Managing Symptoms of Anxiety, Panic, Depression, Apathy, and Pseudobulbar Effect in Individuals with Parkinson Disease

Neuropsychiatric symptoms of Parkinson disease (PD), including anxiety, panic, depression, apathy, and pseudobulbar affect (PBA)—although less recognized than the typical motor symptoms of PD, such as bradykinesia, rigidity, and tremor—are common in people with PD. These symptoms may occur years before the onset of motor symptoms or at any time in the disease course. Diagnosis and treatment of these conditions are crucial because the burden of these nonmotor symptoms can diminish quality of life and sense of well-being. Moreover, untreated mood symptoms can lead to inactivity and disengagement, which can contribute to more rapid disease progression. The Table lists details of medications used to treat neuropsychiatric symptoms of PD.

Anxiety
Anxiety is a common symptom associated with PD and can present in a variety of ways, including generalized anxiety disorder, panic disorder, and social phobia. Studies suggest that up to 40% of individuals with PD may experience debilitating anxiety.¹ Anxiety is associated with worse quality of life and is often underdiagnosed and untreated. 

Despite the high prevalence of anxiety in people with PD, clear treatment guidelines are lacking. Limited evidence suggests that benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are preferred treatments for pharmacologic management of anxiety in PD. Selective noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) also are commonly used. SSRIs, SNRIs, and TCAs are also effective in managing coexisting depression. Buspirone may be helpful in treating isolated anxiety. However, all of these medications can have side effects that affect quality of life, such as insomnia, drowsiness, and sexual dysfunction. Although benzodiazepines can be an effective treatment, they should be used with caution because they are associated with increased confusion, risk of falls, and dependency.

Individuals should be asked about the timing of their anxiety symptoms, as they may correlate with “Off” periods and optimizing dopamine replacement therapy can be helpful in reducing anxiety symptoms. Even with treatment, debilitating symptoms may persist. Further research and recommendations for treatment of anxiety are needed.

Psychotherapy as a nonpharmacologic treatment can be helpful in managing anxiety but is underutilized. 

Depression
Depression is one of the most frequently occurring neuropsychiatric symptoms associated with PD, affecting ~56% of individuals some point during the disease course.² Depressive disorders can develop at any time and frequently predate the onset of motor symptoms.³ The pathophysiology of depression is thought to involve degeneration of dopaminergic neurons leading to disruption in serotonergic neurons and dysfunction of depression-related orbitofrontal–basal ganglia–thalamic circuits.⁴

Clinical features of depression can vary, and include persistent changes in mood, attitude, and behavior; inability or reduced capacity to experience pleasure; somatic signs and complaints (eg, muscle tension, gastrointestinal symptoms); cognitive changes (eg, poor concentration, memory difficulties); and disruptions in sleep and appetite. 

Improved assessment and recognition of depression in PD is imperative for improving PD care.⁴ We recommend screening for depression and depressive symptoms routinely at clinic visits by asking direct questions to patients and caregivers and administering screening questionnaires (eg, 15-item Geriatric Depression Scale [GDS-15], Beck Depression Inventory [BDI], 9-item Patient Health Questionnaire [PHQ-9]) on a regular basis. An international study of >1000 participants with PD found that >50% had clinically significant depressive symptoms based on BDI scores.⁵

For treatment, we suggest an SSRI or a SNRI as first-line therapy over alternative agents such as TCAs due to the higher risk of anticholinergic side effects (eg, dryness, hypotension, cognitive slowing) in this population.⁶ A TCA could be considered when individuals do not respond to an SSRI or SNRI. We do not recommend treatment with antipsychotic medications due to the risk of worsening PD symptoms. According to a 2019 Movement Disorders Society review,⁶ the efficacy of venlafaxine, citalopram, fluoxetine, paroxetine, sertraline, amitriptyline, desipramine, and nortriptyline are all supported by the literature. There is also evidence that dopamine agonists, especially pramipexole, can be useful for the treatment of depression in people with PD, especially when concurrently treating motor symptoms.⁶

Although specific data in PD are lacking, it is generally accepted that a combination of medication and psychotherapy is superior to pharmacotherapy alone, and this approach is recommended for the treatment of depression when available. Transcranial magnetic stimulation may also be useful for treating depression, especially when combined with antidepressants.⁶ Other nonpharmacologic interventions that may be useful for treating depression include exercise, yoga, meditation, and light therapy.⁷

Apathy
Apathy is one of the most difficult-to-treat mood symptoms in people with PD and can be frustrating for patients, caregivers, and clinicians. The diminished initiative, interest, and emotional responsiveness attributable to apathy can impair cognitive function on a daily basis and is also associated with poor response to treatment of motor symptoms.^8,9 Some studies have shown a higher incidence of apathy after deep brain stimulation placement.¹⁰ Apathy is frequently comorbid with depression and anxiety. Amotivation, which may be difficult to distinguish from apathy, also frequently accompanies depression.¹¹

There is no conclusive treatment strategy for apathy. Some nonpharmacologic studies showed that individuals gained benefit from physical exercise, such as Nordic walking.⁹ Other pharmacologic-based studies noted some benefit associated with rivastigmine treatment in reducing apathy as well as caregiver burden.⁹ There is mixed evidence for use of dopamine agonists, such as rotigotine.^9,12 Stimulants are often used clinically, with little evidence.¹² Some individuals benefit from treatment with cholinesterase inhibitors (eg, rivastigmine) or stimulants (eg, methylphenidate), but the evidence for this is mixed. 

Because caregivers can experience great frustration when caring for individuals with PD-related apathy, it is important to spend additional time with families to acknowledge their frustration and emphasize that apathy is a common symptom associated PD. Caregivers have found benefit from PD-based support groups.

Pseudobulbar Affect
PBA is a common syndrome seen in people with neurodegenerative disorders, and is estimated to be present in >25% of people with PD. Falconer et al¹³ define PBA as “emotional lability and a discrepancy between the individual’s emotional expression and emotional experience.” PBA is believed to be the result of degeneration of the motor aspects of emotion control. More specifically, PBA is thought to be caused by degeneration of the cortico-ponto-cerebellar circuitry, which is responsible for emotional expression that aligns with mood.¹⁴

PBA is associated with frequent emotional outbursts that are out of proportion to triggers. PBA can be embarrassing for people with PD and their care partners, and can impair social functioning. As such, PBA necessitates treatment when identified. Due to its frequent comorbidity with other mood disorders in PD, PBA can go unrecognized and may prevent individuals with this condition from receiving proper tretament. For example, PBA can be misdiagnosed as depression or anxiety.¹³ Several scales exist to assess for the presence of PBA in neurologic disorders, but these have not been explicitly validated in the PD population and should not take the place of a formal interview and examination.¹⁴

Antidepressants have been used to treat PBA, although studies assessing the efficacy of these treatments have produced mixed results, likely due to confounding factors such as the coexistence of other mood disorders (eg, anxiety or depression). The only Food and Drug Administration–approved medication for treatment of PBA is dextromethorphan–quinidine (DMQ). The dextromethorphan component exerts antiglutaminergic effects at the NMDA and sigma-1 receptors, most avidly in the brainstem and cerebellum, while the quinidine component blocks the typically rapid metabolism of dextromethorphan.¹⁴ DMQ has been found to be safe and effective in the treatment of PBA in the setting of multiple other neurologic disorders, but evidence for its use in people with PD is lacking. The use of DMQ may also be limited by cost and lack of insurance coverage. As such, SSRIs are used more frequently in this population. 

Conclusion
Anxiety, depression, apathy, and PBA—common neuropsychiatric symptoms associated with PD—can negatively affect quality of life and well-being, and may influence the overall progression and course of the disease if left untreated. Regular screening at all visits is needed to assess for these symptoms, and treatment with pharmacologic and nonpharmacologic interventions should be considered when symptoms interfere with quality of life.