Spotlight on the Management of Depression, Anxiety, and Psychosis in People Living with Parkinson Disease

Roughly 10 million people worldwide have Parkinson disease (PD), with an estimated 90,000 new cases diagnosed per year in the United States.¹ Projected annual health care costs for people with PD grossly underestimate expenses for mental health care and rehabilitation.¹ The pathophysiology of PD often leads to neuropsychiatric symptoms (NPS), which are common at initial presentation and throughout the disease course. NPS are progressive and associated with worse prognosis, accelerated motor disease, and greater disability, necessitating prompt recognition and active management.²

It is not uncommon for specific NPS to fluctuate throughout the day as with motor symptoms; careful history-taking and close follow-up for symptom monitoring should be used to guide treatment.² NPS are varied and can be categorized by their nature and impact. Common NPS include mood disorders, such as depression, anxiety, and apathy; symptoms of psychosis, such as hallucinations and delusions; cognitive impairment, ranging from mild to major neurocognitive disorder; impulse control disorders (eg, hypersexuality, compulsive gambling, other compulsive behaviors); sleep disorders (eg, insomnia, rapid eye movement sleep behavior disorder); dopamine dysregulation syndrome due to overuse of dopaminergic medication; and dopamine agonist withdrawal symptoms.³

NPS can affect quality of life (QoL) considerably. Depression, rather than motor symptoms, is often cited as the primary contributor to reduced QoL in people living with PD.² This review focuses on depression, anxiety, and symptoms of psychosis, which are common comorbidities of PD.² A more detailed description of other NPS, including their prevalence, manifestations, and treatment, can be found elsewhere.^3,4

Prevalence
NPS are prominent among people with PD and contribute to disability.² Depression and anxiety frequently co-occur.^3,5 Affective disorders, such as depression and anxiety, are often treated with the same pharmacologic management strategies, attributed in part to the shared neurodegenerative changes in the dopaminergic, serotonergic, and noradrenergic systems.³ Depression and anxiety may go undetected due to overlap with motor, cognitive, and somatic symptoms of PD.⁶

Depression affects ~38% of people with PD; anxiety affects between 30% and 40%.^3,5 Depression is often cited as the primary predictor of QoL in PD,⁶ highlighting both the prevalence and prominence of mood as part of the PD experience. Symptoms of psychosis (eg, hallucinations, delusions), which are more prominent in later disease, have a cumulative prevalence of up to 60%.^2,7 Psychosis is associated with greater cognitive impairment and advanced disease progression.²

Presentation and Clinical Assessment
NPS can develop at any time during the course of PD and may be present at the time of diagnosis. This is particularly relevant for affective disorders, which may manifest as part of a prodrome, with NPS preceding motor symptoms by 1 to 2 decades.^3,8 These symptoms can increase after diagnosis and tend to persist.⁷ Recent research suggests an equal prevalence of affective symptoms in men and women, in contrast to previous reports of higher prevalence in women.^5,6,9 Affective symptoms may be obscured by other aspects of PD, such as psychomotor retardation or flattened affect, or may fall below traditional thresholds for diagnosing a mood disorder.¹⁰ Nevertheless, these subsyndromal symptoms affect QoL considerably and should be assessed regularly. An inclusive strategy is recommended to promote holistic assessment, documenting symptoms regardless of their attribution to PD or a comorbid mental illness.¹⁰ A comprehensive psychiatric history at initial presentation may reveal a history of depression or anxiety, both of which are risk factors for affective disorders within the context of PD.^3,8

Symptoms of psychosis are less often present at initial diagnosis, but commonly develop and advance with disease progression; mild experiences with retention of insight may progress to severe, pervasive experiences with loss of insight.¹¹ Visual hallucinations and a sense of presence are most common; auditory hallucinations, tactile hallucinations, and delusions can also occur.^9,11 Older individuals, those with longer disease duration, and those with greater cognitive impairment are more likely to experience symptoms of psychosis.¹¹ Prolonged and high-dose use of dopaminergic medications has been implicated as a risk factor for symptoms of psychosis, complicating the clinical course.¹¹

Clinical rating scales can be used to assess symptom burden and monitor progression,¹² including the Movement Disorders Society–sponsored Nonmotor Rating Scale,⁹ Beck Depression Inventory, Geriatric Depression Scale, Parkinson Anxiety Scale, Geriatric Anxiety Inventory, Neuropsychiatric Inventory, and Brief Psychiatric Rating Scale. No single scale is adequate for exploring symptoms of psychosis in PD and a combination may be necessary.¹¹ The Movement Disorders Society has published an inventory of recommended rating scales (see https://www.movementdisorders.org/MDS/Education/Rating-Scales/MDS-Recommended-Rating-Scales.htm). 

Pharmacologic Management
Most clinicians prescribe medications to control NPS despite a lack of robust evidence of efficacy. Optimization of dopamine replacement therapy tailored to both motor and mood symptoms should be the initial approach. In one of the largest randomized controlled trials (RCTs) of treatment of PD-related depression, titration over 12 weeks of the dopamine agonist pramipexole was effective in reducing participants’ depression scores and Unified Parkinson’s Disease Rating Scale part III motor scores. The antidepressive effect of pramipexole accounted for 80% of the improvement in Unified Parkinson’s Disease Rating Scale scores.⁴ In another RCT, the selective monoamine oxidase B inhibitor selegiline in combination with levodopa was found to improve cognitive function and mood symptoms more than levodopa or dopamine agonists alone.³ This effect was more pronounced for participants with a severe akinetic subtype compared with those with a tremor-predominant subtype. As mentioned previously, prolonged use of high-dose dopamine replacement therapy may predispose to the development of symptoms of psychosis and impulse control disorders.¹¹

Depressive symptoms may be resistant to dopamine replacement therapy despite adequate motor symptom control. A meta-analysis of studies conducted through 2016 comparing nondopaminergic treatments for PD-related depression found insufficient or mixed evidence for many of the agents evaluated.⁴ The serotonin-norepinephrine reuptake inhibitor venlafaxine was effective and well-tolerated in a high-quality RCT with >100 participants. Although larger studies are needed, venlafaxine is clinically useful for treating PD-related depression.³ Evidence for effective selective serotonin reuptake inhibitors (SSRIs) was conflicting (for paroxetine) and notable for increased risk of hyponatremia and cardiac arrhythmias at higher dosages in older individuals (for citalopram). However, due to their established efficacy in populations without PD, SSRIs may retain some clinical utility for people with PD. The tricyclic antidepressants (TCAs) nortriptyline and desipramine demonstrated more consistent efficacy but were generally less well-tolerated due to adverse events, side effects, and drug–drug interactions.^3,4

For several reasons, there are few studies evaluating pharmacologic management of anxiety in PD. One small RCT compared the anxiolytic buspirone with placebo, and found it ineffective, mostly due to side effect intolerability.³ SSRIs or venlafaxine remain first-line choices for generalized anxiety management in PD, given the overlap in anxiety and depression pathophysiology and lack of evidence to support other agents. Although clinicians should avoid prolonged benzodiazepine use in older individuals, a short course of low-dose benzodiazepine may be useful for treatment of severe anxiety attacks. Individuals should be monitored for worsening cognition, balance or gait disturbances, and excessive sleepiness.³ For individuals in whom an SSRI or TCA effectively treats depression or anxiety, close monitoring for serotonin syndrome or antimuscarinic effects is necessary. SSRIs may worsen tremor in up to 5% of individuals and the presence of motor fluctuations may obfuscate this side effect.⁴ These data reiterate the complex interplay between mood and motor symptoms, in which improvement in mood may be partially associated with improvement in motor symptoms severity or use of PD medicines (with pramipexole or selegiline) or independent of gross motor changes (with venlafaxine, SSRIs, or TCAs).^3,4,13,14 Thus, adequate treatment of affective disorders will likely improve QoL ratings and neurologic outcomes regardless of pharmaceutical mechanism of action.

First-line management of psychosis in PD includes medication review and reduction in dopamine replacement therapy, if possible.¹¹ The atypical antipsychotic agents clozapine and pimavanserin have demonstrated level I efficacy against symptoms of psychosis in double-blinded placebo-controlled RCTs.³ Frequent laboratory monitoring for agranulocytosis is necessary with clozapine use. Use of antipsychotics requires careful consideration of the risks of increased morbidity and mortality versus the benefits of preventing or controlling symptoms of psychosis that increase mortality risk. 

Any pharmacologic management will require attentive monitoring for worsening PD symptoms, side effects, toxicity, and drug interactions. The most effective agents for depression, anxiety, and symptoms of psychosis discussed previously are summarized in Figure 1.

Figure 1. Among the 10 to 11 million people worldwide with Parkinson disease, the cumulative prevalence of depression, anxiety, and symptoms of psychosis is 38%, 30% to 40%, and 60%, respectively. Untreated symptoms are associated with reduced quality of life, motor disease acceleration, and greater cognitive impairment. The figure includes evidence-based recommendations for pharmacologic and nonpharmacologic management discussed in the article. Created in BioRender (https://BioRender.com/rrqtzod).
*Recommended for generalized anxiety.
†Short-term, severe anxiety attack management only.
^#Reduction in dopamine therapy if possible. 
^$Only available in the United States. 

Nonpharmacologic Management
Considering the possible contraindications, side effects, and narrow therapeutic index of certain medications, many people with PD may opt for nonpharmacologic treatment to manage depression, anxiety, and psychosis. The most widely studied and effective interventions include physical activity, psychotherapy, noninvasive brain stimulation (NIBS), electroconvulsive therapy (ECT), and complementary techniques, such as mindfulness and acupuncture. It is wise to consider a multidisciplinary approach to implement nonpharmacologic treatments, including physical, occupational, exercise, and psychologic therapies. This may not be feasible for every individual, however, due to economic and resource restrictions.

Physical activity is one of the best-documented management strategies for affective NPS in PD, demonstrating both direct neurologic and indirect psychologic effects.¹⁵ Physical activity promotes neuroplasticity by improving cellular metabolism and reducing proinflammatory cytokine levels. Exercise preserves muscle mass, possibly delaying motor complications of PD.¹⁵ In terms of mood-related symptoms, physical activity has been shown to reduce both depression and anxiety severity, proposed by the mechanisms of rebuilding nervous tissue, stimulating related brain areas, and promoting adaptive behaviors.¹⁵ In addition, physical activity can enhance mood and self-perception by boosting self-efficacy, fostering a sense of accomplishment and promoting social engagement.¹⁵ The most beneficial subtypes of physical activity for reducing affective symptoms include aerobics, mind–body, and resistance training, but many meta-analyses report that consistency supersedes modality.¹⁵ Few studies have been able to show an improvement in symptoms of psychosis after physical activity. Figure 2 outlines important considerations for implementation of a physical activity program.

Figure 2. Suggested approach to implementing a physical activity program. Interventions involving physical activity must be tailored to individual motivation, confidence, and functional status; postural instability, bradykinesia, and shuffling may affect the ability to perform certain activities safely. It is essential to understand the individual’s needs, goals, and access to resources. Created in BioRender (https://BioRender.com/yux9b5h).
*Resources include presence of a care partner, financial means, insurance coverage, and geographic proximity to rehabilitation services (physical and occupational therapy). If feasible, care partners and the multidisciplinary team should be involved in safety evaluation and selection of physical activity modality. Regular follow-up with patients and care partners is necessary to evaluate success and make adjustments to the program as needed.

Psychotherapeutic techniques, such as cognitive behavioral therapy (CBT), are commonly used to manage psychosis, depression, and anxiety. CBT leverages neuroplasticity to enhance emotional awareness and develop coping skills through a structured, conditioning-based talk therapy process.¹⁶ CBT is beneficial for management of symptoms of depression and anxiety with a small to moderate effect size comparable to pharmacologic interventions without side effects, drug interactions, or requirement for laboratory monitoring.^17,18 When used for psychosis management, CBT focuses on reestablishing circadian rhythms, optimizing sleep hygiene, and addressing false beliefs to prevent episodes of psychosis.^3,19 Treatment of acute symptoms of psychosis relies on ensuring adequate vision and hearing with frequent reorientation to reality.¹¹ Efficacies of other psychotherapeutic techniques, including acceptance and commitment therapy, social support, and group therapy, are being investigated.

Brain stimulation techniques may also alleviate NPS in PD. Repetitive transcranial magnetic stimulation (rTMS) is a promising NIBS technique for managing both motor and nonmotor symptoms in PD, including depression.²⁰ Application of rTMS over the prefrontal cortex alleviated symptoms of depression in PD comparable to antidepressant medications.²¹ The impact of rTMS on anxiety management is under investigation, but it has shown promise when combined with other interventions. Transcranial direct current stimulation, a NIBS technique with more portable equipment compared with rTMS, has demonstrated some efficacy for affective symptom treatment in preliminary trials, but requires ongoing investigation. In contrast to NIBS, ECT is minimally invasive and conducted under generalized anesthesia; it remains the most effective option for severe, treatment-resistant psychosis and depression in PD.²² ECT promotes long-term dendritic arborization and has been associated with significant improvements in depressive symptoms and psychosis, as well as positive effects on motor function.^3,21,22 Postprocedure memory and attention deficits are generally transient,²² and the therapeutic benefits may outweigh the risks. Further research into mitigating immediate side effects, long-term impact on cognition, and preventing relapse after treatment discontinuation is necessary for optimizing its use in people with PD.

Complementary modalities including mindfulness-based interventions²³ and acupuncture²⁴ have shown promise in RCTs for reduction of symptoms of depression and anxiety and increases in QoL. Mindfulness-based stress reduction strategies have been increasingly used in many chronic conditions to reduce depression and anxiety, particularly PD.²⁵ However, both mindfulness and acupuncture lack evidence supporting utility against symptoms of psychosis.

Conclusion
Depression, anxiety, and psychosis are common and debilitating nonmotor symptoms in PD.^2,3,5-7 Despite their impact on QoL and substantial contribution to disease burden, these symptoms are largely underrecognized and undertreated.^11,12 Affective disorders such as depression and anxiety are more prevalent in the early stages, whereas psychosis tends to develop later in the disease course. The progressive nature of PD makes symptom management complex, and treatments that were effective at one stage may lose their efficacy over time, necessitating adjustments. Therefore, it is crucial to approach treatment as a trial-and-error process, setting realistic expectations with patients and their caregivers. In selecting treatments, an individual-centered, shared decision-making approach should be used, especially when a multidisciplinary team is involved and resources allow. 

The initial approach to NPS management should start with optimization of dopamine replacement therapy for control of motor symptoms.³ Further management should be tailored to the individual’s specific needs, including a combination of pharmacologic and nonpharmacologic treatments.²¹ More studies with larger sample sizes are needed to validate effective therapies and strengthen recommendations for any type of treatment for NPS, especially anxiety and psychosis. Therapies selected on the basis of the individual’s goals and disease stage will have the greatest impact.