Matthew A. Menza, MD

Parkinson disease (PD) is the second most common neurodegenerative illness in the United States, affecting more than 1 million persons. Disease onset is usually after age 50. In persons older than 70 years, the prevalence is 1.5% to 2.5%.

 While the primary pathology involves degeneration of dopaminergic neurons in the substantia nigra, circuits important in emotion and cognition-such as the serotonergic, adrenergic, cholinergic, and frontal dopaminergic pathways-are also variably disrupted. 

The physical aspects of PD, such as tremor, rigidity, and postural imbalance, are the defining characteristics of the disease and, understandably, they are the focus of most research and clinical care. However, PD has a much greater effect on patients’ lives than just physical impairment. Many nonmotor aspects of PD, including depression, drug-induced psychosis and impulse control disorders, cognitive impairment, anxiety, and sleep disturbances, are common and are associated with a variety of poor outcomes.

 These nonmotor symptoms complicate the clinical management of the disorder and are significant determinants of poor quality of life for patients and their caregivers.

PD is in many ways the prototypical neuropsychiatric illness. It is defined by well-described neuropathological findings. However, the variability in the extent of disease in the brain, as well as the impact of medications with considerable CNS effects, influences the diverse psychiatric presentations that, in turn, are influenced by the stress of living with the illness. Because there is such a direct connection between brain dysfunction and psychiatric symptoms, there is hope that understanding the behavioral aspects of PD will lead to a better understanding of psychiatric illness in other populations.

Depression is among the most common neuropsychiatric disturbances found in PD. Roughly 40% of persons with PD are depressed; half meet criteria for major depression and half meet criteria for a less severe form of depression, dysthymia.

Depression is particularly important because in addition to personal suffering, it is associated with a faster progression of physical symptoms, a greater decline in cognitive skills and ability to care for oneself, poorer treatment compliance and quality of life, and greater caregiver distress.

 In fact, compared with the motor disability of PD, depression was found to be more predictive of overall disability and distress.

Many of the symptoms used to make a diagnosis of depression, including poor sleep, decreased energy, psychomotor retardation, and poor concentration, are seen in nearly all patients with PD and are more properly seen as direct manifestations of PD and not of depression. Therefore, while the usual screening instruments are useful, a careful interview, focused on mood, affect, and hedonic capacity, is critical.

One very interesting finding is that the incidence of suicide is lower in patients with PD, despite the extremely high rates of depression.

 This finding may be related to the non–risk-taking personality pattern found in patients with PD that I will discuss later.

There has been considerable debate over the etiology of depression in PD. While many patients are demoralized about having a serious and progressive illness, there is a general consensus that there is something intrinsic to the neurobiology of the illness that increases the risk of depression. Various factors have been investigated, including cerebrospinal fluid levels of neurotransmitter metabolites, autopsy neuropathological findings from various brain regions, and neuroimaging with positron emission tomography and transcranial sonography.

 These studies have led to the hypothesis that patients with PD and depression have damage to serotonergic systems and to dopaminergic basal ganglia-limbic-frontal systems that are involved in mood regulation and in pleasure and reward. These complex systems are probably differentially affected and combine with the psychosocial stress of this chronic illness to produce variable levels of distress.

CHECKPOINTS 
? The prevalence of depression in patients with Parkinson disease (PD) is around 40%. Half of these patients meet criteria for major depression and half meet criteria for less severe forms of depression (eg, dysthymia).

? Optimal control of the physical aspects of PD is a prerequisite to adequate treatment of depression. Studies have shown a tight correlation between “off” periods and depression, and unless there is good control of the fluctuations, antidepressant therapy will be suboptimal.

? Findings suggest that dementia develops within 9 years of the onset of Parkinson disease in about 26% of patients. This percentage rises to about 52% after 13 years, and to about 78% after 17 years.

? The personality traits that frequently accompany PD may be described as decreases in novelty-seeking behaviors. This syndrome of low novelty seeking is characterized by industriousness, inflexibility, punctuality, and cautiousness.

Despite the prevalence of depression in patients with PD, there are few controlled, well-designed studies that direct treatment. In a randomized trial that compared nortriptyline, paroxetine controlled-release (CR), and placebo, nortriptyline was superior to placebo and paroxetine CR.

 The trial also established that treatment of depression leads to improvements in quality of life, sleep, and some aspects of cognition.

 Findings from a short-term, randomized, placebo-controlled pilot study suggest that both citalopram and desipramine are more effective than placebo.

The two studies noted above have led to an increased focus on the role of norepinephrine for depression in patients with PD. As in all of psychiatry, however, there are significant interindividual differences in response to medications and often tolerability is the most important factor to consider. The many tolerability issues include the anticholinergic effects of tricyclics and the risk of a slight worsening of the motor signs of PD with SSRIs.

 In addition, there is a potentially serious interaction between selegiline and rasagiline-monoamine oxidase B inhibitors that are widely used (at low doses) for their mild therapeutic and potential disease-slowing effects-and antidepressants.

In case reports, electroconvulsive therapy (ECT) has been shown to be an effective treatment of depression in patients with PD. In most cases, both the mood and the motor symptoms improve, although the motor improvement is short-lived.

 Despite the adverse image of ECT, patients with severe depression who have PD should consider it when pharmacological agents have failed.

have begun investigation of the feasibility and effectiveness of cognitive-behavioral therapy (CBT) for depression. Results are thus far promising, and it appears that when CBT is modified appropriately, it is effective for PD depression.

There are a number of other relevant treatment issues. Optimal control of the physical aspects of PD is a prerequisite to adequate treatment of depression. Close collaboration of the treating neurologist and psychiatrist (which can be challenging in today’s health care environment) may become particularly important in the later stages of the illness, when motor fluctuations and cognitive impairment become apparent. Numerous studies have demonstrated a tight correlation between “off” periods and depression, and unless there is good control of the fluctuations, antidepressant therapy will be suboptimal.

Patients should be encouraged to exercise, to keep up their social contacts, and to seek out local PD support groups. Furthermore, supportive therapy directed at education and maintenance of activities outside the home is often beneficial.

The study of depression in PD has stimulated some interesting approaches for the rest of psychiatry. Deep brain stimulation (DBS), a procedure widely used to treat the motor complications of PD, has led to progress in mapping the circuits involved in depression. This, in turn, has led investigators to begin treatment trials of DBS in refractory depression.

 Although these treatments are still experimental, they are promising.

Drug reactions: psychosis and impulse control disorders

Great strides have been made in the treatment of PD. Physicians have a wide array of medications with which to relieve parkinsonian symptoms. While these drugs have effects on a variety of CNS neurotransmitter systems, they primarily affect dopamine transmission. Thus, it is not surprising that they often produce dramatic behavioral changes that cause significant difficulties for patients and their families and caregivers.

Psychosis is very rare in untreated patients with PD; however, anti-parkinsonian medications can cause hallucinations, delusions, agitation, and mania-all of which can greatly complicate care. While psychosis does occur with the older levodopa-based drugs, it appears to be more frequently associated with the newer direct postsynaptic dopamine agonists, pramipexole and ropinirole. The anticholinergic agents can cause a worsening of cognitive deficits and can precipitate delirium, which may include a variety of psychotic symptoms.

In patients with PD, visual hallucinations are the most common drug effect, although auditory and tactile hallucinations also occur. Often, these take the form of nonthreatening visual illusions that do not require active intervention. However, overtly threatening hallucinations can develop-human or animal figures that are stereotyped for each patient and are most common at night.

Delusions, uncommon in the first 2 years of therapy, may also occur and, as with hallucinations, are often preceded by vivid dreams. Delusions are usually persecutory: fears of being injured, influenced, poisoned, filmed, or tape-recorded are common.

 In severe cases, the psychotic symptoms are virtually indistinguishable from those seen in schizophrenia.

There are convincing data that suggest that dopaminergic treatments may be associated with the development of a variety of impulse control disorders in some patients.

 The impulse control disorders, which may include severe gambling and hypersexuality as well as shopping and binge eating, can be extremely disruptive to patients and families. As with psychosis, impulse control disorders are more commonly associated with the dopamine agonists pramipexole and ropinirole.

This is a particularly fascinating area for psychiatry because these disorders occur in a population that apparently has a reduced risk of these behaviors before the onset of PD and the use of dopaminergically active drugs. This association between treatments that increase dopamine and impulse control problems is consistent with our understanding of the role of the dopamine system in pleasure and reward, as well as with the known impairment in executive function in PD. Given the impact of these disorders, clinicians need to educate patients and monitor them for the early signs of these disturbances.

Treatment of drug-induced symptoms generally involves a decrease in the dosage of the antiparkinsonian medication. Direct dopamine agonists are the first target, followed by the anticholinergics and by levo-dopa preparations.

 Unfortunately, decreasing the dosage of the antiparkinsonian drugs often results in an increase in the movement disorder. This has been referred to as the “motion-emotion conundrum.”

Atypical antipsychotics may be of help in this setting. A variety of studies have examined the tolerability and efficacy of these drugs in patients with PD; they show that drugs with high affinities for the D2 receptor (typical antipsychotics, risperidone, and aripiprazole) are not tolerated. Low-dose quetiapine is widely used, although results of controlled trials have been equivocal.

Open-label and controlled trials have shown clozapine to be useful in PD patients with psychoses.

 The use of clozapine is more problematic because of the risk of agranulocytosis as well as the anticholinergic, sedative, and orthostatic hypotensive adverse effects. Nonetheless, clozapine causes very few extrapyramidal symptoms, and when it is used in low doses, it can block psychotic symptoms without worsening rigidity. Doses starting at 6.25 to 12.5 mg and titrating to 50 mg are typical. Plasma levels from 4.5 to 16.1 ng/mL are associated with good response.

PD is associated with subtle but widespread cognitive impairment, even in the absence of clinically apparent cognitive decline or frank dementia. Early in the course of the illness or at the time of diagnosis, there are difficulties with memory retrieval, executive functioning, attention, and visuospatial abilities-all of which are associated with significant functional impairment.

 As noted, more severe cognitive impairment, including dementia, also occurs commonly in patients with PD. The average prevalence of dementia, which generally occurs later in the illness, is 39.9%.

 A long-term study of PD patients in a community setting found that dementia had developed in about 26% of them 9 years after the onset of PD; after 13 years, this number increased to about 52%, and after 17 years reached 78%.

While the anticholinesterase drugs are available for treatment of dementia, their use in PD is somewhat limited by their efficacy and tolerability.

 In the largest randomized trial, clinically meaningful improvement occurred in 5.3% more patients who received rivastigmine compared with those who received placebo.

 The most common adverse effects were nausea, vomiting, and tremors. In addition, a small study with memantine found that this medication produced a small effect over placebo and was well tolerated.

Modern Treatment of Nervous and Mental Disease

 noted, “It would seem that paralysis agitans affected mostly those persons whose lives had been devoted to hard work. The people who take their work to bed with them and who never come under the inhibiting influences of tobacco or alcohol are the kind that are most frequently affected. In this respect, the disease may be almost regarded as a badge of respectable endeavor.” Since that time, the association between personality or behavioral traits and PD has been examined more extensively. Epidemiological data from studies show low premorbid rates of smoking, alcohol intake, and coffee drinking.

The personality traits that frequently accompany PD may be described as decreases in novelty-seeking behaviors. This syndrome of low novelty seeking is characterized by industriousness, inflexibility, punctuality, and cautiousness. These behaviors have been related in both animal and human studies to dopaminergic tone in limbic and striatal structures and may be clinical correlates of the decreased dopaminergic tone that occurs premorbidly and defines the clinical illness.

Most researchers suggest that patients in whom PD develops generally show a typical premorbid personality and that these traits persist after the onset of the motor illness. Such a proposition, which is necessarily based on retrospective data and elusive concepts of personality, is, of course, hard to prove and remains controversial.

 Cummings JL. Understanding Parkinson disease [published correction appears in 

 Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. 

 Schrag A. Quality of life and depression in Parkinson’s disease. 

 Cummings JL. Depression and Parkinson’s disease: a review. 

 Ravina B, Camicioli R, Como PG, et al. The impact of depressive symptoms in early Parkinson disease. 

 Global Parkinson’s Disease Survey Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. 

 Devos D, Dujardin K, Poirot I, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. 

Articles

Parkinson disease (PD) is the second most common neurodegenerative illness in the United States, affecting more than 1 million persons. Disease onset is usually after age 50. In persons older than 70 years, the prevalence is 1.5% to 2.5%.1 While the primary pathology involves degeneration of dopaminergic neurons in the substantia nigra, circuits important in emotion and cognition-such as the serotonergic, adrenergic, cholinergic, and frontal dopaminergic pathways-are also variably disrupted.

Matthew A. Menza, MD

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