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| March 2001, Volume 6, Number 2, Pages 134-142 |
| Table of contents Previous Article Next [PDF] |
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| Mechanisms of Drug Action |
| Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly |
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| S Govoni1, M Racchi1, E Masoero1, M Zamboni2 and L Ferini-Strambi2 |
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1Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy
2Department of Neurology, Institute San Raffaele, Milano, Italy
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| Correspondence to: S Govoni, Department of Pharmacology, Viale Taramelli 14, 27100 Pavia, Italy. E-mail: govonis@unipv.it
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| Abstract |
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Depression
is the most prevalent functional psychiatric disorder in late life.
The
problem of motor disorders associated with antidepressant use is
relevant in the elderly. Elderly people are physically more frail and
more likely to be suffering from physical illness, and any drug given
may exacerbate pre-existing diseases, or interact with other drug
treatments being administered for physical conditions.
Antidepressants
have been reported to induce extrapyramidal symptoms, including
parkinsonism. These observations prompted us to review the
neurobiological mechanism that may be involved in this complex interplay
including neurotransmitters and neuronal circuits involved in movement
and emotion control and their changes related to aging and disease. The
study of the correlations between motor and mood disorders and their
putative biochemical bases, as presented in this review, provide a
rationale either to understand or to foresee motor side effects for
psychotropic drugs, in particular antidepressants. Molecular Psychiatry (2001) 6, 134-142. |
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| Keywords |
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| elderly; depression; movement disorders; Parkinson's disease; antidepressant drugs; extrapyramidal symptoms |
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Introduction
Several neuropsychiatric diseases have a characteristic late onset
pattern and therefore predominantly affect the elderly. Moreover, aging
may be a risk factor for the development of neurological and psychiatric
diseases such as motor disorders (in particular Parkinson's disease),
affective disorders (depression) and dementia (Alzheimer's disease or
vascular dementia) due to age-related changes in neurotransmission. A
correlation between these disease states may exist as suggested by a
significant degree of co-morbidity.
Notably, depression in the elderly is an increasingly prevalent
problem. All types of depression may be encountered in the population
over 60 years: major depression, dysthymic disorder, bipolar depression,
and adjustment disorder with depressed mood. The differential diagnosis
of depression in the elderly is also more complicated than for younger
individuals because of the greater likelihood of concomitant medical
problems.1,2
Depression may complicate chronic disorders such as hypertension and
diabetes, as well as be caused by the specific treatment of several
medical disorders. There are also problems concerning drug treatment of
depression in older patients. In the elderly pharmacokinetic changes may
delay drug clearance and increase the risk of drug accumulation,
elderly people are physically more frail and more likely to be suffering
from physical illness, and any drug given may exacerbate pre-existing
diseases, or interact with other treatments being administered for these
conditions.
Treatment studies in old depressed patients have tended
to focus on response rate in terms of specific symptoms or rating scale
scores, but there is a difference between 'efficacy' within the specific
context of a clinical trial and 'effectiveness' in clinical practice.
Another, at least partially, neglected area is the impact of drug side
effects in terms of increased physical morbidity. Some antidepressants
have been reported to induce extrapyramidal symptoms, including
parkinsonism.3 This is an important point because depression often accompanies and contributes to the morbidity of Parkinson's disease (PD).4,5
The observations outlined above prompted us to review the
neurobiological mechanisms that may be involved in this complex
interplay. Specifically, with the support of a vast literature both
clinical and preclinical taken into consideration, we aimed to address
the neurotransmitters and neuronal circuits involved in movement and
emotion control and their possibilities of interaction related to aging
and disease (Figure 1).
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Notes on the neurobiological bases of movement control
Movement disorders, often worsened by cognitive and/or behavioural deficits, include different syndromes correlated to damage and/or
loss of the correct neurotransmitter balance in specific areas of the
central nervous system. The basal ganglia play an important role in this
context due to their dopaminergic innervation which is particularly
sensitive to the aging process,6 and their involvement in both motor (nigro-striatal) and emotional (mesolimbic) control.7
The two major motor syndromes based on basal ganglia dysfunction are:
(1) akinetic-rigid forms, defined as parkinsonian syndromes,
Parkinson's disease being the most frequent and important; and (2)
dyskinesia syndromes represented by dystonia, tremors and myoclonus.
In the brain of patients affected by PD a decrease of dopamine levels
in the basal ganglia is observed. The basal ganglia represent a
modulatory circuitry that regulates the flow of information from the
cerebral cortex to the motor neurons of the spinal cord (Figure 2).
The basal ganglia include the striatum, the globus pallidus (GP),
substantia nigra (SN), subthalamic nucleus (STN) and thalamus. The
caudate and putamen are contiguous and together form the striatum. The
input to the extrapyramidal system from many areas of the cortex is
excitatory and mediated by glutamate, whereas neurons in the substantia
nigra pars compacta (SNpc) provide major dopaminergic input to the
striatum with both excitatory and inhibitory action. The interaction
between the afferent and efferent pathways is modulated by striatal
interneurons, an important subgroup of interconnecting neurons located
within the striatum. Striatal interneurons use acetylcholine as the main
neurotransmitter but several others may co-exist, notably neuropeptides
(reviewed in Lang et al).8
The two output pathways from the striatum include distinct direct and
indirect routes. The direct pathway comprises striatal neurons
projecting to the output nuclei of the basal ganglia (substantia nigra
pars reticulata, SNpr, and medial globus pallidus, MGP). From these
areas connections originate to the ventroanterior and ventrolateral
thalamus which provides excitatory input to the cortex.
Gamma-aminobutyric acid (GABA) is the inhibitory neurotransmitter of
this pathway, ultimately responsible for the increase of the excitatory
outflow from the thalamus to the cortex due to the presence of a
GABA-ergic inhibition of a GABA-ergic inhibitory interneuron. In the
indirect pathway, the striatum connects with neurons in the lateral
globus pallidus (LGP) using GABA; in turn, LGP projects to the
subthalamic nucleus which provides excitatory input to the MGP and SNpr
using glutamate. The final effect of the stimulation of the indirect
pathway at the level of striatum is the reduction of the excitatory
outflow from the thalamus to the cerebral cortex. The substantia nigra
pars compacta provides dopaminergic innervation to all parts of the
striatum from which both the direct and the indirect pathways originate.
The direct pathway is modulated by excitatory D1 dopamine receptors
while the indirect one is modulated by inhibitory D2 dopamine receptors.
Dopamine, released in the striatum, exerts differential effects on
these two distinct pathways, respectively increasing the activity of the
direct pathway and decreasing the activity of the indirect pathway.
The loss of dopaminergic neurons observed in Parkinson's disease
results in opposite effects. The direct pathway to the SNpr and MGP is
less active while there is overactivity of the indirect pathway through
disinhibition of the STN. Increased output from the SNpr and the MGP
causes inhibition of the thalamus and reduction of excitatory input to
the cortex, responsible for the expression of parkinsonian symptoms.
(see Lang et al for review).8
In the brain of Parkinsonian patients neuronal degeneration is also
present in locus coeruleus (rich in noradrenaline), in the nucleus of
Meynert (rich in acetylcholine) and other cholinergic brainstem nuclei,
in the dorsal raphe nuclei (serotoninergic), posterolateral hypothalamus
and multiple limbic systems.9
These alterations in multiple neurotransmitter systems may explain the
concurrent presence of dementia and depression in subsets of patients.
Nevertheless, it remains to be established whether the alterations in
neurotransmitters are truly the primary determinants of the associated
pathologies, most frequently observed in advanced cases. It has been
suggested that depression in PD may be the result of a psychological
reaction to the diagnosis or to the perception of the first stages of
the disease. On the other hand neurobiological factors have been
demonstrated that support a direct involvement of brain alterations,
specifically in limbic structures in the development of depressive
symptoms in PD.10,11
Akinetic-rigid forms can be observed in clinical states other than
idiopathic Parkinson's disease, possibly involving other nervous
structures. It is relevant to mention that parkinsonian syndromes
include iatrogenic parkinsonism and the incidence of drug-induced
parkinsonism is high in the elderly due to the frequent presence of
multiple pathologies and consequent polypharmacotherapy. Motor disorders
are present in a significant percentage of patients treated for long
periods with drugs of different therapeutic classes. Tardive dyskinesia,
akathisia, myoclonus, dystonia (collectively classified as
extrapyramidal and motor side effects) may appear characteristically
following prolonged administration of neuroleptics which block
post-synaptic dopamine receptors, and also as a result of the use of
antidepressants.12
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Notes on brain monoamines, depression and movement disorders
Clinical experience demonstrates that the incidence of depression is
higher in elderly people than in young people. The elderly patient is in
general physically more frail and any drug treatment (antidepressant
included) may present a higher incidence of drug-induced side-effects
(for both pharmacokinetic and pharmacodynamic reasons). Depression
itself is a complex pathogenic process whose biological bases are not
completely clarified and understood.
The monoamine theory of depression postulates that the pathogenesis
of the illness is related to a deficit in the availability of serotonin
and/or noradrenaline.13,14
In support of such hypothesis comes the demonstration that depressed
patients show a reduction of monoamine turnover with low levels of
monoamines and metabolites in cerebrospinal fluid, plasma and urine,
notwithstanding the variability and methodological differences which
have produced contrasting results.
The main pharmacological activity of antidepressant drugs is the inhibition of the synaptic reuptake and/or the inhibition of monoamine catabolism, increasing the levels of synaptic neurotransmitters.15
Nevertheless, these effects are not responsible for the therapeutic
efficacy of antidepressants because it is known that there is
discrepancy between the rapid drug-induced biochemical effects on amine
uptake and catabolism, and the onset of antidepressant action which may
require several days or weeks to develop.16
The delayed onset of action suggests the presence of time-dependent
adaptive changes in neurotransmission such as decreased numbers of  -adrenergic and serotoninergic receptors, alterations in intraneuronal transduction mechanism, such as cyclic AMP activation17,18 and CREB expression.19
Moreover, the effect of long-term antidepressant treatment on the
synaptic machinery may facilitate neurotransmitter release, as shown for
SSRIs by Popoli et al.20 It remains to be established whether this action is exclusive for serotoninergic terminals.
The role of noradrenaline and serotonin
In animal models the electrical stimulation of the mainly
noradrenergic locus coeruleus induces the development of anxiety and
hypervigilancy, and stress situations induce an activation of the
noradrenergic system. It has been suggested that a dysfunction in the
noradrenergic system may be responsible for the development of
depression. In depressed subjects changes in the concentration of
noradrenaline levels and of adrenoceptor density and function have been
observed.21
In addition, levels of noradrenaline and
3-methoxy-4-hydroxyphenylglicole (MHPG), its major metabolite, measured
in cerebrospinal fluid and in urine, are unchanged or increased
according to reduced MHPG levels in CSF and in plasma following
antidepressant chronic treatment. In depressed patients an overactivity
of the noradrenergic system and an increase in -adrenergic sensitivity is observed, possibly linked to the stress component.22 Despite the fact that long-term antidepressant treatment decreases the responsiveness of central -adrenergic receptors,23 the hypothesis of hypersensitive -adrenergic receptors underlying depression is not fully sustained by experimental data.
Serotonin is involved in the regulation of mood, sleep, vigilance,
memory and learning and the current hypotheses suggest that a deficiency
in the serotoninergic system may be involved in the etiology of
depression. Changes in serotoninergic transmission include a decrease in
L-tryptophane levels (the serotonin precursor), alterations in reuptake
mechanisms and in receptor number. In depressed subjects L-tryptophane
and serotonin plasma levels are lower than in healthy subjects and it
seems that a diet poor in L-Trp can induce depressive symptoms. Changes
in CSF levels of 5-hydroxyindoleacetic acid (5-HIAA) have been employed
to provide an indirect measure of serotonin brain turnover24
and, with the limits imposed by the yet unclear relationship between
5-HIIA levels and brain serotonin metabolism, have suggested a reduced
serotoninergic activity in depressed subjects.25,26,27,28
However, these data are not conclusive since in other clinical studies
significant differences in CSF 5-HIAA between depressed and healthy
subjects have not been observed.29
Some forms of depression are related to a decreased responsiveness of
5-HT1A receptors, as suggested by studies employing a 5-HT1-mediated
neuroendocrine model.23
5-HT2 receptors also seem to be involved in depression. In fact,
depressive symptoms could arise from a pathological increase in 5-HT2
receptor function in the limbic region of the brain.30 An increase in 5-HT2 density has been shown in the cortex of suicide victims30 and, further, chronic treatment with various antidepressant drugs appears to reduce 5-HT2 receptor function in the rat brain.22,30
Blood platelets possess an uptake site for serotonin and 5-HT2
receptors structurally similar to their brain counterparts. Thus,
changes in functional activity of the platelet membrane receptor may
represent indirect markers of brain serotonin function.24
Depressed patients present lower platelet serotonin uptake site density
values and higher platelet 5-HT2 receptor density values than controls.31
In addition, depressed patients with a recent suicide attempt or
suicidal ideation have 5-HT2 binding sites significantly higher than
non-suicidal depressed subjects and controls.32 For studying serotonin transport in depressed patients, [3H]-imipramine, and the more reliable [3H]-paroxetine,
platelet binding are used as markers of central serotoninergic
function. While the number of imipramine binding sites is reduced in
platelets of depressed patients,33 no differences were found in [3H]-paroxetine binding between depressed patients and controls.34,35
The role of dopamine
Dopamine contributes significantly to the pathophysiology of
depression. Reduced neurotransmission in the mesolimbic dopamine system
may sustain some of the symptoms of depressive conditions such as
dysthymia36 and melancholic depression.37
Since dopamine plays a crucial role in controlling incentive,
motivation and reward, its deficiency at the mesolimbic level induces
syndromes characterised by anhedonia, low energy, lack of motivation and
psychomotor slowing.38
Dopamine hypoactivity is a relevant factor in the pathogenesis of
psychomotor retardation, considering that this monoamine is essential
also for movement control (see above). It has been shown that depressed
subjects with psychomotor retardation have a marked decrease in
homovanillic acid (HVA, a major dopamine metabolite) in cerebral fluid
indicating a diminished dopamine turnover at the post-synaptic level.25,29 It seems that dysfunction in dopaminergic transmission is due to decreased density of D2/D3 dopamine post-synaptic receptors in the nucleus accumbens. The enhancement of responsiveness of D2/D3 post-synaptic receptors following antidepressant chronic treatment may confirm this hypothesis.12 In elderly people a remarkable decrease in dopamine and HVA has been observed.39
It has been hypothesized that the incidence of dopamine-subtype
depression, existing in a group of depressed elderly, may be due to an
increased monoamine-oxidase B activity, responsible for dopamine
specific metabolism.40
As indicated above, depressive symptoms such as apathy and diminished
self-initiated planning are characteristic of Parkinson's patients,
however we are still facing an unresolved question. Whether the
depressed mood is correlated to a psychological reaction to the loss of
motor ability or directly to a functional deficiency of dopamine is a
key question that needs to be addressed. Pathogenesis of depression in
PD may be correlated not only with the dopaminergic system, but also
with serotoninergic dysfunction. In fact, a decrease in serotonin
concentration in basal ganglia and cerebral cortex has been observed
together with low CSF 5-HIAA levels in patients with concomitant PD and
depression.41
An interaction between dopaminergic and serotoninergic systems is
suggested by the fact that the administration of ritanserin, a 5-HT2
receptor antagonist, increased the dopamine neuron firing rate both in
the substantia nigra and in the ventral tegmental area inducing mood and
motivation enhancement. These data suggest an inhibitory control
exerted by serotonin on midbrain dopaminergic neuron activity.42
The interconnection of neurotransmitter systems underlying the
pathogenesis of depression and PD extends also to the cholinergic system
because of some interesting observations. The loss of dopaminergic
neurons in the striatum results in the disinhibition of cholinergic
neurons leading to a predominance of cholinergic function. Considerable
evidence for dysregulation of the cholinergic system has also been
observed in depression, suggesting that central cholinergic dominance
creating a relative dopamine deficiency may be involved. A marked
increase in muscarinic receptor density in the frontal cortex of suicide
victims has been shown, although these results have not been confirmed
by all studies.30
In addition, the observation that cholinomimetics induce dysphoria, and
the fact that long-term administration of mianserin or desimipramine
results in decreased M2-receptors in rat cortex support this theory.30,40
Moreover it should also be mentioned that acetylcholinesterase
inhibitors may induce psychopathologies reminiscent of post-traumatic
stress disorders characterized by a series of neuropsychiatric symptoms
including depression,43 and also that stress has been shown to induce long lasting changes in cholinergic gene expression.44
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The action of antidepressant drugs on monoaminergic transmission and possible effects on movement control
Advancing age is a predisposing factor to the development of
extrapyramidal side effects considering the greater vulnerability of
elderly subjects and their decreased metabolic capacity.45
As an example the administration of fluoxetine with cimetidine has been
reported to cause parkinson's symptoms, perhaps related to inhibition
of hepatic metabolism by cimetidine, that results in increased serum
levels of fluoxetine metabolites.46
Furthermore it has to be kept in mind that in the aging brain there is a
significant imbalance of the levels and functions of aminergic
transmitters and receptors,47 so that drugs acting on aminergic transmission are more likely to result in unwanted side effects.
The incidence of akathisia, parkinsonian syndromes and tardive
dyskinesia (TD), which are relatively frequent in patients treated with
classical antipsychotic agents, is also similar with tricyclic
antidepressants (TCAs) and selective serotonin reuptake inhibitors
(SSRIs). The literature reports cases in which extrapyramidal side
effects (EPS) have also developed following long-term treatment with
antidepressant drugs.
Amitriptiline, clomipramine, doxepine, trazodone and fluoxetine
induce tardive dyskinesia in patients not previously treated with
neuroleptics48,49,50
and akathisia, acute dystonia and pseudoparkinson have been induced by
some of these drugs, although not all share the same risk for the
development of movement disturbances. The risk appears to be lower for
those molecules with a pharmacological profile that includes a degree of
inhibition also of the reuptake of dopamine.38,51
It seems that these symptoms are dose-related and that there are
predisposing factors such as previous administration of lithium.52
It may be relevant to remember that in some cases motor retardation
and agitation are accompanying symptoms of melancholic depression37 and psychomotor agitation.53 In these conditions the use of antidepressants may exert an action on those motor symptoms related to aminergic transmission.
All antidepressant drugs in the long term induce adaptive changes in
central monoamine transmission which are associated over time with the
clinical response. Chronic antidepressant treatments are known to
produce desensitization and reduced density of -adrenoceptors, particularly the 1 subtype,22,23 decreased  2-autoreceptor function,22,27 and increased 1 post-synaptic receptor sensitivity.22,27 The decreased number of -adrenoreceptors is more evident following TCA and MAOi chronic treatment than following SSRIs administration,54
and it is possible that these adaptive changes do not contribute to the
antidepressant effects but ameliorate the activity in functionally
linked serotoninergic and dopaminergic neuronal systems.
Antidepressants enhance central serotoninergic transmission as
suggested by preclinical studies employing a range of 5-HT1 mediated
behavioural models in which serotoninergic central transmission at the
5-HT1 receptor level is facilitated by long-term antidepressant
treatment.23
Long-term administration of antidepressants to rodents seems to
decrease 5-HT2 receptor function as suggested by 5-HT2 receptor binding
studies.23,24
The use of TCAs results in sensitization of 5-HT1A post-synaptic
receptors while SSRIs and RIMAs desensitize somatodendritic and terminal
serotoninergic autoreceptors (5-HT1A/1D). Mianserin and other antidepressants that do not inhibit serotonin uptake, probably act in a similar manner to the TCAs.30
The fact that noradrenergic denervation in rat forebrain neurons
prevents antidepressant-sensitization to serotonin suggests that
noradrenergic neurons play a permissive role in the dynamic changes of
5-HT receptors.22
In addition to TCAs and SSRIs there are drugs which act by modifying
both noradrenergic and serotoninergic neurotransmission. Mirtazapine, a
pyridine analogue of mianserin, is an antagonist of 2-autoreceptors and 2-heteroreceptors
located on serotoninergic terminals, inducing an increase in
noradrenaline and serotonin release respectively. More recent compounds
are venlafaxine (noradrenaline serotonin reuptake inhibitor) and
milnacipram that inhibits serotonin reuptake at low doses and
noradrenaline reuptake at higher doses.55
Depressed patients not responding to drugs acting on noradrenergic
and serotoninergic systems are often treated with compounds increasing
dopaminergic transmission such as amineptine and bupropion (dopamine
uptake inhibitors). TCAs and other antidepressants inhibit dopamine
uptake within specific central regions. In particular, chronic treatment
induces an increase in post-synaptic responsiveness of D2/D3 receptors restricted to the mesolimbic dopamine system.12
A selective involvement of the mesolimbic area is suggested by the fact
that sulpiride, a selective DA receptor antagonist, blocks the effects
of antidepressants such as desimipramine and amitriptyline in the
nucleus accumbens but not in the caudate nucleus. This observation is
supported by the fact that antidepressants do not increase the intensity
of behavioural stereotypes caused by high doses of amphetamine, which
are mediated by dopamine release within the striatum.12 Imipramine and its active metabolite desimipramine block [3H]-dopamine
uptake in the limbic regions and not in striatum, and imipramine also
induces reduction of DOPAC levels, a dopamine metabolite, in the same
cerebral region.56
It seems that chronic treatment with some antidepressants causes
down-regulation of D1-receptors in the limbic area whereas a decreased
number of receptors is less evident in the striatum.56 In addition to enhanced responsiveness of D2/D3
receptors, antidepressants act by desensitizing dopamine D2 presynaptic
autoreceptors although it is possible that this effect may be developed
as a withdrawal effect following long-term treatment.12
The development of hypersensitivity in striatal post-synaptic
dopamine receptors has been the most prominent theory explaining the
pathophysiology of TD. Considering that concomitant use of
anticholinergic agents increases the risk of TD, it has been
hypothesized that a shift in the balance of dopaminergic and cholinergic
systems in the striatum may be one possible mechanism, as supported by
the relevant anticholinergic activity linked to TCAs.49
However the interaction of multiple neurotransmitter systems has
recently assumed greater relevance and introduced a new degree of
complication in the prediction of possible interference with movement
control systems by antidepressant drugs. It is of primary interest to
recognize the linkage between serotoninergic and dopaminergic systems,
with the suggestion that alterations in striatal dopamine receptor
sensitivity could be secondary to effects on the serotoninergic system.57
Treatment with SSRIs such as fluoxetine inhibits the nigrostriatal
dopaminergic neurons through the increase in serotonin activity in the
raphe nuclei. SSRIs potentiate the inhibitory action of serotonin on
both the metabolic production and release of dopamine by neurons of the
basal ganglia, as demonstrated by the fact that the synthesis of
catecholamines is acutely inhibited by fluoxetine in regions rich in
dopamine such as the rat forebrain, hippocampus and striatum.50
Other observations suggesting a negative effect on dopaminergic
activity by serotonin are the inhibition of apomorphine-induced
stereotyped behaviour following 5-hydroxytryptophan administration and
the increase in apomorphine-induced locomotor behaviour due to lesions
in the serotonin cell bodies in the raphe nuclei.57
It is hypothesized that the potentiation of D2/D3
receptor activity may be due to alterations occurring in
non-dopaminergic systems (eg glutamatergic) interacting with dopamine
neurons located in the nucleus accumbens. This hypothesis is supported
by the observation that antidepressant drugs can induce NMDA-receptor
down-regulation and that NMDA-receptor antagonists cause antidepressant
effects in some animal depression models.12,58 Furthermore, D2/D3
receptors in the nucleus accumbens may represent a final common route
through which chronic antidepressant administration influences
behavioral output systems. In this regard it is of interest to note that
serotonin synapses may distantly influence dopamine function in the
nucleus accumbens through glutamatergic afferents that project to the
nucleus accumbens from the amygdala, hippocampus and prefrontal cortex,
the traditional site of SSRI action12 (Figure 3).
Finally, the involvement of the GABA-ergic system has been suggested
as an explanation for the pathophysiology of TD. The hypothesis of
dysfunction in GABA-mediated neurotransmission suggests that TD may be
due to damage in GABA-ergic neurons located in the striatal area and
innervating the oral musculature.49
GABA-mimetics such as muscimol induce decreased abnormal movements in
subjects affected by TD; in cerebral regions (substantia nigra, medial
segment of the globus pallidus and subthalamic nucleus) of monkeys with
dyskinesia induced by neuroleptic treatment, a reduction in glutamic
acid decarboxylase (a marker of GABA-activity) has been observed; GABA
levels measured in CSF of schizophrenic patients with dyskinetic
symptoms are lower than respective levels in controls. The observation
that administration of the anticholinesterase physostigmine improves
dyskinesia, particularly tongue and mouth involuntary movements,
suggests that the hypocholinergic activity may provide inhibitory
feed-back to the GABA neurons associated with the oral musculature. It
is evident that the functional control of movement needs a balance
between different systems and dysfunction of these may induce the
conditions for development of TD49 (Figure 4).
Roxindole is a dopaminergic antidepressant with several actions. It is an agonist at D2/D3
and 5-HT1A receptors, and inhibits serotonin uptake. Roxindole is used
both in the treatment of negative schizophrenia and in depressed
subjects, confirming that the dual action on both DA and 5-HT may be
useful in the treatment of these neuropsychiatric diseases.16
Similarly, some new dopamine receptor antagonists are also active as
antidepressants. For example, amisulpride is an atypical neuroleptic
with dopamine receptor antagonist properties in vitro and in vivo.59 This benzamide derivative has high selectivity for D2/D3 dopamine receptors and blocks, at low doses, D2/D3 presynaptic autoreceptors preferentially. In vivo amisulpride displays a limbic selectivity with respect to the striatum60,61,62
and the subsequent enhancement of dopaminergic neurotransmission due to
autoreceptor blockade suggests that it may be effective in treatment of
some forms of depression such as dysthymia.63
In clinical trials involving patients suffering from primary dysthymia
or dysthymia with major depression, amisulpride has been compared with
the antidepressants imipramine, amitryptiline, amineptine and
fluoxetine. In comparison with these other antidepressants, amisulpride
has demonstrated similar efficacy and a lower incidence of side effects.
A particular characteristic of this compound is the low risk of
extrapyramidal side effects, even if tardive dyskinesia and parkinsonism
have been reported occasionally. These properties are explained due to
the selectivity of amisulpride for limbic structures.64,65,66
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Conclusions
The frequent coexistence of different neurological/
neuropsychiatric diseases in elderly people, and the physiological
age-related alterations in neurotransmission which decrease the brain's
functional reserve, make the treatment of this group of patients a
complex task due to the increased risk of side effects. The study of the
correlation between motor and mood disorders and their putative
biochemical bases, as presented in this review, provides a rationale to
better understand or foresee motor side effects with psychotropic drugs,
and in particular antidepressants. While it is widely accepted that
elderly people are particularly susceptible to unwanted motor effects
with neuroleptics because of their antidopaminergic activity, the
relationships between antidepressant therapy and motor disorders is less
appreciated. The interactions between serotonin and dopamine terminals
and the balance between dopaminergic and cholinergic transmission in the
striatum suggests that long-term antidepressant therapy may elicit
motor side effects in the elderly, particularly in the presence of
impaired dopaminergic function. When motor disturbances, in particular
tardive dyskinesia, are observed in elderly people treated with
antidepressants (TCAs, iMAO, SSRIs) the possibility that these symptoms
represent side effects of the pharmacotherapy should be considered.
Moreover, the concomitant use of other psychoactive drugs including
lithium should be carefully monitored as potentially increasing the risk
of such effects. In addition, these concepts may acquire a particular
relevance in the case of treatment-resistant depression (for an
operational definition see Souery et al67),
a problem affecting over one-third of older depressed patients, which
requires selection of an appropriate antidepressant agent, switching to a
different agent or to combination therapy in a systematic way. Within
this context drugs with a favourable tolerability and safety profile
should be adopted whenever possible, bearing in mind not only
pharmacokinetic and metabolic properties, but also pharmacodynamic
properties.
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| Figures |
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| Figure 1 Interplay between major neurotransmitter alterations and motor, affective and cognitive disorders. |
Figure 2 A
schematic drawing of basal ganglia connections in the regulation of
movement control. Straight lines represent excitatory stimuli while
dotted lines represent inhibitory stimuli. Only neurochemical
connections relevant for the discussion are included. Abbreviations
include: DA, dopamine; GABA,  -aminobutyric
acid; Glu, glutamate; LGP, lateral globus pallidus; STN, subthalamic
nucleus; SNc, substantia nigra pars compacta; SNpr, substantia nigra
pars reticulata; MGP, medial globus pallidus. |
| Figure 3 Antidepressants and dopamine balance in mesolimbic and nigrostriatal systems (see text and Pehek68 and Ng et al69). |
| Figure 4 Long-term antidepressant treatment may induce tardive dyskinesia through functional inhibition of dopamine neurons. |
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| Received 10 January 2000; revised 10 July 2000; accepted 14 July 2000 |
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| March 2001, Volume 6, Number 2, Pages 134-142 |
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