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Dealing with Depression

Depression affects a whopping 25-40% of PD patients with some reporting an even higher prevalence. Yet, PD patients rarely report their depression. This may partially be explained by the fact that many patients with clinically significant depression do not consider themselves depressed. In fact, only about 20% of PD patients experiencing depression receive professional treatment. Unfortunately, depression in PD (DPD) is one of the greatest predictors of poor quality of life and is associated with poor medication adherence, increased risk of falls, greater decline in motor and cognitive function and increased rates of suicidal ideation.

Many PD patients also experience anxiety, and anxiety and depression can occur together 67-76% of the time. Anxiety can manifest variedly as social phobia, panic disorders, obsessive compulsive disorder, among others. A recent study estimated that the average prevalence of an anxiety disorder is 31% in PD patients with one third of patients having two or more anxiety disorders. Anxiety in PD contributes to greater disability and a poorer quality of life, compared to PD patients without anxiety disorders. Unfortunately, it is estimated that less than half of anxiety is treated in PD.

Symptoms of depression and anxiety may overlap with physical symptoms of PD sometimes making diagnosis challenging. However, PD patients should be in tune with their bodies and emotions, recognizing any persistently negative symptoms (apathy, fatigue, poor appetite, irritability, etc.) as untreated depression may worsen with time. There is a growing body of literature supporting the efficacy of both pharmacological and non-pharmacological treatments in DPD and anxiety. Conventional and investigational approaches that may benefit depression and/or anxiety in PD include:

• Antidepressants of the SSRI, SNRI and TCA classes
• Cognitive-Behavioral Therapy
• Repetitive Transcranial Magnetic Stimulation
• Electroconvulsive therapy
• Bright Light Therapy
• Exercise
• Omega-3 fatty acids

Recognizing depression and seeking help is the first step in the appropriate management of depression. Patients should work with their healthcare professional to identify the optimal treatment approach, which likely involves a combination of both pharmacological and non-pharmacological interventions. Although arriving at the best regimen may involve a series of trial and error, being persistent is rewarding, as successfully treating depression and anxiety may improve patients’ quality of life and reduce overall PD disability.


Pharmacological Approaches

To date there are only a handful of placebo-controlled double blind controlled trials for antidepressants in PD. Relative to placebo, efficacy has been demonstrated for nortriptyline, venlafaxine extended release, paroxetine, desipramine and citalopram. Although debate continues whether conventional antidepressants are effective in DPD, these drugs are widely used in PD.

Conventional Antidepressants

Clinicians most often prescribe selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) due to perceived efficacy and safety concerns associated with older classes of antidepressant drugs. In the largest placebo-controlled trial done to date, paroxetine (SSRI) and venlafaxine XR (SNRI) both showed efficacy over placebo in improving depression of DPD patients without dementia. Importantly, no motor side effects were recorded, providing evidence, along with other studies, against the commonly held belief that SSRIs worsen PD motor symptoms. This study provided the first class I evidence that conventional SSRI and SNRI antidepressants are effective in DPD. Although there is currently no evidence to inform the initial treatment choice of SNRI vs. SSRI, it is recommended to try an agent from the alternate class if the first is not effective or well tolerated.

Having greater depression at baseline was the greatest predictor for improvement during treatment, followed by lower anxiety scores, suggesting that DPD patients who experience more severe anxiety may need more intensive or different treatments. Following treatment with venlafaxine or paroxetine, mood symptoms were first to improve after 4 weeks of treatment, followed by somatic symptoms after 6 weeks and cognitive symptoms (concentration and ideation) after 8 weeks. In clinical practice, patients are advised that full antidepressant response may take up to 12 weeks, underscoring the importance of medication adherence. If clinical response is insufficient, adjustments to medication are warranted.

Tricyclic amines (TCAs) are an older class of antidepressants. In their guidelines, the Movement Disorder Society concluded that desipramine and nortriptline are “likely efficacious” for the treatment of DPD. However, clinical practice shows that TCAs are prescribed less frequently as first-line defense due to their unfavorable side effect profile. This includes dry mouth, constipation, confusion, elevated risks of head rush (i.e., orthostasis), irregular heartbeat (i.e., arrhythmias), malfunction of the autonomic nervous system that controls “automatic” functions of the body (i.e., dysautonomia) and the potential for lethal overdose. Prescribing choice is also influenced by the ease of prescribing SSRIs relative to TCAs, which can require monitoring of serum levels and electrocardiograms.

However, much of the rationale for treating DPD may be based primarily on side effect profiles rather than efficacy. In fact, some studies suggest that both SSRIs and TCAs exert an antidepressant effect with comparable effect size,. The first double-blind, randomized placebo-controlled trial comparing desipramine (TCA) to citalopram (SSRI) showed that both drugs were equally effective in improving depression in DPD patients without dementia, with those in the desipramine group showing an improvement sooner, suggesting that desipramine may be useful in providing fast-acting relief in DPD.

According to the results of a second double-blind, randomized placebo-controlled trial, TCAs be superior to SSRIs in certain patients. In this trial, DPD patients assigned to nortriptyline (TCA) performed better on the Hamilton Depression Rating Scale than those assigned to placebo, while those who were assigned paroxetine CR (SSRI) did not. Only those assigned to nortriptyline showed significant improvements in physician-rated overall improvement, social functioning, sleep and anxiety. Furthermore, nortriptyline was well tolerated. In fact, only those in the paroxetine group experienced more side effects than the placebo group. Interestingly, a recent meta-analysis of randomized controlled trials also found that TCAs were better tolerated than SSRIs.

So which is more effective, TCA or SSRI? The findings of several large-scale studies have been equivocal. Clearly the literature only provides more questions than answers. Although existing studies do demonstrate the benefit of TCAs in treating DPD, clinicians should use caution when extrapolating findings to wide-scale clinical use since benefit is based on only a small number of studies. And, although there is a clear need for more well-designed trials evaluating the efficacy of TCAs in treating DPD, TCAs should not be forgotten as a treatment option in the clinic for some patients.


According to the Movement Disorder Society, the dopamine agonist pramipexole is the only drug categorized as “efficacious” and “clinically useful” in reducing depressive symptoms in PD. In a large randomized, double-blind, placebo-controlled study of PD patients with mild-to-moderate depression, those assigned to pramipexole improved in their depression substantially over the placebo group. It is important to point out that patients enrolled in the study were not allowed to be on dopamine agonists at study entry, so it is unclear whether optimizing the dose of pramipexole in patients already on the drug can reduce depressive symptoms.

Such findings are interesting nonetheless considering the fact that pramipexole may be a useful therapy to improve both motor and depressive symptoms simultaneously. However, its unfavorable side effect profile, which includes impulse control disorders, hallucinations and drowsiness, precludes its first-line therapy designation. Pramipexole is recommended when depression develops after the reduction or cessation of dopaminergic treatments or in PD patients that are not yet using dopaminergic treatments but who are experiencing increasing depression and motor disability,.

Other pharmacological interventions

Bupropion is an antidepressant that may not elicit many of the unwanted side effects common to SSRIs, SNRIs and TCAs, including weight gain, sedation and sexual dysfunction. In an older study of bupropion’s effect on motor symptoms, depression improved in five out of 12 depressed using doses appropriate for motor symptoms but too low for treating depression. Successful treatments have been documented in a number of case reports, including several reports of the success of bupropion following unsuccessful treatment with other antidepressants. Due to its interesting mechanism of action, some experts believe that bupropion should be the first-line treatment in PD patients with depression, although clinical trials are needed to support this hypothesis. Mirtazapine, another antidepressant, has a side effect profile favorable to PD patients, including increasing appetite and improving sleep. In an unpublished randomized double-blind, placebo-controlled study of mirtazapine showed that patients receiving mirtazapine 30 mg/day in combination with brief psychotherapy was superior to placebo in reducing depression. These drugs should be used with caution since limited data exists supporting their efficacy.

Non-pharmacological approaches

Some research suggests that antidepressants may not be as effective in PD patients as they are for otherwise healthy individuals due to underlying differences in the pathophysiology of the depression between the two groups. Even in those cases where there is a significant antidepressant response following pharmacotherapy, many patients experience residual depressive symptoms. Furthermore, in some cases, the unfavorable side effect profile and the potential for adverse drug interactions may preclude patients from routinely using antidepressants. Notably, PD patients identify a greater interest in psychotherapy vs. pharmacotherapy for mental health treatment. Therefore, there is a growing interest in alternative and non-pharmacological treatments for DPD.


Fish oil may have antidepressant effects thanks to its rich omega-3 polyunsaturated fatty acid content, which is thought to be important in neural function and cerebral structure. In the only randomized, placebo-controlled study of omega-3, PD patients with major depression who received omega 3 supplementation for three months significantly improved their depressive symptoms on two depression scales over those taking placebos. Importantly, benefits were seen in both those taking omega-3 as an adjuvant to their regular antidepressant and in those taking omega-3 as a monotherapy. According to a recent meta-analysis, omega-3 exhibited a larger treatment effect than pharmacological therapy for DPD. However, because on the low quality of the study, the Movement Disorder Society concluded there is insufficient evidence to recommend omega-3 fatty acids for treating depression. Nonetheless, they did state that there are no safety concerns associated with its use.

Cognitive Behavior Therapy

Cognitive-Behavioral Therapy (CBT) is a type of psychotherapy that helps patients take control over their behaviors, beliefs and patterns of thinking that influence negative emotions in order to better cope with stressful life situations. CBT can be a first-line or adjunct treatment for mild-to-moderate depressive disturbances in PD. In an NIH-sponsored randomized-controlled trial of CBT vs. clinical monitoring that included some patients already taking antidepressants, more than half of patients receiving 10 weeks of CBT demonstrated significant improvements on all clinician-rated and self-report measures of depression. There were significantly more treatment responders in the CBT group compared to the clinical monitoring group (56% versus 8%). Importantly, half maintained the response four weeks after the therapy’s end, as compared to none of the patients in the control group. The CBT group also reported greater improvements in quality of life, coping, anxiety and, interestingly, less motor decline. Positive results were found in several studies following telephone-based CBT. Group CBT therapies, which have the added benefit of social interaction, have also been shown to be effective for depression and anxiety with one study noting retention and even improvement of benefits within a 6 months follow-up.

Repetitive Transcranial Magnetic Stimulation

Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and non-invasive procedure that uses magnetic fields to stimulate areas of the brain. A recent meta-analysis of eight randomized controlled trials concluded that rTMS was superior to sham-rTMS and possessed the same antidepressant efficacy as SSRIs with the additional benefit of some improvement in motor function. Left prefrontal rTMS stimulation has shown promising results in several” small randomized controlled studies”:https://www.ncbi.nlm.nih.gov/pubmed/24190780. In a more recent Hungarian randomized, double-blind and placebo-controlled study, PD patients with mild-to-moderate depression assigned to bilateral rTMS showed improvements in depression and health-related quality of life. Improvements in depression elicited by 10 consecutive rTMS treatment sessions have been reported to last for at least one month after treatment ended or even showed a further improvement . While rTMS appears promising in depression, several considerations may preclude rTMS from becoming a standard part of care, including its cost and its potentially burdensome treatment requirements, as effective treatment likely necessitates multiple rTMS sessions.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a procedure performed under anesthesia in which electric current is passed through the brain. A recent systematic review of ECT literature consisting mostly of case reports or case series, concluded that ECT may benefit patients suffering from PD and depression. Although cognition did not worsen for the majority of patients, many patients experienced delirium or confusion, sometimes requiring cessation of therapy.

In a recent open-label pilot study conducted jointly by Stanford University and the University of South Carolina, 6 PD patients with severe depression at baseline treated with ECT demonstrated significant improvements in mood directly following treatment with continued improvement at one-month follow-up. Patients also improved in levels of apathy, psychosis and motor symptoms without any cognitive side effects. While the lack of well-designed trials currently precludes ECT from being adopted into routine clinical practice, this therapy may be beneficial for patients with severe depression who are refractory to antidepressant medications, especially those with severe behavior disruptions or psychoses.

Bright Light Therapy

Bright Light Therapy (BLT) has been proposed as a safe and inexpensive at-home approach to restore circadian rhythmicity and improve depressive symptomatology in PD patients. Several small studies have demonstrated improvements in depressive symptoms following BLT. For instance, in a small placebo-controlled double-blind study, patients receiving bright light therapy significantly improved their depression scores over those receiving sham therapy; the effect size was similar to SSRIs and was more pronounced in patients who were more depressive at baseline. While this study was only exploratory in nature, a larger double-blind randomized controlled trial of 84 PD patients will assess the effect of 3 months of BLT on depressive symptoms in a six month follow-up period.


Exercise may also have a positive impact on mood in patients with PD. Although the majority of PD exercise studies have included participants with minimal depressive symptoms at baseline, a variety of exercise programs have been shown to elevate mood in PD patients including aerobic training, yoga and dance. In a recent study, 31 mild-to-moderate PD patients were randomized to an early or late start exercise program consisting of aerobic and strength training, consisting of a combined cardiovascular and strength training, for 24-48 weeks. Although the study could not differentiate whether benefit resulted from the exercise itself or the socialization aspect of group exercise, it was found that those who began the program earlier reported significantly fewer symptoms of depression. To elucidate effects of exercise specifically in DPD, a study is currently underway examining the effect of a home-based exercise intervention in veterans with DPD. Understandably, depression and motor symptoms may make adopting exercise habits challenging; however, once maintained, regular exercise may actually improve both depression and motor symptoms.


To date there is only one randomized, controlled study that assesses the effect of pharmacotherapy on anxiety as a primary outcome in PD using a long-acting benzodiazepine, bromazepam. While showing benefit, long-term use of benzodiazepines may produce unfavorable side effects, including memory impairment, confusion and increase the risk of falling, particularly in elderly patients. According to a recent meta-analysis of four RCTs that examined the effect of treatment on anxiety as a secondary outcome, treatments with the SSRI citalopram, the SNRI atomoxetine and TCAs desipramine and nortriptyline resulted in large and statistically significant reductions in anxiety. While this meta-analysis found that paroxetine did not have an effect on anxiety, another study of 30 depressed PD patients showed that paroxetine reduced psychic and somatic anxiety symptoms (secondary outcomes).

Anxiety is often managed through counselling, education-based strategies and relaxation techniques. CBT has been shown to improve anxiety when administered in-person, via telephone and in group settings. When anxiety is severe, a combined approach of psychotherapy and pharmacotherapy may be useful. In patients with severe therapy refractory anxiety, case reports have suggested ECT may be effective. Since several anxiety symptoms may be present in PD, treatment protocols should be tailored for the specific anxiety disorders in PD.

With an urgent need to address anxiety in PD, researchers are finally responding to the call-to-action. The University of Rochester and Johns Hopkins are currently recruiting patients to assess the efficacy of buspirone and rotigotine transdermal patch, respectively, in treating anxiety in PD patients in randomized double-blind placebo-controlled trials.


Patients experiencing depressive symptomatology should first be screened for underlying metabolic disturbances, such as thyroid disease, testosterone deficiency and anemia, which may imitate symptoms of depression. Additionally, a healthcare provider should review all medications to identify and adjust any drugs that may affect mood.

It is crucial to optimize dopaminergic treatment as depression and anxiety may develop during periods “off state” when the DA treatment begins to wear off. To monitor this effect, patients can keep a diary noting when their depressive and/or anxious symptoms occur in relation to their PD medication schedule, noting any extra, missed or delayed doses. Working with a healthcare provider, it may be possible to prevent these symptoms by shortening dosing intervals, switching to an immediate release formulation for more reliable gastrointestinal absorption or adding other medications to increase total dopamine intake or prolong the effect of current medication,. In early PD or in those already on pramipexole, initiating pramipexole or increasing it (as tolerated), respectively, may reduce symptoms of depression enough to postpone additional antidepressant treatment.

The literature reveals that many treatment choices exist with promising results for DPD. However, a review of recent high quality guidelines from the U.S., Canada and Europe has identified significant gaps in evidence. There is a strong need for clinical double-blind randomized studies on the safety and efficacy of different antidepressant agents in PD patients. Without clear guidance, clinicians’ first-line prescribing decision of SSRI/SNRI vs. TCA varies, although trying an agent from a different class if the first choice is unsuccessful is generally recommended. Evidence supporting the efficacy of both TCA and SSRI exists, therefore the choice of antidepressant should be specific to the PD patients’ clinical situation, including depression severity and general health status, following consideration of both benefits and risks.For instance, a TCA may be considered if drooling is an issue and the patient is not demented.

Mental health services should be engaged from the onset as an integral part of comprehensive care. Such services can empower patients to realize their strengths and resilience, assist with formulating meaningful goals, as well as contribute to patients’ hope and optimism for their future. Supporting the central role of mental health services in PD management, the National Parkinson’s Disease Foundation found that a reduced burden of depression is associated with increased referral to mental health.

It is important for patients to be aware of PD-related mood disturbance as untreated depression may worsen with time. Often patients are surprised when given a diagnosis of depression as they believe that low mood and anxiety are a normal part of living with PD. CBT can help patients understand that their depression is a separate and reversible condition. CBT and exercise may be beneficial adjunct therapies to antidepressants. Good nutrition, adequate sleep and peer support programs may also help. Patients should continue to participate in social activities and hobbies without fear of ridicule or embarrassment.

Other treatments for depression, such as bright light therapy and rTMS, hold promise in DPD and merit further investigation in well-designed studies that assess the efficacy of these interventions as monotherapy and in combination with other therapies. For instance, some believe that a combined approach of rTMS, CBT and physical activity may optimize activity-dependent plasticity in the prefrontal cortex to positively influence mood. In more extreme cases of depression, ECT may be beneficial.

Some believe that the optimal management of PD requires close collaboration and coordination across disciplines to effectively address both the motor and psychiatric needs of the patients. For instance, a study showed that PD patients improved in health-related quality of life, motor symptoms, depression and psychosocial functioning following 8 months of integrated care consisting of a movement disorders specialist, PD nurses and social worker, as compared to those receiving care from a general neurologist. A PD care manager such as a nurse or social worker may act as a liaison between the PD patient and medical care providers, including psychiatrists and neurologists, centralizing all medical records and facilitating follow-up and consultation. Ultimately, it is sensible to conclude that healthcare centers using a multidisciplinary approach that invokes the expertise of various specialists would lead to better patient outcomes.

Proper management of DPD begins with recognizing the symptoms of depression, understanding that depression may be treatable through a variety of pharmacological and alternative approaches and finding a healthcare professional (or team of professionals) who can adequately assess DPD, provide a tailored treatment plan, monitor patients over time and modify treatment as necessary. Patients are an integral partner in the treatment process and should actively participate in all aspects of their care plan.

Full list of Depression_References.docx