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Antidepressants have been reported to induce extrapyramidal symptoms, including parkinsonism.

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March 2001, Volume 6, Number 2, Pages 134-142
Table of contents    Previous  Article  Next   [PDF]
Mechanisms of Drug Action
Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly
S Govoni1, M Racchi1, E Masoero1, M Zamboni2 and L Ferini-Strambi2
1Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy
2Department of Neurology, Institute San Raffaele, Milano, Italy
Correspondence to: S Govoni, Department of Pharmacology, Viale Taramelli 14, 27100 Pavia, Italy. E-mail:
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.
elderly; depression; movement disorders; Parkinson's disease; antidepressant drugs; extrapyramidal symptoms
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).
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
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 beta-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 beta-adrenergic sensitivity is observed, possibly linked to the stress component.22 Despite the fact that long-term antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors,23 the hypothesis of hypersensitive beta-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
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 beta-adrenoceptors, particularly the beta1 subtype,22,23 decreased alpha2-autoreceptor function,22,27 and increased alpha1 post-synaptic receptor sensitivity.22,27 The decreased number of beta-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 alpha2-autoreceptors and alpha2-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
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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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, gamma-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.
Received 10 January 2000; revised 10 July 2000; accepted 14 July 2000
March 2001, Volume 6, Number 2, Pages 134-142
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