Encyclopedia
Please note this is a comparison between Version 1 by Claire Chyrsanthi Karpodini and Version 2 by Sirius Huang.
Depression represents one of the most common non-motor disorders in Parkinson’s disease (PD) and it has been related to worse life quality, higher levels of disability, and cognitive impairment, thereby majorly affecting not only the patients but also their caregivers. Available pharmacological therapeutic options for depression in PD mainly include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants; meanwhile, agents acting on dopaminergic pathways used for motor symptoms, such as levodopa, dopaminergic agonists, and monoamine oxidase B (MAO-B) inhibitors, may also provide beneficial antidepressant effects. There is a growing interest in non-pharmacological interventions, including cognitive behavioral therapy; physical exercise, including dance and mind–body exercises, such as yoga, tai chi, and qigong; acupuncture; therapeutic massage; music therapy; active therapy; repetitive transcranial magnetic stimulation (rTMS); and electroconvulsive therapy (ECT) for refractory cases.
- Parkinson’s disease
- depression
- SSRIs
- SNRIs
- TCAs
- MAO-B inhibitors
- non-pharmacological
- complementary
- CBT
- physical exercise
1. Introduction
Neurodegenerative diseases cause a substantial health burden worldwide and their prevalence is on the rise. After Alzheimer’s disease (AD), Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder, affecting more than 1% of the elderly population [1]. The exact pathogenesis of PD remains obscure; although, several genetic factors and environmental exposures, as well as a complex interaction between them, contribute to its development [2][3][2,3]. Concerning the underlying mechanisms, mitochondrial dysfunction, autophagy dysregulation, neuroinflammation, oxidative stress, and proteasome impairment have been shown to play a pivotal role [2][4][2,4]. The neuropathological hallmarks of PD are the progressive loss of dopaminergic neuronal cells in the substantia nigra pars compacta (SNpc) in the midbrain and the accumulation of Lewy bodies and Lewy neurites, which primarily consist of alpha-synuclein protein aggregates [2]. The cardinal motor features of PD include resting tremors, rigidity, bradykinesia, and postural instability while most PD patients also experience non-motor symptoms, such as sleep disorders, autonomic dysfunction, cognitive decline, psychotic manifestations, anxiety, and depression [5]. Non-motor symptoms may actually be more burdensome compared to motor ones and, although levodopa still represents “the gold standard” approach for the symptomatic treatment of PD motor symptoms, the management of non-motor manifestations is especially challenging [6].
Depression represents one of the most common non-motor disorders in PD, affecting approximately 30–40% of PD patients; although, epidemiological evidence across different studies varies widely [7]. In PD, depression has been associated with reduced quality of life, worse levels of disability, cognitive impairment, and increased mortality and morbidity, thereby majorly affecting both patients and their caregivers [6]. Depression appears in all PD stages and it may precede the onset of motor impairment during the prodromal stages of the disease [6]. Risk factors for depression in PD include female sex, increased physical dependence, higher levodopa dose, more severe motor impairment, pain, and daytime sleepiness [8]. Clinically, PD patients with depression display less prominent guilt and self-hate compared to depressed non-PD individuals; meanwhile, the core symptoms of loss of satisfaction, enjoyment/pleasure, and appetite commonly occur [6]. The underlying pathophysiological mechanisms of PD depression are complex, involving impaired cortico-striatal and limbic brain circuits, an imbalance between neurotransmitter systems (mainly serotoninergic, dopaminergic, and noradrenergic), neuroinflammation, and the dysregulation of neurotrophic factors [8].
Depression in PD might go unrecognized since some symptoms, including weight loss, sleep disturbances, psychomotor slowing, and fatigue, can be attributed to the disease itself, regardless of the co-occurrence of depression [9][10][9,10]. The early diagnosis and effective treatment of PD depression are of paramount importance and involve both pharmacological and non-pharmacological therapeutic interventions. However, evidence of the effectiveness and safety of antidepressant medications used against depression in PD is inconsistent, the optimal treatment approach is uncertain, and its management may be challenging [11]. Definite guidelines for PD depression are also lacking [12]. Furthermore, although several non-pharmacological interventions have shown promising potential in the management of PD depressive symptoms, it is still unclear which of these interventions are the most appropriate and for which PD stage under which circumstances. Currently, dual serotonin and noradrenaline reuptake inhibitors (SNRIs), such as nortriptyline and venlafaxine, and selective serotonin and reuptake inhibitors (SSRIs), such as fluoxetine and citalopram, are generally firstly recommended, followed by tricyclic antidepressants (TCAs) [12]. In addition, physical exercise; psychotherapy mainly in the form of cognitive behavioral therapy (CBT); and repetitive transcranial magnetic stimulation (rTMS) can also be considered, despite the inadequately robust evidence [6][11][13][6,11,13].
2. Pharmacological Treatment Approaches for Depression in PD
The use of antidepressant medications, including SSRIs, SNRIs, and TCAs, is the most common treatment strategy for PD depression [14]. It is estimated that up to 25% of PD patients may be on antidepressants at anytime during the course of the disease [15] and SSRIs are more frequently prescribed compared to TCAs [16]. Agents acting on dopaminergic pathways, such as levodopa, dopaminergic agonists, and monoamine oxidase B (MAO-B) inhibitors, may also display antidepressant effects. The following subsections will discuss recent evidence of the role of pharmacological interventions currently used in PD depression, as well as the potential effects of other drugs that are currently under clinical investigation (Figure 1 and Table 1).
Figure 1.
Overview of the pharmacological and non-pharmacological treatments for depression in Parkinson’s disease.
Table 1.
Main types and examples of pharmacological and non-pharmacological treatments for depression in Parkinson’s disease.
| Pharmacological Treatments | |
|---|---|
| Type | Examples |
| SSRIs | citalopram, sertraline, paroxetine, etc. |
| SNRIs | venlafaxine, duloxetine, etc. |
| TCAs | desipramine, amitriptyline, nortriptyline, etc. |
| Levodopa | |
| Dopaminergic agonists | pramipexole, ropinirole, rotigotine, piribedil, apomorphine |
| MAO-B inhibitors | selegiline, rasagiline, safinamide |
| Others | 5-HTP, trazodone, nefazodone, vortioxetine, pimavanserin, reboxetine, rivastigmine, ketamine, exanetide |
3. Non-Pharmacological Treatments for Depression in PD
Although antidepressant medications remain the mainstay of the management of depression in PD, the detrimental effects of polypharmacy; the potential comorbidities, especially in elderly patients; the possible drug interactions; and the limited therapeutic options for pharmacotherapy-resistant cases have paved the way for the investigation of several non-pharmacological interventions [17][72].
3.1. Psychotherapy (Cognitive Behavioral Therapy, Psychodynamic Psychotherapy)
Psychotherapy represents a useful tool for PD depression, especially for patients who have low tolerances or contraindications for antidepressants [12]. CBT aims to promote coping and problem-solving skills and improve the mood of the patients by analyzing and altering their dysfunctional and maladaptive thinking and behavior. Through CBT, patients can recognize their negative or inaccurate ways of thinking and overcome challenging conditions more effectively. CBT consists of several strategies, including psychoeducation, management of anxiety, behavioral activation, restructuring of cognitive processes (e.g., thoughts), emotional regulation, problem-solving methods, and education on sleep hygiene [18][73]. It is considered that CBT should focus on specific PD-related aspects, including beliefs about illness, dealing with loss of functioning, the scheduling of activities related to motor functioning, preparing for functional disability, and realizing that some activities might be avoided because of dysfunctional beliefs and not an actual disability [19][35]. Furthermore, individualized adaptations for potential executive dysfunction and targeting specific problematic areas are important [18][73]. Mechanistically, CBT may activate the orbitofrontal and anterior cingulate cortexes, which are both closely related to emotional regulation [20][74].
Randomized clinical trials and meta-analyses have demonstrated that CBT is an effective non-pharmacological strategy for PD depression [11][21][22][23][11,75,76,77], with an even greater effect compared to antidepressant medications [24][29]. In particular, a recent meta-analysis of CBT in PD showed that an intervention time period of more than 8 weeks was superior to that of less than 8 weeks and non-group therapy was advantageous compared to group therapy [25][78]. Possible reasons for the smaller efficacy of CBT in groups may include the less targeted and individualized therapeutic process and the reduced distraction of the other patients in non-group sessions [25][78]. Studies with follow-up periods of 1–6 months have shown that the beneficial impact of CBT is sustained [26][79]. Interestingly, a meta-analysis including studies with brief psychotherapy has indicated that psychodynamic psychotherapy is more effective than CBT for depression among PD patients. Psychodynamic psychotherapy is a talk therapy focusing on the formation of a therapeutic relationship exploring the early life experiences of the individuals and how these influence their current thoughts and behaviors [27][80].
Telemedicine allows for the remote provision of healthcare services for patients with neurodegenerative diseases, including PD, thereby overcoming geographical barriers and allowing for better access to specialized medical care [28][29][81,82]. Motor fluctuations and lack of sufficient social support may limit the ability of PD patients to attend psychotherapy sessions in-person [19][35]. In this context, the use of telephone-based and video-based CBT has been shown to be feasible and effective for patients with PD and depression [30][31][83,84]. The remote online delivery (telephone- or video-based) of CBT has shown similar efficacy to the offline approach in a recent meta-analysis, highlighting the equal efficacy of both intervention methods [25][78].
Hence, there is a substantial amount of evidence indicating that CBT, and potentially brief psychodynamic psychotherapeutic approaches, provide significant benefits for PD patients with depression. However, some aspects should also be considered, including affordability issues, inadequate support from caregivers, and the long-term effects of this approach, since the progressive neurodegenerative process might limit the more than 1–6 months maintenance of its therapeutic benefits after the cessation of the treatment [19][35].
3.2. Physical Activity and Exercise
Physical activity is a broad term referring to any movement generated by the skeletal muscles, which leads to the expenditure of energy, and it involves sports, occupational, or household activities [32][85]. Although the term “physical exercise” is usually used interchangeably, it implies structured, purposeful, and repetitive movements with the aim to maintain or improve physical fitness, such as aerobic exercise, resistance training, treadmill training, and stationary cycling [32][85]. Physical activity and exercise have shown significant benefits in a wide range of clinical conditions, including depression and PD. Both motor and non-motor symptoms, such as depression, can be improved with physical exercise [32][85]. The cellular processes that contribute to the beneficial effects of physical exercise on depression are supposed to involve increased levels of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF); beta-endorphins; and neurotransmitters, such as dopamine, serotonin, and norepinephrine [33][86]. In PD, physical exercise can promote mesolimbic function and induce the release of dopamine in the striatum [34][87]. In addition, it can inhibit neuroinflammation, mitochondrial impairment, and oxidative stress, as well as regulating synaptogenesis, neuroplasticity, angiogenesis, and the release of neurotrophic factors [35][88]. It has been proposed that physical exercise may improve depression in PD by promoting hippocampal neurogenesis, serotonin biosynthesis, the activation of the endogenous cannabinoid system, and cerebral blood flow [36][89].
Several meta-analyses have confirmed that compared to control interventions, physical activity and exercise could significantly reduce depressive symptomatology in PD patients [32][36][37][38][85,89,90,91]. In particular, general and aerobic exercise, as well as balance training, could ameliorate depressive symptoms of PD patients while stretching exercises did not have significant antidepressant effects [32][85]. Regarding intensity, both light-to-moderate and moderate-to-vigorous exercises provided significant benefits, as shown by a recent meta-analysis [38][91]. Combined training interventions displayed significant effects while aerobic exercise alone did not reach a level of statistical significance in the moderator analysis of this study [38][91], suggesting that exercise type rather than intensity might substantially affect the antidepressant effects of physical exercise. Another recent meta-analysis demonstrated that, regarding disease duration, physical activity provides significant benefits for depression in PD patients for more than 5 years [36][89]. Furthermore, the duration and frequency of physical activity are also important since a total duration of more than 12 weeks, for at least than four times weekly, and 60–90 sessions provided the most benefits in the subgroup analyses of this work [36][89].
Regarding other specific types of physical exercise, a recent meta-analysis showed that although resistance training could improve PD depression, it was not superior to other forms of physical activity [39][92]. However, a subgroup analysis of another meta-analysis showed that resistance training for 60–90 min, more than four times per week for up to 12 weeks, was the most effective exercise type for alleviating depressive symptoms in PD patients with a disease duration of more than 5 years [36][89]. Therefore, the determination of the duration and frequency of the physical activity interventions, as well as disease duration among the relevant studies, further limits the comparability of their results.
Despite their beneficial effects on postural balance, aquatic exercise programs could not significantly affect depressive symptoms in PD patients, as shown in another recent meta-analysis [40][93].
Thus, physical exercise can provide significant benefits for patients with PD and coexisting depression; although, the best exercise type for this population needs to be further explored. In addition, given the diverse requirements of each activity type, therapeutic physical exercise protocols need to be tailored to each patient’s needs and general medical conditions, along with their PD stage, cognitive status, and personal preferences.
3.3. Dance
Dance is a multidimensional activity that combines physical exercise with music and rhythm, social interaction, and cognitive regulation, entailing the maintenance of visual, auditory, and sensory reactions, together with perception, memory, and expression [41][101]. Dance is considered to induce a sense of pleasure and improvement of mood by promoting dopamine release from the ventral tegmental area and the ventral striatum, thereby activating the reward system and basal ganglia circuits [13][42][13,102]. Despite the positive results of several relative clinical trials, two meta-analyses demonstrated that dance was not significantly effective at alleviating depression in PD [43][44][103,104]. Potential reasons for these findings include the large heterogeneity of the relative studies regarding the age of the patients, the PD stage and duration, the short periods of follow-up, small sample sizes in some of the studies, and methodological biases [44][104]. However, a recent network meta-analysis showed that dance was the best non-pharmacological approach for improving depression [11]. This is in line with another recent network meta-analysis, demonstrating that dance is the most appropriate exercise for depression [45][105]. Notably, dance has been linked to increased compliance among PD patients compared to participation in other physical exercise programs [44][104]. Therefore, despite the lack of very strong evidence, dance remains a promising non-pharmacological treatment approach for PD depression in clinical practice. Future studies with larger sample sizes, longer follow-ups, and a higher methodological quality focusing on standardized dance protocols are required in order to confirm its effects on depressive symptoms in PD.3.4. Electroconvulsive Therapy (ECT)
ECT is a well-established treatment approach for psychiatric diseases, including refractory psychosis and depression, with a favorable safety profile in the elderly population [46][106]. Several case series, several observational studies, and one randomized controlled trial have demonstrated that ECT may be beneficial not only for psychotic and depressive symptoms in PD but also for motor impairment, even in patients without comorbid psychiatric manifestations [46][106].
Importantly, systematic reviews have shown that ECT can significantly improve severe depressive symptoms in PD patients without affecting, and even improving in some studies, cognitive function [10][46][10,106]. However, temporary confusion, disorientation, and delirium have been reported in some cases, occasionally resulting in the cessation of ECT [10]. In this context, pulse width alterations and electrode placement adjustments have been recently proposed to be related to fewer side effects on cognition [46][106]. Importantly, ECT was shown to be beneficial for pharmacotherapy-resistant psychotic and depressive manifestations in PD [46][106]. On the other hand, the optimal treatment protocol for the use of ECT in PD depression (duration, number of sessions, necessity of a tapering course) still remains unclear. Nevertheless, before the initiation of ECT sessions, a detailed medical evaluation is needed, including cardiac history, medications, and consent obtainment, in collaboration with the family members of the patient [12].
Although the mechanism underlying the beneficial effects of ECT in depression has not been elucidated yet, it has been suggested to involve neuroplastic modulation in the hippocampal area [46][106]. In rat models of PD, ECT can promote dopamine D1 and D3 receptor binding in the striatum [47][107]; patients with PD display higher homovanillic acid levels in the cerebrospinal fluid after ECT therapy [48][108]. Hence, it seems that dopaminergic regulation may contribute to the antiparkinsonian effects of ECT while further evidence is needed to elucidate its specific effects on PD depression.
3.5. Deep Brain Stimulation (DBS)
DBS in the subthalamic nucleus (STN), which is successfully used for motor symptoms, may also exert beneficial effects for depressive symptoms and impulse control disorders in PD [49][109]. In particular, stimulation in the ventral, anterior, and medial sites of the STN connected with limbic areas is linked to a more pronounced impact on non-motor symptoms [50][110]; meanwhile, pallidal and thalamic stimulation is considered rather neutral for depression [6]. On the other hand, a higher risk for postoperative suicide behavior has been shown to be possibly related to the DBS of the STN compared to the general population [51][111]; although, there is also evidence not supporting this observation [52][112].
Recently, a meta-analysis indicated that, postoperatively, DBS in the STN is associated with improved anxiety and depressive symptoms in PD patients [53][113]. In addition, despite the described reports of mania after DBS, no significant alterations in manic symptomatology were identified in this study [53][113]. However, another meta-analysis that aimed to compare various neuropsychological and neuropsychiatric outcomes after DBS in the STN, compared to that in the globuspallidus internus (GPi) in patients with PD, demonstrated no significant differences regarding depressive symptoms [54][114]. In agreement with this evidence, compared to that of the GPi, DBS in the STN caused similar effects on depressive symptomatology after the intervention [55][115]. Post-surgery, depressive symptoms were shown to be reduced after DBS in the STN and GPi in another meta-analysis [56][116]. In summary, it seems that DBS in the STN might provide some benefits for depressive symptoms in PD; although, the current evidence is too inconsistent to draw definite conclusions.
3.6. Non-Invasive Brain Stimulation (NIBS)
Non-invasive brain stimulation (NIBS) utilizes weak currents or magnetic pulses in order to alter neurophysiological activity in the brain that is considered to be related to clinical conditions. The m frequently used forms of NIBS include rTMS and transcranial direct current stimulation (tDCS) [57][117]. rTMS creates a focal and strong pulsed electromagnetic field via a coil over the patients’ scalp, thereby depolarizing the neurons underneath [58][118]. The rTMS application may also affect the activity of various molecules and regulate several cellular processes, including oxidative stress, neurotransmission, neuroplasticity, gene expression, cell apoptosis, and neuroinflammation [57][117]. On the other hand, via tDCS, the weak current is applied through scalp electrodes, resulting in the depolarization of neurons, modulation of neuronal excitability, and alteration of cerebral blood flow [57][117].
Several studies have demonstrated that rTMS provides significant benefits for PD patients with depression [59][60][119,120]; although, there is also evidence not confirming these findings [61][121]. These contradictory results might be attributed to methodological discrepancies, including the different baseline characteristics of the patients regarding age, the stage and duration of the disease, the simultaneous use of antidepressants, and the type and method of the control group (sham stimulation, clinical monitoring, or other), as well as the different protocol used for the rTMS application [22][76]. Meta-analyses have revealed that rTMS in the prefrontal cortex can indeed alleviate depressive symptoms in PD patients [22][57][62][63][64][65][66][76,117,122,123,124,125,126]. However, high-frequency rTMS was not superior compared to sham rTMS or SSRIs [67][127], or a placebo [68][128], for depression in PD. Importantly, studies that compared the effectiveness of rTMS with that of antidepressants did not show significant differences [22][65][76,125]. However, it has also been shown that rTMS in combination with antidepressant treatment was more effective for PD depression than the use of antidepressants alone [57][117]. Concerning safety, rTMS was well-tolerated and no serious adverse effects were reported; while transient, mild headache and neck pain were the most frequent complications [22][76]. The different statistical methods and inclusion criteria may account for the partially conflicting results of the abovementioned studies.
Depression has been associated with reduced regional cerebral blood flow (rCBF) in the prefrontal cortex of patients with PD [69][129]; rCBF was found to be higher after rTMS treatment in depressed PD patients [70][130]. This evidence suggests that the restoration of hypoperfusion in the prefrontal cortex may underly the antidepressant effects of rTMS in PD depression. Notably, the antidepressant effect of rTMS has been proposed to be mediated by an intact functional connection between the cortex, close to the site of the stimulation, and deeper brain areas [71][131]. Therefore, it could be speculated that the effectiveness of rTMS against depression might be diminished during the course of neurodegeneration at more advanced stages of PD due to the greater and more widespread damage of involved pathways. This mechanism might also partially explain the conflicting results of some relative studies that included patients at different stages of the disease.
Regarding tDCS, the number of studies that have investigated its utility in PD is much fewer compared to the number of those investigating rTMS and sample sizes are small. A recent meta-analysis was inconclusive about the effectiveness of tDCS in PD depression due to insufficient evidence [57][117].
Collectively, despite the lack of strong evidence, rTMS seems to be a possibly useful complementary treatment option for PD patients suffering from depression. However, it would be important to elucidate the patients’ characteristics that may facilitate its antidepressant effects via sufficient randomization, larger sample sizes, and subgroup analyses of future studies.
3.7. Bright Light Therapy (BLT)
Bright light therapy (BLT) is effective for sleep disorders associated with circadian rhythm disturbances and seasonal affective disorder; it does so by modulating circadian rhythm through melatonin [72][73][132,133]. Retinal exposure to light suppresses melatonin release from the pineal gland, which inhibits sleep. Light may promote alertness by inhibiting melatonin, stimulating the monoaminergic system that is related to arousal, and suppressing the activity of the ventrolateral preoptic nucleus, which induces sleep [72][132]. Furthermore, light can reduce the levels of serotonin reuptake transporters and elevate that of serotonin in the brain regions implicated in emotional modulation [74][134].
A randomized controlled trial has indicated that BLT can exert beneficial effects on PD patients with depression; although, it was not superior enough to control light [75][135]. However, BLT was more effective in ameliorating depressive symptoms in PD compared to the placebo group in another study [76][136]. A recent review and meta-analysis found that although among the open-label non-controlled clinical studies BLT could effectively improve depression in PD patients, no significant effects were identified in the following meta-analysis of randomized controlled trials [72][132]. Researchers proposed that the relatively small sample sizes of the included studies and the inconsistent protocols of BLT application, including diverse doses, timings, and durations of treatment, might explain the lack of statistical significance [72][132]. On the contrary, another more recent meta-analysis indicated that light therapy, including BLT and blue–green light therapy, exerted beneficial effects on PD depression compared to the control groups [77][137]. Future studies with more standardized treatment BLT protocols are needed to clarify its effects on PD depression in clinical practice.
3.8. Acupuncture
The broader term of acupuncture refers to the stimulation of specific body sites with needles, electricity, lasers, or pressure [78][138]. Acupuncture has been widely used for various psychiatric and neurological disorders, including motor and non-motor symptoms of PD. A meta-analysis demonstrated that acupuncture-related therapies showed inefficacy in improving depressive symptoms in PD patients [78][138]; another one showed that it was effective in alleviating depression in PD [79][139] and a 2-month course was found to represent the optimal intervention duration [79][139]. The different inclusion criteria and the broader definition of acupuncture therapies in the first meta-analysis may explain the different findings. Mechanistically, it has been recently revealed that acupuncture may alleviate depressive behavior in rat models of PD, possibly by upregulating the mTOR pathway, suppressing autophagy, increasing dopamine levels, reducing alpha-synuclein content, and enhancing the expression of synaptic proteins [80][140]. Hence, acupuncture may represent an effective complementary treatment approach for PD depression; although, the optimal methods and techniques for this population need further investigation.
3.9. Lee Silverman Voice Treatment (LSVT)re
3.9. Lee Silverman Voice Treatment (LSVT)
The Lee Silverman Voice Treatment (LSVT) is an exercise-based behavioral therapy program that involves amplitude training combined with sustained attention of a sole movement, thereby enabling long-term maintained physical and cognitive participation in functional activities [81][141]. There are mainly two types of LSVT: the LSVT-LOUD, which focuses on speech, and the LSVT-BIG, which focuses on the limb motor system [81][141]. Interestingly, a clinical trial indicated that the LSVT-BIG could improve depressive symptoms in PD patients compared to general exercise [82][142]; although, there is also evidence not replicating these effects [83][143]. However, a recent meta-analysis showed that the LSVT-BIG was the second most effective non-pharmacological intervention for PD depression after dance intervention [11], suggesting that the LSVT holds a promising potential and its efficacy in PD depression needs to be further examined.
3.10. Other Non-Pharmacological Treatments (Music Therapy, Active Theater, Massage Therapy, Cognitive Training, Virtual Reality)
There is also a variety of other non-pharmacological treatments, such as music; music-contingent gait training via a technique called Ambulosono, which utilizes step size for controlling the real-time playing of motivational music, could reduce anxiety and depressive symptoms in patients with PD [84][144]. However, no significant effects on depressive symptoms were detected in patients with PD as a result of group music therapy with voice and singing intervention in another study [85][145].
Another example is active theater. A randomized controlled single-blinded study indicated that participation in active theater for 3 years could significantly improve depression in PD patients compared to the control group receiving physiotherapy [86][146]. Another study demonstrated that psychodrama with role-playing in groups significantly alleviated depressive symptoms in PD patients compared to the control group that received no intervention [87][147]. Social interaction, combined with the necessity of controlling body movements in order to impersonate a theater character, has been proposed as a potential mechanism [86][146].
Regarding massage therapy, a recent systematic review indicated that several non-motor symptoms in PD patients, including depression, were improved via traditional Japanese, Thai, Yin Tui Na, and classical deep therapeutic massage [88][148]; the neurobiological processes that may contribute to these effects remain largely unknown.
Cognitive training incorporates the structured teaching of various strategies or guided practices on particular tasks focusing on specific cognitive domains [89][149]. Cognitive training has shown beneficial effects on cognitive function in patients with mild cognitive impairments and healthy-aged individuals [89][149]. In PD, a meta-analysis of randomized controlled trials indicated that cognitive training could indeed improve cognitive function; but, the results were statistically insignificant for depression [89][149].
More recently, rehabilitation methods have been expanded by the use of virtual reality, which represents an innovative technological method, via which the simultaneously auditory, visual, and tactile stimulation can promote cognitive and motor function [90][150]. Rehabilitation training based on virtual reality has gained increasing attention for neurodegenerative diseases, including PD. A recent systematic review and meta-analysis concluded that virtual reality rehabilitation training could improve depressive symptoms in PD compared to control groups; video game consoles were shown to enhance the beneficial effects [90][150]. Virtual reality dance exercises could alleviate depressive symptoms in PD patients compared to controls [91][151], suggesting that virtual reality holds a promising potential for aiding in the management of PD depression.
As a general recommendation, pharmacological therapy is usually first suggested; non-pharmacological interventions could be additionally used or possibly proposed as even a first choice for patients with mild symptoms.
