Parkinson's disease (PD) produces dysfunction of motor performance and requires long-term treatment. Chronic exposure to L-dopa and related dopaminergic agents is associated with the increased disability¹. The neurological features of PD are now well understood, but efforts are required to understand the psychological aspects of PD and initiate further investigations into the underlying mechanisms of the disorder so that therapeutic strategies are further improved.

Major neuropsychiatric co-morbidities such as depression, anxiety, and psychotic symptoms result in a major impact on the quality of life of the patients and their caregivers. About 64.7% of PD patients express at least one of these psychiatric symptoms like depression², hallucinations, anxiety and psychoses^3,4,5. Early-onset PD, advanced progression of PD, female gender, anxiety, cognitive impairment, and psychosis are considered to be main factors consistently correlated with depression in PD⁶. PD patients with depression tend to experience less guilt and self-blame, and greater rates of anxiety, cognitive deficits, irritability, and suicidal ideation than major depression patients without PD⁷.

The underlying mechanism behind the correlation between Parkinson's disease and depression is still unclear. It has been thought that patients with PD often present depressive symptoms during the course of their disease (not surprising given that it is a chronic, life-limiting disorder that affects dopamine neurotransmission) On the other hand, several prospective studies have reported a higher risk of developing PD among individuals with depressive symptoms or taking antidepressants. Some proposed mechanisms to explain this link include a reactive drop-off in serotonin as a consequence of the dopaminergic depletion observed in PD, mood alterations following basal ganglia dysfunction or involvement of dopaminergic structures both in depression and PD. It is therefore unclear whether: (1) depression increases the risk of PD; (2) depressive symptoms are just another clinical manifestation of PD, preceding in some cases the onset of the classical motor symptoms; or (3) depression and PD are different consequences of common pathophysio-logical mechanisms⁸.

In various studies, depression in PD is reported to be a combination of medical, neurochemical, and psychosocial phenomena. It has been reported that pathologic degeneration of mesolimbic dopamine, norepinephrine, and serotonin pathways in conjunction with degeneration of orbital–frontal circuits and subcortical structures, such as the locus coeruleus, dorsal raphe nuclei, and ventral tegmental area, are suggested to be associated with the development of depressive symptoms⁹. However, Kim et al have not found any correlation between serotonergic dysfunction and depressive symptoms in PD patients with PD but there are studies that have evidence that the dysfunction of noradrenergic and limbic monoaminergic projections was associated with depression¹⁰.

The prevalence of depression in PD varies widely from 2.7 to 76% because of lack of appropriate diagnostic criteria applied to define depression, and the diversity of the study populations assessed. Marsh et al recently proposed provisional diagnostic criteria for depression in PD¹¹. In the majority of cases, untreated depressive symptoms persist or worsen, but the best treatment to treat depressive symptoms in PD patients is still uncertain. A recent meta-analysis study revealed that the efficacy of antidepressant treatment in Parkinson's disease patients has not been adequately evaluated, with less than 30 studies having addressed the issue. Therefore, although oral antidepressants, behavioral therapy or electroconvulsive therapy are currently used in the treatment of depression in Parkinson's disease, evidence-based recommendations are still scarce¹²,¹³,¹⁴,¹⁵.

One concern regarding the prescription of oral antidepressants in PD patients is the risk of deterioration of Parkinsonism as well as interactions between the medications used to treat PD and antidepressants¹⁶. Selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants in PD. Psychotherapeutic treatment options are especially worth considering since there is the possibility of adverse interactions between antidepressant and antiparkinsonian medications, although no published psychotherapy trials in PD patients are available. Initiation of any antidepressant therapy was associated with a higher risk of PD in the 2 years after the start of treatment, which suggests that depressive symptoms could be an early manifestation of PD, preceding motor dysfunction. The observed association between antidepressants and PD risk could have implications for clinical practice. Therefore, patients with depression that start developing motor symptoms, should be promptly evaluated to rule out a diagnosis of PD ⁸.

Several studies revealed a high prevalence of anxiety in PD¹⁷ while some others¹⁸ have shown that anxiety/depression comorbidity is common in PD. Anxiety disorders frequently occur in 40% of patients. Anxiety may also contribute to the significant deterioration of parkinsonian symptoms. Anxiety in PD may be related to the neurochemical alterations of the neurodegenerative disease itself¹⁹. There is evidence for the involvement of central noradrenergic systems, but other neurotransmitters (e.g., serotonin, dopamine) may also be involved²⁰. Anxiety in PD could be due to interactions between dopaminergic deficits and the variable deficits in norepinephrine and serotonin that are known to occur in PD. Both the ventral tegmental area and the locus coeruleus are characterized by significant neuronal loss in PD. There is evidence of the effectiveness of SSRIs against anxiety in PD patients⁹,¹⁹. Hitherto, there has been no evidence from randomized, placebo-controlled trials as to the treatment of anxiety in patients with PD.

Psychotic symptoms occur rarely as compared to depression in PD patients. Usually patients with comorbid dementia, depression, or delirium bear the greatest risk of concomitant psychotic symptoms²¹. Prevalence of hallucinations in treated PD patients vary from 15 to 52%. Delusions occur in 7–16% of patients who have PD, usually in addition to hallucinations.²²,²³ Parkinson's disease patients manifest psychotic symptoms • 10 years after the initial diagnosis. The underlying mechanism of psychosis in PD remains uncertain, but stimulation of mesolimbic and mesocortical dopamine receptors by dopaminergic agents has been implicated as a major cause of psychotic symptoms.

The treatment of psychosis in PD is a challenge, since optimizing the management of motor symptoms with dopaminergic medication typically worsens psychosis, and treating psychosis with an antipsychotic can worsen Parkinsonism.²⁴,²⁵ A recent review discussed the efficay of quetiapine as common choice for treating PD psychosis.²⁶ While atypical antipsychotics continue to be the most commonly prescribed pharmacologic agents in the treatment of PD psychosis, it has been found that they are associated with an increased risk of mortality when used in elderly patients with dementia. This finding is particularly relevant for PD psychosis considering the age and frailty of the late-stage PD patients who typically experience psychosis. Since the mechanisms by which atypical antipsychotics cause increased mortality has not been fully elucidated, alternative therapies are currently being evaluated. Recently, cholinesterase inhibitors have been described to have an effect on psychosis in PD but further research is necessary before cholinesterase inhibitors can be recommended as a first-line treatment for PD psychosis.

It has been reported that reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. This provide evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.²⁷

Some studies reported the allelic variation of serotonin transporter expression which might be associated with depression in Parkinson's disease.²⁸ They found that patients with the short allele of the 5HTTLPR had significantly higher scores on the Hamilton Depression Scale. A functional promoter polymorphism of the monoamine oxidase A (MAOA) gene showed no association in this study. Dissanayaka et al observed no significant genotype or haplotype associations of serotonin and dopamine transporter gene suggesting that common genetic variables around the dopamine and serotonin transporter genes do not play a significant role in the etiology of depression in PD.²⁹

Arabia et al studied the risk of depressive disorders and anxiety disorders among first-degree relatives of patients with PD compared with first-degree relatives of controls. They studied 1000 first degree relatives of 162 patients with PD and 850 first degree relatives of 147 controls and found an increased risk of several psychiatric disorders in first-degree relatives of patients with PD compared with first-degree relatives of controls.³⁰ As for now, there is no clear picture of genes involved in comorbid condition of PD and neuropsychiatric conditions. Even though genetic studies offer the most promising approach to clarifying the etiology of neurodegenerative disorders like PD, the underlying mechanisms of this comorbidity with neuropsychiatric complications needs further exploration.

Deep brain stimulation (DBS) represents a major advance in the treatment of various movement disorders and neuropsychiatric diseases. A recent study by Wang et al reported the long-term effects of deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) on depression in patients with Parkinson's disease (PD), the evaluation of the depression and motor function was performed a total of six times. Depression was evaluated by the Self-Rating depression Scale (SDS) and Hamilton Rating Scale for Depression (HAMD). Motor function was evaluated by the third part of the Unified Parkinson's Disease Rating Scale (UPDRS-III). They concluded that the improvement in motor symptoms resulting from STN-DBS can improve depression in PD patients, but its long-term effects were average³¹.

Another study reported a randomized clinical trial of cognitive and mood effects of STN versus GPi DBS directly compared the effects of unilateral DBS in subthalamic nucleus (STN) or globus pallidus (GPi) on QoL in 42 non-demented patients with medication-refractory PD. They found that all patients endorsed better overall QoL after surgery. However, despite similar motor and mood improvements, GPi patients improved more than STN patients. Patients reported better QoL on subscales of mobility, activities of daily living (ADLs), emotional well-being, stigma, cognition and discomfort, but not on those of social support and communication. Improvements on the mobility, ADLs, stigma and social support subscales were greater amongst GPi patients³². DBS of non-motor areas like the Anterior Cingulate Cortex and Nucleus Accumbens have also been used in the treatment of medication-resistant depression not associated with PD.

Reconsidering the data dealing with effects of DBS on psychiatric symptoms, DBS has proven to be capable of providing significant benefits for several neuro-pathologies including QoL in PD patients. It seems that these symptoms are treatable with the use of deep-brain stimulation of appropriate targets in the brain.

Depression, anxiety and psychotic symptoms are frequent non-motor symptoms in PD patients with a significant impact on health-related quality of life and caregiver distress. These non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, unrecognized and untreated by physicians and are a key determinant of quality of life. Even when identified, there is a common perception that many of these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD, although clinically recognized, has received little attention. Therefore, more research needs to be done in the detection and treatment of psychiatric symptoms in PD patients.