Review Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Neurol. Mar 28, 2015; 5(1): 17-38
Published online Mar 28, 2015. doi: 10.5316/wjn.v5.i1.17
Prevalence, clinical features and treatment of depression in Parkinson’s disease: An update
Omar ME Abdel-Salam
Omar ME Abdel-Salam, Department of Toxicology and Narcotics, Medical Division, National Research Centre, Cairo 12311, Egypt
Author contributions: Abdel-Salam OME solely contributed to this paper.
Conflict-of-interest: The author declares that there are no conflicting of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Omar ME Abdel-Salam, MD, PhD, Department of Toxicology and Narcotics, Medical Division, National Research Centre, Tahrir St., Dokki, Cairo 12311, Egypt. omasalam@hotmail.com
Telephone: Fax: +20-2-33370931
Received: September 28, 2014
Peer-review started: September 29, 2014
First decision: December 3, 2014
Revised: January 18, 2015
Accepted: February 4, 2015
Article in press: February 9, 2015
Published online: March 28, 2015

Abstract

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases which typically affects individuals over 65 years. Although the symptomatology is predominantly motor, neuropsychiatric manifestations, e.g., depression, apathy, anxiety, and cognitive impairment occur in the course of the illness and can have a great impact on the quality of life in these patients. Parkinson’s disease is commonly comorbid with depression with prevalence rates of depression, generally higher than those reported in general population. Depression in PD is frequently underestimated and consequently undertreated, which have significant effects on the quality of life in these patients. The neurobiology of depression in PD is complex and involves alterations in dopaminergic, serotonergic, noradrenergic and possibly other neurotransmitter systems which are affected in the course of the disease. The tricyclic antidepressants and the selective serotonin reuptake inhibitors are the two classes of antidepressant drugs used for depressive symptoms in PD. Several published studies suggested that both classes are of comparable efficacy. Other serotonergic antidepressants, e.g., nefazodone and trazodone have also been of benefit. Meanwhile, there are limited data available on other drugs but these suggest a benefit from the serotonin and noradrenaline reuptake inhibitors such as mirtazapine, venlafaxine, atomoxetine and duloxetine. Some of the drugs used in symptomatic treatment of PD, e.g., the irreversible selective inhibitors of the enzyme monoamine oxidase-B, rasagiline and selegiline as well as the dopamine receptor agonist pramipexole are likely to have direct antidepressant activity independent of their motor improving action. This would make these drugs an attractive option in depressed subjects with PD. The aim of this review is to provide an updated data on the prevalence, clinical features of depression in subjects with PD. The effects of antiparkinsonian and antidepressant drugs on depressive symptoms in these patients are also discussed.

Key Words: Antidepressant drugs, Depression, Serotonin reuptake inhibitors, Parkinson’s disease, Tricyclic antidepressants

Core tip: The development of depressive symptoms in Parkinson’s disease (PD) has important implications on the daily functioning and quality of life. It is thus important to diagnose and treat depression effectively in these patients. This review aims to discuss the prevalence, associated factors and drugs used to treat depressive symptoms in PD.



INTRODUCTION

Idiopathic Parkinson’s disease (PD), also known as primary PD or paralysis agitans is the second most common neurodegenerative disease[1]. The disease affects about 1% of the population over the age of 65 years[1,2]. Estimates of the prevalence of PD in Europe vary from 65.6-12500 per 100000, while annual incidence estimates vary from 5-346 per 100000[3,4]. The disease is characterized by a triad of motor symptoms, bradykinesia, rigidity and resting tremors[5]. These symptoms result from the loss of dopaminergic neurons in the substantia nigra pars compacta, with consequent depletion of dopamine in the striatum[6,7]. Other neuronal populations are also affected including serotonergic, noradrenergic and cholinergic systems, which contributes to the development of non-motor symptoms during the course of the disease[8]. Neuropsychiatric symptoms such as depression, apathy, anxiety, sleep disturbances, cognitive impairment occur in the premotor or presymptomatic phase of the disease, as well as in the advanced disease, and can substantially affect the quality of life and activities of daily living[9-11]. The pathophysiology of these symptoms is complex, and reflects the widespread cortical and brainstem pathology and affection of several neurotransmitter pathways[12]. Depression is particularly common in PD patients, is frequently overlooked, and is known to cause significant morbidity[13]. In this paper it is aimed to provide a comprehensive and an updated account on the prevalence and clinical features of depression in subjects with PD. The effect of antiparkinsonian drugs on the course of depression in these patients as well as the tolerability and efficacy of antidepressant medications are presented. Non-pharmacological approaches to treat depression in patients with PD are also discussed.

DEPRESSION

Mood disorders can be subdivided into: (1) unipolar (depressive) disorders; (2) bipolar disorders (formerly manic-depressive illness); and (3) other mood disorders, e.g., psychotic mood disorders, postpartum mood episodes with psychotic features, mood disorders due to a general medical condition, and substance/medication-induced mood disorder[14-16]. The term depression describes a range of mood disturbance in the form of an unhappy or sad mood to markedly decreased mood[16]. There are two diagnostic classifications for depressive disorders. One is the “International Classification of Disorders’’, 10th edition (ICD-10) system of the World Health Organization[14]. The other is the “Diagnostic and Statistical Manual of Mental Disorder’’, 5th edition (DSM-V) from the American psychiatric association[15]. The diagnosis of major depression illness depends on the presence of a number of symptoms that include depressed mood, loss of interest or pleasure, significant weight loss, or weight gain, sleep disturbances, psychomotor agitation or retardation, fatigue, loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, or indecisiveness, recurrent thoughts of death or suicidal ideation. One of the symptoms should be either depressed mood or loss of interest or pleasure in usual activities (DSM-V)[15] (Table 1). Symptoms must have been present almost every day for a minimum of 2 wk, represent a change from previous functioning, result in clinically significant distress or impairment in social, occupational, or other important areas of functioning, and are not due to a medication, substance abuse or a general medical condition.

Table 1 Diagnostic criteria for major depressive episode.
Depressed mood most of the day, nearly every day
Markedly diminished interest or pleasure in all or almost all activities
Significant weight loss when not dieting or weight gain
Insomnia or hypersomnia nearly every day
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive or inappropriate guilt
Diminished ability to think or concentrate, or indecisiveness
Recurrent thoughts of death or suicidal ideation

Other types of depressive disorders include disruptive mood dysregulation disorder, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder[15]. Depression might occur in the sitting of medical diseases, especially chronic illnesses such as diabetes mellitus, congestive heart failure, myocardial infarction, rheumatologic disorders. Depressive symptoms can be associated with other psychological diseases, including psychotic disorders[17] or caused by a number of medications including β-adrenoceptor blockers, α-adrenoceptor blockers, digoxin, calcium channel blockers, methyldopa, corticosteroids, psychostimulants , isotretinoin, and interferon-α[18-21]. Depressive symptoms are also a common and often characteristic feature in a number of neurological disorders such as stroke, PD, multiple sclerosis, or epilepsy, in which depression has a strong impact on both quality of life and outcome of the primary neurological disorder[22].

PREVALENCE AND FEATURES OF DEPRESSION IN PD

The estimated lifetime prevalence of depression in the general population is approximately 17%-20%[23,24]. It is estimated that up to 85% of patients will have more than one episode in their lifetimes[23,25]. Moreover, up to 20% of patients with depression will have symptoms lasting for 2 years or more, i.e., chronic depression[23,25]. Prevalence estimates for depression in PD vary in different studies, but are clearly higher than those reported in general population. Studies in general report a prevalence rate between 21% and 40%[26-32]. Prevalence rates as low as 2.5% and as high as 66% have also been reported[33-52] (Table 2). It has been found that persons treated with antiparkinson drugs had significantly increased rate of subsequent antidepressant drug treatment compared with controls, indicating the high frequency of depression in PD[53]. Moreover, initiation of any antidepressant drug therapy was associated with a higher risk of PD in the 2 years from the beginning of treatment. This suggested that depressive symptoms were an early manifestation of PD, before the appearance of motor symptoms[54]. Jasinska-Myga et al[36] found that 72% of patients developed depression within ten years of symptomatic PD onset (mean time to depression: 7.9 years). Becker et al[55] reported approximately twofold increased risk of developing depression in PD patients when compared to PD-free population.

Table 2 Classification, mechanism of action and dosage range of antidepressants.
ClassMechanism of actionGeneric name (trade name)Dose range (mg/d)
Older antidepressants
Mixed serotonin and norepinephrine reuptake inhibitors
First-generation tricyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninAmitriptyline (elavil) Clomipramine (anafranil) Doxepin (adapin) Imipramine (tofranil) Trimipramine (surmontil) Protriptyline (vivactil) Lofepramine100-300 100-250 100-300 50-300 100-300 75-200 15-60
Second-generation tricyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninDesipramine (norpramin) Nortriptyline (pamelor)100-300 50-150
Tetracyclic antidepressantsInhibit neuronal reuptake of norepinephrine and serotoninMaprotiline (ludiomil)100-200
Amoxapine (asendin)50-300
Heterocyclic agents TriazolopyridinesMixed serotonin effects: Serotonin (5-HT2A) receptor blockade with serotonin reuptake inhibitionTrazodone (desyrel)150-400
Monoamine oxidase inhibitorsNonselective inhibitor of monoamine oxidase A and BPhenelzine (nardil) Tranylcypromine (parnate) Selegiline (eldepryl)60-90 20-60 5-10
Newer antidepressants
Selective serotonin reuptake inhibitorsSelectively inhibit the reuptake of 5HT at the presynaptic neuronal membrane. Sertraline also markedly inhibits dopamine reuptakeFluoxetine (prozac) Fluvoxamine (luvox) Paroxetine (paxil) Sertraline (zoloft) Citalopram (celexa) Escitalopram (lexapro)20-60 100-300 20-50 50-200 20-40 5-20
Serotonin and noradrenaline reuptake InhibitorsPotent inhibitors of 5HT and norepinephrine uptake; weak inhibitors of dopamine reuptakeVenlafaxine (effexor) Milnacipran (savella) Duloxetine (cymbalta)75-350 12.5-100 60
Norepinephrine reuptake inhibitorsNoradrenaline reuptake inhibitor. Inhibits norepinephrine reuptake without inhibiting serotonin reuptakeViloxazine Reboxetine (edronax) Atomoxetine (strattera)150-300 4-8 40-80
Reversible inhibitors of monoamine oxidase ASelective, reversible inhibitors of monoamine oxidase A: resulting in increased concentrations of NE, 5-HT, and dopamine in synapseMoclobemide Brofaromine300-600 75-150
5HT2 receptor antagonists/reuptake inhibitor serotonin modulatorsMixed serotonin effects. Inhibition of the reuptake of serotonin and selective postsynaptic 5-HT2A blockadeNefazodone (serzone) Desvenlafaxine (pristiq) Ritanserin300-600 50 mg once daily 5-10
5HT1a receptor agonistsPartial agonist of serotonin 5-HT1aGepirone, ipsapirone, tandospirone, felsinoxan
α2-noradrenergic antagonistsComplex action on serotonin and noradrenaline via Serotonin (5-HT2A and 2C) receptor blockade and presynaptic α2-receptor blockadeMirtazapine (remeron)15-45
GABA-mimeticsGABAA and GABAB receptor agonistsFengabine900-1800
Dopamine reuptake inhibitorsIncreases activity of norepinephrine and dopamine only; no significant effect on serotoninBuproprion (wellbutrin)200-450
Melatonin receptor agonistsMelatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonistAgomelatine (valdoxan)25-50
Herbal remedy: Hypericumperforatum/ St. John’s wortUnclear: inhibits the reuptake of several neurotransmitters, including 5HT, NE, dopamine, and γ-aminobutyric acidHypericum perforatum300-900

Depression itself might be an independent risk factor for developing PD. This is because in patients with depression followed up for 10 years, 1.42% developed PD compared with 0.52% in the control group. In this study, patients with depression were 3.24 times more likely to develop PD compared with the those of the control group[56]. Moreover, patients with psychiatric illnesses exhibited 2.38-fold increased risk for developing PD compared with nonpsychiatric individuals. The highest risk for developing PD was observed in patients with schizophrenia[57]. The risk of the onset of major depression is influenced by genetic factors. This is due at least in part to the effect of genetic factors in modulating the individual’s response to the depression-inducing effect of stressful life events[58]. Vanderheyden et al[37] found that 30% of PD patients had a history of mood disorder and 46% were prescribed an anxiolytic, an antidepressant, or an atypical neuroleptic, or a combination of these drugs. A study on first-degree relatives of patients with PD showed increased risk of depressive and anxiety disorders compared with first-degree relatives in the control group[59]. Puschmann et al[60] described a family with mild and slowly progressive L-dopa responsive autosomal dominant PD whose members also had depression. This suggests a common genetic vulnerability for mood disorders and PD.

The clinical manifestations of PD depression include apathy, psychomotor retardation, memory impairment, pessimism, irrationality, and suicidal ideation without suicidal behavior[61]. Depressed PD patients share many features that are present in depressed subjects without PD such as apathy, loss of initiative and decisiveness, insomnia, lack of energy and fatigue. The clinical spectrum of depression in PD patients differs in that features such as anhedonia, sadness, feelings of self-blame, feelings of guilt, sense of failure, self-destructive thoughts, suicide or suicidal ideation are much less common compared to patients with major depression not having PD. Concentration problems, however, are more common compared with depressed control subjects[62,63]. Suicidal ideation is not only a feature of major depression illness but also occurs in other neurological diseases, e.g., multiple sclerosis, epilepsy, Huntington’s disease, and PD. The most common risk factors being hopelessness, depression, and social isolation[64-66]. Major depression is a major risk factor for suicide and suicidal acts, which usually occur during major depressive episodes or mixed episodes[67]. Sokero et al[68] found that during the current major depressive episode, 58% of all patients had experienced suicidal ideation and 15% had attempted suicide most of whom (95%) had also had suicidal ideation. The severity of depression and current alcohol dependence or abuse was among factors that predicted suicide attempts. In their study, Subramaniam et al[69], reported that the prevalence of suicidal ideation, plan, and attempt to commit suicide among patients with lifetime major depressive illness was 43.6%, 13.7% and 12.3%, respectively. Inagaki et al[70] reported current suicidal ideation in 71.4% of patients with major depressive illness.

Suicide or death ideation are also common in depressed patients with PD. Kostić et al[71] found that in PD patients, followed for 8 years, the suicide-specific mortality was 5.3 times higher than expected. Current death and/or suicidal ideation were present in 22.7% of the patients. Major depression, psychosis, and hopelessness were associated with such ideation. Nazem et al[72] found that death ideation or suicide ideation were present in one-third of the sample, and 4% had a lifetime suicide attempt; increasing severity of depression, impulse control disorder, and psychosis were associated with either ideation. A lifetime prevalence of suicidal ideation in 11.6% of PD patients was also reported; the presence of depression and history of impulse-control disorder behaviors were important risk factors[73]. Other workers reported a prevalence of suicidal ideation in 14.4% of their sample but no attempted suicide; major depression being the main predictor of suicidal ideation. Other factors were lower age of disease onset, panic disorder, and social anxiety disorder[74]. Interestingly, these figures are not higher than those reported in non-parkinsonian patients with major depression. It is noteworthy to mention that active suicidal ideation, lifetime suicidal attempts are associated with early-onset depression and young age[75]. The lower prevalence of suicidal ideation in depressed PD patients might be due to the fact that the disease occurs in old age.

FACTORS ASSOCIATED WITH DEPRESSION

Factors associated with depression include increased severity of motor disability, greater impairment in activities of daily living[28,34,36,39,43,76], and longer disease durations[25,33,31,39,42,61]. Depression is more frequent in the young onset PD[34,43,45,76-78]. Similarly, those with subthreshold depression are younger (approximately 5 years) than non-depressed patients[27]. In contrast, Riedel et al[39] found that depression rates were already substantially elevated at early PD stages and that depression was not linked with age, age at onset of PD, or disease duration. In their study, van der Hoek[42] observed no difference in the prevalence of depression among the motor subtypes of PD. The authors, however, noted a trend towards higher prevalence of depression in the tremor dominant group of patients. In contrast, Dewey et al[79] found that patients with right-sided onset of tremor had a lower risk of depressive symptoms compared with other presentations. Meanwhile, the side and type of initial motor symptoms were not related to the risk of later cognitive impairment.

Gender imbalance is common in depression in non-PD subjects. McKercher et al[80] reported a prevalence of major depression of 5.5% for men and 11.6% for women. The prevalence of atypical depression is also higher in women than in men (24.6% vs 17.3%)[81]. Studies also suggested that depressive symptoms were more likely to occur in females than in males[42,82,83]. Other researchers observed no significant difference in the prevalence of depression between men and women with PD[42].

Stressful life events have been implicated in the onset of episodes of major depression[58]. Stressful life events are independent predictors of depressive symptoms in older adults[84] and in those who experience depression recurrence, exposure to acute life events predicts the evolution of residual symptoms to recurrence[85]. Depression in PD is associated with a history of anxiety disorder and memory problems[34] and with dementia[39]. Having a history of depression prior to onset of PD was predictive of depression with PD[45]. Significantly more serious depression also occurs in subjects with a history of depression before PD compared with those without such history[86]. Rod et al[46] suggested an important role for life events in onset of depression in patients with PD. The authors found that more than 50% of their sample experienced major life events since diagnosed with PD with major depression occurring in 9.9%. It was also noted that each additional event was associated with a 56% higher risk of depression. These observations stress the importance of social support in the management of PD patients with depression. Stressful life events are also important in non-PD depressed subjects.

Anxiety, memory problems, hallucinations, sleep disturbances are more common in depressed PD patients compared with PD patients without depression[34,76]. Apathy, a possible feature of depression, can exist independently and is often associated with cognitive impairment[87]. Depression in PD is often associated with anxiety[28,34,41,50] and both depression and anxiety might be early symptoms during the prodromal phase of PD[88]. Anxiety and apathy are significant comorbid conditions of moderate and severe depression[89]. Anxiety coexisted with depression in 8.6%[66] or 41% of the PD patients[50]. The figures are not higher than those encountered in non-PD patients. Thus, in patients with current episode of depression, generalized anxiety disorder and panic disorder comorbidities were associated with unipolar depression in 37.1% and 31.4% of patients, respectively[90]. In late-life depression in non-PD subjects, the prevalence rate of comorbid anxiety disorders was 38.6%[91]. Brown et al[44] suggested the presence of two clinical phenotypes of depression in depressed PD subjects, “anxious-depressed” and “depressed”, with a large proportion of patients have relatively isolated anxiety. Depression and anxiety disorders were often unrecognized and untreated and the comorbidity greatly exacerbated PD symptoms[92]. It is likely that anxiety and depression in PD are due to different pathophysiological mechanisms[41].

COURSE OF DEPRESSION AND THE EFFECT OF DOPAMINERGIC DRUGS

Symptoms of depression are among the most frequent non-motor symptoms in the premotor phase of the disease. de la Riva et al[9] reported that newly diagnosed, untreated patients with PD experienced more depression, fatigue, apathy, and anxiety than healthy controls all time points; these remained relatively stable in early disease. Depression and other neuropsychiatric symptoms appear to be amenable to antiparkinsonian drug therapy, suggesting that they are related to or part of the disease process. In this context, Nègre-Pagès et al[41] found that patients with depressive symptoms received more frequently levodopa and less frequently a dopamine agonist. Similar observations were reported by Hanganu et al[93] who found that higher levodopa (L-dopa) dosages correlated with worse depressive symptoms. In contrast, there was no significant correlation between dopamine agonists and worsening of depressive symptoms. Spalletta et al[10] found significant improvement over time in the depression severity (also memory performance, and motor symptoms) in newly diagnosed patients with PD after 6-12 mo of antiparkinsonian therapy. Kulisevsky et al[94] found that among neuropsychiatric symptoms in PD, only depression was influenced by the type of medication, being less prevalent following treatment with dopaminergic receptor agonists. This suggested that depression in these patients is related to the dopaminergic deficit. Other neuropsychiatric symptoms such as impulse control disorders and excessive daytime sleepiness, however, are increasingly associated with the use of these drugs[9]. Even et al[95] identified three possible subtypes of comorbid depression associated with PD. The first category of patients is those who would develop depression even if they had no PD (nonspecific-casual comorbid dPD). The second subtype includes patients who would be depressed because of another disabling medical illness (nonspecific-reactive comorbid dPD). The third group of patients are those in whom depression is directly related to the underlying pathophysiology of PD (specific comorbid dPD). This latter subtype might be partly responsive to dopamine replacement, suggesting a role for other neurotransmitter systems in its pathogenesis. There are data, however, that suggest a negative impact of dopaminergic pharmacotherapy on cognitive function in depressed PD patients in contrast to non-depressed patients who performed better while on dopaminergic medication[96].

Some dopaminergic medications appear to have antidepressant action unrelated to their influences on motor function. Pramipexole is a non-ergot dopamine receptor agonist which has been shown to be effective in reducing unified Parkinson’s Disease Rating Scale (UPDRS) in early PD and as an “add on” therapy in advanced disease[97,98]. The UPDRS is used to assess both motor and nonmotor symptoms by listing numerous items to be scored by the examiner[5]. Studies suggest that pramipexole possesses a direct antidepressant effect. Thus, Barone et al[99] compared pramipexole to sertraline in a randomized trial in PD patients with major depression but no motor complications. They found that both agents decreased depression scores throughout treatment. The proportion of patients who recovered was significantly higher in the pramipexole compared to the sertraline group (60.6% vs 27.3%). In an open study of pramipexole as an add-on to L-dopa therapy or single administration, the scores of depressive symptoms, UPDR Scale III, and freezing of gait improved. No correlation was observed between depression scores and motor functions, suggesting an antidepressant effect for pramipexole[100]. Barone et al[101] conducted a 14-wk randomized trial comparing pramipexole with placebo in patients with mild-to-moderate PD without motor fluctuations who had depressive symptoms. The authors found that pramipexole improved depressive symptoms. Selegiline and rasagiline are irreversible selective inhibitors of the enzyme MAO-B that are effective as an initial monotherapy in early PD and as adjunct therapy to L-dopa in advanced PD[102-104]. Frampton et al[105] tested the efficacy of selegiline transdermal application in a randomized, double-blind, multicentre studies in adult outpatients with major depressive disorder. They found that short-term treatment with selegiline (6-12 mg/d) was superior to placebo on most measures of antidepressant activity. Long-term treatment with a fixed dose of 6 mg/d selegiline was also superior to placebo as maintenance therapy. In addition to improving motor performance, treatment with rasagiline (2 mg/d) in newly diagnosed PD patients who also have comorbid untreated depression, has been shown to improve depression symptoms. Rasagiline appears to have direct antidepressant action since it especially improved symptoms uninfluenced by motor function such as mood, guilt, psychic anxiety, and hypochondria[106].

NEURO-IMAGING STUDIES

It has been suggested that the development of depression in PD is likely to represent an advanced and widespread neurodegeneration of both serotonergic and dopaminergic neurons[76]. Imaging studies suggested that brain dopamine deficiency might have a role in depression in PD patients. Studies with 18F-fluorodopa-PET in de novo unmedicated PD patients showed that higher depression scores were associated with lower striatal 18F-fluorodopa uptake, suggesting that impaired striatal dopaminergic function is related to depressive symptoms in these subjects[107]. Other studies using [(123) I] FP-CIT single photon emission computed tomography (SPECT) tracer binding to the dopamine transporter (DAT) reported significant decrease in DAT availability in patients with PD. There was an association between dopamine loss in the caudate nucleus (lower DAT binding) and depressive symptoms[108,109]. In one study, reduced DAT binding was reported in the striatum in the majority of patients with major depression, indicating a role for dopamine hypofunction in this disorder. A more pronounced decrease in DAT binding occurred in PD patients (SPECT imaging using 99mTc-TRODAT-1)[110]. Bui et al[111] suggested that the decrease in striatal uptake in the context of a depressive episode might be reversible. The authors observed improved PD symptoms and increased DAT uptake {[(123) I] FP-CIT SPECT} in a depressed PD patient following treatment with electroconvulsive therapy. Ceravolo et al[112], however, reported increased bilateral striatal (123) I-FP-CIT uptake (DAT density) associated with the severity of both depressive and anxious symptoms in newly diagnosed PD patients. This was attributed to a lack of compensatory mechanisms and that it might have a pathogenic role in affective symptoms by reducing the dopaminergic tone in the synaptic cleft.

Not only dopaminergic pathways are affected in PD, but also cholinergic, serotonergic, and noradrenergic ones[113,114]. The neurobiology of depressive disorders involves alterations in serotonergic, dopaminergic and noradrenergic neurotransmission[115,116]. This forms the basis for the use of drugs such as tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, noradrenaline reuptake inhibitors in the pharmacological management of depressive disorders[117,118]. Politis et al[119] used ¹¹C-DASB PET, a selective in vivo marker of 5-HT transporter binding to assess serotonergic function in patients with PD. They found relatively higher ¹¹C-DASB binding in raphe nuclei and limbic structures in those with highest scores for depression symptoms which might reflect reduced extracellular serotonin levels and decreased serotonergic neurotransmission. Beucke et al[120] suggested that un-medicated PD patients have a low serotonergic activity which might be related to the dopamine deficit. Thus, auditory evoked potentials (indicator of central serotonergic function) were decreased in patients with PD compared with healthy subjects, but this difference was abolished following L-dopa treatment for 12 wk. The authors also noted a trend towards a correlation between auditory evoked potentials and DAT of the unmedicated patients [using (123) I-FP-CIT SPECT].

NEED FOR ANTIDEPRESSANT DRUG THERAPY

The presence of depression in PD subjects is under-recognized and consequently untreated. For instance, Althaus et al[121] reported a prevalence of depressive symptoms in 35.4% of their sample. Antidepressant drugs, however, were prescribed in 25.0% of patients suffering from moderate to severe depression. Moreover, depression was largely undertreated because a significant proportion of patients continued to experience depressive symptoms despite antidepressant drug therapy. In another study minor and major depression were found in 36.3% and 12.9% of the subjects, respectively. Only 8.6% of the minor depressed patients and 30.3% of the major depressed patients were prescribed antidepressant drugs[42]. Moreover, de la Riva et al[9] found that approximately two-thirds of patients with PD who screened positive for depression were not taking an antidepressant.

The development of depression in subjects with PD has a major impact on the quality of life and activities of daily living. The presence of neuropsychiatric symptoms such as depression, apathy, sleep disturbance and anxiety is associated with more severe parkinsonism compared with patients without these symptoms[29]. Depression also impacts on other cognitive functions. In one study, significant subjective memory complaints were reported by approximately 15% of PD patients and these worsen with increasing severity of depressive symptoms[32]. Subjects with left hemibody onset of motor symptoms and depression exhibited worse working memory, greater disability and lower quality of life compared with those without depression (and also relative to depressed subjects with left hemibody onset of motor symptoms)[122]. It has also been suggested that the presence of depressive symptoms (as well as dopaminergic drugs, disease severity and the occurrence of cognitive impairment) might underlie the onset of psychotic type symptoms in the early stages of PD[123]. Successful treatment of depression leads to important, sustained improvements in the quality of life and disability in PD patients[124].

ANTIDEPRESSANT DRUGS

The TCAs and the monoamine oxidase inhibitors (MAOIs) were the first classes of drugs employed in the pharmacological management of depressive symptoms. These agents work by increasing the synaptic concentration of the monoamine neurotransmitters; norepinephrine (NE), serotonin [(5-hydroxytryptamine, (5HT)] and dopamine. The MAOIs inhibit the enzymatic metabolism of neurotransmitters. The TCAs inhibit the neuronal uptake of NE and 5HT. The TCAs dominated the pharmacological management of depressive disorders for more than 30 years. With the advent of the new generations of antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), the serotonin and noradrenaline reuptake inhibitors (SNRIs) and the noradrenaline reuptake inhibitors (NRIs), TCAs are no longer considered first-line treatments[125-127]. Table 2 lists different classes of antidepressant drugs and their mechanism of action.

ANTIDEPRESSANTS USED IN PD
TCAs

These include the tertiary-amine tricyclics, such as clomipramine, imipramine, amitriptyline, doxepin and trimipramine, and the secondary amines, such as desipramine, protriptyline and nortriptyline. These drugs owe their antidepressant properties to inhibition of the neuronal uptake of the monoamine neurotransmitters; norepinephrine, and serotonin (5-hydroxytryptamine, 5HT). Individual agents differ in their relative potency to inhibit the reuptake of either NE or 5HT. The tertiary tricyclics, amitriptyline, imipramine, and clomipramine are more potent in blocking the serotonin transporter while the secondary tricyclics are much more potent in blocking the norepinephrine transporter. These drugs as well as the tetracyclic compounds maprotiline and amoxapine have been approved for use in major depression with the exception of clomipramine, which in the United States is approved for use only in obsessive-compulsive disorder[128,129]. The TCAs dominated the pharmacological management of depressive disorders for more than 30 years. With the advent of the new generations of antidepressants such as the SSRIs, SNRIs and the NRIs, TCAs are no longer considered first-line treatments[125-127]. The TCAs have the capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors. The side effects include anticholinergic effects such as dry mouth, blurred vision, urinary retention and constipation. Sedative and cognitive effects should make their use in the elderly be largely avoided. Their slowed clearance in old age leads to drug accumulation and increased frequency and severity of side effects[13,130]. TCAs also cause weight gain, and sexual dysfunction[131]. TCAs cause cardiac conduction defects and arrhythmias by blocking fast inward Na+ channels on myocardial cells. Blockade of postsynaptic peripheral α-adrenergic receptors contributes to the postural hypotension associated with TCA use[132]. The use of antidepressants in general and in particular TCAs is associated with tachycardia[133].

TRICYCLIC ANTIDEPRESSANT DRUGS IN PARKINSON’S DISEASE

TCAs were the first class of antidepressant medications to be used for the treatment of depression in patients with PD. These agents were found more effective than placebo and even better than some of the SSRIs. Thus, Andersen et al[134] treated patients with nortriptyline for 16 wk and observed larger improvement compared with placebo. A meta-analysis by Frisina et al[135] of 24 placebo-controlled trials found that TCAs had a greater antidepressant effect relative to SSRIs and the mono-amine-oxidase inhibitor, selegiline. Side effect profile was, however, in favor of SSRIs. A more recent meta-analysis by Liu et al[136] concluded that TCAs might be the best choice when starting antidepressant treatment in patients of PD. In a study comparing amitriptyline and fluoxetine, Serrano-Dueñas[137] found that amitriptyline (approximately 35 mg/d) was better than fluoxetine at controlling the depression. Side effects that occurred in 15% of the patients on amitriptyline treatment, however, led these patients to abandon the drug. Antonini et al[138] compared low-dose amitriptyline (25 mg) to the SSRI sertraline (50 mg) on depression and quality of life in a prospective single-blind randomized study. Drugs were administered for 3 mo. Responder and completion rates were 83.3% and 75% for sertraline and 72.7% and 73% for amitriptyline, respectively. Sertraline and not amitriptyline treatment had a significant benefit on quality of life. (Whether the dopamine reuptake inhibition by sertraline is involved is an intriguing possibility!).

The short-term efficacy of desipramine was compared to that of citalopram, a SSRI in a double-blind, randomized, placebo-controlled study. The authors found that desipramine induced a more rapid improvement (after 14 d) in depression score than did an SSRI and placebo. After 30 d both drugs significantly improved depression. Thus a predominantly noradrenergic reuptake inhibitor TCA was faster than an SSRI in controlling depression in PD[139]. Moreover, nortriptyline, another TCA which mainly inhibits noradrenaline reuptake was found superior to placebo in decreasing depression scores. In this randomized, placebo controlled trial, the SSRI paroxetine controlled release (CR), however, was not efficacious. Response rates for nortriptyline, paroxetine CR, and placebo were 53%, 11%, and 24%, respectively[140].

TCAs possess antihistaminic effects which might be of benefit in those suffering from insomnia. One randomized pilot study assessed non-pharmacologic treatment or doxepin, compared to placebo in PD patients with insomnia. Compared to placebo, doxepin improved insomnia, sleep quality, clinical global impression of change. The drug also reduced fatigue severity and improved cognitive scores[141]. Clomipramine, a drug with prominent 5HT reuptake inhibitory action was reported to improve delusions and hallucinations in a parkinsonian patient with psychosis and comorbid depression[142].

Recently, a study by Paumier et al[143] in early PD patients showed that TCAs resulted in delaying the time to initiation of dopaminergic therapy compared with patients not on antidepressants. There were no changes in Unified PD Rating Scale (UPDRS) scores. The effect of TCAs thus could not be attributed to symptomatic effects.

Table 3 lists selected studies on the effect of TCAs on depressive symptoms in subjects with PD.

Table 3 Prevalence of depressive symptoms in subjects with Parkinson’s disease in different studies.
Stage of PD/type of patientsNo. of patients/Prevalence of depression/ depressive symptomsPrevalence of other neuropsychatricRef.
sample sizesymptoms
Outpatients, non-fluctuating (21 de novo, 69 treated with levodopa or dopamine agonists)90Major depression in 21.1% (vs in 3.3% controls)Panic disorders in 30% (vs 5.5% in controls) Dystimia in 18.8% (vs 4.4% in controls)[26]
Outpatients with established PD100Major depression in 35%[35]
Patients with PD presenting with non-motor symptoms. Retrospective study of pathologically-proven PD91Depression in 2.5%Anxiety in 3.9%[33]
Outpatients with established PD50Major depression in 42% (vs 10% of geriatric patients)[28]
Nondemented patients with moderate to severe PD111Depression in 26.1% Subthreshold depression in 28.8%[27]
Early untreated PD175Depression in 37%Apathy in 27% Sleep disturbance in 18% Anxiety in 17%[29]
New-onset PD patients685Depression in 72% (developed depression within ten years of symptomatic PD onset)[36]
Outpatients with established PD1086Major depression in 15.6%[37]
Outpatients with established PD Outpatients with established PD Outpatients with established PD1449 1449 150Depression in 25% Depression in 33.6% Depression in 43% Depression without apathy in 13%Anxiety in 20% Dementia in 29% Psychotic syndromes in 12.7% Sleep disturbances in 49% Apathy only in in 17% Apathy + depression in 43%[38] [39] [40]
Non-demented PD subjects10538% borderline depression Major depression in 4.8%[30]
Non-demented PD subjects450Depressive symptoms in 40% (vs 10% of controls)Probable anxious signs in 51% (vs 29% of controls)[41]
Patients with established PD256Minor depression in 36.3% Major depression in 12.9%[42]
Patients with established PD360Depression in 41.3%Only apathy in 23% Apathy + depression in 36.9%[43]
Patients with established PD202Depression in 37.3%Anxiety in 31.3%, Dementia in 25.3% Excessive daytime sleepiness in 59.4%[31]
Patients with established PD513Depression in 8.6%Anxiety alone in 22.0% Anxiety + depressive symptoms in 8.6%[44]
Outpatients with established PD158Depression in 11% to 57% (depending on the definition of depression)[45]
Outpatients with established PD New-onset PD patients639 221Depression in 66% Major depression in 9.9% (developed depression over 3-4 yr)[34] [46]
Outpatients with established PD1449Depression in 18.8%Dementia in 13.9% had Dementia + depression in 14.3%[47]
Non-demented PD subjects Early stage PD95 36Depression in 28% Depression in 36.1%Anxiety in 27% Obsessive-compulsive symptoms in 52.8% Somatization in 66.7%[48] [49]
Outpatients with established PD117Depression in 56%Anxiety in 55%[50]
Patients with established PD (ambulatory and home residents)886Depression in 24.4%28.4% dementia (20.6 % of ambulatory and 85.7 % of home residents)[51]
PD patients with mild cognitive impairment104Depression in 40.4% (vs 16.6% in controls)Subjective memory complaints 16.3% (vs 7.7% of controls)[32]
Non-demented PD subjects115Major depression in 28.7% Subthreshold depression in 26.10%[52]
SSRIs

These agents are considered first line treatments of depression due to their more safety profile compared to the TCAs[144]. The SSRIs differ in their potency and selectivity in inhibiting serotonin reuptake and in their pharmacokinetics. The prototype SSRIs is fluoxetine which acts by blocking the reuptake of 5HT at the presynaptic neuronal membrane, thereby increasing its concentration in the synaptic cleft[145]. Fluoxetine has longer elimination half-life of 1-3 d after acute administration, while its active metabolite norfluoxetine has a half life of 7-15 d[128]. Its abrupt cessation is not likely to cause discontinuation reactions[146].

Fluvoxamine and paroxetine are other potent SSRIs with an elimination half-life of 15 and 21 h, respectively[144,147]. The abrupt discontinuation of paroxetine results in withdrawal symptoms, including nightmares, tremor, dizziness, insomnia, myalgias, and a “flu-like” syndrome[148]. It is thus advisable to taper the medication over several days, particularly in patients receiving more than 20 mg per day[145]. The drug is a first-line treatment option for major depressive disorder, dysthymia or minor depression[149].

The inability of citalopram to cause significant inhibition of hepatic enzymes made the agent an attractive agent for the treatment of depression, especially among the elderly and patients with comorbid illness requiring concomitant medicines[150,151]. Escitalopram is the pure S-enantiomer of the racemic compound citalopram and the pharmacologically active enantiomer of the racemate which have a more potent antidepressant than that of citalopram. Escitalopram is approximately 30-fold more potent than R-citalopram[152,153].

The SSRIs affect the reuptake of other neurotransmitters. Thus, fluoxetine also acutely increases the extracellular concentrations of NE and dopamine (as well as 5HT) in prefrontal cortex[154] and unlike the other SSRIs possesses moderate affinity for the serotonin 2C receptor[152]. Paroxetine and sertraline possess moderate affinity for the human NE transporter and dopamine transporter, respectively[152]. Sertraline has been shown to increase extracellular levels of dopamine in the nucleus accumbens and striatum[155] which might have important clinical consequences. Paroxetine displays affinity for the muscarinic cholinergic receptor and causes a higher rate of anticholinergic effects, such as dry mouth, constipation, and cognitive disruption, compared with other SSRIs. These effects may be particularly difficult to tolerate for elderly or concomitantly medically ill patients[156]. There are also data to suggest that long-term treatment with paroxetine increases GABA, glutamate, dopamine and noradrenaline levels in the brain[157].

The most common side effects associated with SSRIs include initial nervousness or agitation, anxiety, headache, insomnia, dizziness, dry mouth, gastrointestinal symptoms (nausea, diarrhea, constipation) and sexual dysfunction[144,158]. The use of SSRIs is likely to increase the risk of upper GI bleeding, and this effect is potentiated when these drugs are used in combination with nonsteroidal anti-inflammatory drugs or low-dose aspirin. Other antidepressant drugs did not appear to have an effect on the risk of upper GI bleeding[159]. Other studies reported increased risk of upper gastrointestinal bleeding after short-term SSRI use (7-28 d) intake in male but not female patients[160]. Prior use of SSRIs has also been implicated in increased stroke severity and mortality in patients with hemorrhagic stroke. This, however, was not seen in in SSRI users with ischemic stroke[161]. SSRI/SNRI antidepressants and in particular sertraline and escitalopram have been shown to increase the risk of hyponatraemia, especially in depressed patients aged > 63 years[162]. Recent evidence also implicates SSRIs with decreased bone mineral density and increased risk of hip fracture which appear to decline after discontinuation of these agents[163,164]. SSRIs are associated with a modest but statistically significant increase in the QTc interval with citalopram being associated with more QTc prolongation than most other SSRIs. The increase in QTc by TCAs is however, significantly greater than that of SSRIs[165].

SSRIs in PD

Case reports have associated some of the SSRIs with extrapyramidal side effects. Leo[166] in a review of case reports and case series of movement disorders attributed to SSRIs found that among the 71 cases reported in the literature, the most common side effect was akathisia, dystonia, parkinsonism, and tardive dyskinesia-like states, with a frequency of 45.1%, 292.%, 14.1% and 11.3% respectively. Fluoxetine was implicated in 74.6% of cases of SSRI-induced extrapyramidal symptoms. Other concomitant drugs that can contribute to the development of extrapyramidal symptoms were likely in 57.7% of reports. Caley et al[167] in a retrospective study of medical records of 23 outpatients with Parkinson’s disease who were receiving or had received fluoxetine up to 40 mg/d, found that 20/23 of patients experienced no worsening of their symptoms.

Studies in PD patients with depression, however, have shown treatment with SSRIs to be mostly safe and efficacious. A study of 66 patients with non-fluctuating, depressed patients with PD found a significant improvement in depressive symptoms with citalopram, fluoxetine, fluvoxamine, and sertraline 6 months after starting treatment. There was no significant change in UPDRS scores. The study, however, comprised a small number of patients (15-16) in each drug subgroup[168]. Rampello et al[169] treated depressed (n = 16) and nondepressed (n = 14) PD patients with citalopram (up to 20 mg/d) and observed improved depressive symptoms in 15/16 patients with depression. Moreover, citalopram did not worsen motor performance and on the contrary improved bradykinesia and finger taps in subjects with and without depression on levodopa.

Studies have also indicated an ability of paroxetine to improve depression in depressed PD patients. Tesei et al[170] administered paroxetine (10-20 mg/d) to 65 outpatients with PD and depression and found improved depression scores in 52 patients after approximately 3 mo. Adverse reactions which occurred in 13 patients led them to stop treatment. There were also increased “off” time and tremor in 2 patients that reversed after stopping paroxetine. In another study by Ceravolo et al[171] 6 mo therapy of paroxetine (20 mg/d) improved depression without an effect on motor function (UPDRS scores). Reversible worsening of tremor was observed in one patient. Chung et al[172] who examined the motor effects of 2 wk of paroxetine and placebo on responses to 2-h levodopa infusions, found no effect for the drug on tapping scores or dyskinesia. Paroxetine increased baseline walking speed (prior to infusion) but with increased subjective perception of worsened balance. In a randomized, double-blind, placebo-controlled trial, both paroxetine and venlafaxine XR were efficacious in improving depression without effects on motor function. The mean 12-wk reductions in depression score were 6.2 points for paroxetine group and 4.2 points for venlafaxine XR[173]. A randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression, however, failed to demonstrate a benefit from paroxetine[142].

In their study, Kostić et al[174] administered fluoxetine at daily dose of 20 mg to patients with PD and mild depression. The authors reported significant improvement in depression and UPDRS scores. These correlated with steady state plasma concentrations of fluoxetine and its metabolite norfluoxetine. In an open label trial of 10 patients with PD and major depression, citalopram improved depression, anxiety and functional impairment significantly[175]. In another open-label study of 14 PD patients with major depression, escitalopram treatment was well tolerated with a significant decrease in depressive symptoms, although response rate was only 21%[176]. In a double-blind, randomized, placebo-controlled study of PD patients with major depression, citalopram (and desipramine) produced significant improvements in the depression score after 30 d[139].

Sertraline was found effective in relieving depression in patients with PD without significant effect on motor performance[177]. Sertraline was of comparable efficacy to amitriptyline in decreasing depression scores in PD patients with depression. In this prospective single-blind randomized study, the responder rates were 83.3% and 72.7% for sertraline and amitriptyline, respectively. Sertraline but not amitriptyline, improved quality of life (mobility, activities of daily living)[138]. Kulisevsky et al[178] in a large sample of 374 depressed PD patients of whom 310 completed the study found that treatment with sertraline decreased depressive scores and also improved UPDRS scores. There was worsening of tremor in some patients. Sertraline in both the usual formulation and in the liquid oral concentrate was found efficacious in deceasing depressive scores. Quality of life improved with sertraline (clinical global impression-severity of illness scale and clinical global impression-global improvement scale scores) after 6 mo of treatment. This occurred without change in UPPDR Scale motor scores[179].

OTHER ANTIDEPRESSANTS
Trazodone and nefazodone

Trazodone and nefazodone are chemically related with complex serotonergic actions. These drugs antagonize 5HT2A and 2C postsynaptic receptors. Blockade of these receptors leads to facilitated neurotransmission through 5HT1A receptors, which reduces anxiety levels. In addition both drugs inhibit the reuptake of 5HT to some extent. They thus possess antidepressant, and also some anxiolytic and hypnotic activity, and have favorable sleep architecture profile[180]. Nefazodone has weak affinity for cholinergic and noradrenaline α1- adrenergic receptors and, therefore, is associated with less sedation and orthostatic hypotension than trazodone. The drug has favorable effect on sleep pattern in contrast to fluoxetine which has been shown to not improve sleep in depressed patients[181,182]. Thus, nefazodone would be suitable for depressed patients with prominent features of anxiety and agitation and loss of sleep[105]. Sedation, dry mouth, nausea, and dizziness are the more common adverse effects of nefazodone[183]. In the treatment of major depression, these agents do not differ from the SSRIs with respect to overall efficacy and tolerability[184].

In PD patients with depression, Avila et al[185] provided data suggestive of motor improvement (UPDRS score) after nefazodone, but not after fluoxetine treatment. Meanwhile, both drugs were equally effective as antidepressants. In another study, by Werneck et al[186] trazodone improved depression and motor function improved in the depressed patients treated with the drug.

Mirtazapine

Mirtazapine is a noradrenergic and specific serotonergic antidepressant. The drug increases noradrenergic and 5HT transmission via presynaptic α2-antagonism. Mirtazapine increases the release of NE from central noradrenergic neurons by blocking the presynaptic inhibitory α2-autoreceptors. It blocks the inhibitory α2 heteroreceptors on serotonergic neurons, resulting in increased release of serotonin. Mirtazapine also blocks histamine H1 receptors, thus causing sedation, but has little effect on acetylcholine, dopamine or noradrenaline α1 receptors. The most common side effects are dry mouth, sedation, increased appetite, and weight gain[144,187]. Mirtazapine has a faster onset of action compared with to SSRIs[188,189]. Case reports suggested a positive effect of mirtazapine on auditory[190] and visual[191] hallucinations in patients with PD and persistent psychosis without worsening motor symptoms. This antipsychotic effect of mirtazapine was attributed to 5HT-2 A and/or 5HT-2C antagonism leading to dopamine release[190].

Venlafaxine

Venlafaxine is a serotonin and SNRI[144]. Venlafaxine has a rapid onset of clinical action (one week or two). In the treatment of in-patients with major depression venlafaxine was superior to fluoxetine[192]. It is used to treat melancholia (endogenous depression) and treatment-refractory depression[128]. Remission rates were significantly higher with venlafaxine than with an SSRI[193]. A single-blind study in elderly patients suffering from resistant major depression, found venlafaxine to be significantly superior to paroxetine in improving depression[194]. Adverse effects of the drug include nausea, somnolence, insomnia, and dizziness, constipation, sweating, nervousness, and abnormal ejaculation, cardiac conduction changes[128]. In non-fluctuating PD patients with depression, venlafaxine treatment for 8 wk improved depression without changes in UPDRS scores[195]. In a randomized, double-blind, placebo-controlled trial in depressed PD patients, venlafaxine extended release was effective in improving depression. The mean 12-wk reductions in depression score were 6.2 points for paroxetine group and 4.2 points for venlafaxine extended release[173].

Atomoxetine

In subjects with PD and depression, treatment with the SNRI atomoxetine was not found efficacious in relieving depressive symptoms. Global cognitive performance and daytime sleepiness, however, significantly improved[196].

Duloxetine

Duloxetine is a serotonin and noradrenaline reuptake inhibitor. In an open-label study in PD patients with major depression, duloxetine 60 mg once daily significantly improved depression scores and activities of daily living without worsening rigidity or tremor[197].

Table 4 lists selected studies on the effect of SSRIs and other antidepressant drugs on depressive symptoms in subjects with PD.

Table 4 Studies on the effect of antidepressant drugs on depressive symptoms in Parkinson’s disease subjects with depression.
DrugStudy designSample sizeStudy objectivesOutcomesAdverse effectsRef.
Fluoxetine23Effects of fluoxetine (up to 40 mg/d) on motor performance20/23 patients experienced no worsening of parkinsonism[167]
Fluoxetine, fluvoxamine, citalopram, and sertralineOpen-label prospective study62 depressed patients with PD (without dementia or motor fluctuation) (15 patients received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline)Effects of SSRIs on motor performance and depressive symptoms↓↑ UPDRS scores Significant improvements in depression with all SSRIs[168]
Fluoxetine/amitriptylineRandomized study77 patients with PD (37 received fluoxetine and 40 received amitriptyline)Comparing fluoxetine (20-40 mg/d) and amitriptyline (25-75 mg/d) at low doses on depressive symptomsAmitriptyline better controlled depression at 3, 6, 9 and 12 mo, respectively15% abandoned amitriptyline because of side effects[137]
FluoxetineProspective, controlled, open-label study18 patients with PD and mild depression without dementiaInfluence of fluoxetine (20 mg/d) on motor functionsSignificant improvements in scores of depression and Parkinson’s disability[174]
ParoxetineTo assess the tolerability of paroxetine (20 mg once per day)Improved depression UPDRS scores ↓↑Reversible worsening of tremor in one patient[171]
Paroxetine65 outpatients with PD and depressionTo assess the tolerability of paroxetine (10-20 mg once per day)Improved depression20% stopped paroxetine because of adverse reactions Increased “off” time and tremor in 2 patients (reversible)[170]
Paroxetine CR/nortriptylineRandomized, placebo controlled trial52 patients with PD and depressionTo evaluate the efficacy of paroxetine CR and nortriptyline in treating depressionNortriptyline was superior to placebo for the change in depressive scores Paroxetine CR was not[140]
Paroxetine/venlafaxineRandomized, double-blind, placebo-controlled trial115 subjects with PDTo compare efficacy and safety paroxetine and venlafaxine extended release in treating depression in PDBoth paroxetine and venlafaxine XR significantly improved depression UPDRS scores ↓↑[173]
Citalopram46 non-demented patients with PD. 18 depressed and 28 non-depressedEffect of citalopram on motor and nonmotor symptoms of depressed and nondepressed patients with IPDImprovement in mood in 15/16 patients Motor performance ↓↑ Improved bradykinesia and finger taps in patients with and without depression[169]
CitalopramProspective, open label trial10 patients with PD and major depression, without dementiaEffects of citalopram on depressive symptomsSignificant improvement in depression and in anxiety symptoms and functional impairment[175]
EscitalopramOpen-label study14 Parkinson’s disease patients with major depressionEffects of escitalopram on depressive symptoms↓ in depressive symptomatology score (response and remission rates were only 21% and 14%)[176]
SertralineOpen-label pilot study15 patients with PD and depressionTo evaluate the safety and efficacy of sertraline to treat depression in PDSignificant improvement in depression UPDRS scores ↓↑Side effects in 1/3 2 patients discontinued sertraline[177]
Sertraline Sertraline54 PD patients with depressive disorders 374 PD patients with depressive symptomsComparing efficacy of sertraline in the usual formulation and in the liquid oral concentrate Long-term effects of sertraline on motor statusImproved depression on both formulations Improved clinical global impression-severity of illness scale Improved UPDRS ↓ Anxiety ↓ Depression8% discontinued medication for adverse events (gastrointestinal) Worsening of tremor in some patients[179] [178]
Sertraline/amitriptylineProspective single-blind randomized study31 patients with PD and depressionAssessment of the effect of sertraline (50 mg) or low-dose amitriptyline (25 mg) on depression and quality of life↓ Depression by both drugs Sertraline improved quality of life ↓↑ UPDRS scores[138]
Sertraline/pramipexoleRandomized trial67 outpatients with PD and major depression but no motor fluctuations and/or dyskinesiaTo compare pramipexole with sertralineBoth sertraline and pramipexole improved depression Pramipexole caused more recovery compared to sertraline (60.6% vs 27.3%) Pramipexole improved UPDRS motor subscore14.7% withdrew from the sertraline group[99]
Nefazodone/fluoxetineA pilot randomized trialDepressed patients with PDTo assess the effect of nefazodone on extrapyramidal symptoms in depressed PD patientsNefazodone significantly improved UPDRS score Both nefazodone and fluoxetine were equally effective in treating depression[185]
TrazodoneRandomized trial20 PD patients with and without depressionTo test the ability of trazodone to improve depression and motor functionSignificantly improved depression Improves motor function in depressed patients[186]
VenlafaxineProspective study14 non-fluctuating PD patients with depressionTo investigate the therapeutic efficacy of venlafaxineImproved depression scores UPDRS scores ↓↑[195]
Atomoxetine, a SNRIRandomized placebo- controlled study55 subjects with PD depression atomoxetine or placeboTo assess efficacy of atomoxetine (80 mg/d) in treating depressionFailed to improved depression Improved global cognition Improved daytime sleepiness[196]
DuloxetineNon-comparative, open-label, multi-center study151 patientsTo evaluate the tolerability, safety, and efficacy of duloxetine 60 mg once daily in PD patients with major depressive disorderImproved depressive scores Improved activities of daily living Tremor ↓↑ Rigidity ↓↑8.6% discontinued the study due to side effects[197]
NON-PHARMACOLOGICAL TREATMENT MODALITIES
Neurostimulation

Electrical neurostimulation techniques include deep brain stimulation (DBS) of subthalamic motor nuclei or globus pallidus internus, transcranial magnetic stimulation (TMS), and electroconvulsive therapy.

DBS surgery

This involves inserting microelectrodes into the basal ganglia nuclei, e.g., subthalamic nucleus or globus pallidus internus. In advanced stage PD, deep brain stimulation of subthalamic nucleus improves motor function, motor fluctuations, dyskinesia, activities of daily living, quality of life and allows dopaminergic treatment reduction or withdrawal in a subset of patients[198-206]. Improvement in anxiety, depression, and fatigue has also been reported following subthalamic stimulation[199,200,202,206-208]. In addition, patients with severe PD subjected to bilateral subthalamic nucleus DBS were reported to have had significantly longer survival[209]. The effect of subthalamic DBS on depression, however, might not be maintained. In one study, motor UPDRS-III scores decreased within 18 mo postoperatively compared with preoperative and the medication control group. Self-Rating Depression Scale and Hamilton Rating Scale for Depression decreased within 6 and 3 mo postoperatively, respectively[202]. Cognitive deterioration[203,207,210], decline in verbal fluency and in abstract reasoning, episodic memory and executive function[211], depression[202,205,212,213], apathy[212], worsening of apathy[214] as well as the unmasking of previous psychiatric problems[215] might complicate the procedure. The increase in affective-cognitive symptoms of depression after DBS might reduce the procedure-induced motor improvement[213]. Suicide has also been reported among patients undergoing subthalamic nucleus DBS, despite clear motor improvements[213,216]. Other studies, however, reported no increased risk for suicide ideation and behaviors among PD patients subjected to subthalamic nucleus or globus pallidus interna DBS surgery[217]. Operative complications include infection, intracerebral hematoma, chronic subdural hematoma, electrode fracture, and incorrect lead placement, phlebitis, and pulmonary embolism[204,205,218].

TMS

Brain stimulation with TMS is a noninvasive approach of electrically stimulating neurons in the human cerebral cortex that is capable of modifying neuronal activity both locally and at distant sites[219]. The technique of TMS involves the passage of an electrical current through a copper-wire coil placed on the scalp. A brief, rapid time changing magnetic field is created at the level of the coil which then induces a small electrical current in the underlying brain. Depolarization of neuronal membranes and generation of action potentials follows. In repetitive TMS (rTMS), repeated electrical pulses are generated in the cortex[220,221]. Repetitive TMS of the left dorsolateral prefrontal cortex was approved for the treatment of major depression in United States in 2008[222]. The technique appears to be without side effects[222,223]. Maruo et al[223] observed that three consecutive days of HF-rTMS over the M1 foot area in patients with PD failed to improve depression and apathy scales, despite significant improvement in UPDRS-III compared to sham stimulation.

Electroconvulsive therapy

In PD patients with refractory psychiatric symptoms, electroconvulsive therapy (ECT) led to improvement in symptoms of psychosis and motor symptoms with no adverse effects[224]. There are case reports that ECT was successful in the treatment of severe anxiety[225], and obsessive compulsive disorder[226] in PD, depression and parkinsonism in drug-induced parkinsonism[227]. Usui et al[228] reported improvement of psychosis and severity of PD in eight patients with levodopa or dopamine agonist-induced psychosis. The technique has also been used to treat depression in patients implanted with DBS. Chou et al[229] found that ECT dramatically improved major depression with psychotic features that occurred after bilateral subthalamic nucleus DBS surgery. Nasr et al[230] reported the treatment of severe depression with psychotic features and the decline in physical and mental states using ECT in a patient implanted with DBS. A randomized, double-blind trial of transcranial electrostimulation in early PD, however, found no significant effect on anxiety or depression and also on motor symptoms[231].

Neurosurgical ablation techniques

Surgery, e.g., pallidotomy, subthalamotomy are sometimes used to alleviate motor symptoms in advanced PD patients refractory to medical treatment[232]. Surgery still might be resorted to in some instances where DBS is contraindicated or following complications necessitating removal of the implanted device[233]. In one study, lasting improvement in depression and apathy and no cognitive deterioration were reported in patients with advanced PD subjected to simultaneous bilateral subthalamotomies[234]. In another study, advanced PD subjects with depressed mood subjected to left-posteroventral pallidotomy performed worse on measures of verbal list learning and story recall when compared to non-depressed subjects or right-posteroventral pallidotomy subjects with depressed mood[235].

Cognitive behavior therapy

This psychotherapeutic treatment option improves comorbid depression and anxiety and the quality of life in PD patients[236,237]. In one study, patients on cognitive behavior therapy reported greater reductions in depression scores, anxiety, and improved quality of life compared with the clinical monitoring group[238]. Cognitive behavior therapy delivered via telephone to persons with PD also proved useful in improving psychiatric symptoms[239].

Insight from animal studies

The use of animal models of PD has greatly enabled our understanding of the pathogenetic mechanisms of depression in PD and also helped to identify potential therapeutic targets. Many studies employed the neurotoxin 6-hydroxydopamine (6-OHDA) which when injected into the striatum of rats induces marked depletion of dopamine, serotonin and also noradrenaline in the striatum[240]. Using this model, Tadaiesky et al[241] demonstrated that anxiogenic- and depressive-like behaviors occur early in the course of experimental parkinsonism analogous to that in early phases of human PD. This occurred along with alterations of dopamine, serotonin and noradrenaline in the striatum. Mild anxiogenic effects were also reported in 6-OHDA-lesioned rats. These effects were not amenable to treatment with L-dopa[242]. Branchi et al[243] found depressive-like behavior but reduced anxiety and a marked change in social behavior and no learning or memory difficulties in 6-OHDA-lesioned rats. Courtière et al[244] using the reaction time task test provided data that 6-OHDA lesioned rats had cognitive impairment similar to PD patients. These studies indicated that behavioral changes also occur in early phases of experimental PD. Studies in rodents also allowed the evaluation of such techniques as, TMS, rTMS and DBS. Thus high-frequency electrical stimulation of the subthalamic nucleus in rats was shown to increase striatal dopamine efflux, thereby indicating that the benefit from this technique is probably due to enhanced dopamine release within the basal ganglia[245]. Extracellular levels of 5HT in both striatum and medial prefrontal cortex also decreased following high-frequency electrical stimulation of the subthalamic nucleus even in dopamine-denervated rats. Changes in 5HT neurotransmission might therefore account for the depression seen in some patients following DBS of the subthalamic nucleus[246]. Ghiglieri et al[247] found that rTMS increases striatal excitability and rescues corticostriatal long-term depression in experimental parkinsonism in rats.

Footnotes

P- Reviewer: Dremencov E, O'Leary OF S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK

References
1.  de Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, Manubens-Bertran JM, Alpérovitch A, Rocca WA. Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1997;62:10-15.  [PubMed]  [DOI]
2.  Zhang ZX, Román GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology. 1993;12:195-208.  [PubMed]  [DOI]
3.  von Campenhausen S, Bornschein B, Wick R, Bötzel K, Sampaio C, Poewe W, Oertel W, Siebert U, Berger K, Dodel R. Prevalence and incidence of Parkinson’s disease in Europe. Eur Neuropsychopharmacol. 2005;15:473-490.  [PubMed]  [DOI]
4.  Fahn S. Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci. 2003;991:1-14.  [PubMed]  [DOI]
5.  Gunzler SA, Schoenberg MR, Riley DE, Walter B, Maciunas RJ. Parkinson’s disease and other movement Disorders. The Little Black Book of Neuropsychology: A Syndrome-Based Approach. United States: Springer Science Business Media, LLC 2011; 567-646.  [PubMed]  [DOI]
6.  Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20:415-455.  [PubMed]  [DOI]
7.  Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181-184.  [PubMed]  [DOI]
8.  Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci. 2013;36:543-554.  [PubMed]  [DOI]
9.  de la Riva P, Smith K, Xie SX, Weintraub D. Course of psychiatric symptoms and global cognition in early Parkinson disease. Neurology. 2014;83:1096-1103.  [PubMed]  [DOI]
10.  Spalletta G, Robinson RG, Cravello L, Pontieri FE, Pierantozzi M, Stefani A, Long JD, Caltagirone C, Assogna F. The early course of affective and cognitive symptoms in de novo patients with Parkinson’s disease. J Neurol. 2014;261:1126-1132.  [PubMed]  [DOI]
11.  McLaughlin NC, Piryatinsky I, Epstein-Lubow G, Marino L, Friedman JH. Neuropsychiatric symptoms in an inpatient Parkinson’s disease sample. Parkinsons Dis. 2014;2014:420240.  [PubMed]  [DOI]
12.  Gallagher DA, Schrag A. Psychosis, apathy, depression and anxiety in Parkinson’s disease. Neurobiol Dis. 2012;46:581-589.  [PubMed]  [DOI]
13.  Cummings JL, Masterman DL. Depression in patients with Parkinson’s disease. Int J Geriatr Psychiatry. 1999;14:711-718.  [PubMed]  [DOI]
14.  World Health Organization Tenth revision of the international classification of diseases and related health problems (ICD-10). Geneva: WHO 1992; .  [PubMed]  [DOI]
15.  American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association 2013; .  [PubMed]  [DOI]
16.  Feliciano L, Gum AM. Mood Disorders. Diagnostic Interviewing: 4th ed. Springer Science Business Media, LLC 2010; 153-176.  [PubMed]  [DOI]
17.  Roberts C, Bishop B. Depression. Handbook of Adolescent Behavioral Problems. Evidence-Based Approaches to Prevention and Treatment. United States: Springer Science Business Media, Inc 2005; 205-230.  [PubMed]  [DOI]
18.  Bishop S, Lee A. Drug-induced mental health disorders. Pharm J. 1998;261:935-939.  [PubMed]  [DOI]
19.  Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60 Suppl 4:4-11; discussion 12-13.  [PubMed]  [DOI]
20.  Patten SB, Love EJ. Drug-induced depression. Psychother Psychosom. 1997;66:63-73.  [PubMed]  [DOI]
21.  Botts S, Ryan M. Drug-Induced Psychiatric Diseases. Drug-Induced Diseases: Prevention, Detection, and Management, American Society of Health-System Pharmacists, Inc 2010; 317-332.  [PubMed]  [DOI]
22.  Hellmann-Regen J, Piber D, Hinkelmann K, Gold SM, Heesen C, Spitzer C, Endres M, Otte C. Depressive syndromes in neurological disorders. Eur Arch Psychiatry Clin Neurosci. 2013;263 Suppl 2:S123-S136.  [PubMed]  [DOI]
23.  Keller MB, Klerman GL, Lavori PW, Coryell W, Endicott J, Taylor J. Long-term outcome of episodes of major depression. Clinical and public health significance. JAMA. 1984;252:788-792.  [PubMed]  [DOI]
24.  Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry. 1994;151:979-986.  [PubMed]  [DOI]
25.  Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL, Leon AC, Mueller TI. A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry. 1998;55:694-700.  [PubMed]  [DOI]
26.  Nuti A, Ceravolo R, Piccinni A, Dell’Agnello G, Bellini G, Gambaccini G, Rossi C, Logi C, Dell’Osso L, Bonuccelli U. Psychiatric comorbidity in a population of Parkinson’s disease patients. Eur J Neurol. 2004;11:315-320.  [PubMed]  [DOI]
27.  Nation DA, Katzen HL, Papapetropoulos S, Scanlon BK, Levin BE. Subthreshold depression in Parkinson’s disease. Int J Geriatr Psychiatry. 2009;24:937-943.  [PubMed]  [DOI]
28.  Veiga BA, Borges V, Silva SM, Goulart Fde O, Cendoroglo MS, Ferraz HB. Depression in Parkinson’s disease: clinical-epidemiological correlates and comparison with a controlled group of non-parkinsonian geriatric patients. Rev Bras Psiquiatr. 2009;31:39-42.  [PubMed]  [DOI]
29.  Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord. 2009;24:2175-2186.  [PubMed]  [DOI]
30.  Inoue T, Kitagawa M, Tanaka T, Nakagawa S, Koyama T. Depression and major depressive disorder in patients with Parkinson’s disease. Mov Disord. 2010;25:44-49.  [PubMed]  [DOI]
31.  Hu M, Cooper J, Beamish R, Jones E, Butterworth R, Catterall L, Ben-Shlomo Y. How well do we recognise non-motor symptoms in a British Parkinson’s disease population? J Neurol. 2011;258:1513-1517.  [PubMed]  [DOI]
32.  Lehrner J, Moser D, Klug S, Gleiß A, Auff E, Pirker W, Pusswald G. Subjective memory complaints, depressive symptoms and cognition in Parkinson’s disease patients. Eur J Neurol. 2014;21:1276-184, e77.  [PubMed]  [DOI]
33.  O’Sullivan SS, Williams DR, Gallagher DA, Massey LA, Silveira-Moriyama L, Lees AJ. Nonmotor symptoms as presenting complaints in Parkinson’s disease: a clinicopathological study. Mov Disord. 2008;23:101-106.  [PubMed]  [DOI]
34.  Dissanayaka NN, O’Sullivan JD, Silburn PA, Mellick GD. Assessment methods and factors associated with depression in Parkinson’s disease. J Neurol Sci. 2011;310:208-210.  [PubMed]  [DOI]
35.  Wichowicz HM, Sławek J, Derejko M, Cubała WJ. Factors associated with depression in Parkinson’s disease: a cross-sectional study in a Polish population. Eur Psychiatry. 2006;21:516-520.  [PubMed]  [DOI]
36.  Jasinska-Myga B, Putzke JD, Wider C, Wszolek ZK, Uitti RJ. Depression in Parkinson’s disease. Can J Neurol Sci. 2010;37:61-66.  [PubMed]  [DOI]
37.  Vanderheyden JE, Gonce M, Bourgeois P, Cras P, De Nayer AR, Flamez A, Supiot F, Donneau AF, Albert A, Berlaimont V. Epidemiology of major depression in Belgian parkinsonian patients. Acta Neurol Belg. 2010;110:148-156.  [PubMed]  [DOI]
38.  Riedel O, Klotsche J, Spottke A, Deuschl G, Förstl H, Henn F, Heuser I, Oertel W, Reichmann H, Riederer P. Frequency of dementia, depression, and other neuropsychiatric symptoms in 1,449 outpatients with Parkinson’s disease. J Neurol. 2010;257:1073-1082.  [PubMed]  [DOI]
39.  Riedel O, Heuser I, Klotsche J, Dodel R, Wittchen HU. Occurrence risk and structure of depression in Parkinson disease with and without dementia: results from the GEPAD Study. J Geriatr Psychiatry Neurol. 2010;23:27-34.  [PubMed]  [DOI]
40.  Oguru M, Tachibana H, Toda K, Okuda B, Oka N. Apathy and depression in Parkinson disease. J Geriatr Psychiatry Neurol. 2010;23:35-41.  [PubMed]  [DOI]
41.  Nègre-Pagès L, Grandjean H, Lapeyre-Mestre M, Montastruc JL, Fourrier A, Lépine JP, Rascol O. Anxious and depressive symptoms in Parkinson’s disease: the French cross-sectionnal DoPaMiP study. Mov Disord. 2010;25:157-166.  [PubMed]  [DOI]
42.  van der Hoek TC, Bus BA, Matui P, van der Marck MA, Esselink RA, Tendolkar I. Prevalence of depression in Parkinson’s disease: effects of disease stage, motor subtype and gender. J Neurol Sci. 2011;310:220-224.  [PubMed]  [DOI]
43.  Ziropadja Lj, Stefanova E, Petrovic M, Stojkovic T, Kostic VS. Apathy and depression in Parkinson’s disease: the Belgrade PD study report. Parkinsonism Relat Disord. 2012;18:339-342.  [PubMed]  [DOI]
44.  Brown RG, Landau S, Hindle JV, Playfer J, Samuel M, Wilson KC, Hurt CS, Anderson RJ, Carnell J, Dickinson L. Depression and anxiety related subtypes in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2011;82:803-809.  [PubMed]  [DOI]
45.  Farabaugh AH, Locascio JJ, Yap L, Fava M, Bitran S, Sousa JL, Growdon JH. Assessing depression and factors possibly associated with depression during the course of Parkinson’s disease. Ann Clin Psychiatry. 2011;23:171-177.  [PubMed]  [DOI]
46.  Rod NH, Bordelon Y, Thompson A, Marcotte E, Ritz B. Major life events and development of major depression in Parkinson’s disease patients. Eur J Neurol. 2013;20:663-670.  [PubMed]  [DOI]
47.  Riedel O, Dodel R, Deuschl G, Klotsche J, Förstl H, Heuser I, Oertel W, Reichmann H, Riederer P, Trenkwalder C. Depression and care-dependency in Parkinson’s disease: results from a nationwide study of 1449 outpatients. Parkinsonism Relat Disord. 2012;18:598-601.  [PubMed]  [DOI]
48.  Zahodne LB, Marsiske M, Okun MS, Bowers D. Components of depression in Parkinson disease. J Geriatr Psychiatry Neurol. 2012;25:131-137.  [PubMed]  [DOI]
49.  Bugalho P, da Silva JA, Cargaleiro I, Serra M, Neto B. Psychiatric symptoms screening in the early stages of Parkinson’s disease. J Neurol. 2012;259:124-131.  [PubMed]  [DOI]
50.  Yamanishi T, Tachibana H, Oguru M, Matsui K, Toda K, Okuda B, Oka N. Anxiety and depression in patients with Parkinson’s disease. Intern Med. 2013;52:539-545.  [PubMed]  [DOI]
51.  Riedel O, Schneider C, Klotsche J, Reichmann H, Storch A, Wittchen HU. [The prevalence of Parkinson’s disease, associated dementia, and depression in Dresden]. Fortschr Neurol Psychiatr. 2013;81:81-87.  [PubMed]  [DOI]
52.  Santangelo G, Vitale C, Trojano L, Angrisano MG, Picillo M, Errico D, Agosti V, Grossi D, Barone P. Subthreshold depression and subjective cognitive complaints in Parkinson’s disease. Eur J Neurol. 2014;21:541-544.  [PubMed]  [DOI]
53.  Brandt-Christensen M, Kvist K, Nilsson FM, Andersen PK, Kessing LV. Treatment with antiparkinson and antidepressant drugs: a register-based, pharmaco-epidemiological study. Mov Disord. 2007;22:2037-2042.  [PubMed]  [DOI]
54.  Alonso A, Rodríguez LA, Logroscino G, Hernán MA. Use of antidepressants and the risk of Parkinson’s disease: a prospective study. J Neurol Neurosurg Psychiatry. 2009;80:671-674.  [PubMed]  [DOI]
55.  Becker C, Brobert GP, Johansson S, Jick SS, Meier CR. Risk of incident depression in patients with Parkinson disease in the UK. Eur J Neurol. 2011;18:448-453.  [PubMed]  [DOI]
56.  Shen CC, Tsai SJ, Perng CL, Kuo BI, Yang AC. Risk of Parkinson disease after depression: a nationwide population-based study. Neurology. 2013;81:1538-1544.  [PubMed]  [DOI]
57.  Lin HL, Lin HC, Chen YH. Psychiatric diseases predated the occurrence of Parkinson disease: a retrospective cohort study. Ann Epidemiol. 2014;24:206-213.  [PubMed]  [DOI]
58.  Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 1999;156:837-841.  [PubMed]  [DOI]
59.  Arabia G, Grossardt BR, Geda YE, Carlin JM, Bower JH, Ahlskog JE, Maraganore DM, Rocca WA. Increased risk of depressive and anxiety disorders in relatives of patients with Parkinson disease. Arch Gen Psychiatry. 2007;64:1385-1392.  [PubMed]  [DOI]
60.  Puschmann A, Pfeiffer RF, Stoessl AJ, Kuriakose R, Lash JL, Searcy JA, Strongosky AJ, Vilariño-Güell C, Farrer MJ, Ross OA. A family with Parkinsonism, essential tremor, restless legs syndrome, and depression. Neurology. 2011;76:1623-1630.  [PubMed]  [DOI]
61.  Slaughter JR, Slaughter KA, Nichols D, Holmes SE, Martens MP. Prevalence, clinical manifestations, etiology, and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2001;13:187-196.  [PubMed]  [DOI]
62.  Poewe W. Depression in Parkinson’s disease. J Neurol. 2007;254:49-55.  [PubMed]  [DOI]
63.  Ehrt U, Brønnick K, Leentjens AF, Larsen JP, Aarsland D. Depressive symptom profile in Parkinson’s disease: a comparison with depression in elderly patients without Parkinson’s disease. Int J Geriatr Psychiatry. 2006;21:252-258.  [PubMed]  [DOI]
64.  Viner R, Patten SB, Berzins S, Bulloch AG, Fiest KM. Prevalence and risk factors for suicidal ideation in a multiple sclerosis population. J Psychosom Res. 2014;76:312-316.  [PubMed]  [DOI]
65.  Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC. Suicidality in Huntington’s disease. J Affect Disord. 2012;136:550-557.  [PubMed]  [DOI]
66.  Lewis DS, Anderson KH, Feuchtinger J. Suicide prevention in neurology patients: evidence to guide practice. J Neurosci Nurs. 2014;46:241-248.  [PubMed]  [DOI]
67.  Isometsä E. Suicidal behaviour in mood disorders--who, when, and why? Can J Psychiatry. 2014;59:120-130.  [PubMed]  [DOI]
68.  Sokero TP, Melartin TK, Rytsälä HJ, Leskelä US, Lestelä-Mielonen PS, Isometsä ET. Suicidal ideation and attempts among psychiatric patients with major depressive disorder. J Clin Psychiatry. 2003;64:1094-1100.  [PubMed]  [DOI]
69.  Subramaniam M, Abdin E, Seow EL, Picco L, Vaingankar JA, Chong SA. Suicidal ideation, suicidal plan and suicidal attempts among those with major depressive disorder. Ann Acad Med Singapore. 2014;43:412-421.  [PubMed]  [DOI]
70.  Inagaki M, Ohtsuki T, Yonemoto N, Oikawa Y, Kurosawa M, Muramatsu K, Furukawa TA, Yamada M. Prevalence of depression among outpatients visiting a general internal medicine polyclinic in rural Japan. Gen Hosp Psychiatry. 2013;35:286-290.  [PubMed]  [DOI]
71.  Kostić VS, Pekmezović T, Tomić A, Jecmenica-Lukić M, Stojković T, Spica V, Svetel M, Stefanova E, Petrović I, Dzoljić E. Suicide and suicidal ideation in Parkinson’s disease. J Neurol Sci. 2010;289:40-43.  [PubMed]  [DOI]
72.  Nazem S, Siderowf AD, Duda JE, Brown GK, Ten Have T, Stern MB, Weintraub D. Suicidal and death ideation in Parkinson’s disease. Mov Disord. 2008;23:1573-1579.  [PubMed]  [DOI]
73.  Ozdilek B, Gultekin BK. Suicidal behavior among Turkish patients with Parkinson’s disease. Neuropsychiatr Dis Treat. 2014;10:541-545.  [PubMed]  [DOI]
74.  Kummer A, Cardoso F, Teixeira AL. Suicidal ideation in Parkinson’s disease. CNS Spectr. 2009;14:431-436.  [PubMed]  [DOI]
75.  Wilkowska-Chmielewska J, Szelenberger W, Wojnar M. Age-dependent symptomatology of depression in hospitalized patients and its implications for DSM-5. J Affect Disord. 2013;150:142-145.  [PubMed]  [DOI]
76.  Pålhagen SE, Carlsson M, Curman E, Wålinder J, Granérus AK. Depressive illness in Parkinson’s disease--indication of a more advanced and widespread neurodegenerative process? Acta Neurol Scand. 2008;117:295-304.  [PubMed]  [DOI]
77.  Mehanna R, Moore S, Hou JG, Sarwar AI, Lai EC. Comparing clinical features of young onset, middle onset and late onset Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:530-534.  [PubMed]  [DOI]
78.  Willis AW, Schootman M, Kung N, Racette BA. Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson’s Disease in the United States. Parkinsonism Relat Disord. 2013;19:202-206.  [PubMed]  [DOI]
79.  Dewey RB, Taneja A, McClintock SM, Cullum CM, Dewey RB, Bernstein I, Husain MM. Motor symptoms at onset of Parkinson disease and risk for cognitive impairment and depression. Cogn Behav Neurol. 2012;25:115-120.  [PubMed]  [DOI]
80.  McKercher C, Patton GC, Schmidt MD, Venn AJ, Dwyer T, Sanderson K. Physical activity and depression symptom profiles in young men and women with major depression. Psychosom Med. 2013;75:366-374.  [PubMed]  [DOI]
81.  Schuch JJ, Roest AM, Nolen WA, Penninx BW, de Jonge P. Gender differences in major depressive disorder: results from the Netherlands study of depression and anxiety. J Affect Disord. 2014;156:156-163.  [PubMed]  [DOI]
82.  Siri C, Cilia R, De Gaspari D, Villa F, Goldwurm S, Marco C, Pezzoli G, Antonini A. Psychiatric symptoms in Parkinson’s disease assessed with the SCL-90R self-reported questionnaire. Neurol Sci. 2010;31:35-40.  [PubMed]  [DOI]
83.  Solla P, Cannas A, Ibba FC, Loi F, Corona M, Orofino G, Marrosu MG, Marrosu F. Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson’s disease. J Neurol Sci. 2012;323:33-39.  [PubMed]  [DOI]
84.  Musliner KL, Seifuddin F, Judy JA, Pirooznia M, Goes FS, Zandi PP. Polygenic risk, stressful life events and depressive symptoms in older adults: a polygenic score analysis. Psychol Med. 2014;9:1-12.  [PubMed]  [DOI]
85.  Harkness KL, Theriault JE, Stewart JG, Bagby RM. Acute and chronic stress exposure predicts 1-year recurrence in adult outpatients with residual depression symptoms following response to treatment. Depress Anxiety. 2014;31:1-8.  [PubMed]  [DOI]
86.  Farabaugh AH, Locascio JJ, Yap L, Weintraub D, McDonald WM, Agoston M, Alpert JE, Growdon J, Fava M. Pattern of depressive symptoms in Parkinson’s disease. Psychosomatics. 2009;50:448-454.  [PubMed]  [DOI]
87.  Richard IH. Depression in Parkinson’s Disease. Curr Treat Options Neurol. 2000;2:263-274.  [PubMed]  [DOI]
88.  Jacob EL, Gatto NM, Thompson A, Bordelon Y, Ritz B. Occurrence of depression and anxiety prior to Parkinson’s disease. Parkinsonism Relat Disord. 2010;16:576-581.  [PubMed]  [DOI]
89.  Starkstein S, Dragovic M, Jorge R, Brockman S, Merello M, Robinson RG, Bruce D, Wilson M. Diagnostic criteria for depression in Parkinson’s disease: a study of symptom patterns using latent class analysis. Mov Disord. 2011;26:2239-2245.  [PubMed]  [DOI]
90.  Pini S, Cassano GB, Simonini E, Savino M, Russo A, Montgomery SA. Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia. J Affect Disord. 1997;42:145-153.  [PubMed]  [DOI]
91.  Pini S, Cassano GB, Simonini E, Savino M, Russo A, Montgomery SA. Comorbid anxiety disorders in late-life depression: results of a cohort study. Int Psychogeriatr. 2014;42:1-9.  [PubMed]  [DOI]
92.  Sagna A, Gallo JJ, Pontone GM. Systematic review of factors associated with depression and anxiety disorders among older adults with Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:708-715.  [PubMed]  [DOI]
93.  Hanganu A, Degroot C, Monchi O, Bedetti C, Mejia-Constain B, Lafontaine AL, Chouinard S, Bruneau MA. Influence of depressive symptoms on dopaminergic treatment of Parkinson’s disease. Front Neurol. 2014;5:188.  [PubMed]  [DOI]
94.  Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, García-Sánchez C, Gironell A. Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia. Mov Disord. 2008;23:1889-1896.  [PubMed]  [DOI]
95.  Even C, Weintraub D. Is depression in Parkinson’s disease (PD) a specific entity? J Affect Disord. 2012;139:103-112.  [PubMed]  [DOI]
96.  Blonder LX, Slevin JT, Kryscio RJ, Martin CA, Andersen AH, Smith CD, Schmitt FA. Dopaminergic modulation of memory and affective processing in Parkinson depression. Psychiatry Res. 2013;210:146-149.  [PubMed]  [DOI]
97.  Kieburtz K. Twice-daily, low-dose pramipexole in early Parkinson’s disease: a randomized, placebo-controlled trial. Mov Disord. 2011;26:37-44.  [PubMed]  [DOI]
98.  Takanashi M, Shimo Y, Hatano T, Oyama G, Hattori N. Efficacy and safety of a once-daily extended-release formulation of pramipexole switched from an immediate-release formulation in patients with advanced Parkinson’s disease: results from an open-label study. Drug Res (Stuttg). 2013;63:639-643.  [PubMed]  [DOI]
99.  Barone P, Scarzella L, Marconi R, Antonini A, Morgante L, Bracco F, Zappia M, Musch B. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253:601-607.  [PubMed]  [DOI]
100.  Kano O, Ikeda K, Kiyozuka T, Iwamoto K, Ito H, Kawase Y, Sato R, Fujioka T, Araki Y, Baba S. Beneficial effect of pramipexole for motor function and depression in Parkinson’s disease. Neuropsychiatr Dis Treat. 2008;4:707-710.  [PubMed]  [DOI]
101.  Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, Tolosa E, Weintraub D. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9:573-580.  [PubMed]  [DOI]
102.  Mizuno Y, Kondo T, Kuno S, Nomoto M, Yanagisawa N. Early addition of selegiline to L-Dopa treatment is beneficial for patients with Parkinson disease. Clin Neuropharmacol. 2010;33:1-4.  [PubMed]  [DOI]
103.  Lew MF, Hauser RA, Hurtig HI, Ondo WG, Wojcieszek J, Goren T, Fitzer-Attas CJ. Long-term efficacy of rasagiline in early Parkinson’s disease. Int J Neurosci. 2010;120:404-408.  [PubMed]  [DOI]
104.  Stocchi F, Rabey JM. Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson’s disease. Eur J Neurol. 2011;18:1373-1378.  [PubMed]  [DOI]
105.  Frampton JE, Plosker GL. Selegiline transdermal system in major depressive disorder: profile report. CNS Drugs. 2007;21:521-524.  [PubMed]  [DOI]
106.  Korchounov A, Winter Y, Rössy W. Combined beneficial effect of rasagiline on motor function and depression in de novo PD. Clin Neuropharmacol. 2012;35:121-124.  [PubMed]  [DOI]
107.  Joutsa J, Martikainen K, Vahlberg T, Kaasinen V. Effects of dopamine agonist dose and gender on the prognosis of impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:1079-1083.  [PubMed]  [DOI]
108.  Di Giuda D, Camardese G, Bentivoglio AR, Cocciolillo F, Guidubaldi A, Pucci L, Bruno I, Janiri L, Giordano A, Fasano A. Dopaminergic dysfunction and psychiatric symptoms in movement disorders: a 123I-FP-CIT SPECT study. Eur J Nucl Med Mol Imaging. 2012;39:1937-1948.  [PubMed]  [DOI]
109.  Vriend C, Raijmakers P, Veltman DJ, van Dijk KD, van der Werf YD, Foncke EM, Smit JH, Berendse HW, van den Heuvel OA. Depressive symptoms in Parkinson’s disease are related to reduced [123I]FP-CIT binding in the caudate nucleus. J Neurol Neurosurg Psychiatry. 2014;85:159-164.  [PubMed]  [DOI]
110.  Wu H, Lou C, Huang Z, Shi G. SPECT imaging of dopamine transporters with (99m)Tc-TRODAT-1 in major depression and Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2011;23:63-67.  [PubMed]  [DOI]
111.  Bui E, Delrieu J, Wagner T, Rieu J, Véry E, Letamendia C, Payoux P, Schmitt L. Iodine-123 fluoropropyl-carbomethoxy-3-β-(4-iodophenyltropane) single-photon emission computed tomography findings before and after electroconvulsive therapy in major depressive disorder with Parkinsonism. J ECT. 2011;27:331-333.  [PubMed]  [DOI]
112.  Ceravolo R, Frosini D, Poletti M, Kiferle L, Pagni C, Mazzucchi S, Volterrani D, Bonuccelli U. Mild affective symptoms in de novo Parkinson’s disease patients: relationship with dopaminergic dysfunction. Eur J Neurol. 2013;20:480-485.  [PubMed]  [DOI]
113.  Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain. 2005;128:1314-1322.  [PubMed]  [DOI]
114.  Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novère N. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov. 2006;5:845-854.  [PubMed]  [DOI]
115.  Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64:327-337.  [PubMed]  [DOI]
116.  Brunswick DJ, Amsterdam JD, Mozley PD, Newberg A. Greater availability of brain dopamine transporters in major depression shown by [99m Tc]TRODAT-1 SPECT imaging. Am J Psychiatry. 2003;160:1836-1841.  [PubMed]  [DOI]
117.  Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13-25.  [PubMed]  [DOI]
118.  Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, Carrasco JL, Stahl S. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21:461-471.  [PubMed]  [DOI]
119.  Politis M, Wu K, Loane C, Kiferle L, Molloy S, Brooks DJ, Piccini P. Staging of serotonergic dysfunction in Parkinson’s disease: an in vivo 11C-DASB PET study. Neurobiol Dis. 2010;40:216-221.  [PubMed]  [DOI]
120.  Beucke JC, Uhl I, Plotkin M, Winter C, Assion HJ, Endrass T, Amthauer H, Kupsch A, Juckel G. Serotonergic neurotransmission in early Parkinson’s disease: a pilot study to assess implications for depression in this disorder. World J Biol Psychiatry. 2010;11:781-787.  [PubMed]  [DOI]
121.  Althaus A, Becker OA, Spottke A, Dengler R, Schneider F, Kloss M, Eggert K, Oertel WH, Dillmann U, Herting B. Frequency and treatment of depressive symptoms in a Parkinson’s disease registry. Parkinsonism Relat Disord. 2008;14:626-632.  [PubMed]  [DOI]
122.  Foster PS, Yung RC, Drago V, Crucian GP, Heilman KM. Working memory in Parkinson’s disease: the effects of depression and side of onset of motor symptoms. Neuropsychology. 2013;27:303-313.  [PubMed]  [DOI]
123.  Morgante L, Colosimo C, Antonini A, Marconi R, Meco G, Pederzoli M, Pontieri FE, Cicarelli G, Abbruzzese G, Zappulla S. Psychosis associated to Parkinson’s disease in the early stages: relevance of cognitive decline and depression. J Neurol Neurosurg Psychiatry. 2012;83:76-82.  [PubMed]  [DOI]
124.  Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, Bienfait K, Dicke A. The impact of treatment of depression on quality of life, disability and relapse in patients with Parkinson’s disease. Mov Disord. 2009;24:1325-1332.  [PubMed]  [DOI]
125.  Boyce P, Judd F. The place for the tricyclic antidepressants in the treatment of depression. Aust N Z J Psychiatry. 1999;33:323-327.  [PubMed]  [DOI]
126.  Gibbons SS Antidepressants. In: Edmunds MW, Mayhew MS, editors. Pharmacology for the Primary Care Provider, Mosby INC. St. Louis, Missouri, USA 2000; 602-620.  [PubMed]  [DOI]
127.  Brown CH. Pharmacotherapy of major depressive disorder. US Pharm. 2011;36:HS3-HS8 Available from: http: //www.uspharmacist.com/content/d/feature/c/31081/.  [PubMed]  [DOI]
128.  Nelson JC. Diagnosing and treating depression in the elderly. J Clin Psychiatry. 2001;62 Suppl 24:18-22.  [PubMed]  [DOI]
129.  Nelson JC. Tricyclic and tetracyclic drugs. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed. Washington, DC: American Psychiatric Publishing 2009; .  [PubMed]  [DOI]
130.  Williams GO. Management of depression in the elderly. Prim Care. 1989;16:451-474.  [PubMed]  [DOI]
131.  Fraser K, Martin M, Hunter R, Hudson S. Mood disorders: drug treatment of depression. Pharm J. 2001;266:433-442.  [PubMed]  [DOI]
132.  Baldessarini RJ. Drugs and the treatment of psychiatric disorders: depression and anxiety disorders. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill 2001; 447-483.  [PubMed]  [DOI]
133.  Kemp AH, Brunoni AR, Santos IS, Nunes MA, Dantas EM, Carvalho de Figueiredo R, Pereira AC, Ribeiro AL, Mill JG, Andreão RV. Effects of Depression, Anxiety, Comorbidity, and Antidepressants on Resting-State Heart Rate and Its Variability: An ELSA-Brasil Cohort Baseline Study. Am J Psychiatry. 2014;171:1328-1334.  [PubMed]  [DOI]
134.  Andersen J, Aabro E, Gulmann N, Hjelmsted A, Pedersen HE. Anti-depressive treatment in Parkinson’s disease. A controlled trial of the effect of nortriptyline in patients with Parkinson’s disease treated with L-DOPA. Acta Neurol Scand. 1980;62:210-219.  [PubMed]  [DOI]
135.  Frisina PG, Tenenbaum HR, Borod JC, Foldi NS. The effects of antidepressants in Parkinson’s disease: a meta-analysis. Int J Neurosci. 2008;118:667-682.  [PubMed]  [DOI]
136.  Liu J, Dong J, Wang L, Su Y, Yan P, Sun S. Comparative efficacy and acceptability of antidepressants in Parkinson’s disease: a network meta-analysis. PLoS One. 2013;8:e76651.  [PubMed]  [DOI]
137.  Serrano-Dueñas M. [A comparison between low doses of amitriptyline and low doses of fluoxetin used in the control of depression in patients suffering from Parkinson’s disease]. Rev Neurol. 2002;35:1010-1014.  [PubMed]  [DOI]
138.  Antonini A, Tesei S, Zecchinelli A, Barone P, De Gaspari D, Canesi M, Sacilotto G, Meucci N, Mariani C, Pezzoli G. Randomized study of sertraline and low-dose amitriptyline in patients with Parkinson’s disease and depression: effect on quality of life. Mov Disord. 2006;21:1119-1122.  [PubMed]  [DOI]
139.  Devos D, Dujardin K, Poirot I, Moreau C, Cottencin O, Thomas P, Destée A, Bordet R, Defebvre L. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord. 2008;23:850-857.  [PubMed]  [DOI]
140.  Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, Bienfait K, Dicke A. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology. 2009;72:886-892.  [PubMed]  [DOI]
141.  Rios Romenets S, Creti L, Fichten C, Bailes S, Libman E, Pelletier A, Postuma RB. Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson’s disease -- a randomized study. Parkinsonism Relat Disord. 2013;19:670-675.  [PubMed]  [DOI]
142.  Meco G, Bernardi S. Antidepressant use in treatment of psychosis with comorbid depression in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:311-313.  [PubMed]  [DOI]
143.  Paumier KL, Siderowf AD, Auinger P, Oakes D, Madhavan L, Espay AJ, Revilla FJ, Collier TJ. Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson’s disease. Mov Disord. 2012;27:880-887.  [PubMed]  [DOI]
144.  Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58:19-36.  [PubMed]  [DOI]
145.  Ward HE. The newer antidepressants. IM Internal Medicin. 1997;18:65-76.  [PubMed]  [DOI]
146.  Anderson IM, Edwards JG. Guidelines for choice of selective serotonin reuptake inhibitor in depressive illness. Advan Psychiatry Treat. 2001;7:170-180.  [PubMed]  [DOI]
147.  Figgitt DP, McClellan KJ. Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders. Drugs. 2000;60:925-954.  [PubMed]  [DOI]
148.  Dominguez RA, Goodnick PJ. Adverse events after the abrupt discontinuation of paroxetine. Pharmacotherapy. 1995;15:778-780.  [PubMed]  [DOI]
149.  Wagstaff AJ, Cheer SM, Matheson AJ, Ormrod D, Goa KL. Paroxetine: an update of its use in psychiatric disorders in adults. Drugs. 2002;62:655-703.  [PubMed]  [DOI]
150.  Parker NG, Brown CS. Citalopram in the treatment of depression. Ann Pharmacother. 2000;34:761-771.  [PubMed]  [DOI]
151.  Keller MB. Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. J Clin Psychiatry. 2000;61:896-908.  [PubMed]  [DOI]
152.  Owens JM, Knight DL, Nemeroff CB. [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]. Encephale. 2001;28:350-355.  [PubMed]  [DOI]
153.  Mnie-Filali O, El Mansari M, Scarna H, Zimmer L, Sánchez C, Haddjeri N. [Escitalopram: a selective inhibitor and allosteric modulator of the serotonin transporter]. Encephale. 2007;33:965-972.  [PubMed]  [DOI]
154.  Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, Wong DT, Perry KW. Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berl). 2002;160:353-361.  [PubMed]  [DOI]
155.  Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, Koyama T. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol. 2010;647:90-96.  [PubMed]  [DOI]
156.  Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology. J Psychopharmacol. 1998;12:S5-20.  [PubMed]  [DOI]
157.  Ballesteros-Zebadua P, Manjarrez-Marmolejo J, Franco-Perez J. Chronic paroxetine treatment: effects on other non-serotonergic neurotransmitter systems. CNS Neurol Disord Drug Targets. 2013;12:1226-1232.  [PubMed]  [DOI]
158.  Snow V, Lascher S, Mottur-Pilson C. Pharmacologic treatment of acute major depression and dysthymia. American College of Physicians-American Society of Internal Medicine. Ann Intern Med. 2000;132:738-742.  [PubMed]  [DOI]
159.  Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:811-819.  [PubMed]  [DOI]
160.  Wang YP, Chen YT, Tsai CF, Li SY, Luo JC, Wang SJ, Tang CH, Liu CJ, Lin HC, Lee FY. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54-61.  [PubMed]  [DOI]
161.  Mortensen JK, Larsson H, Johnsen SP, Andersen G. Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality. Stroke. 2014;45:2121-2123.  [PubMed]  [DOI]
162.  Giorlando F, Teister J, Dodd S, Udina M, Berk M. Hyponatraemia: an audit of aged psychiatry patients taking SSRIs and SNRIs. Curr Drug Saf. 2013;8:175-180.  [PubMed]  [DOI]
163.  Bakken MS, Engeland A, Engesæter LB, Ranhoff AH, Hunskaar S, Ruths S. Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry. Age Ageing. 2013;42:514-520.  [PubMed]  [DOI]
164.  Bruyère O, Reginster JY. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine. 2015;48:65-68.  [PubMed]  [DOI]
165.  Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA, Huffman JC. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014;75:e441-e449.  [PubMed]  [DOI]
166.  Leo RJ. Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry. 1996;57:449-454.  [PubMed]  [DOI]
167.  Caley CF, Friedman JH. Does fluoxetine exacerbate Parkinson’s disease? J Clin Psychiatry. 1992;53:278-282.  [PubMed]  [DOI]
168.  Dell’Agnello G, Ceravolo R, Nuti A, Bellini G, Piccinni A, D’Avino C, Dell’Osso L, Bonuccelli U. SSRIs do not worsen Parkinson’s disease: evidence from an open-label, prospective study. Clin Neuropharmacol. 2001;24:221-227.  [PubMed]  [DOI]
169.  Rampello L, Chiechio S, Raffaele R, Vecchio I, Nicoletti F. The SSRI, citalopram, improves bradykinesia in patients with Parkinson’s disease treated with L-dopa. Clin Neuropharmacol. 2002;25:21-24.  [PubMed]  [DOI]
170.  Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani CB, Pezzoli G. Tolerability of paroxetine in Parkinson’s disease: a prospective study. Mov Disord. 2000;15:986-989.  [PubMed]  [DOI]
171.  Ceravolo R, Nuti A, Piccinni A, Dell’Agnello G, Bellini G, Gambaccini G, Dell’Osso L, Murri L, Bonuccelli U. Paroxetine in Parkinson’s disease: effects on motor and depressive symptoms. Neurology. 2000;55:1216-1218.  [PubMed]  [DOI]
172.  Chung KA, Carlson NE, Nutt JG. Short-term paroxetine treatment does not alter the motor response to levodopa in PD. Neurology. 2005;64:1797-1798.  [PubMed]  [DOI]
173.  Richard IH, McDermott MP, Kurlan R, Lyness JM, Como PG, Pearson N, Factor SA, Juncos J, Serrano Ramos C, Brodsky M. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012;78:1229-1236.  [PubMed]  [DOI]
174.  Kostić V, Dzoljić E, Todorović Z, Mijajlović M, Svetel M, Stefanova E, Dragasević N, Petrović I, Milosević M, Kovacević I. Fluoxetine does not impair motor function in patients with Parkinson’s disease: correlation between mood and motor functions with plasma concentrations of fluoxetine/norfluoxetine. Vojnosanit Pregl. 2012;69:1067-1075.  [PubMed]  [DOI]
175.  Menza M, Marin H, Kaufman K, Mark M, Lauritano M. Citalopram treatment of depression in Parkinson’s disease: the impact on anxiety, disability, and cognition. J Neuropsychiatry Clin Neurosci. 2004;16:315-319.  [PubMed]  [DOI]
176.  Weintraub D, Taraborelli D, Morales KH, Duda JE, Katz IR, Stern MB. Escitalopram for major depression in Parkinson’s disease: an open-label, flexible-dosage study. J Neuropsychiatry Clin Neurosci. 2006;18:377-383.  [PubMed]  [DOI]
177.  Hauser RA, Zesiewicz TA. Sertraline for the treatment of depression in Parkinson’s disease. Mov Disord. 1997;12:756-759.  [PubMed]  [DOI]
178.  Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, Gironell A, García-Sánchez C, Martínez-Corral M. Motor changes during sertraline treatment in depressed patients with Parkinson’s disease*. Eur J Neurol. 2008;15:953-959.  [PubMed]  [DOI]
179.  Marino S, Sessa E, Di Lorenzo G, Digangi G, Alagna A, Bramanti P, Di Bella P. Sertraline in the treatment of depressive disorders in patients with Parkinson’s disease. Neurol Sci. 2008;29:391-395.  [PubMed]  [DOI]
180.  Schatzberg AF, Cole JO, DeBattista C.  Manual of Clinical Psychopharmacology 7th ed. Washington, DC: American Psychiatric Publishing Inc 2010; 85.  [PubMed]  [DOI]
181.  Rush AJ, Armitage R, Gillin JC, Yonkers KA, Winokur A, Moldofsky H, Vogel GW, Kaplita SB, Fleming JB, Montplaisir J. Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry. 1998;44:3-14.  [PubMed]  [DOI]
182.  Thase ME, Rush AJ, Manber R, Kornstein SG, Klein DN, Markowitz JC, Ninan PT, Friedman ES, Dunner DL, Schatzberg AF. Differential effects of nefazodone and cognitive behavioral analysis system of psychotherapy on insomnia associated with chronic forms of major depression. J Clin Psychiatry. 2002;63:493-500.  [PubMed]  [DOI]
183.  Cyr M, Brown CS. Nefazodone: its place among antidepressants. Ann Pharmacother. 1996;30:1006-1012.  [PubMed]  [DOI]
184.  Papakostas GI, Fava M. A meta-analysis of clinical trials comparing the serotonin (5HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. Eur Psychiatry. 2007;22:444-447.  [PubMed]  [DOI]
185.  Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F, Bello J. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol. 2003;23:509-513.  [PubMed]  [DOI]
186.  Werneck AL, Rosso AL, Vincent MB. The use of an antagonist 5-HT2a/c for depression and motor function in Parkinson’ disease. Arq Neuropsiquiatr. 2009;67:407-412.  [PubMed]  [DOI]
187.  Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord. 1998;51:267-285.  [PubMed]  [DOI]
188.  Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression. J Clin Psychiatry. 2000;61:656-663.  [PubMed]  [DOI]
189.  Holm KJ, Jarvis B, Foster RH. Mirtazapine. A pharmacoeconomic review of its use in depression. Pharmacoeconomics. 2000;17:515-534.  [PubMed]  [DOI]
190.  Godschalx-Dekker JA, Siegers HP. Reduction of parkinsonism and psychosis with mirtazapine: a case report. Pharmacopsychiatry. 2014;47:81-83.  [PubMed]  [DOI]
191.  Tagai K, Nagata T, Shinagawa S, Tsuno N, Ozone M, Nakayama K. Mirtazapine improves visual hallucinations in Parkinson’s disease: a case report. Psychogeriatrics. 2013;13:103-107.  [PubMed]  [DOI]
192.  Tzanakaki M, Guazzelli M, Nimatoudis I, Zissis NP, Smeraldi E, Rizzo F. Increased remission rates with venlafaxine compared with fluoxetine in hospitalized patients with major depression and melancholia. Int Clin Psychopharmacol. 2000;15:29-34.  [PubMed]  [DOI]
193.  Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.  [PubMed]  [DOI]
194.  Mazeh D, Shahal B, Aviv A, Zemishlani H, Barak Y. A randomized, single-blind, comparison of venlafaxine with paroxetine in elderly patients suffering from resistant depression. Int Clin Psychopharmacol. 2007;22:371-375.  [PubMed]  [DOI]
195.  Torun F, Bayulkem K, Torun SD. The efficacy of venlafaxine in treatment of depression in Parkinson`s disease. BCP. 2011;21:18-23.  [PubMed]  [DOI]
196.  Weintraub D, Mavandadi S, Mamikonyan E, Siderowf AD, Duda JE, Hurtig HI, Colcher A, Horn SS, Nazem S, Ten Have TR. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology. 2010;75:448-455.  [PubMed]  [DOI]
197.  Bonuccelli U, Meco G, Fabbrini G, Tessitore A, Pierantozzi M, Stocchi F, Ceravolo R, Caltagirone C, Silvestrini M, Morgante F. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson’s disease. Expert Opin Pharmacother. 2012;13:2269-2280.  [PubMed]  [DOI]
198.  Okun MS, Wu SS, Foote KD, Bowers D, Gogna S, Price C, Malaty I, Rodriguez RL, Jacobson CE, Ward H. Do stable patients with a premorbid depression history have a worse outcome after deep brain stimulation for Parkinson disease? Neurosurgery. 2011;69:357-360; discussion 360-361.  [PubMed]  [DOI]
199.  Chopra A, Abulseoud OA, Sampson S, Lee KH, Klassen BT, Fields JA, Matsumoto JY, Adams AC, Stoppel CJ, Geske JR. Mood stability in Parkinson disease following deep brain stimulation: a 6-month prospective follow-up study. Psychosomatics. 2014;55:478-484.  [PubMed]  [DOI]
200.  Tao Y, Liang G. Effect of subthalamic nuclei electrical stimulation in the treatment of Parkinson’s disease. Cell Biochem Biophys. 2015;71:113-117.  [PubMed]  [DOI]
201.  Tykocki T, Szalecki K, Koziara H, Nauman P, Mandat T. Quality of life and depressive symptoms in Parkinson’s disease after subthalamic deep brain stimulation: a 2-year follow-up study. Turk Neurosurg. 2013;23:379-384.  [PubMed]  [DOI]
202.  Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ, Rothlind J, Sagher O, Moy C. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362:2077-2091.  [PubMed]  [DOI]
203.  Wang X, Chang C, Geng N, Li N, Wang J, Ma J, Xue W, Zhao W, Wu H, Wang P. Long-term effects of bilateral deep brain stimulation of the subthalamic nucleus on depression in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2009;15:587-591.  [PubMed]  [DOI]
204.  Gervais-Bernard H, Xie-Brustolin J, Mertens P, Polo G, Klinger H, Adamec D, Broussolle E, Thobois S. Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: five year follow-up. J Neurol. 2009;256:225-233.  [PubMed]  [DOI]
205.  Tir M, Devos D, Blond S, Touzet G, Reyns N, Duhamel A, Cottencin O, Dujardin K, Cassim F, Destée A. Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients. Neurosurgery. 2007;61:297-304; discussion 304-305.  [PubMed]  [DOI]
206.  Zhang JG, Zhang K, Ma Y, Hu WH, Yang AC, Chu JS, Wu ST, Ge M, Zhang Y, Wang ZC. Follow-up of bilateral subthalamic deep brain stimulation for Parkinson’s disease. Acta Neurochir Suppl. 2006;99:43-47.  [PubMed]  [DOI]
207.  Mahdavi R, Malakouti SK, Shahidi GA, Parvaresh-Rizi M. The effects of bilateral subthalamic nucleus stimulation on cognitive and neuropsychiatric functions in Parkinson’s disease: a case-control study (#). Basic Clin Neurosci. 2013;4:217-223.  [PubMed]  [DOI]
208.  Wolz M, Hauschild J, Koy J, Fauser M, Klingelhöfer L, Schackert G, Reichmann H, Storch A. Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:994-997.  [PubMed]  [DOI]
209.  Ngoga D, Mitchell R, Kausar J, Hodson J, Harries A, Pall H. Deep brain stimulation improves survival in severe Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2014;85:17-22.  [PubMed]  [DOI]
210.  Aono M, Iga J, Ueno S, Agawa M, Tsuda T, Ohmori T. Neuropsychological and psychiatric assessments following bilateral deep brain stimulation of the subthalamic nucleus in Japanese patients with Parkinson’s disease. J Clin Neurosci. 2014;21:1595-1598.  [PubMed]  [DOI]
211.  Fasano A, Romito LM, Daniele A, Piano C, Zinno M, Bentivoglio AR, Albanese A. Motor and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic implants. Brain. 2010;133:2664-2676.  [PubMed]  [DOI]
212.  Thobois S, Ardouin C, Lhommée E, Klinger H, Lagrange C, Xie J, Fraix V, Coelho Braga MC, Hassani R, Kistner A. Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation. Brain. 2010;133:1111-1127.  [PubMed]  [DOI]
213.  Strutt AM, Simpson R, Jankovic J, York MK. Changes in cognitive-emotional and physiological symptoms of depression following STN-DBS for the treatment of Parkinson’s disease. Eur J Neurol. 2012;19:121-127.  [PubMed]  [DOI]
214.  Le Jeune F, Drapier D, Bourguignon A, Péron J, Mesbah H, Drapier S, Sauleau P, Haegelen C, Travers D, Garin E. Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study. Neurology. 2009;73:1746-1751.  [PubMed]  [DOI]
215.  Lilleeng B, Dietrichs E. Unmasking psychiatric symptoms after STN deep brain stimulation in Parkinson’s disease. Acta Neurol Scand Suppl. 2008;188:41-45.  [PubMed]  [DOI]
216.  Soulas T, Sultan S, Gurruchaga JM, Palfi S, Fénelon G. Changes in quality of life, burden and mood among spouses of Parkinson’s disease patients receiving neurostimulation. Parkinsonism Relat Disord. 2012;18:602-605.  [PubMed]  [DOI]
217.  Weintraub D, Duda JE, Carlson K, Luo P, Sagher O, Stern M, Follett KA, Reda D, Weaver FM. Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson’s disease: results from a randomised, controlled trial. J Neurol Neurosurg Psychiatry. 2013;84:1113-1118.  [PubMed]  [DOI]
218.  Umemura A, Oka Y, Yamamoto K, Okita K, Matsukawa N, Yamada K. Complications of subthalamic nucleus stimulation in Parkinson’s disease. Neurol Med Chir (Tokyo). 2011;51:749-755.  [PubMed]  [DOI]
219.  Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol. 2001;112:1367-1377.  [PubMed]  [DOI]
220.  Maeda F, Pascual-Leone A. Transcranial magnetic stimulation: studying motor neurophysiology of psychiatric disorders. Psychopharmacology (Berl). 2003;168:359-376.  [PubMed]  [DOI]
221.  Holtzheimer P. Treatment refractory depression in the elderly: a possible role for repetitive transcranial magnetic stimulation. Curr Psychos Ther Rep. 2006;4:74-78.  [PubMed]  [DOI]
222.  Saitoh Y. Validation and the future of stimulation therapy of the primary motor cortex. Neurol Med Chir (Tokyo). 2012;52:451-456.  [PubMed]  [DOI]
223.  Maruo T, Hosomi K, Shimokawa T, Kishima H, Oshino S, Morris S, Kageyama Y, Yokoe M, Yoshimine T, Saitoh Y. High-frequency repetitive transcranial magnetic stimulation over the primary foot motor area in Parkinson’s disease. Brain Stimul. 2013;6:884-891.  [PubMed]  [DOI]
224.  Nishioka K, Tanaka R, Shimura H, Hirano K, Hatano T, Miyakawa K, Arai H, Hattori N, Urabe T. Quantitative evaluation of electroconvulsive therapy for Parkinson’s disease with refractory psychiatric symptoms. J Neural Transm. 2014;121:1405-1410.  [PubMed]  [DOI]
225.  Marino L, Friedman JH. Letter to the editor: successful use of electroconvulsive therapy for refractory anxiety in Parkinson’s disease. Int J Neurosci. 2013;123:70-71.  [PubMed]  [DOI]
226.  Gadit AM, Smigas T. Efficacy of ECT in severe obsessive-compulsive disorder with Parkinson’s disease. BMJ Case Rep. 2012;2012:pii: bcr0120125675.  [PubMed]  [DOI]
227.  Baez MA, Avery J. Improvement in drug-induced parkinsonism with electroconvulsive therapy. Am J Geriatr Pharmacother. 2011;9:190-193.  [PubMed]  [DOI]
228.  Usui C, Hatta K, Doi N, Kubo S, Kamigaichi R, Nakanishi A, Nakamura H, Hattori N, Arai H. Improvements in both psychosis and motor signs in Parkinson’s disease, and changes in regional cerebral blood flow after electroconvulsive therapy. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1704-1708.  [PubMed]  [DOI]
229.  Chou KL, Hurtig HI, Jaggi JL, Baltuch GH, Pelchat RJ, Weintraub D. Electroconvulsive therapy for depression in a Parkinson’s disease patient with bilateral subthalamic nucleus deep brain stimulators. Parkinsonism Relat Disord. 2005;11:403-406.  [PubMed]  [DOI]
230.  Nasr S, Murillo A, Katariwala N, Mothkur V, Wendt B. Case report of electroconvulsive therapy in a patient with Parkinson disease concomitant with deep brain stimulation. J ECT. 2011;27:89-90.  [PubMed]  [DOI]
231.  Shill HA, Obradov S, Katsnelson Y, Pizinger R. A randomized, double-blind trial of transcranial electrostimulation in early Parkinson’s disease. Mov Disord. 2011;26:1477-1480.  [PubMed]  [DOI]
232.  Valldeoriola F, Martínez-Rodríguez J, Tolosa E, Rumià J, Alegret M, Pilleri M, Ferrer E. Four year follow-up study after unilateral pallidotomy in advanced Parkinson’s disease. J Neurol. 2002;249:1671-1677.  [PubMed]  [DOI]
233.  Obeso JA, Alvarez L, Macias R, Pavon N, Lopez G, Rodriguez-Rojas R, Rodriguez-Oroz MC, Guridi J.  Subthalamotomy for Parkinson’s disease. In: Lozano AM, Gildenberg PL, Tasker RR, editors. Textbook of Stereotactic and Functional Neurosurgery. Springer-Verlag Berlin/Heidelberg 2009; 1570-1576.  [PubMed]  [DOI]
234.  Bickel S, Alvarez L, Macias R, Pavon N, Leon M, Fernandez C, Houghton DJ, Salazar S, Rodríguez-Oroz MC, Juncos J. Cognitive and neuropsychiatric effects of subthalamotomy for Parkinson’s disease. Parkinsonism Relat Disord. 2010;16:535-539.  [PubMed]  [DOI]
235.  Dulay MF, Strutt AM, Levin HS, Jankovic J, Lai EC, Grossman RG, York MK. Depressed mood and memory impairment before and after unilateral posteroventral pallidotomy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2008;20:357-363.  [PubMed]  [DOI]
236.  Sproesser E, Viana MA, Quagliato EM, de Souza EA. The effect of psychotherapy in patients with PD: a controlled study. Parkinsonism Relat Disord. 2010;16:298-300.  [PubMed]  [DOI]
237.  Armento ME, Stanley MA, Marsh L, Kunik ME, York MK, Bush AL, Calleo JS. Cognitive behavioral therapy for depression and anxiety in Parkinson’s disease: a clinical review. J Parkinsons Dis. 2012;2:135-151.  [PubMed]  [DOI]
238.  Dobkin RD, Menza M, Allen LA, Gara MA, Mark MH, Tiu J, Bienfait KL, Friedman J. Cognitive-behavioral therapy for depression in Parkinson’s disease: a randomized, controlled trial. Am J Psychiatry. 2011;168:1066-1074.  [PubMed]  [DOI]
239.  Veazey C, Cook KF, Stanley M, Lai EC, Kunik ME. Telephone-administered cognitive behavioral therapy: a case study of anxiety and depression in Parkinson’s disease. J Clin Psychol Med Settings. 2009;16:243-253.  [PubMed]  [DOI]
240.  da Conceição FS, Ngo-Abdalla S, Houzel JC, Rehen SK. Murine model for Parkinson’s disease: from 6-OH dopamine lesion to behavioral test. J Vis Exp. 2010;1376.  [PubMed]  [DOI]
241.  Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, Da Cunha C, Takahashi RN. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience. 2008;156:830-840.  [PubMed]  [DOI]
242.  Eskow Jaunarajs KL, Dupre KB, Ostock CY, Button T, Deak T, Bishop C. Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat. Behav Pharmacol. 2010;21:627-637.  [PubMed]  [DOI]
243.  Branchi I, D’Andrea I, Armida M, Cassano T, Pèzzola A, Potenza RL, Morgese MG, Popoli P, Alleva E. Nonmotor symptoms in Parkinson’s disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model. J Neurosci Res. 2008;86:2050-2061.  [PubMed]  [DOI]
244.  Courtière A, Hardouin J, Burle B, Vidal F, Turle-Lorenzo N, Amalric M, Hasbroucq T. Dynamics of executive control and motor deficits in parkinsonian rats. J Neurosci. 2011;31:11929-11933.  [PubMed]  [DOI]
245.  Lee KH, Blaha CD, Harris BT, Cooper S, Hitti FL, Leiter JC, Roberts DW, Kim U. Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson’s disease. Eur J Neurosci. 2006;23:1005-1014.  [PubMed]  [DOI]
246.  Tan SK, Hartung H, Visser-Vandewalle V, Steinbusch HW, Temel Y, Sharp T. A combined in vivo neurochemical and electrophysiological analysis of the effect of high-frequency stimulation of the subthalamic nucleus on 5-HT transmission. Exp Neurol. 2012;233:145-153.  [PubMed]  [DOI]
247.  Ghiglieri V, Pendolino V, Sgobio C, Bagetta V, Picconi B, Calabresi P. Θ-burst stimulation and striatal plasticity in experimental parkinsonism. Exp Neurol. 2012;236:395-398.  [PubMed]  [DOI]