necesare plasticităţii neuronale şi
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Vol. 7, Nr. 1, 2
ca urmare a unor stimuli anormali. De exemplu, expunerea prelungită la stress alterează markerii
moleculari şi celulari ai plasticităţii neuronale şi pot contribui la apariţia tulburărilor afective.
Efectele rapide ce stau la baza plasticităţii neuronale acute sunt mediate de activarea
neurotransmiţătorului excitator - glutamat şi reglarea cascadelor intracelulare (1). Glutamatul
cauzează depolarizarea neuronală prin activarea receptorilor postsinaptici ionotropici care cresc
cantitatea de Na+ intracelular. Aceasta conduce la activarea subsecventă a receptorilor NMDA cu
creşterea influxului de Ca+2. Ca+2 este o moleculă de semnalizare intracelulară care activează o
cascadă de semnalizare, incluzând proteinkinaza dependentă de Ca+2/calmodulină. Prin activarea
glutamatului şi a căilor dependente de Ca+2 rezultă o alterare structurală la nivelul spinelor
dentritice. Aceste modificări de formă şi număr a spinelor dentritice pot apărea relativ rapid (minute
sau ore) după stimularea glutamatului, dar ele pot deveni permanente în momentul în care sunt
consolidate prin expresia genică şi sinteza proteică (2).
CREB este unul din factorii transcripţionali majori care mediază acţiunea Ca şi semnalizarea
AMPc. CREB joacă un rol în modelele celulare şi comportamentale ale învăţării (3). Ţintele genice
ale Ca, AMPc şi CREB sunt reprezentate de factorii neurotrofici care sunt implicaţi în procesul de
învăţare şi ocupă un rol important în efectele stresului şi a ale tratamentului antidepresiv. De un
particular interes se bucură BDNF, unul din cei mai abundenţi factori neurotrofici din creier.
Ultimele cercetări arată că răspunsurile moleculare şi celulare sunt alterate la stress şi acest
lucru este relaţionat cu tulburările psihiatrice în legătură cu stresul.
Stresul exercită o puternică influenţă asupra învăţării, efectele fiind dependente de tipul,
durata şi intensitatea stresorului. Trezirea emoţională creşte învăţarea prin intermediul plasticităţii
neuronale de la nivelul amigdalei ceea ce se crede că reprezintă substratul memoriei de lungă durată
legată de evenimente psihotraumatice şi al tulburării de stres posttraumatic (4,5). De asemenea,
stresul poate impieta învăţarea şi poate duce chiar la amnezie (6).
Situaţia cea mai ilustrativă o întâlnim la nivelul hipocampului, acolo unde se înregistrează o
alterare a plasticităţii neuronale, stresul generând atrofie hipocampal[. Această atrofie priveşte
dendrirele de la nivelul regiunii CA3 în ceea ce priveşte scăderea numărului şi a lungimii dendritelor
apicale. Reducerea arborizaţiei dendritice este dependentă de expunerea repetată, pe termen lung şi
este reversibilă când stimulul stresant este îndepărtat (7). Atrofia celulelor piramidale din regiunea
CA3 rezultă din creşterea nivelului de glucocorticoizi ce intervine în condiţii de stress, fapt
demonstrat prin faptul că administrarea cronică de corticosteron la şoareci conduce la o descreştere
a numărului şi lungimii dendritelor (8).
Stresul influenţează multe sisteme de neurotransmisie, căi de semnalizare celulară, expresii
genice. Semnul marcant al răspunsului la stres este activarea axei hipotalamo-hipofizo-adrenale, cu
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creşterea nivelelor circulante de glucocorticoizi. Hipocampul conţine o cantitate mare de receptori
glucocorticoizi şi de aceea este puternic impactat de stres.
Adiţional, stresul influenţează CREB şi BDNF în hipocamp şi alte regiuni ale creierului.
Activitatea factorului transcripţional CREB este reglată prin fosforilarea, nivelul de fosfoCREB fiind utilizat ca o măsură indirectă a activităţii CREB. Reglarea activităţii CREB este
dependentă de regiunea cerebrală şi de modul de stres-acut sau cronic. Stresul acut creşte nivelul de
fosfo-CREB în multe regiuni limbice asociat cu tulburările afective şi aceasta reprezintă un răspuns
adaptativ. În contrast, stresul cronic conduce la scăderea nivelului de fosfo-CREB în multe regiuni
limbice, cu scăderea plasticităţii (9).
Stresul are efecte importante şi asupra expresiei BDNF în hipocamp. Nivelul expresiei
BDNF în hipocamp este scăzut atât de stresul acut cât şi de stresul cronic, acest efect contribuind la
atrofie şi scăderea neurogenezei (10).
În contrast cu efectele stresului, tratamentul antidepresiv produce creşterea plasticităţii
neuronale.
Una din cele mai recente descoperiri pe tărâmul depresiei este aceea că tratamentul
antidepresiv reglează neurogeneza la nivelul hipocampului. În contrast cu acţiunea stresului asupra
hipocampului, tratamentul cronic cu antidepresive creşte numărul de neuroni noi în hipocampul
adult la şoareci.. Activarea neurogenezei este dependentă de tratamentul cronic cu antidepresive,
corespunzând timpului de acţiune terapeutică a antidepresivelor. (11). Mai mult decât atât, diferite
clase de antidepresive, cum sunt inhibitorii de recaptare ai serotoninei, respectiv ai noradrenalinei
precum şi şocurile electrice cresc neurogeneza (12). Tratamentul cu antidepresive influenţează două
aspecte importante ale neurogenezei şi anume rata proliferării celulare (numărul de neuroni noi) şi
supravieţuirea neuronilor nou apăruţi (13). Creşterea numărului de neuroni poate contribui la
reversia atrofiei hipocampale prezente la pacienţii depresivi.
A fost studiată influenţa tratamentului antidepresiv în contextul existenţei stresului. Studiile
demonstrează că tratamentul cronic cu antidepresive poate bloca scăderea neurogenezei care rezultă prin
expunerea la stres. Au fost testate mai multe tipuri de stres, cum ar fi, de exemplu, separarea maternală
(14) şi diferite tipuri de antidepresivele atipice, tianeptina (15), inhibitorii selectivi ai serotoninei (16).
De asemenea, a fost studiată influenţa tratamentul antidepresiv asupra atrofiei neuronilor
piramidali ce a rezultat în urma expunerii cronice la stress. Rezultatul a fost acela că administrarea
cronică a tianeptinei blochează atrofia dendritelor apicale de la nivelul regiunii CA3 a hipocampului
date de stress (17).
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Plasticitatea neuronală indusă de tratamentul antidepresiv implică o adaptare a unor multiple
cascade intracelulare şi a interrelaţiilor dintre acestea. Una din aceste căi care este reglată de către
antidepresive este cascada AMPc-CREB.
Tratamentul cronic cu antidepresive potenţează cascada AMPc la diferite nivele. Aceasta
include creşterea cuplării proteinei Gs cu adenil ciclaza, creşterea nivelului protein kinazei A şi, de
asemenea, creşterea nivelului CREB (18). Fosforilarea CREB este realizată atât de către PKA, dar
şi de kinazele dependente de Ca - protein kinaza dependentă de Ca+2/calmodulina, dar şi către calea
protein kinazelor activate mitogen. Astfel, CREB reprezintă ţinta de acţiune a multiplelor căi de
semnalizare celulară şi a receptorilor acţionaţi de neurotransmiţători care activează aceste cascade.
Reglarea CREB de către antidepresive indică faptul că şi reglarea expresiei genice joacă un
rol în acţiunea antidepresivelor. Au fost identificate mai multe gene ţintă ale antidepresivelor (19),
dar BDNF este un factor care beneficiază de cea mai mare atenţie în prezent.
Factorii neurotrofici au fost studiaţi la început pentru rolul lor în dezvoltare şi supravieţuirea
neuronală. Este cunoscut faptul că aceşti factori sunt exprimaţi în creierul adult sunt reglaţi în mod
dinamic de către activitatea neuronală şi au o importanţă majoră în supravieţuirea şi funcţionarea
creierului adult. Având la bază aceste considerente, este evident de ce expresia scăzută a BDNF poate
avea consecinţe serioase pentru funcţionarea structurilor limbice care controlează dispoziţia şi cogniţia.
În contrast, tratamentul antidepresiv conduce la o semnificantă creştere a BDNF în
hipocamp şi cortexul cerebral la şoareci (20). Creşterea expresiei BDNF este dependentă de
tratamentul cronic cu antidepresive, nefiind valabil pentru alte psihotrope. Inducerea BDNF ar fi de
aşteptat să protejeze neuronii împotriva deteriorărilor produse de stress, de către nivelul crescut de
glucocorticoizi sau de alte tipuri de insulte neuronale.
Cercetările ce au avut în centrul lor BDNF au condus la ipoteza neurotrofică a depresiei şi a
acţiunii antidepresivelor (21). Ipoteza neurotrofică are la bază studiile ce demonstrează că stresul
descreşte BDNF, reduce neurogeneza şi cauzează atrofia neuronilor piramidali din regiunea CA3 a
hipocampului. Investigaţiile imagistice şi studiile postmortem demonstrează atrofia structurilor
limbice precum hipocampul, cortexul prefrontal şi amigdala. În contrast, tratamentul antidepresiv
opune acestor efecte ale stresului şi depresiei creşterea nivelului de BDNF, creşterea neurogenezei
şi blocarea atrofiei cauzate de stress şi depresie.
Studiul mecanismelor moleculare şi celulare ale plasticităţii neuronale, ca proces subiacent
învăţării, depresiei, abuzului de substanţe etc., precum şi implicaţiile terapeutice ce derivă din aceasta
reprezintă unul din cele mai dinamice domenii arii de investigaţie neurobiologică în psihiatrie.
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memories. Nat Rev Neurosci., 3, 453-462.
7. Wooley CS, Gould E, McEwen BS, 1990 – Exposure to excess glucocorticoids alters
dendritic morphology of adult hippocampal pyramidal neurons. Brain Res., 531, 225-231.
8. Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS, 1992 – Tianeptine
attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol.,
222, 157-162.
9. Trentani A, Kuipers SD, Ter Horst GJ, Den Boer JA, 2002 – Selective chronic stressinduced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites:
implications for stress-related cortical pathology? Eur J Neurosci., 15, 1681-1691.
10. Duman R, 2004 – Role of neurotrophic factors in the etiology and treatment of mood
disorders. Neuromol Med., 5, 11-26.
11. Malberg J, Eisch AJ, Nestler EJ, Duman RS, 2000 – Chronic antidepressant treatment
increases neurogenesis in adult hippocampus. J Neurosci., 20, 9104-9110.
12. Manev H, Uz T, Smalheiser NR, Manev R, 2001 – Antidepressants alter cell
proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol.,
411, 67-70.
13. Nakagawa S, Kim JE, Lee R, et al – Regulation of neurogenesis in adult mouse
hippocampus by cAMP and cAMP response element-binding protein.
14. Lee H, Kim JW, Yim SV, et al., 2001 – Fluoxetine enhances cell proliferation and prevents
apoptosis in dentate gyrus of maternally separated rats. Mol Psychiatry, 6, 725-728.
15. Czeh B, Michaelis T, Watanabe T, et al., 2001 – Stress-induced changes in cerebral
metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant
treatment with tianeptine. Proc Natl Acad Sci USA, 98, 12796-12801.
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16. Malberg J, Duman RS, 2003 – Cell proliferation in adult hippocampus is decreased by
inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 28,
1562-1571.
17. Nestler E, Terwilliger RZ, Duman RS, 1989 – Chronic antidepressant administration
alters the subcellular distribution of cAMP-dependent protein kinase in rat frontal cortex.
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18. Nibuya M, Nestler EJ, Duman RS, 1996 – Chronic antidepressant administration
increases the expression of cAMP response element binding protein (CREB) in rat
hippocampus. J Neurosci., 16, 2365-2372.
19. Thome J, Sakai N, Shin KH, et al, 2000 – cAMP response element-mediated gene
transcription is upregulated by chronic antidepressant treatment. J Neurosci., 20, 4030-4036.
20. Nestler E, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ. Monteggia LM, 2002 –
Neurobiology of depression. Neuron., 34, 13-2.
21. Duman R, J Malberg, S. Nakagawa, C D’Sa, 2000 – Neuronal plasticity and survival in
mood disorders. Biol Psychiatry. 48, 732-739.
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STRATEGII TERAPEUTICE ÎN
TULBURAREA OBSESIV-COMPULSIVĂ (TOC)
Delia Marina Podea, Ramona Maria Chendereş
Universitatea de Vest „Vasile Goldiş” Arad
Rezumat
Strategiile terapeutice ale TOC includ atât tratamentul farmacologic cât şi pe
cel psihoterapeutic. Scopul tratamentului este atât ameliorarea simptomelor
cât si a calităţii vieţii pacientului: îmbunătăţirea funcţionalităţii profesionale,
sociale, familiale si interpersonale.
Tratamentul de elecţie este cel antidepresiv, preferaţi fiind inhibitorii
selectivi ai recaptării serotoninei (ISRS) in doze similare sau superioare
tratamentului depresiei majore, timp de 12 săptămâni, doza maximă fiind
administrată cel puţin 6 săptămâni. Pot fi utilizate: sertralina (200 mg/zi),
fluvoxamina (300 mg/zi), fluoxetina (60 mg/zi), paroxetina (60 mg/zi)
citalopramul (40-60mg/zi) sau escitalopramul (20-40mg/zi). Daca rezultatele
antiobsesive întârzie să se instaleze sau persoana nu poate tolera reacţiile
adverse, se poate utiliza un alt ISRS aceeaşi perioadă sau un antidepresiv
mai puţin selectiv, ca de exemplu clomipramina (200-250 mg/zi). Pentru
cazurile nonresponsive se poate recurge la perfuzii iv cu clomipramina, in
doză echivalentă, cu instalarea efectului antiobsesional in 4-5 zile.
Actualmente, in tratamentul farmacologic al TOC se recomandă si utilizarea
venlafaxinei, antidepresiv cu acţiune duală: serotonina/norepinefrina, doza
recomandată fiind 37,5-225mg/zi.
În al treilea rând se recomandă augmentarea efectului antiobsesiv cu:
buspironă, clonazepam, litiu, gabapentină, inositol, L-triptofan, fenfluramină.
Antipsihoticele sunt utilizate ca si strategie alternativă de augmentare in
cazurile refractare de TOC: haloperidol (0,25-6mg/zi), pimozide (0,54mg/zi), risperidona (0,5-6mg/zi), olanzapina (2,5-10mg/zi)
Pentru cazurile deosebit de refractare se recomandă terapia
electroconvulsivantă sau tehnici de psihochirurgie: capsulotomie anterioară,
cingulotomie, leucotomie.
Psihoterapia de tip comportamental, se aplică cu destul de bune rezultate de
sine stătător sau împreună cu tratamentul farmacologic.
Rezultate benefice pot fi obţinute si prin programele educaţionale adresate
atât pacienţilor cât si familiilor acestora.
Comorbiditatea cu tulburarea depresivă majoră, fobia socială, tulburarea de
panică sau cu tulburarea de personalitate de tip evitant sau dependent
influenţează atât alegerea tratamentului farmacologic cat si a celui
psihoterapeutic.
Cuvinte cheie: TOC, strategii terapeutice, tratament farmacologic, tratament
psihoterapeutic, comorbiditate.
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Vol. 7, Nr. 1, 2
THERAPEUTIC STRATEGIES IN OBSESSIVE-COMPULSIVE
DISORDER (OCD)
Abstract
The therapeutic strategies of obsessive-compulsive disorder (OCD) include
pharmacotherapy and psychotherapy.
The goals of therapy are to diminish symptoms and to ameliorate or reverse
their effects on the patient’s interpersonal, work place and social functioning.
The selective serotonin reuptake inhibitors (SSRIs): sertraline (200mg/day),
fluvoxamine (300mg/day), fluoxetine (60mg/day), paroxetine (60mg/day),
citalopram (40mg/day), escitalopram (20-40mg/day) are the preferred
medication choice for OCD because of their tolerability and safety in overdose.
The optimal doses of SSRIs for patients with OCD are often higher than for
major depression. Compared with major depression, patients with OCD
require a longer period of treatment before clinical response is achieved: at
least 10 to 12 weeks of continuous treatment at the maximally tolered dose.
Patients who do not respond to lower SRI doses often respond to higher one
or respond to another SRI. The SSRIs are better tolerated than the tricyclic
antidepressant – clomipramine.
Many patients will require the addition of an augmenting drug. Drugs that
can be considered include: buspirone, clonazepam, fenfluramine, gabapentin,
inositol, lithium, L-tryptophan, or the addition of clomipramine to an SSRI.
The most promising pharmacotherapy interventions in treatment-refractory
patients appear to be the use of intravenous clomipramine or the addition of
antipshychotics: haloperidol (0,5-5 mg/day), phenelzine, risperidone (0,54mg/day), olanzapine (2.5-10mg/day).
Neurosurgical procedures or electroconvulsive therapy (ECT) are an option
in patients with refractory OCD.
Among psychotherapy, only exposure and response prevention(ERP) is
effective in treating OCD. Educating the patient and the family regarding the
nature and treatment of OCD is always a first step in therapy and precedes
attempts to engage the patient in psychotherapy.
Patients presenting OCD will frequently be suffering from one or more
comorbid disorders. Common comorbid disorders are: major depression,
social phobia, panic disorder, avoidant and dependent personality disorders
or traits. The management of more complex combinations of disorders
depends on clinical judgment applied to the individual case.
Key words: OCD, therapeutic strategies, pharmacological treatment,
psychotherapy, comorbidity.
Tulburarea obsesiv-compulsivă (TOC) are ca trăsături esenţiale obsesiile şi compulsiile.
Termenul de obsesie se referă la trăiri strict subiective, iar cel de compulsie la comportamente
ritualice. Obsesiile sunt idei, imagini, reprezentări, amintiri, ruminaţii, intenţii de act nefinalizate,
provocatoare de anxietate şi au un caracter repetitiv, intruziv, parazitar fiind percepute de pacient ca
lipsite de sens şi deranjante. Compulsiile sau ritualurile includ atât activităţi mintale cum ar fi
numărătoarea repetată cât şi comportamente repetitive fără sens, realizate într-o manieră stereotipă
cu scopul de a reduce anxietatea.
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Criteriile de diagnostic ale TOC, conform DSM-IV-TR (1) sunt prezentate în tabelul următor:
A. Fie obsesii, fie compulsiuni:
OBSESII conform definiţiei de la (1), (2), (3) şi (4):
(1) gânduri, impulsuri sau imagini recurente şi persistente, care sunt trăite, într-un anumit
timp de pe parcursul tulburării, ca intruzive şi neadecvate şi care produc anxietate sau
suferinţă marcate;
(2) gândurile, impulsurile sau imaginile nu sunt doar îngrijorări excesive legate de
problemele vieţii reale;
(3) persoana încearcă să ignore sau să suprime gândurile, impulsurile sau imaginile
respective sau să le neutralizeze, printr-un gând sau acţiune;
(4) persoana recunoaşte că gândurile, impulsurile sau imaginile obsesive sunt un produs al
propriei minţi (nu sunt impuse din afară, ca în inserţia gândurilor).
COMPULSIUNI conform definiţiei de la (1) şi (2):
(1) comportamente repetitive (de ex., spălatul mâinilor, punere în ordine, verificări) sau acte
mintale (de ex., rugăciuni, numărat, repetarea în gând a unor cuvinte) pe care persoana
se simte nevoită să le efectueze ca răspuns la o obsesie sau în conformitate cu reguli care
trebuie aplicate rigid;
(2) comportamentele sau actele mintale respective urmăresc să preîntâmpine sau să reducă
suferinţa sau să preîntâmpine un anumit eveniment sau situaţie temută; totuşi,
comportamentele sau actele mintale fie că nu sunt legate în mod realist de ceea ce sunt
menite să neutralizeze sau să prevină, fie sunt evident excesiv.
B. Într-un anumit moment de pe parcursul tulburării, persoana a recunoscut că obsesiile sau
compulsiunile sunt excesive sau nerezonabile. Notă: Acest criteriu nu se aplică la copii.
C. Obsesiile sau compulsiunile cauzează suferinţă marcată, consumă timp (necesită mai
mult de o oră pe zi) sau interferează marcat cu activitatea obişnuită a persoanei, cu funcţionarea
ocupaţională (sau academică) sau cu activităţile sau relaţiile sociale uzuale.
D. Dacă este prevăzută o altă tulburare de pe Axa I, conţinutul obsesiilor sau compulsiunilor
nu se restrânge la aceasta (de ex., preocuparea cu alimente în prezenţa unei tulburări alimentare,
smulgerea părului în prezenţa tricotilomaniei; preocuparea cu drogurile în prezenţa unei tulburări
prin uz de substanţe; preocuparea cu aspectul în prezenţa unei tulburări de dismorfie corporală;
preocuparea cu îmbolnăvirea de o boală gravă în prezenţa hipocondriazei; preocuparea cu dorinţe
sau fantezii sexuale în prezenţa unei parafilii; sau ruminaţii pe teme de vinovăţie în prezenţa unei
tulburări depresive majore).
E. Tulburarea nu se datorează efectului fiziologic direct al unei substanţe (de ex., un drog
de abuz, un medicament) sau al unei condiţii medicale generale.
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Tulburarea obsesiv-compulsivă poate avea uneori o intensitate marginal psihotică, cu
ritualuri complicate si multiple, cu trăiri din seria sindromului de depersonalizare, derealizare.
Pacienţii obsesivi pot solicita consult medical pentru diverse acuze care maschează
simptomatologia obsesiv compulsivă (dureri cronice, afecţiuni dermatologice în cazul ritualului de
spălare, etc.).
Deseori, în evoluţia TOC se asociază simptome depresive (3). În unele cazuri sunt reacţii
comprehensibile la simptomatologia obsesivă iar în altele apar ca episod independent recurent.
Tulburările anxioase (tulburarea de panică, fobia simplă), tulburările de alimentaţie, schizofrenia şi
tulburarea schizoafectivă, sindromul Tourette sau alte afecţiuni din spectrul obsesiv-compulsiv pot
apare în evoluţie (Karno şi colab. 1988) (3). Dintre tulburările de personalitate, se întâlnesc mai
frecvent tulburarea evitantă şi dependentă decât cea de tip obsesiv-compulsiv (Baer şi colab., 1990;
Baer şi Jenike, 1992; Thomsen şi Mikkelsen, 1993) (3). Un studiu recent sugerează existenţa unui
spectru familial pentru TOC şi personalitatea obsesiv-compulsivă (Bienvenu si colab., 2000) (3).
TOC are importante consecinţe socio-profesionale şi economice atât pentru pacient, familia
acestuia cât şi pentru societate, determinând scăderea calităţii vieţii.
Scopul tratamentului va consta atât în ameliorarea simptomelor cât şi a calităţii vieţii
pacientului: îmbunătăţirea funcţionalităţii familiale, interpersonale, profesionale şi sociale.
Strategiile terapeutice ale
TOC includ atât tratamentul farmacologic cât şi pe cel
psihoterapeutic.
Tratamentul farmacologic de elecţie este cel antidepresiv, preferaţi fiind inhibitorii selectivi
ai recaptării serotoninei (ISRS) în doze similare sau superioare tratamentului depresiei timp de 12
săptămâni, doza maximă fiind administrată, cel puţin, 6 săptămâni. Tratamentul poate fi început cu
sertralină (dozând de la 50 mg la 200 mg) sau fluvoxamină (300mg), putând fi însă utilizaţi cu
rezultate similare şi alţi ISRS: fluoxetina: 60mg/zi, paroxetina, 60 mg/zi, citalopram: 40 mg/zi. În
caz că rezultatele antiobsesive întârzie să se instaleze sau persoana un poate tolera reacţiile adverse,
se comută pe un alt ISRS aceeaşi perioadă. Tot ca a doua obţiune se poate apela la un antidepresiv
mai puţin selectiv ca de pildă clomipramina. Atingerea dozei de 200 – 250 mg/zi asigură în 4-6
săptămâni un efect antiobsesional evident. Pentru cazurile nonresponsive sau cu efecte adverse
multiple se poate recurge la perfuzii i.v. cu clomipramină, în doză echivalentă cu instalarea
efectului antiobsesional în 4-5 zile (Der Boer, Westenberg, 1997).
În tabelul următor este prezentat tratamentul de primă linie al tulburării obsesiv-compulsive
şi anume inhibitorii selectivi ai recaptării serotoninei (ISRS) şi clomipramina: dozele uzuale şi
efectele secundare.
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Vol. 7, Nr. 1, 2
Medicaţia
FLUOXETINA
FLUVOXAMINA
SERTRALINA
PAROXETINA
CLOMIPRAMINA
Doza uzuală
(mg)
20-80
(40-80)
50–300
(spre 300)
50-150
(până la 200)
20-60
(40-60)
25 - 250
(creşterea cu
3mg/kg/zi până
la doza maximă
de 200 mg/zi,
doză
administrată
copiilor şi
adolescenţilor)
Durata
(săpt.)
12
12
12
12
12
Efecte secundare
Observaţii
Tremor, irascibilitate, insomnie,
greaţă, anorexie, scăderea libidoului,
astenie
 Monitorizarea interacţiunilor
medicamentoase cu inhibitorii
citocromului P4502D6;
 Interacţiune semnificativă cu
antidepresivele triciclice (nivelul
plasmatic al acestora creşte de 2-3
ori mai mare decât normal)
Tremor, nervozitate, tulburări de
somn, greaţă, anorexie, tulburări ale
libidoului, astenie
antidepresivele triciclice,
warfarina, teofilina, propranolol,
benzodiazepine
 Se contraindică administrarea
IMAO, pimozid, tioridazină,
terfenadină, astemizole
Tremor, nervozitate, ameţeli, tulburări
de somn, greaţă, anorexie, tulburări
ale libidoului, astenie
 Interacţiuni medicamentoase
importante cu antidepresivele
triciclice;
 Este contraindicată
coadministrarea IMAO.
Tremor, tulburări de somn, gură
uscată, greaţă, anorexie, constipaţie,
transpiraţii, ejaculare precoce;
 Monitorizarea interacţiunilor cu
medicamente cu efect inhibitor la
nivelul citocromului P450 2D6;
antidepresivele triciclice
(creşterea de 2-3 ori a nivelului
plasmatic al antidepresivelor
triciclice);
 Se contraindică coadministrarea
IMAO sau a Tioridazinului
Gură uscată, constipaţie, disurie,
hipotensiune
posturala,
sedare,
dificultăţi de concentrare ale atenţiei,
creştere ponderală, convulsii;
 Coadministrare cu prudenta a
SSRI, datorita cresterii de 2-3 ori a
nivelului plasmatic al
Clomipraminei;
 Se contraindica administrarea de
IMAO
 5 săptămâni de „wash-out”
înaintea administrării IMAO
 Modificarea dozelor o dată pe
săptămână
 Doza va fi fracţionată dacă
depăşeşte 100 mg/zi
 Modificarea dozei la fiecare
3-4 zile
 Se administrează doze mici
pacienţilor cu afectare
hepatică sau vârstnicilor
 Doză unică de administrare
(dimineaţa sau seara)
 Modificarea dozei o dată pe
săptămână
 Se administrează doze mici în
disfuncţiile hepatice
 Modificarea dozei odată pe
săptămână;
 Se administrează cu prudenţă
în glaucomul cu unghi închis.
 Examen cardiologic şi
neurologic la iniţierea
tratamentului;
 EKG la iniţierea
tratamentului;
 Nivelul plasmatic al
Clomipraminei şi a
Desmethyl-Clomipramiei
ghidează clinicianul în
anumite situaţii (efecte
secundare, nonresponsivitate,
coadministrare SSRI).
Actualmente, in tratamentul TOC este utilizat atât citalopramul cât şi escitalopramul, care şiau dovedit eficienţa la doze de 20-40 mg/zi (doza maximă admisă: 60 mg/zi) şi respectiv 10-20
mg/zi (doza maximă admisă: 40 mg/zi) (Expert Consensus Guideline for Treatment of OCD; March
si colab., 1997; Montgomery, 1988; Mundo, Bianchi si Bellodi, 1997; Koponen si colab., 1997;
Thomsen, 1997).
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Vol. 7, Nr. 1, 2
Studiile recente (Yaryura, Tobias si Neziroglu, 1996; Grossman si Hollander, 1966; Zajecka,
Fawcett si Guy, 1990) recomandă, în tratamentul farmacologic al TOC şi utilizarea venlafaxinei, un
antidepresiv cu acţiune duală: serotonina/norepinefrina. Doza recomandată este de 37,5-225 mg/zi,
doza maximă admisă fiind 375mg/zi (March si colab., 1997).
În al treilea rând se recomandă augmentarea efectului antiobsesiv cu:
 anxiolitice:

buspirona: 20-60mg/zi (doza maximă admisă: 90 mg/zi);

clonazepam: 0,5-3 mg/zi (doza maximă admisă: 4 mg/zi);
 litiu: 300-600 mg/zi (în funcţie de nivelul litemiei: 0,6-1,2 mEq/l);
 gabapentina: 300-1800/2400 mg/zi (doza maximă admisă: 3600 mg/zi);
 inositol: 6-18 mg/zi (doza maximă admisă: 18 mg/zi);
 l-triptofan: 2 g/zi – 4-6g/zi (doza maximă admisă: 8 g/zi);
 fenfluramina: 20-60 mg/zi (doza maximă admisă: 160 mg/zi);
 antipsihotice: în doze mici

haloperidol: 0,25-6 mg/zi (doza maximă admisă: 6 mg/zi);

risperidona: 0,5-5 mg/zi (doza maximă admisă: 6 mg/zi);

olanzapina: 2,5-10 mg/zi;

pimozide: 0,5-6 mg/zi (doza maximă admisă: 6 mg/zi).
Antipsihoticele sunt utilizate ca şi strategie alternativă de augmentare în cazurile refractare
de TOC (Jenike si Rauch, 1994; Rasmussen, Eisen si Pato, 1993; Piccinelli si colab., 1995).
Pentru cazurile deosebit de refractare se poate recomanda terapia electroconvulsivantă şi cu
totul excepţional tehnici de psihochirurgie: capsulotomie anterioară, cingulotomie, leucotomie
practicată prin tehnici stereotactice (Pato, Eissen, Phillips, 2003).
Terapia electroconvulsivantă şi metodele de psihochirurgie se practica doar în condiţii de
internare.
Tratamentul medicamentos este menţinut la doza eficientă timp de un an. Daca pacientul
este asimptomatic se poate încerca reducerea treptată a dozelor cu 20% la 3-4 săptămâni timp de
şase luni.
Psihoterapia de tip comportamental se poate aplica cu destul de bune rezultate de sine
stătător sau împreună cu tratamentul farmacologic. Tehnicile comportamentale vizează blocarea
obsesiilor şi prevenirea compulsiilor. Doua tehnici sunt deosebit de eficiente: expunerea şi
prevenirea răspunsului.
Rezultate benefice pot fi obţinute si prin programele educaţionale adresate atât pacienţilor
cât şi familiilor acestora (Black si Blum, 1990).
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Vol. 7, Nr. 1, 2
În evoluţie, tulburarea obsesiv-compulsivă este frecvent asociată cu tulburarea depresivă
majoră, fobia socială, tulburarea de panică (Rasmussen şi Eisen, 1992) sau cu tulburarea de
personalitate de tip evitant sau dependent (Oldham şi colab., 1995, Torres şi Del Porto, 1995).
Comorbiditatea cu aceste tulburări influenţează atât alegerea tratamentului farmacologic cât şi a
celui psihoterapeutic.
Dacă TOC este asociată cu tulburarea depresivă majoră tratamentul farmacologic utilizat
este:
Medicaţie prescrisă în cazul TOC fără
comorbiditate
Un SSRI
Un antidepresiv triciclic
O benzodiazepină
Buspironă
Un neuroleptic
Valproat
Medicaţie prescrisă în cazul comorbidităţii
TOC cu tulburarea depresivă majoră
Acelaşi SSRI, în doze mai mari
Litiu
Desipramină sau nortriptilină
Buspironă
Pindolol
Bupropion
Un alt SSRI pentru ambele condiţii medicale
Litiu
Triiodotironină
Un SSRI
Un SSRI sau un antidepresiv triciclic sunt de
primă alegere, dar pot fi folosite şi alte clase de
antidepresive.
Ca metode de psihoterapie pot fi utilizate psihoterapia psihodinamică sau psihoanaliza
pentru TOC şi psihoterapia interpersonală şi/sau psihoterapia cognitiv-comportamentală pentru
tratamentul depresiei de intensitate uşoară/moderată (Clarkin, Pilkonig şi Magruder, 1996).
În comorbiditatea fobiei sociale cu tulburarea obsesiv-compulsivă, în tratamentul farmacologic,
fenelzina (Liebowitz şi colab, 1992), IMAO (inhibitorii de monoaminooxidază),
clonazepamul
(Davidson, Tulper şi Potts, 1994), fluvoxamina (Van Vliet den Boer şi Westenberg, 1994) şi sertralina
(Jeferson, 1995) şi-au dovedit eficienţa alături de fluoxetină, paroxetină şi alprazolam (Jefferson, 1995).
Citalopramul (Lepold si Koponow 1994) şi mai recent escitalopramul şi-au dovedit şi ele eficacitatea în
tratamentul fobiei sociale comorbide cu tulburarea obsesiv-compulsivă.
Deşi fenelzina la doza de 60-90 mg/zi, după 8 săptămâni de tratament şi-a dovedit eficienţa,
este folosită cu deosebite precauţii necesitând o dietă strictă şi făcând imposibilă prescrierea unor
medicamente cum ar fi: SSRI (inhibitorii selectivi de recaptare de serotonină) sau buspirona
(Liebowitz şi colab., 1992; Jefferson, 1995).
Clonazepamul în doză de 1-8 mg/zi, ameliorează simptomatologia după numai 1-2
săptămâni de tratament (Davidson şi colab., 1994), doza iniţială este de 0,5 mg/zi crescând treptat
cu 0,5-1mg la fiecare 5-7 zile, până la atingerea dozei optime. În primele zile de tratament poate
apare somnolenţa. Alte efecte secundare sunt tulburările de coordonare motorie, ataxia sau
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tulburările memoriei recente. Se administrează cu prudenţă şoferilor deoarece determină scăderea
vigilenţei. Durata tratamentului este de 12 luni (Connor şi colab, 1998).
Rezultate favorabile au fost obţinute şi la administrarea a 50-60 mg buspironă/zi (Schneider
şi colab., 1993), timp de 4 săptămâni. Efectele secundare sunt reprezentate de ameţeli, greaţă,
cefalee şi fatigabilitate.
Tratamentul de elecţie este reprezentat de fluvoxamină 150mg/zi (Van Vliet şi colab., 1994)
şi sertralină în doză de 50-200mg/zi administrate timp de 8-12 săptămâni. Rezultate similare s-au
obţinut şi la administrarea fluoxetinei.
Tratamentul farmacologic utilizat este sintetizat în tabelul următor:
Medicaţie prescrisă în cazul TOC fără
comorbiditate
Medicaţie prescrisă în cazul comorbidităţii
cu fobia socială
Acelaşi SSRI
Clonazepam
Buspironă
Un alt SSRI pentru ambele condiţii medicale
Un SSRI
Clonazepam
Buspironă
Se înlocuieşte cu clonazepam
Un SSRI
Fenelzină
O doză crescută de buspironă
Un SSRI
Un SSRI
Clonazepam
Fenelzină
Clonazepam
Un SSRI
Fenelzină
Un SSRI
Clonazepam
Un SSRI
Un antidepresiv triciclic
O benzodiazepină
Buspironă
Un neuroleptic
Litiu
Valproat
Psihoterapia cognitiv-comportamentală şi-a dovedit parţial eficienţa în tratamentul tulburării
obsesiv-compulsive comorbidă cu fobia socială (Heimberg, 1993). Tehnicile utilizate sunt
psihoeducaţia, training-ul aptitudinilor sociale, restructurarea cognitivă, expunerea gradată şi
training-ul management-ului anxietăţii (Heimberg, 1993).
În cazul comorbidităţii tulburării de panică cu tulburarea obsesiv-compulsivă scopul
tratamentului este „abolirea” atacurilor de panică, nu ameliorarea acestora. Tulburarea de panică
răspunde favorabil la administrarea de antidepresive triciclice, SSRI, benzodiazepine „incisive”
(alprazolam) şi MAOI, administrate timp de 1 an.
Fluvoxamina: 150-200mg/zi, sertralina: 50-200 mg/zi, citalopram-ul: 20-60 mg/zi,
paroxetina: 40 mg/zi şi fluoxetina si-au dovedit eficienta în tratamentul farmacologic (Jefferson,
1997, Wade şi colab., 1997, Lepola şi colab., 1998, Pollack, 1998). Iniţial dozele utilizate sunt mici,
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creşterea fiind gradată pentru a se evita efectele secundare şi noncomplianţa. În anumite situaţii,
pentru a se evita exacerbarea simptomatologiei anxioase, se administrează timp de 4-6 săptămâni o
benzodiazepină „incisivă”.
Antidepresivele triciclice (imipramina) şi clomipramina şi-au dovedit si ele eficienţa în
tratamentul farmacologic. Dozele utilizate sunt de 200 mg/zi pentru imipramină (Mavissakalian şi
Perel, 1989) şi de 75-250 mg/zi pentru clomipramină (Papp şi colab., 1997). Dozele optime sunt
atinse treptat, pentru a se evita efectele secundare: hipotensiunea posturală, creşterea frecvenţei
cardiace, creşterea ponderală şi efectele anticolinergice. Dacă un SSRI este primul medicament
prescris (pentru tulburarea obsesiv-compulsivă), nivelul plasmatic al triciclicelor trebuie urmărit cu
atenţie pentru a se evita efectele secundare sau toxicitatea.
Eficacitatea benzodiazepinelor „incisive” cum ar fi clonazepam-ul (1.8mg/zi), lorazepamul
(1,5-8 mg/zi) şi alprazolamul (1-10 mg/zi), este pe deplin recunoscută şi dovedită în tulburarea de
panică (Schweizer şi colab., 1990; Davidson, 1997). Printre avantaje remarcăm acţiunea rapidă
(încă din prima săptămână de tratament), eficacitatea în anxietatea anticipatorie şi gradul crescut al
complianţei pacienţilor. Dacă pacienţii nu au un istoric de abuz de substanţă, dependenţa survine
mult mai rar (Pollack şi colab, 1993).
Dintre benzodiazepinele incisive, clonazepam-ul are anumite particularităţi şi anume: durata
sa lungă de acţiune determină mai rar apariţia dependenţei „clock-watching”-ul şi a apariţiei
simptomelor de sevraj în perioada de „tapering”.
Un număr mic de pacienţi prezintă în timpul tratamentului cu clonazepam, simptomatologie
depresivă, necesitând tratament de urgenţă prin scăderea dozei, discontinuarea tratamentului cu
clonazepam sau a iniţierii unui tratament cu un antidepresiv. Efectele secundare ale tratamentului cu
benzodiazepine „incisive” sunt reprezentate de sedare, lentoare psihomotorie, tulburări ale
memoriei recente şi apariţia sindromului de sevraj. Întrucât concentrarea plasmatică a
alprazolamului este crescută de fluoxetină, fluvoxamină şi nefazodonă (Nemeroff şi colab., 1996),
în aceste situaţii se utilizează cu predilecţie clonazepam-ul şi lorazepam-ul.
Deşi fenelzina (MAOI) şi-a dovedit eficienţa în tulburarea de panică (Jefferson, 1997),
restricţiile alimentare (tiramină) şi mai ales nerespectarea acestora, imposibilitatea combinării
acesteia cu SSRI sau buspirona şi importantele efecte secundare, îi limitează mult utilizarea în
tratamentul comorbidităţii tulburării obsesiv-compulsive cu tulburarea de panică.
Psihoterapia cognitiv-comportamentală şi-a dovedit eficienţa în comorbiditatea tulburării de
panică cu tulburarea obsesiv-compulsivă (Barlow, 1997). Tehnicile utilizate sunt reconstrucţia
cognitivă, tehnici respiratorii şi expunerea structurată.
În cazul comorbidităţii tulburării evitante de personalitate cu tulburarea obsesiv-compulsivă
tratamentul farmacologic utilizat este acelaşi ca şi în cazul comorbidităţii cu fobia socială.
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Vol. 7, Nr. 1, 2
Tratamentul psihoterapeutic utilizat timp de 10-14 săptămâni vizează training-ul abilităţilor
sociale, expunerea gradată (Alden, 1989; Stravynski şi colab., 1994), psihoterapia dinamică,
interpersonală, cognitiv-comportamentală, de cuplu şi familială.
Nu există studii clinice în ceea ce priveşte tratamentul farmacologic al comorbidităţii
tulburării dependente de personalitate cu tulburarea obsesiv-compulsivă. Pot fi folosite SSRI
(inhibitorii selectivi ai recaptării serotoninei) sau antidepresivele triciclice. Utilizarea anxioliticelor
datorită riscului crescut de dependenţă impune prudenţă.
Ca metode de psihoterapie pot fi utilizate: psihoterapia eclectică combinată cu terapia de
cuplu sau familială sau tehnici de psihoterapie de tip cognitiv-comportamentala însă cu rezultate
modeste (Fleming, 1990).
Bibliografie
1. Diagnostic and Statistical Manual for Mental Disorders, American Psychiatric
Association, Bucureşti, 2003.
2. Fineberg N., Marazziti D., Stein D.J., 2001 – Obsessive Compulsive Disorder: A
practical Guide. Martin Dunitz Ltd.
3. Hollander E., Simeon D., 2002 – Concise Guide to Anxiety Disorders. American
Psychiatric Publishing, Inc.
4. Kasper S., Zohar J., Stein D.J., 2002 – Decision Making in Psychopharmacology.
Martin Dunitz Ltd.
5. Koran, L.M., 1999 – Obsessive-compulsive and related disorder in adults. Cambridge
University Press.
6. Montgomery S., Zohar J., 1999 – Obsessive Compulsive Disorder. Martin Dunitz Ltd.
7. Nutt D., Ballenger J., 2005 – Anxiety Disorders, Blackwell Publishing Ltd.
8. Podea, D.M., 2005 – Tulburările Anxioase. Editura Mirton, Timişoara.
9. Stein D.J., 2004 – Clinical Manual of Anxiety Disorders. American Psychiatric
Publishing, Inc.
10. Tallis F., 1995 – Obsessive Compulsive Disorder, A Cognitive Neuropsychological
Perspective. John Wiley & Sons.
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CAUSES AND MANAGEMENT OF
ANTIPSYCHOTIC-INDUCED HYPERPROLACTINEMIA
A. Chimorgiachis, D. Marinescu
Universitatea de Medicină şi Farmacie Craiova
Abstract
Hyperprolactinaemia is one of the many side effects caused by the antipsychotic
medication, frequently occurring with first generation antipsychotics and some
of the second generation antipsychotics such as risperidone and amisulprid.
Antipsychotic agents such as aripiprazole, olanzapine, ziprasidone, quetiapine
and clozapine rarely cause this condition. Although hyperprolactinaemia may be
asymptomatic, it is frequently under-diagnosed, patients hesitating to mention its
symptoms such as sexual dysfunction considering them embarrassing. Symptoms
of hyperprolactinaemia include sexual dysfunction, galactorrhea,
gynaecomastia, menstrual disturbances, obesity, infertility and possible risk of
osteoporosis and breast cancer, frequently leading to poor compliance and
relapse of psychiatric illness.
To the patients who present a confirmed hyperprolactinaemia it is important
to exclude other causes of prolactin elevation such as tumours in the
hypothalamic-pituitary area, pregnancy, hypothyroidism, chronic renal
insufficiency. Management options include reducing the dose of the
antipsychotic agent, switching to an atypical antipsychotic which do not
influence prolactin levels, introducing a dopamine receptor agonist.
Considering these new options of modern treatment, hyperprolactinaemia
should gain an important position in the management of the patient treated
with an antipsychotic agent and this period of neglection towards this
syndrome should end. The proper investigation and an effective management
can prevent adverse effects and long term consequences.
Key words: hyperprolactinaemia, typical and atypical antipsychotic agents.
CAUZELE ŞI MANAGEMENTUL HIPERPROLACTINEMIEI
INDUSE DE ANTIPSIHOTICE
Rezumat
Hiperprolactinemia este unul din multele efecte cauzate de medicaţia
antipsihotică, care survine frecvent în urma tratamentului cu antipsihotice
din prima generaţie şi unele din cele de generaţia a doua, aşa cum sunt
risperidona şi amisulpridul. Antipsihoticele precum aripiprazolul,
olanzapina, ziprasidona, quetiapina şi clozapina cauzează mai rar această
condiţie. Deşi hiperprolactinemia poate fi asimptomatică, este frecvent
subdiagnosticată, pacienţii ezitând să menţioneze simptome precum
disfuncţia sexuală considerându-le ruşinoase. Simptomele date de
hiperprolactinemie includ disfuncţia sexuală, galactoreea, ginecomastia,
dereglări menstruale, obezitate, infertilitate, existând şi riscul de osteoporoză
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şi cancer mamar, motive care frecvent conduc la o proastă complianţă la
tratament şi la recăderi ale bolilor psihiatrice.
Pacienţilor care prezintă o hiperprolactinemie confirmată, este important să
excludem celelalte cauze care cresc prolactina, precum tumorile zonei
hipotalamo-hipofizară, sarcina, hipotiroidismul sau insuficienţa renală
cronică. Managementul hiperprolactinemiei include scăderea dozei de
antipsihotic, schimbarea la un antipsihotic cu potenţial mic de creştere al
prolactinei şi introducerea unui agonist al receptorilor dopaminici.
Luând în considerare aceste opţiuni moderne de tratament,
hiperprolactinemia ar trebui să obţină un loc important în managementul
pacienţilor trataţi cu antipsihotice, iar această perioadă de neglijare a
acestui sindrom ar trebuie să ia sfârşit. O investigare corectă a pacientului şi
un management eficient pot preveni efectele adverse şi consecinţele pe
termen lung.
Cuvinte cheie: hiperprolactinemia, antipsihotice tipice şi atipice.
Introduction. General aspects
Prolactin is a 199-amino acid polypeptide hormone secreted by the lactotroph cells in the
anterior pituitary. Transient and mild increase of prolactin levels occur in response to stress, sexual
activity and meals. Women, durind mild cycle and second part of menstrual cycle, have an elevated
prolactin levels. Pregnancy can raise prolactin levels up to 20 times comparing to non pregnant
women, and tend to normalise 3 weeks after child birth to non breast-feeding. The upper limit is
considered to be 500mU/L, both to men and women. The threshold at which hyperprolactinaemia
symptoms occur vary among individuals although clinically significant symptoms tend to occur in
the range of 600 – 1200 mU/L or higher.
Factors involved in prolactin secretion
Curr Med Res Opin®2004Librapharm Limited
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Stimulatory factors
Serotonin was demonstrated to stimulate prolactin secretion by stimulating 5HT2A receptors. The
serotonergic neurons involved project from the dorsal raphe nucleus to the medial basal hypothalamus.
Fig. 1. Serotonin stimulates prolactin release from pituitary lactotroph cells
in the pituitary gland (red circle) (Stahl, Second edition).
Thus, serotonin and dopamine have a reciprocal regulatory action on prolactin release, and
oppose each other's actions.
Estrogens bind to specific intracellular receptors in lactotrophs and can enhance gene
transcription and synthesis as well as DNA synthesis and mitotic activity (Molitch, 1995)
Animal studies demonstrated that TRH and cholecystokinin have prolactin releasing
properties (Freeman, 2000).
Inhibitory factors
Dopamine inhibits prolactin release by stimulating D2 receptors. It is produced by the
tuberoinfundibular neurons in the hypothalamus. Is released from their nerve endings and reaches
the pituitary transported by the portal hypophyseal circulation (Gudelky, 1981) – Fig. 2.
Acetylcholine was identified as prolactin-inhibiting factor to animals without being certain of
its significance to humans.
Symptoms and Adverse effects
Hyperprolactinaemia can cause a wide range of clinical symptoms such as infertility,
gynaecomastia, galactorhoea, menstrula irregularities such as oligomenorrhoea and amenorhoea,
decreased libido, impaired arousal, impaird orgasm, priapism, hirsutism, obesity. There is an
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individual variation in plasma prolactin level at which symptoms appear. Chronic gonadal
hypofunction may lead to long term effects such as decreased bone mineral density which can lead
to osteoporosis. Although a series of clinical trial demonstrated that antipsychotic treatment has a
higher incidence for breast cancer, other showed no relation between these two.
Fig. 2. Dopamine inhibits prolactin release from pituitary lactotroph cells
in the pituitary gland (red circle) (Stahl, Second edition).
Causes of hyperprolactinaemia
The causes of hyperprolactinaemia are:
Physiological:
 Pregnancy
 Lactation
 Breast stimulation
 Sexual activity
 Stress
 Sleep
Pathological:
 Pituitary diseases

Micro- and macro-prolactinomas

Empty sella syndrome

Pituitary stalk lesions
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 Hypothalamic diseases

Tumors

Sarcoidosis

Postencephalitis
 Endocrine diseases

Cushing’s disease

Hypothiroidism

Polycystic ovary syndrome
 Other

Breast neoplasm

Chronic renal insufficiency

Cirrhosis
Pharmacological
 Pshychotropic medication

Typical antipsychotics

Atypical antipsychotics (Amisulpride, Risperidone,Olanzapine)

Antidepressants (SSRIs and TCAs)
 Histamine H2 receptor agonists

Ranitidine

Cimetidine
 Hormones

Estrogens (contraceptives)
 Antihypertensives

Verapamil

Reserpine
 Other

Amphetamine

Opioids
Effects of antipsychotic agents on prolactin
These agents rely on their dopamine antagonistic properties (the capacity to block D2
receptors in mesolimbic and mesocorical areas) to provide their antipsychotic effects. However, this
also removes the brake on prolactin secretion, leading to hyperprolactinaemia. Though, blocking D2
receptors in the limbic system, it decreases positive psychotic symptoms, in the tuberoinfundibular
system, it causes hyperprolactinaemia (D2 blockade on lactotroph cells) and in the nigrostriatal
system, it can result in extrapyramidal symptoms (EPS) – Table 1.
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First Generation Antipsychotics
It was demostrated that first generation antipsychotics are associated with up to ten-fold
increase in prolactin levels (Fig. 3).
Table 1. Risk of hyperprolactinaemia with antipsychotics
Antipshychotic
Haloperidol
Chlorpromazine
Fluphenazine
Amisulpride
Risperidone
Olanzapine
Ziprasidone
Quetiapine
Clozapine
Aripiprazole
Risk
HIGH
HIGH
HIGH
HIGH
HIGH
LOW
NONE
NONE
NONE
NONE
Fig. 3. Conventional antipsychotic drugs are D2 antagonists
and thus oppose dopamine's inhibitory role on prolactin secretion
from pituitary lactotrophs. Therefore, drugs that block D2 receptors
increase prolactin levels (red circle) (Stahl, Second edition)
Haloperidol is a high-potency antipsychotic indicated for the symptomatic treatment of psychotic
disorders, tics and severe behavioural problems. Among its other adverse effects caused by the D2 receptor
blockade we can enumerate EPS, tardive diskinesia, hyperprolactinaemia with gynaecomastia,
galactorrhoea, impotence, infertility and ejaculation dysfunction, retinopathy and haematological
disturbances In two double-blind, randomised studies, haloperidol produced a significantly larger increase
in prolactin levels in schizophrenia patients than either placebo or olanzapine.
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Chlorpromazine is an aliphatic phenothiazine used mainly as an antipsychotic in psychotic
disorders and severe behavioural abnormalities. Hiperprolactinaemia occurs same as to haloperidol.
Fluphenazine is a piperazine phenothiazine antipsychotic agent indicated for the treatment
of schizophrenia. Elevated prolactin levels are more prevalent in the elderly, especially in women.
Furthermore, menstrual irregularities, impotence in men and increased libido in women have
occurred.
Other conventional antipsychotic agents such as Levosulpiride, Tiapride also raise prolactin
levels.
The increase in prolactin that occurs through the use of conventional antipsychotics
develops within a few hours of starting treatment and remains elevated throughout the period of use.
Once treatment stops, prolactin levels return to normal within 2-3 weeks. It has been suggested that
with chronic treatment, a partial tolerance may occur although patients treated for long periods of
time still have higher prolactin levels compared to untreated healthy controls.
Second generation antipsychotics
Second-generation antipsychotics produce lower increases in prolactin than first generation
antipsychotic agents. Olanzapine, Ziprasidone, Quetiapine, Aripiprazole and Clozapine have been
shown to produce no significant or sustained increase in prolactin in adult patients, in contrast with
Risperidone and Amisulpride which elevate prolactin levels.
Amisulpride is an antipsychotic with high affinity for presynaptic D2/D3 dopamine receptors,
having no affinity for serotonergic, cholinergic, histaminic or 1-adrenergic receptors. Low doses
may improve negative symptoms in schizophrenic patients, being used and in the treatment of
patients with dysthymia, by enhancing dopaminergic transmission at the level of the mesolimbic
system. High dosages (> 600 mg/day) have antidopaminergic activity, therefore it is used for
treating positive symptoms or acute delusional attacks. In schizophrenia patients treated with
amisulpride for 12 months, prolactin secretion was significantly increased over baseline after 1
month of high dosing (1000 mg/day) during the acute phase. Prolactin levels remained elevated
above baseline for the 12-month dosing period but gradually declined during the maintenance phase
(amisulpride 200-600mg/day).
Risperidone is a benzisoxazole derivative, with a high propensity to elevate plasma
prolactine levels. Risperidone’s effectiveness on positive and negative symptoms of schizophrenia
is thought to be the combined 5-HT2A and D2 antagonism. It antagonises dopamine receptors in the
limbic system only, having effect on positive symptoms, while in the mesocortical tract it exhibits
selective 5-HT2 receptor blockade, which causes an excess of dopamine and an increase in
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dopamine transmission, having an effect on negative symptoms. As it does not affect dopamine in
the nigrostriatal pathway, excepting very high doses, EPS are usually avoided. Another dose-related
adverse effect is dopamine receptor blockade in the tubero-infundibular tract, resulting in prolactin
release, weight gain and menstrual irregularity. 1-Receptor blockade may cause hypotension.
Studies have produced fairly high rated of prolactin-related effects, such as menstrual changes,
sexual disfunction and reproductive adverse effects. For women were commonly reported menstrual
irregularities, even to doses of 1 mg/day, amenorrhoea and galactorrhoea. For men were reported
cases of gynaecomastia, ejaculatory difficulties, priapism and galactorrhoea.
Clozapine is a dibenzodiazepine derivative. Clozapine has the typical antipsychotic effects,
with greater specificity for the limbic system having a low incidence of EPS, proven to be efficient
in the treatment of the refractory to other medications schizophrenia, agranulocitoisis being its
severe adverse effect. There were only isolated case reports of prolactin elevation during treatment
with clozapine. In a 6 week double-blind, parallel group design Breier et al compared the effects of
ripseridone and clozapine. Patients underwent a period of 2 weeks of baseline fluphenayine
treatment at a dose of 20 mg/daz and switched either to risperidone at a mean dose of 6 mg/day or
to clozapine at a mean dose of 400 mg/day. Plasma prolactine levels at the moment of the switch
were increased about 2-fold above the normal interval to both groups. After the switch, in the
clozapine group levels decreased significantly into the normal interval, whereas in the risperidone
group did not change significantly.
Olanzapine is an atypical antipsychotic agent similar to clozapine in chemical structure and
in mechanism of action. It causes transient elevations in plasma prolactin levels. During treatment,
in adults, prolactin levels remained slightly elevated to aproximately 33% of the patients during
treatment (Tran, 1997), its elevation appearing to be a dose-related phenomenon. Rare sexual
dysfunction and menstrual changes were mentioned during the treatment with olanzapine. Few
cases of priapism were mentioned that may be due to the α-aderenergic receptors and to muscarinic
receptors blockade of olanzapine.
Quetiapine and Ziprasidone seem to have negligible effects on the prolactin elevation. One
case for each of these two atypical antipsychotic agents were mentioned in literature, for quetiapine
being related to an overdose, postulated to be secondary to α1-adrenergic receptor antagonism.
Aripiprazole was found to decrease serum prolactin levels durind medical trials. The lack of
increase prolactin levels may be explained by the partial agonism at D2 receptors, in contrast with
the D2 receptor antagonism of the other atypical antipsychotics.
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Management of hyperprolactinaemia
Evaluation
 Clinicians should inquire as many patients are reluctant to raise hyperprolactinaemia
symptoms, during treatment with an antipsychotic drug.
 Diagnosis of hyperprolactinaemia exceeds 500 mU/L in more than two separate occasions.
 Levels over 2000 mU/L should increase suspicion of pituitary tumours especially if other
symptoms such as headache, visual changes and other neurological symptoms are present.
 In case of hyperprolactinaemia, exclude other causes that may elevate prolactin
psysiologically – pregnancy, lactation, stress, sleep, or pathologically – pituitary
tumours, chronic reanla insufficiency, polychistic ovarian syndrome, hypothyroidism.
 Verify if patient is under treatment with high propensity for prolactin elevation drugs.
Treatment
 Decrease the dose of existing antipsychotic
 Effective against all hyperprolactinaemia symptoms
 Risk of relapses
 Switch to an antipsychotic with low propensity of elevating prolactin
 Confirmation that hiperprolactinaemia was caused by the antipsychotic
 Difficult to non compliant patients treated with long-acting depot injection
 Dopamine receptor agonists (Bromocriptine, Cabergoline, Amantadine)
 Allows continuing treatment with existing antipsychotic
 Caution for adverse effects (postural hypotension, GI symptoms)
 Estrogens (oral contraceptives) !!! Women ONLY
 effective against symptoms of estrogen deficiency
 Breast cancer
 Thromboembolism
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Conclusions
Considering its long-term adverse effects, hyperprolactinaemia must become a focus of
interest among physicians. With the proper management, hyperprolactinaemia can be avoided or
corrected, especially with the actual antipsychotic medication. We must not neglect these side
effects, which often lead to discontinuation of the treatment and implicit to relapse, with severe
consequences on the patient’s evolution.
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11. Mental Health NHS Trust, 2003 – Guidelines: Management of Antipsychotic Induced
Hyperprolactinaemia.
12. Molitch ME, 1995 – Prolactin. In: Melmed S, editor. The pituitary. Cambridge (MA):
Blackwell Science, 136-86.
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13. Mullen B, Brar JS, Vagnucci AH, et al, 2001 – Frequency of sexual dysfunction in
patients with schizophrenia on haloperidol, clozapine, or risperidone. Schizophr Res,
48, 155-8.
14. Nicholson R, McCurley R, 1997 – Risperidone-associated priapism. J Clin
Psychopharmacol, 7(2), 133-4.
15. Pais VM, Ayvazian PJ, 2001 – Priapism from quetiapine overdose: first report and
proposal of mechanism. Urology, 58(3), 462.
16. Shiwach RS, Carmody TJ, 1998 – Prolactogenic effects of risperidone in male patients:
a preliminary study. Acta Psychiatr Scand, 98, 81-3.
17. Smith S, 1992 – Neuroleptic-associated hyperprolactinaemia: can it be treated with
bromocriptine? J Reprod Med, 37, 737-40.
18. Stahl SM – Essential Psychopharmocology, Second edition, Cambridge University
Press, 406-435.
19. Tran PV, Hamilton SH, Kuntz AJ, et al, 1997 – Double-blind comparison of olanzapine
versus risperidone in the treatment of schizophrenia and other psychotic disorders. J
Clin Psychopharmacol, 17, 407-18.
20. Udriştoiu.T, Marinescu D, Gheorghe MD, 2000 – Terapia Psihofarmacologică
Actualităţi, Editura Scorillo, Craiova, 1-5.
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DEPRESSION IN SCHIZOPHRENIA
Maria Toma1, A. Chimorgiachis2
1
Spitalul ”Prof. Dr. Alexandru Obregia”, Bucuresti
2
Clinica de Psihiatrie Craiova
Abstract
Depression is a frequently occurring symptom in schizophrenia. Depressive
symptoms are important not only because they contribute significantly to the
suffering caused by the illness, but also because they exacerbate deficits in
psychosocial functioning and commonly precede attempted and completed
suicide.
Some studies have found that depressive symptoms in patients with
schizophrenia may be secondary to negative symptoms, medications, or
neuroleptic-induced movement disorders, whereas others have reported that
in patients with chronic schizophrenia and even first-episode schizophrenia,
depressive symptoms may be a core component of various stages of this
illness. Estimates of the frequency of depressive episodes in patients with
schizophrenia range from 20% to 80%.
Despite a long history of debate, the presence of depression in schizophrenia
remains quite controversial. Recently, “Postpsychotic Depressive Disorder of
Schizophrenia” was listed in the Diagnostic and Statistical manual of Mental
Disorders 4th ed. (DSM IV; American Psychiatric Association), as a possible
diagnostic category requiring further research.
Key words: depression, schizophrenia, suicide.
DEPRESIA ÎN SCHIZOFRENIE
Rezumat
Depresia este un simptom frecvent întâlnit în schizofrenie. Simptomele
depresive sunt importante nu numai pentru că ele contribuie semnificativ la
suferinţa cauzată de boală, dar şi pentru că ele exacerbează deficitul în
funcţionarea psihosocială şi adesea precedă tentativele de suicid şi suicidul.
O serie de studii au relevat faptul că simptomele depresive la pacienţii cu
schizofrenie ar putea fi secundare simptomatologiei negative, medicaţiei, sau
efectelor secundare extrapiramidale, în timp ce altele susţin ideea că la
pacienţii cu schizofrenie cronică şi chiar la cei aflaţi la primul episod,
simptomele depresive ar putea fi o componentă de bază a diferitelor stadii de
boală. Frecvenţa estimată a episoadelor depresive la pacienţii cu
schizofrenie se situează la valori cuprinse între 20 şi 80%.
În ciuda numeroaselor dezbateri pe această temă, prezenţa depresiei în
schizofrenie rămâne controversată. De curând, depresia postpsihotică în
schizofrenie a fost inclusă ca diagnostic în DSM IV, încurajând cercetările în
această direcţie.
Cuvinte cheie: depresie, schizofrenie, suicid.
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There are a number of important differential diagnoses of depressive symptoms in
schizophrenia. Differential diagnoses to consider include schizoaffective disorder, organic
conditions and the negative symptoms of schizophrenia. It has been argued by some that depression
may in some way be ‘caused’ by antipsychotic medication and this issue will be discussed in detail.
Depression may also be an understandable psychological reaction to schizophrenia. When all of
these possibilities have been excluded, there is evidence that depression is perhaps most often an
integral part of the schizophrenic process itself.
Differentiating schizophrenia with clinically significant depressive symptoms from
schizoaffective disorder is not always easy. Clearly, the exact dividing line between the two
conditions is a conceptual one.
Diagnostic Criteria for Schizoaffective Disorder – depressive episode
A. An uninterrupted period of illness during which, at some time, there is either (1) a major
depressive episode , (2) a manic episode, or (3) a mixed episode concurrent with
symptoms that meet (4) criterion A for schizophrenia
Note: The Major Depressive Episode must include depressed mood.
Criteria for Major Depressive Episode
Five (or more) of the following symptoms have been present during the same 2-week period
and represent a change from previous functioning; at least one of the symptoms is either (1)
depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly due to a general medical condition, or
mood-incongruent delusions or hallucinations.
1. depressed mood most of the day, nearly every day, as indicated by either subjective
report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).
Note: In children and adolescents, can be irritable mood.
2. markedly diminished interest or pleasure in all, or almost all, activities most of the day,
nearly every day (as indicated by either subjective account or observation made by others)
3. significant weight loss when not dieting or weight gain (e.g., a change of more than 5%
of body weight in a month), or decrease or increase in appetite nearly every day.
Note: In children, consider failure to make expected weight gains.
4. insomnia or hypersomnia nearly every day.
5. psychomotor agitation or retardation nearly every day (observable by others, not merely
subjective feelings of restlessness or being slowed down).
6. fatigue or loss of energy nearly every day.
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7. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional)
nearly every day (not merely self-reproach or guilt about being sick).
8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by
subjective account or as observed by others).
9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide.

The symptoms do not meet criteria for a Mixed Episode.

The symptoms cause clinically significant distress or impairment in social, occupational,
or other important areas of functioning.

The symptoms are not due to the direct physiological effects of a substance (e.g., a drug
of abuse, a medication) or a general medical condition (e.g., hypothyroidism).

The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved
one, the symptoms persist for longer than 2 months or are characterized by marked
functional impairment, morbid preoccupation with worthlessness, suicidal ideation,
psychotic symptoms, or psychomotor retardation.
Depression-like syndromes can occur secondary to a range of medical conditions Neoplasms,
anaemias, infections, neurological disorders and endocrine disorders can induce psychological
symptoms directly in the person with schizophrenia, or depressive symptoms may occur as a reaction
to illness. The medication used to treat medical disorders may also cause depressive symptoms as a
side-effect. Antihypertensives, corticosteroids, anticonvulsants and L-dopa, among others, may give
rise to problems. The medical history of any patient presenting with depressive symptoms should thus
be carefully scrutinised. In addition, the entire range of medication that they receive, not just their
psychotropic medication, and any recent changes in medication, should be considered as possible
aetiological factors. Substance misuse is also a common cause of depressive symptoms, either as a
direct effect of the substance concerned or as a withdrawal phenomenon. Alcohol is undoubtedly the
most common substance causing problems. Arguably, cannabis can cause depressive symptoms with
long-term use, and nicotine and caffeine may cause dysphoria upon withdrawal. Cocaine, less
commonly used and more often associated with manic symptoms, can cause depression upon
withdrawal. The same applies to other psychostimulants.
The “negative” symptoms of schizophrenia have many clinical similarities to the syndrome
of depression. Lack of energy, anhedonia and social withdrawal may cause particular problems
when attempting to differentiate between the two syndromes. Observed sadness is an unreliable
indicator of depression in schizophrenia. Prominent subjectively low mood, suggesting depression,
and prominent blunting of affect, suggesting negative symptoms, are the two features which are
most helpful in differentiating the two syndromes. Other symptoms that help to establish the
diagnosis of depression include some of the main psychological features that occur in primary
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depressive illness, such as hopelessness, helplessness, worthlessness, guilt, anxiety and suicidal
thinking. In schizophrenia, the biological features of the depressive syndrome, such as insomnia and
retardation, are not always present – and if they are present, they can be more difficult to
disentangle from negative symptoms and can be an intrinsic part of the illness separate from any
superimposed depressive syndrome.
Neuroleptic-Induced Dysphoria
Dopamine synapses are involved in brain pathways mediating “reward”. Therefore,
dopamine blockade by a neuroleptic drug could theoretically lead to anhedonia and, perhaps,
depression. Indeed, a state of dysphoria is commonly described by neuroleptic-treated patients , a
number of older reports have suggested a link between neuroleptic use and depression , and one
study found more anhedonia and depression in maintenance-phase schizophrenic patients who were
taking neuroleptics than in others who were not . Another study found a positive relationship
between haloperidol plasma levels and depressive symptoms in the context of a positive association
between extrapyramidal symptoms and depressive symptoms, and impairments of quality of life
related to neuroleptic-induced dysphoria have been reported. Studies that compared patients with
schizophrenia who were being treated with neuroleptic medications versus those who were not did
not find that neuroleptic-treated patients manifested more depression. Nevertheless, one biological
possibility is that schizophrenia may represent a basic disorder of dopamine regulation in which
"brittle" patients are vulnerable to dopamine storms (psychosis) and droughts (negative symptoms).
In this situation, the administration of more than the minimum required neuroleptic (dopamineblocking) medication could exacerbate negative symptoms, thereby possibly contributing to the
impression of neuroleptic-induced depression.
Neuroleptic-Induced Akinesia
Rifkin et al. and Van Putten and May went beyond the original “large muscle stiffness”
definition of akinesia to describe a more subtle but equally debilitating extrapyramidal side effect of
neuroleptic treatment involving impaired ability to initiate and sustain motor behavior. Patients with
this form of akinesia may or may not have the classical parkinsonian feature of decreased accessory
motor movements. However, they act “as if their starter motor is broken”, and they consequently
appear to lack spontaneity. Since so much of human interchange, such as holding a conversation or
participating in activities, involves the initiation or maintenance of motor behavior, this side effect
leads to exclusion from much of what is normal in life. Patients themselves may attribute this effect
to “laziness”, experiencing guilt or shame. Blue mood can also accompany this condition, possibly
as a primary issue, making it virtually indistinguishable clinically from depression. Unfortunately,
most studies of depression in neuroleptic-treated patients have not adequately considered this form
of akinesia as a potentially confounding factor.
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Neuroleptic-Induced Akathisia
Akathisia is another extrapyramidal side effect of neuroleptic treatment that, in subtle
presentation, can easily be confounded with depression. Patients with akathisia behave “as if their
starter motor won’t stop” and often experience this state as substantially dysphoric. Indeed,
akathisia has been associated with both suicidal ideation and – perhaps as a consequence of a
general tendency toward motor action – suicidal behavior. As with akinesia, akathisia has seldom
been considered as a possible confound in studies of depression in schizophrenia.
Depression as a prodromal syndrome
Depressive symptoms are common in the prodromal period prior to acute psychotic
episodes. The symptoms most frequently mentioned by patients and their families were: “symptoms
of dysphoria that non-psychotic individuals experience under stress, such as eating less, having
trouble concentrating, having trouble sleeping, depression and seeing friends less”.
Indeed, depression, as described above, was described by 60% of patients and more than
75% of their relatives. The emergence of affective symptoms may represent a psychological
reaction to impending relapse, may reflect an underlying biological process mediating both these
symptoms and positive psychotic symptoms, or may be an epiphenomenon. In any event, newly
emerging affective symptoms are a useful early warning sign of impending relapse.
Depressive symptoms during acute episodes
Depressive symptoms are most frequently associated with the acute phase of the illness.
Such symptoms are most prevalent before medication is commenced and occur in more than half of
first-episode or drug-free patients. The prevalence of depressive symptoms falls dramatically during
the course of an admission for an acute relapse, and occurs in approximately 25% of patients during
the six months following discharge. The close association between depressive symptoms and acute
episodes adds weight to the hypotheses that such symptoms are a core feature of schizophrenia and
suggests that depressive symptoms and more typically schizophrenic symptoms may share common
pathophysiological processes.
Depressive symptoms in chronic schizophrenia
Lower rates of depressive symptoms are seen in the chronic phase of the illness with a range
of 4–25% and an estimated mean of 15%. Most of the reported studies on chronic patients do not
define the clinical stability or otherwise of the patients involved. In one study, only patients who
were clinically stable (not hospitalised in the previous six months, no medication changes in
previous six weeks and judged by their clinician to be stable) and who were living in the community
were assessed, and 9% were found to be currently depressed. Persistent positive symptoms in the
chronic phase of the illness may lead to distress, demoralisation and depression.
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Post-psychotic depression
In earlier times, the term “postpsychotic depression” was used to describe a dysphoric state
that immediately followed a psychotic episode. In the sense that this was reactive to disappointment
or stress, such an episode might belong in the previous category. DSM-IV now suggests that the
term “postpsychotic depression” be used to describe depression that occurs at any time after a
psychotic episode in schizophrenia – even after a prolonged interval. This definition would include
many of the other defined categories in this article.
The occurrence of depressive symptoms during the chronic phase of schizophrenia has been
given close attention in recent years. The terms ‘post-psychotic depression’, ‘post-schizophrenic
depression’ and ‘secondary depression’ have been used to describe this phenomenon. Unfortunately,
as Siris (1990) has argued, the term ‘post-psychotic depression’ has been used to describe three
similar, but clinically distinct, groups of patients. In one group, depressive symptoms are clearly
present during an acute psychotic episode and resolve as the positive psychotic symptoms resolve,
although sometimes more slowly. These depressive symptoms only become apparent as the positive
symptoms resolve, and the term ‘revealed depression’ is sometimes applied. The second definition
overlaps somewhat with the first but describes patients who develop depressive symptoms as their
positive psychotic symptoms resolve. The third group of patients are those in whom significant
depressive symptoms appear after the acute episode has resolved. The multiplicity of terms and the
different ways in which they have been used has not added to the clarity of the literature. The studies
in this area have varied widely in methodology, including their definitions of significant depression.
In summary, depression is well known to occur during the course of schizophrenia in many
patients and contributes substantially to the morbidity – even mortality – of this disorder.
“
Depression” in schizophrenia, however, is heterogeneous, and the best approaches to its
understanding and treatment are based on an appropriate differential diagnosis.
References
1. Drake, R. E. & Ehrlich, J., 1985 – Suicide attempts associated with akathisia. Am. J.
Psychiat., 142, 499–501.
2. Drake, R. E. & Cotton, P. G., 1986 – Depression, hopelessness and suicide in chronic
schizophrenia. Brit. J. Psychiat., 148, 554–559.
3. De Alarcon, R. & Carney, M. W. P., 1969 – Severe depressive mood changes following
slow-release intra-muscular fluphenazine injection. Brit. Med. J., III, 564–567.
4. Cheadle, A. J., Freeman, H. L. & Korer, J., 1978 – Chronic schizophrenic patients in the
community. Brit. J. Psychiat., 133, 221–227.
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5. Herz, M. & Melville, C., 1980 – Relapse in schizophrenia. Am. J. Psychiat., 137, 801–805.
6. Addington, D., Addington, J. & Patten, S., 1996 – Gender and affect in schizophrenia.
Can. J. Psychiat., 41, 265–268.
7. American Psychiatric Association, 1994 – Diagnostic and Statistical Manual of Mental
Disorders (4th edn) (DSM–IV). Washington, DC: APA.
8. Cooper, S. J., Kelly, C. B. & McClelland, R. J., 1995 – Affective disorders: 3.
Electroconvulsive therapy. In Seminars in Clinical Psychopharmacology (ed. D. J.
King), 224–258. London: Gaskell.
9. Johnson, D. A. W., 1981a – Studies of depressive symptoms in schizophrenia: I. The
prevalence of depression and its possible causes; II. A two-year longitudinal study of
symptoms; III. A double-blind trial of orphenadrine against placebo; IV. A double-blind
trial of nortriptyline for depression in chronic schizophrenia. Brit. J. Psychiat., 139, 89–101.
10. Falloon, I., Watt, D. C. & Shepherd, M., 1978 – A comparative controlled trial of
pimozide and fluphenazine decanoate in the continuation therapy of schizophrenia.
Psychological Medicine, 8, 59–70.
11. Glazer, W., Prusoff, B., John, K., et al, 1981 – Depression and social adjustment among
chronic schizophrenic outpatients. Journal of Nervous and Mental Disease, 169, 712–717.
12. Hirsch, S. R., Gaind, R., Rohde, P. D., et al, 1973 – Outpatient maintenance of chronic
schizophrenic patients with long-term fluphenazine: double-blind placebo trial. British
Medical Journal, I, 633–637.
13. Hirsch, S. R., Jolley, A. G., Barnes, T. R. E., et al, 1989 – Dysphoric and depressive
symptoms in chronic schizophrenia. Schizophr. Res., 2, 259–264
14. Siris, S. G., 1990 – Depressive symptoms in the course of schizophrenia. In Depression in
Schizophrenia (ed. L. E. DeLisi), pp. 3–23. Washington, DC: American Psychiatric Press.
15. Siris, S. G., 1994 – Assessment and treatment of depression in schizophrenia.
Psychiatric Annals, 24, 463–467.
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CLINICAL AND THERAPEUTICAL ASPECTS
IN PSYCHIATRIC PATHOLOGY
ASSOCIATED WITH THE HIV INFECTION
Angela Dumitrescu1, D.M. Dumitrescu2, Carmen Dumitrescu3
1
Psychiatry University Hospital “Socola” Iaşi
2
University of Medicine “Gr. T. Popa” Iaşi
3
Infectious Diseases Regional Hospital, Slatina
Abstract
After a short period of time from the identification of the HIV virus,
neurologists described a few neurological syndromes related to the infection,
and the specialists in psychiatry and psychology tried to support these
patients. The medical specialized literature mentions that some psychiatric
disorders appear often in HIV-infected subjects, but the data available
referring to their prevalence are significantly different depending on the
studied population, and on the infection stage.
Identifying the psychiatric disorders in due time and establishing an
appropriate therapeutic plan is important, taking into account their negative
effects on the patient’s health state, implying the modification of the
compliance of the plan to the treatment.
Key words: HIV, HAART, antipsychotics.
ASPECTE CLINICE ŞI DE INTERVENŢIE TERAPEUTICĂ ÎN
PATOLOGIA PSIHIATRICĂ ASOCIATĂ INFECŢIEI HIV
Rezumat
După o perioadă scurtă de timp de la identificarea virusului HIV neurologii
au descris câteva sindroame neurologice legate de infecţie, iar specialiştii în
psihiatrie şi psihologie au încercat să susţină aceşti pacienţi. Literatura
medicală de specialitate menţionează că unele tulburări psihiatrice apar
frecvent la subiecţii infectaţi cu HIV, dar datele disponibile referitoare la
prevalenţa lor sunt considerabil diferite depinzând de populaţia luată în
studiu, de stadiul infecţiei.
Recunoaşterea în timp util a tulburărilor psihiatrice şi stabilirea unei scheme
terapeutice adecvate este importantă ţinând cont de efectele negative pe care
le produc asupra stării de sănătate a pacientului, implicând modificarea
complianţei la tratament a acestuia.
Cuvinte cheie: HIV, HAART, antipsihotice.
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The infection with human immunodeficiency viruses (1 and 2) is a disease specific to
humans characterized by a long stage evolution with original clinical manifestations of acute benign
disease, followed by a long period of apparent health and eventually by the clinical re-expression of
progressive severity with a lethal end.
The disease produces a specific slowly progressing degradation of the mechanisms for
defense against infections, which explains the fact that, under a certain immune deficit threshold,
the patient easily gets opportunist infections, can develop different tumors or disorders of the
central nervous system (with important manifestations in the psychiatric sphere), which leads to the
lethal end [1].
HIV is a virus that infects selectively the immune cells, especially the T lymphocytes and
macrophages, generating the lysis of CD4 lymphocytes, with an essential role in the cell-mediated
immunity. If their number is cut down 200/uL, the immune system is compromised, the cell
immunity decreases and eventually disappears, and thus the vulnerability degree increases for a
varied range of diseases.
The HIV-infected patients’ brain can be affected by a large range of morbid processes, even
in the absence of other AIDS signs or symptoms. It is known that the virus itself has
neuropathological effects and there are data in the literature that confirm the fact that the infection
of the microglia leads to the neuronal lesion because of the neurotoxins. The primary
neurobiological complications are those attributed directly to the virus, and the secondary ones are
those deriving from the diseases and treatments associated with the HIV [16].
After a short period of time from the identification of the HIV virus, neurologists described
a few neurological syndromes related to the infection, and specialists in psychiatry and psychology
tried to support these patients. The medical specialized literature mentions that some psychiatric
disorders often appear in HIV-infected subjects, but the data available referring to their prevalence
are significantly different depending on the studied population, and on the infection stage [7].
The psychiatric pathology associated with the HIV infection includes the following:
1. The delirium that can derive from the same different causes that also produce dementia in
HIV-infected patients. Its prevalence in the HIV-infected population is between 43 and 65%. In
untreated cases the mortality percent is approximately 20% in hospitalized patients [10].
In its etiopathogeny risk factors (old age, multiple medical problems, multiple medication,
previous delirium episodes, dementia associated to HIV) and toxic, infectious, cardiovascular,
traumatic factors etc. are involved. From the clinical point of view the patient may manifest
delirious non-systematized ideation, complex psycho-productive displays, disorganized judgment or
confusion, attention disorders, dysthymias.
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2. Anxious disorders – HIV-infected patients may have certain anxious disorders, but the
most frequent are the disorder through generalized anxiety, post-traumatic stress disorder and the
obsessive-compulsive disorder [9].
3. Adjusting disorder – According to the literature reports the adjusting disorder is present in
5-20% of the HIV-infected people [2].
4. Depressive disorders – The proportion of HIV-infected patients who, according to the
literature reports, fulfill the diagnostic criteria for depressive disorders vary between 4 and 40% [5].
The depression – HIV relation can be looked at in two ways: major depression can be a risk
factor for HIV (by the intensification of the consumption and/or abuse of substance, the
accentuation of the selfdistructive behaviours) and the HIV high risk population has increased
depression rates (homosexuals and drug addicts suffer from a major depression more frequently).
The usual symptoms are the decrease in the energy and the loss of interest, hypobulia,
anhedonia, a sense of guilt and self-depreciation, to which neurovegetative and somatic phenomena
are associated, such as: lack of appetite, morning insomnias, pains, dental-psychic discomfort.
5. Suicide – The suicidal ideation and the suicide attempts are high in HIV-infected people or
people with AIDS. They represent a true problem for HIV-infected patients, and the people most
exposed to this type of risk are the HIV-infected during the first two years from the infection; the suicide
rate decreased lately, most likely due to the new and efficient treatment methods (HAART) [8].
The suicide risk factors are the following: the decease of friends of AIDS-related causes; the recent
acknowledgment of the HIV infection; difficult social problems related to homosexuality; inappropriate
social and financial support and the presence of dementia and delirium and substance consumption.
6. Bipolar affective disorder – The HIV-infected patients are exposed to a high risk
regarding this disorder because of the two display forms: the depressive episode and the maniacal
one. In the event of a maniacal episode, the risk is greater due to the decrease in the
consumption/abuse of substances, and of the impulsive behaviour.
Unlike the bipolar disorder, there is a mania form that seems to be specifically associated to
the HIV infection – tardy stage; it is called AIDS mania and it is characterized by – besides the
maniacal symptoms – the cognitive affection and by the lack of previous affective episodes or
positive family antecedents. The irritability is a stronger characteristic than euphoria from the
affective point of view and the psychic-motor slow-down often accompanies the cognitive
retardation, replacing the activity specific to the mania.
The specialized literature certifies the fact that the AIDS mania has usually quite a severe
presentation and is malign from the evolution point of view. Hence there are HIV-infected patients
with a pre-existent bipolar disorder and individuals with a secondary mania; whichever the
classification of the maniacal syndromes, they appear certainly more frequent in HIV-infected
people than in the general population.
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7. Dementia – In the early stages there are slight cognitive disorders as well as in HIV-free
people, in which cases the dementia may be preceded by the slight cognitive disorder.
The symptomatology is minimum, thus the disorder is often identified starting from a minor
complaint from the patient, such as the motor or cognitive slow-down.
The deeper disorders include severe hypomnesia, severe spontaneous and volunteer
hypoprosexia marked by bradypsychia and dyslexia, abulia. The apathy is frequent and it appears in
early stages and contributes to the patients’ social withdrawal. Sometimes the depressive syndrome
is emphasized by irritability and anhedonia, the psychotic symptoms constituted from psychoproductive, the delirious paranoide ideas and the maniacal syndrome. The mixed hypnic disorders
are present in most sick people, as well as the weight loss.
The neuropsychological test reveals major deficits; even the Mini-Mental State Examination
results are slightly abnormal. Dementia can progress until severe apathy, confusion and total disability.
The cerebral imaging can reveal cerebral atrophy and hypertransparent areas in the white
substance as a result of the CT, as well as abnormal intense signal areas as a result of the RMN,
besides the metabolic abnormalities as a result of the PET. EEG shows slow routes. The LCR
examination reveals high levels of B2-microglobuline and increased levels of neopterin and
quinolinic acid. The size of the viral charge in LCR is related to the severity of the dementia.
The necropsy of the sick people with HIV dementia market out modifications characteristic
to the level of the white substance, demyelinization, microglial nodules, gigantic cells with multiple
nuclei, perivascular infiltrates, all these in the absence of the virus inside the neurons; there are
observations that led to the theory of neuronal losses under the action of macrophages, the
activation of cytokines and other specific modifications. Important decreases in the number of
neurons were revealed especially among neurons in the frontal and temporal lobes [11].
The appearance of dementia has unfavourable forecast significance, as 50-75% of the sick
people decease within six months. The dementia incidence decreased significantly once the
HAART therapy (Highly Active Anti-Retroviral Therapy) began to be used – up to 50% [14].
The diseases that occasionally cause dementia in AIDS people include cerebral
toxoplasmosis, cryptococcic meningitis and the primary cerebral lymphoma.
8. Personality disorders – The personality disorders are frequent both in HIV-infected
persons and in people exposed to a high risk of getting infected in comparison to the general
population. The antisocial personality disorder is associated with the highest risk and because of the
consumption or addiction to drugs that are preferentially administrated parenterally and because of
a large number of sexual partners and unprotected sex.
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Medical literature reveals that among 60-65% of the personality disorders, the psychopathy
is most often associated with the drug consumption [3]. There is an obvious positive intension
between these two disorders: drug addiction appears often on the background of a psychopathic or
antisocial personality, and the trajectory of a drug addict leads him/her rapidly to delinquency in
order to finance his/her needs.
The characteristic personality traits of the patient with AIDS are extroversion and instability,
which are associated with non-conformity to treatment; in fact these same traits are risk factors for
the HIV infection.
9. The substance abuse – Drug addiction is a much more complex process that has to be
understood as a triple concurrence between a certain product, a personality and a specific socialcultural context. Thus the first factor includes the availability of the drug, the acceptance or
rejection by a group of the drug consumption; the second refers to the euphorising pharmacologic
effects of the substance, and the last is represented by the psychological structure, the individual’s
personality, “which explains why some consumers become addicts and others do not”.
Though it is improper to say that there is a certain type of personality for addicts, the
psychic structure of individuals with addictive behaviours include the following constants: affective
dependence, separation anguish, isolation, anxiety in the relationships with the others, intolerance to
frustration, need for affection, approval and valorization, immediate fulfilling of personal wishes,
lack of self-confidence and passivity, stubbornness and irritability, shyness and hypersensitivity,
lack of ambitions and competitiveness [12].
Emotional flattening of the sick persons could generate a sort of indifference to the HIV
infection risk. The introverted personalities are less common (approximately 14%), are more
frequently instable and are characterized by anxiety, pessimism, sadness; they have a preventive
and protective behaviour, avoiding the negative consequences of the present.
10. Psychotic disorders – The primary psychotic disorders appear independently of the HIV
infection; in comorbid circumstances, they can be represented by schizophrenia, schizophreniform
disorders, short psychotic disorders.
The secondary psychotic disorders are generated in patients with AIDS by infections with
opportunistic germs, by cerebral lymphomas, HIV encephalopathy, medicamentary interactions.
Symptomatologically speaking, the deliriums and psycho-productive manifestations have
the following characteristics: the delirious topics include grandour-related, religious, persecutionrelated and somatic delirious ideation, and the disorders of the perception sphere include aural,
visual, olfactory, gustatory or tactile hallucinations. The disease implies the affection of the
subcortical or temporal structures. The LCR and MRI examinations will be carried out in all cases
of HIV infection with acute psychiatric syndromes.
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Schizophrenia is not caused by the HIV infection (at least there are no data in this regard),
but it is responsible for the appearance of some behaviours that may lead to the HIV infection [13]
(disorders of the control over impulses, sexual behaviour, positive symptoms of schizophrenia).
11. The worried healthy individual (worried welf) – This category includes the persons of high
risk groups who, though seronegative and not sick, are anxious or develop an obsession related to
the infection with the virus. The symptoms can include generalized anxiety, panic attacks,
obsessive-compulsive disorder and hypochondriasis. The repeated negative results to the serologic
test can reassure some sick people. The people who cannot be reassured are recommended the
supportive therapy.
The therapeutic interventions in the psychiatric pathology associated with the HIV infection
include several stages:
A. Prevention
All persons with high risk of HIV infection must be informed regarding the safety sex
practices and the necessity to avoid the usage, together with other people, of those contaminated
hypodermics. The preventive strategies are complicated by the complex preconceived values and
ideas around the sexual acts, sexual orientations, the birth control and drugs abuse.
B. Pharmacotherapy
1. The antiretroviral therapy – It aims to completely suppress the virus, because the viral
charge governs the rate of CD4 cell decrease. The combined therapy with agents that act in different
points of viral transcription has become a standard in the field.
The two classes of used agents inhibit the reverse transcriptase of nucleosidic type
(Zidovudine, Didanosine, Stavudine, Abacavir) and of non-nucleosidic type (Nevirapine) and
inhibit the proteases (Saquinavir, Ritonavir, Indinavir, Nelfinavir, Aprenavir).
The treatment is recommended when the plasmatic levels of the HIV ribonucleic acid are
higher than 5000 to 10000 of copies per mL, regardless of the CD cell number.
For efficiency and for preventing the resistance’s occurrence it is necessary to strictly comply
with complex therapeutic regimes [17]. The indications for changing the treatment include the toxicity
increase of the viral charge, the non-compliance with the treatment and the intolerance to the
medicaments. The antiretroviral agents must be used in relation to the drugs that prevent or treat the
complications associated with HIV that are being produced by the different opportunist infections.
2. The therapy with medicaments – The approach protocol of psychiatric pathology associated
with HIV doesn’t significantly differ from the one used for persons not infected with HIV.
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In the cases of advanced AIDS disease there are necessary smaller doses of medicaments
(initial doses between a half and a quarter from the usual initial doses) due to the higher sensitivity
towards the side effects; these doses will be gradually and slowly increased. The hepatic or renal
dysfunctions can alter the metabolism and can eliminate the drug.
In case of delirium associated to a psycho-motor agitation the butyrophenones is the
recommended one from the D2 dopaminic receptors’ antagonists and from the antagonists of the
serotoninic-dopaminic receptor it is usually preferred the tienobenzodiazepines and benzoxazole.
One should take into consideration the increase of the risk of anticholinergic delirium, the
apparition of convulsions and of extra pyramidal side effects at this population.
The patients with neurocognitive syndromes can benefit from psycho analeptic medicaments
(no analeptics used as stimulants of vigilance or psycho energizers, the timo analeptics – as
disposition’s stimulants) (for example: 2.5 mg methylphenidate twice a day with a slow increase till
20 mg/day) [10].
If it is registered a neuro-cognitive deterioration associated with HIV, the complex
antiretroviral therapy has demonstrated the fact that it is possible to obtain a significant amelioration
at the neuropsychological testing with the recuperation of the signal’s abnormal functionalities, a
signal that comes from the white substance to the RMN (imagery through magnetic resonance); the
amelioration can be observed in two – three months from the beginning of the treatment.
The specialty literature mentions the fact that one can use the mono-therapy with zidovudine
in large doses (due to the good capacity to pass over the hematoencephalic barrier). The inhibitors
of the proteases successfully prevent or stop the progression of the neuro-cognitive connected with
HIV under the conditions of its association with zidovudine [2]. Among the nucleosidic and nonnucleosidic inhibitors, the stavudine and nevirapine reach reasonable concentrations in the central
nervous system, efficiently stopping the psycho-cognitive deterioration.
In case of depressive disorders one usually administrates the selective inhibitors of
serotonin’s recaptures (SSRI): sertraline, paroxetine, fluoxetine, tianeptine, fluvoxamine, citalopram
or the tricycle antidepressant (nortriptyline, protriptyline, clomipramine, desipramine, imipramine)
that need the gradual increase of the doses. The side effects include anticholinergic effect aside
from the delay potential of cardiac conduction and the potential of orthostatic hypotension. For
establishing the optimal dosage and the efficiency of the therapeutic trial it is useful to determine
the sanguine levels.
The dezipramine, the antidepressant with the smallest anticholergetic activity possible is
preferred for treating the depression connected to HIV infection. For the major depression and for
fatigability – anergy, the injections with maximum 400 mg testosterone every two weeks, for eight
weeks can be very efficient [12].
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If no satisfactory therapeutic answer under the antidepressants’ action is obtained, one can
administrate psycho-stimulants.
The anxious disturbances associated with HIV infection is generally treated with
benzodiazepine in a relative small or medium plasmatic concentration (nitrazepam, lorasepam,
clorazepate, dipotasic) or with buspirone. The non-psychotic anxiety is electively treated with
benzodiazepine [7]. The oxazepam and other drugs with relatively short elimination are preferred in
case of the patients with hepatic affectation.
The treatment of the delusion in the precocious HIV stages doesn’t significantly differ from
the treatment of bipolar delusion: timostabilizers (lithium, antiepileptic drug – valproic acid,
carbamazepine, lamotrigine) and antipsychotic drugs from the second generation (olazapine,
risperidone, quetiapine, clozapine).
For this population it was established that the antiepileptic drugs are better tolerated in
comparison to the lithium. The secondary dissolution of zidovudine was successfully treated with
lithium in order to allow the continuation of zidovudine [10].
The treatment of HIV dementia consists mainly of antiviral medicaments (retrovir, zidovudine),
that proved themselves to ameliorate the state of the cognition. The patients that begin the treatment
with HAART suffer, along from a clinical amelioration, also from a retraction of the abnormalities
highlighted by the MRI (Magnetic Resonance Imaging) being deep in the white substance; after 9
months of treatment one can also see a normalization of the cerebral metabolites [16]. Along with the
antiviral therapy it must be also treated the depression, apathy (if this is not ameliorated as a result of the
depression treatment, it can be prescribed the methylphenidate or other stimulants).
The agitation associated with the dementia can be treated with small doses of antipsychotic
drugs of high potency (haloperidol) or with atypical antipsychotic drugs (risperidone, olanzapine).
The psychotic episodes at a HIV infected immuno-depressed patient can be coupled with
classical antipsychotic drugs from the first generation or with new atypical antipsychotic drugs; the
used doses are adapted according to the severity of the manifestations [18].
The treatment of schizophrenia doesn’t differ from the one that is not associated with
somatic diseases.
The interactions of the psychotropic and antiretroviral medicaments
Due to combination of the treatments for patients suffering from AIDS, it must be carefully
taken into consideration the interactions of the medicaments, among which the potentate effect of
the analgesics that contain opium and of the psychoactive medicaments are the most notorious.
The proteases inhibitors are metabolized first of all by the P450 3A isoenzyme (CYP 3A) of
the cytochrome and secondly by the 2D6 system. These metabolic tracts are followed also by more
psychotropic medicaments.
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All the inhibitors of the proteases increase the concentrations of the psychotropic
medicaments when the major tract of their metabolization is the CYP 3A system. [12]. If the major
tract of metabolization of psychoactive drugs is 2D6, as in the case of SSRI and of tricycle AD, the
ritonavir will inhibit specifically the metabolism of these medicaments.
The inhibitors of the proteases specifically inhibit the metabolism of the antidepressants,
antipsychotic drugs and of the benzodiazepines. They can increase the concentrations of
alprazolam, midazolam, triazolam and zolpidem, and so it can be possible to reduce the doses for
preventing the oversedation. It was reported the fact that the inhibitors of the proteases increase the
levels of the bupropion and fluoxetine, reaching toxic levels and increase the levels of the
desipramine from 100% to 150%. [10] The zidovudine increases the plasmatic concentrations of the
antipsychotic drugs. It can also increase the levels of the methadone.
The carbamazepine and phenobarbital reduce the plasmatic concentrations of the proteases’
inhibitors. It was established the fact that the nefazodone and fluoxetine diminish the metabolism of
the proteases’ inhibitors but increase the side effects of the proteases’ inhibitors.
C. The psychotherapy
The persons infected with HIV present the same basic necessities as any other individuals.
From the point of view of the neuro-psychiatrical assistance, these needs can be synthesized in the
following way: establishing a safe environment, ensuring movement and mobilization, the possibility
of expression and communication, maintaining the work and game, ensuring the rest and sleep,
maintaining of psychic equilibrium and not lastly the necessities connected to the moment of death.
The persons involved in attending the sick people must permanently take into consideration
these necessities according to which they must identify the actual problems and to anticipate the
potential ones.
The individual and group therapy are important for helping the patients to overcome the
problems connected to the sense of guilt and self depreciation and to the possible death [14]. Many
HIV infected individuals consider themselves to be punished for their deviant life style. One should
explore the difficult health decisions that a patient must make (for example if he is to participate or
not to an experimental drug trial or problems connected to the assistance of the terminal state and to
the usage or non-usage of external systems for vital support).
The infected persons must be informed in respect to the safe sexual practices. It is often
justified the implication of the husband / wife or of another sexual partner of the patient. The
treatment of the HIV infected persons often implies helping them to better approach their families
and to face the possible rejection problems, the culpability and anger. The practical themes imply
the service, the rights regarding the medical insurance, life insurance, the plans of a carrier, as well
as the relationships with the family and friends.
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Along the psychotherapy and the treatment specific to the psychiatric affections connected
to the disease, there are also special psycho-educational and psycho-therapeutic interventions. The
majority of measures aims to increase the treatment adherence and among these one should mention
the formation of a support psychosocial network, the access to resources, the control of the
behaviour as well as the cognitive and behavioural psychotherapy, the structured psychoeducational psychotherapy, the supportive psychotherapy, the group psychotherapy.
References
1. Broun J, A. Daermonn, 2004 – Ghid clinic de medicină internă. Ed. Medicală, Bucureşti
& Urban - Fischer, München.
2. Chiotan M., 2003 – Boli infecţioase. Ed. Naţional, Bucureşti.
3. Chiriţă R., Chiriţă V., Papari A., 2002 – Manual de psihiatrie şi Psihologie medicală.
Edit. Fundaţiei „Andrei Şaguna”, Constanţa.
4. Feldman
R.S.
Mezer
J.S.,
Quenzer
L.F.,
1997
–
Principles
of
Neuropsychopharmacology. vol. 1-2, Sinaneur Associates, Inc. Publishers Sunderland,
USA.
5. Gheorghe, M.D., 2002 – Semiologie şi sindromologie psihiatrice. Ed. Universitară
„Carol Davila”.
6. Hăulică I., Dobrescu Gioconda, 1999 – Transmiterea sinaptică - repere structurale şi
funcţionale. Ed. Academiei Române, Bucureşti.
7. Holdevici, Irina, 2002 – Psihoterapia anxietăţii - abordări cognitiv-comportamentale.
Editura Dual Tech, Bucureşti.
8. Hope R.A., Longmore G.M., Hodgetts T.S, Romrakha P.S., 1995 – Manual de medicinã
clinică. Ed. Medicală, Bucureşti, Oxford University Press.
9. Kaplan H.J. & Sadock B.J., 2001 – Manual de Buzunar de Psihiatrie Clinică. Edit.
Medicală, Ediţia a treia.
10. Kaplan H.J. & Sadock B.J., 2002 – Terapie Medicamentoasă în Psihiatrie. Edit.
Medicală Callisto.
11. Marinescu, D., Udriştoiu, T., Chiriţă, V., 2001 – Ghid terapeutic – schizofrenia. Ed.
Med. Universitaria, Craiova.
12. Mendell, Bennett, Dollin (edit)., 2005 – Principles and Practice of Infectiona Diseases,
Churchill-Livingstone, NY, Phil, ed. VI.
13. Millon, T, Davis, R., 2005 – Personality disorders in modern life. Wiley, New-York.
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14. Pont, H.B., 1995 – Maladjustement and socio-cognitive problem solving: The validity
of quantitative and qualitative assessment. British Journal of Clinical Psychology, 34,
53-65.
15. Prelipceanu D. , Mihăescu R., Teodorescu R., 2000 – Tratat de Sănătate Mintală.
Volumul 1, Edit. Enciclopedică, Bucureşti.
16. Rang H.P., Dale M.M., Ritler J.M., 2001 – Pharmacology. 4th ed., Churchill
Livingstone Edinburg.
17. Root R.K. (edit), 1999 – Clinical Infectious diseases - A practical aproach. Oxford
University Press, NY.
18. 18.Udriştoiu, T., Marinescu, D., Gheorghe, M. D., 2000 – Terapia psihofarmacologică.
Actualităţi, Ed. Scorilo, Craiova.
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NEUROBIOLOGICAL IMPLICATIONS IN
COGNITIVE IMPAIRMENT.
PARALLEL STUDY DEPRESSION-DEMENTIA
Emanuela Alina Stoica Spahiu, Elena Albu
Spitalul Clinic de Neuropsihiatrie Craiova
Abstract
It was used the dexametazone suppression test to prove that a large number
of depressive patients, which follows no treatment, exhibit failure to suppress
secretion of cortisol following administration of dexamethasone, discovery
known as dexametazone non-supression (DST-NS). It suggests the fact that
DST-NS is a biological marker for depression (Caroll, 1982).
The increased cortisol levels which are present for long periods of time are
producing hippocampus dysfunctions. The main effect is the hippocampus
volume decreasing – fact that was presented in neuro-imagistic studies
(Sapolsky, 2000).
It was presented that the hipercortisolemia, hypothalamic-pituitary-adrenal
axis alterations and reduced hippocampal volumes are usually present in
major depression (Lucassen et al., 2001).
It is present the cognitive impairment because the correct functioning of the
cognitive circuits is controlled by hippocampus. The hippocampus interacts
with the neocortex (frontal lobe – with an important role in cognitive process)
and it is stimulated by the following path: dorsal medial nucleus of the
thalamus – septal nuclei – hypothalamus – amygdala. It can also provide
excitatory inputs to the subcortical structures and in indirectly to the
neocortex via the entorhinal cortex and dorsal medial nucleus.
The main neuromediator involved in cognitive circuit neurotransmission is
acetylcholine. It helps adjusting the operating modes in hippocampus and
cortex. The acetylcholine depletion, which was induced by high level of
cortisol, is an important factor for cerebral atrophy (Lupien, 1999).
Cognitive impairment is also present in patients with dementia, especially the
old ones.
The present study reviews the history of searches considering neurobiological
changes leading to cognitive impairment in depression, comparing with
dementia.
Key words: depression, cognitive impairment, neurobiological changes.
IMPLICAŢII NEUROBIOLOGICE ÎN DEFICITUL COGNITIV.
STUDIU PARALEL DEPRESIE-DEMENŢĂ
Rezumat
Utilizând testul de supresie la dexametazonă, s-a demonstrat că un număr
mare de pacienţi cu depresie, care nu urmează nici un tratament, nu prezintă
supresia secreţiei de cortizol, descoperire cunoscută sub numele de
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nonsupresie la dexametazonă (DST-NS), sugerând faptul ca DST-NS ar fi un
marker biologic pentru depresie (Caroll, 1982).
Niveluri crescute de cortizol prezente timp îndelungat produc disfuncţii ale
hipocampului, cu scăderea în volum a acestuia, fapt evidenţiat prin studii de
neuroimagistică (Sapolsky, 2000).
A fost constatat faptul că hipercortizolemia, alterarea funcţionării axei
hipotalamo-hipofizo-adrenergică şi reducerea volumului hipocampal sunt în
mod obişnuit observate în depresia majoră (Lucassen et al., 2001).
Apare deteriorarea cognitivă, funcţionarea corectă a circuitelor cognitive
fiind controlată de hipocamp. Hipocampul interacţionează cu neocortexul
(lobul frontal – cu rol important în procesele cognitive), fiind stimulat pe
calea: nucleu medial dorsal al talamusului – nucleul septal – hipotalamus –
amigdală şi de asemenea poate trimite aferenţe excitatorii către structurile
subcorticale şi indirect către neocortex prin intermediul cortexului entorinal
şi a nucleului medial dorsal.
Principalul neuromediator implicat în realizarea neurotransmisiei în cadrul
circuitelor cognitive este acetilcolina, luând parte la reglarea modurilor de
operare în hipocamp şi cortex. S-a constatat că depleţia de acetilcolină –
indusă probabil de nivele crescute ale cortizolului – contribuie la atrofia
cerebrală (Lupien, 1999).
Deteriorarea cognitivă apare şi la pacienţi cu demenţă, în special la
vârstnici.
Lucrarea de faţă este un review al cercetărilor efectuate de-a lungul timpului
asupra modificărilor neurobiologice care duc la deteriorare cognitivă în
depresie, luând ca punct de comparaţie modificările ce au loc în demenţe.
Cuvinte cheie: depresie, deteriorare cognitivă, modificări neurobiologice.
Hipercortisolemia
Increased cortisol levels and hypothalamic-pituitary-adrenal axis alterations are frequently
found in major depression.
One of the first endocrine tests used for hypothalamic-pituitary-adrenal axis evaluation in
psychiatric disorders was the dexamethasone suppression test, initially conceived for Cushing
syndrome diagnosis. Small doses of dexamethasone, a synthetic glucocorticoid, are orally
administered at 23:00 hours, and plasma cortisol concentrations are measured at 2 or 3 time points
on the following day. Dexamethasone reduces the secretion of adrenocorticotropic hormone
(ACTH), acting at the level of the anterior pituitary corticotrophs. Result a decrease in the synthesis
and release of cortisol from the adrenal cortex. Failure to suppress plasma cortisol concentrations
after dexamethasone administration suggests impaired feedback regulation and hyperactivity of the
HPA axis (Gillespie, 2005).
It was demonstrated the fact that a large number of depressed patients, which follows no
treatment, exhibit failure to suppress secretion of cortisol following administration of
dexamethasone, discovery known as dexametazone non-supression (DST-NS). It suggests the fact
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that DST-NS is a biological marker for depression (Caroll, 1982). Most studies have found greater
cognitive impairment in patients with DST non-suppression than patients with suppression (Brown,
1999; Wauthy et al. 1991).
At present, there are two hypothesis refering to the hypothalamic-pituitary-adrenal axis
hyperactivity in depression:

high central levels of corticotropin-releasing hormone (CRH) due to hypothalamicpituitary-adrenal axis hiperactivity (Nemeroff, 1996);

negative feedback changes of pituitary CRH and central glucocorticoids receptors
(Young, 1991).

Based on this hypothesis it can be proved that the hypothalamic-pituitary-adrenal axis
regulation can be consider as possible treatment in depression (Dinan, 1996). This fact
implies searching for new sites where the new antidepressants (glucocorticoids
antagonists, cortisol sinthesis inhibitors, CRH antagonists, vasopressin) can act on. Have
been achieved important progress in studies regarding glucocorticoids and their receptors.
It was identified at cerebral level two glucocorticoids receptors types:

mineralcorticoid receptors (MR) – I type, located in hippocampus, responsible for
hypothalamic-pituitary-adrenal axis basic control;

glucocorticoid receptors (GR) sau II type, located in adenohypophysis, controling
hypothalamic-pituitary-adrenal axis feedback mechanisms (Gheorghe, 2003).
Hippocampus volume reduction
Studies have shown that a chronic stress and a persistent hypercortisolemia induce a
reduction in hippocampal volumes. This change was presented in neuro-imagistic studies in
depressed patients (Bremner, 2000; Sapolsky, 2000).
Hippocampus suffers a reorganisation and reshaping process, in particular in C3 area, beein
influenced by stress, glucocorticoids, stimulating aminoacids and NMDA receptors (Fig. nr. 1).
Magnetic resonance imaging was used in order to evaluate hippocampus volumes in
depressed patients in remission and in nondepressed comparison subjects. It was observed an
important decrease of the hippocampus volume without any volume changes for other cerebral
regions (tensile, caudate nucleus, frontal lobe, temporal lobe) (Bremner, 2000).
It was analyzed the hippocampal tissue in animals and humans in order to study the
glucocorticoids effect. There was no important cell loss, but rare and obvious. This proves that neuronal
apoptosis is involved in hippocampus changes generated by the glucocorticoids (Lucassen, 2001).
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Fig.nr. 1
Cognitive impairment and hypercortisolemia
The patients with a prolonged exposure to a glucocorticoid excess (as Cushing syndrome
patients) were evaluated for the cognitive functions.
The patients were divided in two groups: before surgical treatment (Cushing) and after
surgical treatment (post-Cushing). They were evaluated for etiology using clinical and biochemical
criteria. Cognitive functions were evaluated using psychometric tests: Rey Auditory Verbal
Learning test, BCR2 battery to evaluate the general intellectual potential and the Prague test for
divided attention and resistance to psychic fatigue. For both groups were obtained the following
results: an altered pattern of incremental learning and very low total scores for intellectual potential.
The post-Cushing group score were significantly better than the Cushing group for only one
nonverbal test (complex perceptual analysis). It looks that there is no important effect of excessive
cortisol exposure on distributive attention. There is an alteration in the resistance to psychic fatigue.
For both groups was a positive correlation between the daily average cortisol exposure and the
number of errors in learning. A negative correlation existed between the duration of illness and: the total
learning score for post-Cushing group, and the general performance and verbal scores for Cushing.
The results suggest a complex alteration of the cognitive functions, for both groups, and
possible residual cognitive impairment, indicated by the presence of some changes after correction
of hypercortisolemia in post-Cushing group (Dobrescu Ruxandra, 2006).
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Cerebral changes
There have been observed both cerebral structural changes and deficiency in sanguine flux
and glucose metabolism in depressed patients. The metabolism decrease in the frontal lobe was
associated with cognitive changes.
Hippocampus is involved in the control of the cognitive circuits. It has close connections
with the amygdala – a relay between thalamus and cortex (Udriştoiu, 2001).
The cerebral structural and functional changes in major depression
The hippocampus interacts with the neocortex (frontal lobe – with an important role in the
cognitive process) is regard to arousal via dorsal medial nucleus of the thalamus – septal nuclei –
hypothalamus – amygdala. It can also provide excitatory input to the subcortical structures and
indirectly the neocortex via the entorhinal cortex and dorsal medial nucleus (Fig. nr. 2).
Fig. nr. 2
Acetylcholine
The acetylcholine is the main neuromediator involved in the cognitive circuits. This fact was
relieved by the fact that the forebrain base complex destruction and the administration of
cholinergic antagonistic generate profound deficits in a variety of forms of cognition, including
learning and memory. The lesions of the cholinergic subnuclei within basal forebrain (in particular
medial septum / diagonal band) generated impaired performances in learning, memory and attention
(Picciotto, 2002) – Fig. nr. 3.
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Fig. nr. 3. Anatomy of major cholinergic pathways in the brain. The principal source of cholinergic input to
the cortex and hippocampus is the basal forebrain complex whereas the pedunculopontine and laterodorsal
tegmental areas innervate brain stem and midbrain targets preferentially. Cholinergic interneurons are found
in the olfactory tubercle, striatum, nucleus accumbens, and islands of Calleja. BFC, basal forebrain complex;
VTA, ventral tegmental area; IPN, interpeduncular nucleus; PPT, pedunculopontine tegmental nucleus; LTD,
laterodorsal tegmental nucleus.(Picciotto, 2002)
It was observed that the increased levels of cortisol generate a decrease of acetylcholine to
the cerebral level. The acetylcholine depletion is one of the factors that generate cerebral atrophy in
Alzheimer disease (Lupien, 1999).
Dementia and hipercortisolemia
A study made by Csernansky (2006) analyzed the cortisol levels in the blood from the
patients having Alzheimer dementia. There were used two groups of patients: one was having
Alzheimer dementia, and the other – nondemented comparison subjects. The groups were analyzed
for 4 years, using the Clinical Dementia Rating (C.D.R.) and a set of neuropsychological tests. The
patients in Alzheimer group had higher plasma cortisol levels, compared with the patients from the
other group. The conclusion was that an increased level of cortisol is associated with more rapid
disease progression and evolution of the cognitive impairment (Csernansky J et al. 2006).
The cognitive deficits profiles for depression and incipient dementia are very similar. The
clinic and psychometric distinction between these two diseases is considered to be one of the most
difficult. One of the possible explanations for the existence and evolution of the cognitive
dysfunction is that at least a part of these patients could be in the early stages of Alzheimer disease.
Alzheimer dementia can have sometimes a long preclinic phase, and depressed patients,
especially the old ones have an increased risk to develop this kind of illness (Nebes et al, 2001).
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Conclusions

Cognitive impairment is present both in depression and dementia, but more emphasized
in dementia.

The exposure to a high level of cortisol for a long period of time generates cognitive
impairment both in depression and dementia. The conclusion is the hypercortisolemia is
a risk factor for cognitive impairment.

The cortisol level is correlated with the degree of cognitive impairment.

The presence of depression does not imply cognitive impairment, but the untreated
depression for a long period of time might generate cognitive impairment.

It is important to know the mechanisms involved in cognitive impairment for patients
with depression. This way it can be searched new methods to treat depression that will
stop the cognitive impairment to these patients.
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On the Cover:
ION ŢUCULESCU (1910-1962)
Mască africană
African Mask

romanian journal of psychopharmacology

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