Antiparkinsonian treatment for depression in Parkinson's disease： Are selective serotonin reuptake inhibitors recommended？

Philippe De Deurwaerdère（✉）， Yuqiang Ding

1Institut des Maladies Neurodégénératives； Centre National de la Recherche Scientifique （Unité Mixte de Recherche 5293） 146 rue Léo Saignat， Bordeaux Cedex F-33000， France

2Key Laboratory of Arrhythmias， Ministry of Education， East Hospital， Tongji University School of Medicine， Shanghai 200120， China

3Department of Anatomy and Neurobiology， Collaborative Innovation Center for Brain Science， Tongji University School of Medicine， Shanghai 200092， China

Antiparkinsonian treatment for depression in Parkinson's disease： Are selective serotonin reuptake inhibitors recommended？

Philippe De Deurwaerdère1（✉）， Yuqiang Ding2，3

1Institut des Maladies Neurodégénératives； Centre National de la Recherche Scientifique （Unité Mixte de Recherche 5293） 146 rue Léo Saignat， Bordeaux Cedex F-33000， France

2Key Laboratory of Arrhythmias， Ministry of Education， East Hospital， Tongji University School of Medicine， Shanghai 200120， China

3Department of Anatomy and Neurobiology， Collaborative Innovation Center for Brain Science， Tongji University School of Medicine， Shanghai 200092， China

ARTICLE INFO

Received： 9 May 2016

Revised： 27 May 2016

Accepted： 30 June 2016

© The authors 2016. This article

is published with open access

at www.TNCjournal.com

antidepressant drugs；

animal behavior；

high-frequency stimulation of the subthalamic nucleus； L-DOPA；

monoamine；

neurochemistry

Depression is a frequent comorbid syndrome in Parkinson's disease. It is a difficult symptom to manage， as patients continuously receive antiparkinsonian medication and may also have to be treated for the amelioration of the side-effects of antiparkinsonian therapy. The first-line treatment for depression in Parkinson's disease is the use of selective serotonin reuptake inhibitors （SSRIs）. The clinical efficacy of these medications in patients with Parkinson's disease is questionable. In fact， based on their mechanism of action， which requires at least a functional serotonergic system， it is predicted that SSRIs will have lower efficacy in patients with Parkinson's disease. Here， we consider the mechanism of action of SSRIs in the context of Parkinson's disease by investigating the fall in the levels of serotonergic markers and the inhibitory outcomes of antiparkinsonian treatment on serotonergic nerve activity. Because certain classes of antidepressant drugs are widely available， it is necessary to perform translational research to address different strategies used to manage depression in Parkinson's disease.

1 Instructions

Parkinson's disease （PD） is a neurodegenerative disease characterized by motor symptoms， including bradykinesia， postural instability， rigidity， and tremor at rest. This neurological condition has been linked to the degeneration of dopaminergic neurons located in the substantia nigra pars compacta （SNc）， which innervate the putamen and caudate nucleus［1-4］. Patients are treated with dopamine （DA） receptor agonists， which mainly stimulate D2/D3 receptor subtypes， or inhibitors of the peripheral L-aromatic amino acid decarboxylase plus L-DOPA， the metabolic precursor of DA， or undergo surgery for the continuous stimulation of the subthalamic nucleus［4］. These strategies allow for the correction of motor symptoms， but can also unmask non-motor symptoms or even aggravate them. Approximately 30%-50% of patientswith PD exhibit mood disorders， including depression and anxiety. This proportion is much higher than that for age-matched individuals without PD［5， 6］. Even though antiparkinsonian treatments are able to modify mood disorders， it is noteworthy that depression in parkinsonian patients can be detected and diagnosed before the onset of parkinsonism［7， 8］. Mood disorders impair the efficacy of antiparkinsonian treatments and the quality of life of patients［9］.

Numerous classes of antidepressant drugs are available in the market. These drugs target different transporters， enzymes， and receptors. Classically， selective serotonin reuptake inhibitors （SSRIs） are prescribed as a first-line treatment in depression. This strategy is used in the context of PD［10］. Nonetheless， clinical and preclinical evidences suggest that the efficacy of SSRIs may be lower in PD［10］. Indeed， the serotonergic system， which is presumably the foundation of the therapeutic benefits of SSRIs［11， 12］（see below）， is inhibited in the disease and by antiparkinsonian treatments.

The aim of this short review is to present a viewpoint regarding the use of SSRIs in patients with PD receiving the antiparkinsonian treatments L-DOPA or high-frequency stimulation of the subthalamic nucleus （HFS-STN）.

2 Body

2.1 Serotonergic system

Serotonergic cell bodies located in the dorsal raphe nucleus （DRN） and median raphe nucleus （MRN） are responsible for at least six ascending 5-HT pathways innervating the entire mammalian brain［13， 14］. The DRN is the main source of 5-HT in the brain and， depending on the mammalian species， contains 30%-56% of the 5-HT neurons in the central nervous system［15， 16］. Six parts of the DRN have been described based on anatomy， hodology， and functional topography［17］. MRN 5-HT neurons are lower in number［15］. Although preferentially innervating the dorsal hippocampus and the septum， these neurons also send 5-HT projections to several brain regions with the exception of the basal ganglia. The 5-HT innervation of the cerebellum is slightly different and specific. The cerebellum receives projections from the reticularis gigantocellularis， the reticularis paragigantocellularis and the pontis oralis raphe nuclei［18， 19］. In addition to their distinct origins， 5-HT neurons exhibit functional heterogeneity. First， as with many systems of neurotransmission， 5-HT neurons differ in that they co-express and release other neurotransmitters， including glutamate， gamma- aminobutyric acid （GABA）， and neuropeptides such as corticotropin-releasing factor［15， 20-23］. Second， distinct expression of differentiation factors such as pet-1［24-26］or Lmx1b［27］confers specific anatomical and biochemical features to these neurons. These differences may be important in the context of PD， as some 5-HT neurons are destroyed in this disease （see below）.

Serotonergic neurons carry out neurohumoral transmission via a diffusion process［28-30］. Indeed， the axons of these neurons are long and marked by the presence of many varicosities， which are the sites of potential 5-HT release. The release of 5-HT and its extracellular concentrations are regulated by numerous processes. Serotonergic neurons express at least three distinct 5-HT receptors that can play roles in the autoregulatory mechanisms controlling 5-HT neuron activity. These are the 5-HT1A， 5-HT1B， and 5-HT2Breceptors. While the function of 5-HT2Breceptors is less known and is presumably related to serotonin transporter （SERT） function［31， 32］， 5-HT1Aand 5-HT1Breceptors have been the subjects of numerous studies. Of these receptor subtypes， 5-HT1Aautoreceptors are found exclusively at the somatodendritic regions of 5-HT neurons［33-35］. Their stimulation inhibits 5-HT neuron activity and 5-HT release in the raphe nuclei and in the terminal fields of 5-HT neurons［12， 36-38］. In contrast， 5-HT1Bautoreceptors are exclusively found at the terminals of 5-HT neurons［39， 40］. Their stimulation， which occurs when the excitability of 5-HT terminals is reduced， also inhibits 5-HT release in various brain regions［41］. In addition to being regulated by the above metabotropic regulations， 5-HT neurons express SERT， which is found in the somatodendritic areas， axons， and terminals of 5-HT neurons. SERTs are mainly responsible for 5-HT reuptake in normal situations， while other transporters， expressed by neurons and glial cells， can be recruited when there are excessive concentrations of 5-HT in the extracellular space［42］.

2.2 Depression and mechanism of action of SSRIs

Depression is a complex and multifaceted disease. Itsetiology is still not understood and likely involves complex interactions between psychosocial （personality traits）， biological （genetic， epigenetic， neuroendocrine and neuroimmune）， developmental， and environmental factors. According to the monoaminergic theory， depression may be associated with 5-HT and noradrenaline （NA） deficits in different brain regions. Nonetheless， in terms of the translational value of preclinical research， one should remember that impairments of 5-HT transmission， or NA transmission or both， do not produce depressive-like behaviors in rodents［43-47］. The relationship between these neurotransmitters and depression is much more complex. On the other hand， functional 5-HT and NA neurons have roles in the mechanism of action of antidepressants targeting monoamine transporters. In fact the preclinical efficacy of SSRIs and/or tricyclic antidepressant drugs， which target both 5-HT and NA transporters， is abolished in animals with impaired 5-HT and/or NA transmission［43， 46， 47］. These data are important， as they stress the need for functional 5-HT and NA systems for SSRI antidepressant efficacy.

The mechanism of action of SSRIs involves at least three sequential steps， which may be involved in the clinical delay of these drugs' antidepressant efficacy［11， 12］. First， they block SERTs， which leads to the enhancement of 5-HT extracellular levels in the terminal fields， as well as higher levels in cell bodies. The latter increase is prominent and leads to the indirect stimulation of 5-HT1Aautoreceptors. It thus inhibits 5-HT electrical neuron activity and impulse-dependent 5-HT release at terminal fields. Thus， the increase in 5-HT extracellular levels at the terminal fields induced by the blockade of SERTs is dampened by the activation of 5-HT1Aautoreceptors in the raphe and 5-HT1Breceptors at the terminals［12， 36， 37， 41， 48］. Second， 5-HT1Aautoreceptors in the DRN are subject to desensitization， which can be observed in rodents as a decrease in 5-HT1Areceptor binding sites in the raphe， a reduction of coupling efficacy， or a reduction of the inhibitory effects of 5-HT1Areceptor agonists in inhibiting 5-HT neuron activity［37］. Consequently， while SSRIs block SERTs， the increase in the extracellular levels of 5-HT will be much more prominent because of the reduced inhibitory impact of 5-HT1Aautoreceptors on 5-HT electrical neuron activity［37， 49］. Decrease in raphe 5-HT1Areceptors after long-term treatment with citalopram has been observed in humans［50］. The above two events are prerequisites to the third effect of SSRIs， which is its main effect， and is the reorganization of 5-HT receptors in 5-HT- receptive cells. Other mechanisms may lead to this final response. These include the blockade of NETs and actions of adrenergic receptors on 5-HT neuron activity［51］. Thus， 5-HT1Areceptors expressed by 5-HT-receptive cells in the hippocampus or the cortex are not modified while 5-HT2Aand 5-HT2Creceptor levels are reduced in some brain areas after chronic treatment with SSRIs［11， 12， 51］.

2.3 Functional status of 5-HT neurons in PD： Toward a decrease in 5-HT innervation

The entire 5-HT system has been shown to be modified in PD［52-56］. Although conflicting data have been published， most studies report a drop in 5-HT biochemical markers in patients with PD compared to normal individuals［53， 57-59］. The tissue levels of 5-HT and its metabolite 5-hydroxyindole acetic acid （5-HIAA） may be reduced by up to 50% in the striatum［60-62］. The transporter density can be studied in post-mortem tissue or by using appropriate ligands in positron emission tomography studies. In all cases， the density of SERTs is decreased in multiple brain regions［61， 63-65］with some regional specificities［61， 66-68］. In cases of diagnosed depression， strong decreases have been reported in some cortical areas， including the cingulate and the orbitofrontal and prefrontal cortices［69］. The density of 5-HT1Areceptors may be reduced by up to 27% in the DRN［70］. These changes support the presence of a putative loss of 5-HT neurons in PD［53， 71-73］. The delivery of antiparkinsonian or other medications to patients has been often considered a confounding factor in determining whether the decrease in 5-HT markers is related to the disease process［53， 61］. In fact， in de novo patients， it has been reported that SERT labeling is preserved compared to controls， even in cases of depression［74］. Increases in SERT labeling have also been reported in PD patients with depression［69］. The situation in humans appears to be complicated in terms of the integrity of 5-HT terminals and neurons， although most studies report modest decreases in SERT labeling in patients with PD.

The data in animals are not very clear either. Briefly， the main approaches to mimic PD in animals arethe use of the neurotoxins 1-methyl-4-phenyl-1，2，3，6- tetrahydropyridine （MPTP） in monkeys or mice and 6-hydroxydopamine （6-OHDA）-induced DA lesions in mice and rats［75-78］. MPTP can decrease the levels of 5-HT in brain tissue in association with drastic lesions of DA neurons［79-81］. The consequent modifications in basal 5-HT release in the striatum of MPTP-treated monkeys are not homogenous［82］. Alterations in 5-HT neurons by MPTP are dependent on the protocol used for MPTP intoxication［83］. Indeed， a progressive administration strategy using lower MPTP doses has been used to induce strong alterations in DA neurons of the SNc without causing any alterations in 5-HT biochemical markers in monkeys［83］. In mice， MPTP may reduce 5-HT concentrations， but the decrease is less consistent in various brain regions. This may be related to the MPTP treatment protocol and the survival period of the mice［84-87］， as sprouting of 5-HT afferents into the striatum has been observed in adult MPTP-treated mice［88］.

The unilateral destruction of DA neurons in adult rats using 6-OHDA does not alter 5-HT or 5-HIAA

tissue levels［89-92］. However， the overall set of data is controversial. Some studies have reported a hyperinnervation of forebrain 5-HT fibers in the striatum［93］and enhanced brain tissue levels of 5-HT［94］. In addition， DRN and MRN 5-HT neurons have been reported to be hyperactive after 6-OHDA lesions［95-97］. Conversely， some studies have reported a significant decrease in 5-HT fibers in the striatum［98］or a decreased activity of DRN 5-HT neurons［99］. Finally， some studies have not found any changes in 5-HT tissue levels， 5-HT release， or DRN 5-HT neuron firing rates［92， 100-102］.

2.4 Antiparkinsonian treatments tend to reduce 5-HT release： Consequences on SSRI action

Here we consider the mechanisms of action of the antiparkinsonian treatments HFS-STN and L-DOPA on 5-HT nerve function. HFS-STN has been reported to reduce the electrical activity of DRN 5-HT neurons［96， 103， 104］. In parallel， HFS-STN reduces 5-HT extracellular levels in the striatum， prefrontal cortex， and hippocampus［103， 105］. The inhibitory effects of HFS- STN are suppressed by the co-administration of the 5-HT1Areceptor agonist 8-hydroxy-2-（di-n-propylamino） tetralin （8-OHDPAT）， suggesting that they share the same mechanism in decreasing 5-HT release［105］. Thus， the decrease in 5-HT release induced by HFS-STN is related to its inhibitory effect on 5-HT neuron electrical activity［96］. The functional impact of this decrease is unknown， but HFS-STN can lead to some side-effects， including mood disorders， and it is believed that the reduction in 5-HT tone in the brain may play a role in these side-effects［106］.

The mechanism of action of L-DOPA on 5-HT neuron activity is much more complicated. Indeed， extracellular levels of 5-HT depend on multiple competing processes triggered by L-DOPA inside 5-HT neurons. L-DOPA enters 5-HT neurons［107-109］and the decarboxylation of L-DOPA into DA by L-aromatic acid decarboxylase leads the newly synthesized DA to （1） compete with 5-HT on the vesicular monoamine transporter 2 （VMAT2）［92， 110］and （2） enhance oxidative metabolism， in part through monoamine oxidase B［111， 112］. Thus， 6-OHDA-lesioned rats have non-homogenous decreases in 5-HT extracellular levels in the substantia nigra， the prefrontal cortex， and the hippocampus， but not in the striatum［102］. Other studies have reported no changes in nigral or striatal 5-HT release［113， 114］while reporting decreases in cortical 5-HT［114］. The above mechanism is thus complicated， as exocytic vesicles are flushed by DA［115］， leading to less 5-HT release in response to the same 5-HT neuronal activity. It is important to note that L-DOPA does not reduce DRN neuron firing rates at 6 or 12 mg/kg［100， 101， 116］. In parallel， L-DOPA reduces tissue 5-HT levels in various brain regions， including the striatum and the cerebellum， which have distinct origins of innervation in the raphe nuclei［55， 102， 116， 117］. According to this mechanism， we should then expect a general decrease in 5-HT extracellular levels in all brain regions. The fact that this is not observed suggests the existence of another level of complexity. Indeed， DA may compete with 5-HT binding to SERTs， although its Kd is almost 100 higher and its translocation is 4 times faster when compared to 5-HT［118］. If DA competes extracellularly with 5-HT， then it may lower the reuptake of 5-HT. Finally， we have recently reported that， in microdialysis experiments， a lack of Ca2+ions in the perfusion medium leads to an output of 5-HT induced in response to the systemic injection of moderate to very high doses of L-DOPA （12 or 100 mg/kg）［116］. This suggests that 5-HT may be released as a results of the reversal of SERT function and that the raise in cytosolicDA inside 5-HT neurons favors a non-exocytic release of 5-HT.

In summary， 5-HT release would be reduced by both antiparkinsonian treatments. This should dampen the efficacy of SSRIs in the treatment of depression in patients with PD patients.

The efficacy of SSRIs in treating depression in patients with PD in the clinic is not completely satisfactory［10， 119-121］. In fact， some authors argue that SSRIs lack efficacy［10］or recommend SSRI treatment as a last choice in patients with PD［122］. On the other hand， some studies report similar efficacies of the SSRI paroxetine and the selective noradrenaline reuptake inhibitor venlafaxine［123， 124］. Tricyclic antidepressants or DA receptor agonists may have better efficacies than SSRIs［122， 125， 126］. In any case， in spite of the prevalence of depression， systematic analyses of this disorder in PD are pending the collection of additional clinical data， which warrants the collection of additional clinical data［127］. Furthermore， clinical reports are not always clear regarding the use of pharmacological and non- pharmacological treatments， which would be controlled in trials［120］.

It has been elegantly reported in rats that the noxious consequences of HFS-STN are counteracted by the administration of citalopram， which is an SSRI［96］. This suggests that the enhancement of 5-HT extracellular levels can limit the affective outcomes of HFS-STN. Because citalopram and other SSRIs reduce 5-HT neuron firing rates， the easiest explanation for their effects is that these compounds mask the inhibitory effects of HFS-STN on 5-HT release， as observed with 8-OHDPAT［105］. In clinical practice， HFS-STN is continuously applied， which implies that SSRIs can act on lower 5-HT levels. Thus， SSRIs may have some benefits， which may then be dampened by the effects of HFS- STN. The appearance of depression in HFS-STN-treated patients is unclear［128-131］. However， mood and cognitive deficits are exclusion criteria for operating on patients with PD. HFS-STN in humans tends to improve anxiety［131］， an effect which has recently been observed in rats［45］. It is noteworthy that the improvements in anxiety in parkinsonian rats following HFS-STN require the presence of 5-HT and NA neurons， while improvements in depressive-like symptoms do not［45］.

There is a growing array of evidence suggesting that SSRIs are less efficacious in the presence of L-DOPA. While no data support this assumption in preclinical models of depression， there is evidence that the use of SSRIs may be of interest in the treatment of L-DOPA-induced dyskinesia. Some clinical data support this possibility［132， 133］. In preclinical studies， SSRIs have been shown to reduce L-DOPA-induced dyskinesia［134-136］. The mechanism of action could be consistent with that described above， namely an enhancement of 5-HT release stimulating 5-HT1Aautoreceptors and thereby reducing the activities of 5-HT neurons. Thus， the use of SSRIs may be an interesting alternative to the use of 5-HT1Areceptor agonists， which efficaciously reduce L-DOPA-induced dyskinesia， but aggravates motor scores［137， 138］. Nevertheless， as predicted from the mechanism of action， the dose of SSRI needed to achieve the antidyskinetic effect needs to be increased［136］. In rats， it has been reported that the ability of fluoxetine to inhibit 5-HT neuron firing is right-shifted in the presence of L-DOPA［101］. Thus， the intracellular effects of L-DOPA indeed limit the normal regulatory mechanisms in 5-HT neurons.

2.5 Depression and other antidepressant drugs

Neurochemical and behavioral findings indicate that selective NET inhibitors may be interesting［123， 124］. Their effects on NA neuron activity， as well as their antidepressant-like efficacy in rodents， are boosted by L-DOPA［100］. We found an unexpected increase in extracellular 5-HT levels when reboxetine or desipramine was co-administered with L-DOPA［114］. While desipramine may have detrimental effects in L-DOPA-induced dyskinesia， such negative effects have not been reported with reboxetine［139］. A similar strategy may be investigated in preclinical and clinical studies for the treatment of depression. The only concern regarding the use of this approach is the status of NA neurons in patients， which is probably different in one patient to the next. Similarly， monoamine oxidase inhibitors may be envisioned as treatments for depression， but their antidepressant efficacy is thought to depend on monoaminergic cells.

We thus need to develop other possibilities for the treatment of depression. For example， there are other strategies that may be tested in preclinical studies in the context of PD. Agomelatin stimulates melatoninergic receptors and blocks central 5-HT2Creceptors［140， 141］. Blockade of 5-HT2Creceptors may have many benefits in the context of PD， such as improvements in motor function and mood disorders， although the full picture is unclear［142-144］. Drugs such as agomelatin should be tested and their effects should be compared to those of drugs targeting transporters.

Furthermore， 5-HT4receptors have been implicated in the mechanism of action of fast-onset antidepressant medications［145］. They act downstream 5-HT terminals and indirectly affect 5-HT transmission. A 5-HT4 receptor agonist was shown to modulate DA release induced by L-DOPA in some， but not all regions of the brain. While this agonist does not alter DA release in the striatum， it increases L-DOPA-stimulated DA release in the cortex［146］.

Because the numbers of monoaminergic cells and their activities are modified by the disease or/and the treatment in various manners， it may be more interesting to consider strategies directly modulating monoaminergic receptive fields.

3 Conclusion

The therapeutic approach for the treatment of mood disorders in PD is complicated and the rationale for prescribing SSRIs as a first-line treatment in combination with L-DOPA or HFS-STN is presently unclear. Additional data are needed to better address this question. The translational value of tests developed in rodents， which are prerequisites for better studies regarding antidepressant strategies in the context of PD， has been exemplified in this review.

Acknowledgements

This work was supported by “Centre National de la Recherche Scientifique” and the “conseil Régional d'Aquitaine”.

Conflict of interests

All contributing authors have no conflict of interests.

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✉ Corresponding author： Philippe De Deurwaerdère， Email： deurwaer@u-bordeaux.fr

Supported by “Centre National de la Recherche Scientifique” and the “conseil Régional d'Aquitaine”.