Click here to listen to the state officials

Click here to listen to the state officials

Click here to listen to the state officials

Although the title of April’s cover story (“Benzodiazepines: A versatile clinical tool,” Current Psychiatry, April 2012, p. 54-63; http://bit.ly/1zkanU3) seems to encourage the use of benzodiazepines, the authors state benzodiazepines are second-or third-line treatments for most conditions, particularly for chronic problems.

As an addiction medicine physician, I see well-intentioned doctors prescribing benzodiazepines to patients with chronic ailments. I would like to emphasize the addictive nature of benzodiazepines. “When used appropriately” is contradictory if benzodiazepines are used daily. Tolerance manifests as an exacerbation of the original symptoms, usually leading to a dosage increase. Every day, I see patients in a state of chronic withdrawal manifested in unpleasant ways because they took benzodiazepines “exactly as prescribed, 3 times per day for 4 years.”

Alprazolam is the bane of an addiction medicine practice because it crosses the blood-brain barrier immediately and is relatively short acting. This is a recipe for almost certain addiction, and there are better medications. I regularly transition patients from addictive substances, including benzodiazepines, and no matter what condition I am treating—panic attacks, obsessive-compulsive disorder, depression, generalized anxiety, social anxiety, posttraumatic stress disorder, or situational anxiety—I can almost always control the patient’s symptoms using non-addictive medications.

If benzodiazepines are used for almost anything other than a short-lived condition, we are doing a tremendous disservice to our patients and exhibiting the “just give them a pill and get to the next patient” mentality we are accused of.

Terrance Reeves, MD, ABAM
Medical Director
South Walton Medical Center
Miramar Beach, FL

The authors respond

We thank Dr. Reeves for his comments and reminders of the downside to routine and long-term prescribing of benzodiazepines. As an addiction specialist, he is well positioned to see patients who are struggling with syndromes related to benzodiazepine abuse. We stand by our review of the evidence-based studies of the appropriateness of judicious benzodiazepine use in various psychiatric syndromes. The section of our article labeled “Risks of benzodiazepine use” addresses Dr. Reeves’ concerns.

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy
University of Michigan College of Pharmacy
Clinical Pharmacist

Michael I. Casher, MD
Clinical Assistant Professor
Department of Psychiatry
University of Michigan Medical School
Director of Inpatient Adult Psychiatry

Shinji Yasugi, MDFirst-Year Psychiatry ResidentUniversity of Michigan Health SystemAnn Arbor, MI

Although the title of April’s cover story (“Benzodiazepines: A versatile clinical tool,” Current Psychiatry, April 2012, p. 54-63; http://bit.ly/1zkanU3) seems to encourage the use of benzodiazepines, the authors state benzodiazepines are second-or third-line treatments for most conditions, particularly for chronic problems.

As an addiction medicine physician, I see well-intentioned doctors prescribing benzodiazepines to patients with chronic ailments. I would like to emphasize the addictive nature of benzodiazepines. “When used appropriately” is contradictory if benzodiazepines are used daily. Tolerance manifests as an exacerbation of the original symptoms, usually leading to a dosage increase. Every day, I see patients in a state of chronic withdrawal manifested in unpleasant ways because they took benzodiazepines “exactly as prescribed, 3 times per day for 4 years.”

Alprazolam is the bane of an addiction medicine practice because it crosses the blood-brain barrier immediately and is relatively short acting. This is a recipe for almost certain addiction, and there are better medications. I regularly transition patients from addictive substances, including benzodiazepines, and no matter what condition I am treating—panic attacks, obsessive-compulsive disorder, depression, generalized anxiety, social anxiety, posttraumatic stress disorder, or situational anxiety—I can almost always control the patient’s symptoms using non-addictive medications.

If benzodiazepines are used for almost anything other than a short-lived condition, we are doing a tremendous disservice to our patients and exhibiting the “just give them a pill and get to the next patient” mentality we are accused of.

Terrance Reeves, MD, ABAM
Medical Director
South Walton Medical Center
Miramar Beach, FL

The authors respond

We thank Dr. Reeves for his comments and reminders of the downside to routine and long-term prescribing of benzodiazepines. As an addiction specialist, he is well positioned to see patients who are struggling with syndromes related to benzodiazepine abuse. We stand by our review of the evidence-based studies of the appropriateness of judicious benzodiazepine use in various psychiatric syndromes. The section of our article labeled “Risks of benzodiazepine use” addresses Dr. Reeves’ concerns.

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy
University of Michigan College of Pharmacy
Clinical Pharmacist

Michael I. Casher, MD
Clinical Assistant Professor
Department of Psychiatry
University of Michigan Medical School
Director of Inpatient Adult Psychiatry

Shinji Yasugi, MDFirst-Year Psychiatry ResidentUniversity of Michigan Health SystemAnn Arbor, MI

Although the title of April’s cover story (“Benzodiazepines: A versatile clinical tool,” Current Psychiatry, April 2012, p. 54-63; http://bit.ly/1zkanU3) seems to encourage the use of benzodiazepines, the authors state benzodiazepines are second-or third-line treatments for most conditions, particularly for chronic problems.

As an addiction medicine physician, I see well-intentioned doctors prescribing benzodiazepines to patients with chronic ailments. I would like to emphasize the addictive nature of benzodiazepines. “When used appropriately” is contradictory if benzodiazepines are used daily. Tolerance manifests as an exacerbation of the original symptoms, usually leading to a dosage increase. Every day, I see patients in a state of chronic withdrawal manifested in unpleasant ways because they took benzodiazepines “exactly as prescribed, 3 times per day for 4 years.”

Alprazolam is the bane of an addiction medicine practice because it crosses the blood-brain barrier immediately and is relatively short acting. This is a recipe for almost certain addiction, and there are better medications. I regularly transition patients from addictive substances, including benzodiazepines, and no matter what condition I am treating—panic attacks, obsessive-compulsive disorder, depression, generalized anxiety, social anxiety, posttraumatic stress disorder, or situational anxiety—I can almost always control the patient’s symptoms using non-addictive medications.

If benzodiazepines are used for almost anything other than a short-lived condition, we are doing a tremendous disservice to our patients and exhibiting the “just give them a pill and get to the next patient” mentality we are accused of.

Terrance Reeves, MD, ABAM
Medical Director
South Walton Medical Center
Miramar Beach, FL

The authors respond

We thank Dr. Reeves for his comments and reminders of the downside to routine and long-term prescribing of benzodiazepines. As an addiction specialist, he is well positioned to see patients who are struggling with syndromes related to benzodiazepine abuse. We stand by our review of the evidence-based studies of the appropriateness of judicious benzodiazepine use in various psychiatric syndromes. The section of our article labeled “Risks of benzodiazepine use” addresses Dr. Reeves’ concerns.

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy
University of Michigan College of Pharmacy
Clinical Pharmacist

Michael I. Casher, MD
Clinical Assistant Professor
Department of Psychiatry
University of Michigan Medical School
Director of Inpatient Adult Psychiatry

Shinji Yasugi, MDFirst-Year Psychiatry ResidentUniversity of Michigan Health SystemAnn Arbor, MI

Ixabepilone has been studied in the neoadjuvant setting, as first-line treatment of metastatic disease and in combination with other agents. The efficacy of ixabepilone in triple-negative breast cancer has been the focus of much research. Dose reduction is an effective strategy to manage adverse events associated with ixabepilone and does not result in diminished clinical outcomes. In addition, weekly administration of ixabepilone may decrease toxicity; however, this may come at the expense of lower progression-free survival but not overall survival. The optimal schedule and dosing of this agent will be clarified with the results of upcoming trials...

*For a PDF of the full article, click on the link to the left of this introduction.

Ixabepilone has been studied in the neoadjuvant setting, as first-line treatment of metastatic disease and in combination with other agents. The efficacy of ixabepilone in triple-negative breast cancer has been the focus of much research. Dose reduction is an effective strategy to manage adverse events associated with ixabepilone and does not result in diminished clinical outcomes. In addition, weekly administration of ixabepilone may decrease toxicity; however, this may come at the expense of lower progression-free survival but not overall survival. The optimal schedule and dosing of this agent will be clarified with the results of upcoming trials...

*For a PDF of the full article, click on the link to the left of this introduction.

Ixabepilone has been studied in the neoadjuvant setting, as first-line treatment of metastatic disease and in combination with other agents. The efficacy of ixabepilone in triple-negative breast cancer has been the focus of much research. Dose reduction is an effective strategy to manage adverse events associated with ixabepilone and does not result in diminished clinical outcomes. In addition, weekly administration of ixabepilone may decrease toxicity; however, this may come at the expense of lower progression-free survival but not overall survival. The optimal schedule and dosing of this agent will be clarified with the results of upcoming trials...

*For a PDF of the full article, click on the link to the left of this introduction.

Background  The prevalence of concomitant depression among cancer survivors is not well established, although half of those diagnosed with cancer are reported to experience depression at some stage during the cancer experience.

Objectives  To establish rates of diagnosed depression in a cohort of nonelderly adult cancer survivors by cancer site, to characterize those with diagnosed depression, and to assess the impact of diagnosed depression on patterns of health care utilization and costs.

Methods  Medical and pharmacy claims data on military health care beneficiaries were used to develop a cohort of survivors across all cancer sites. Selected cases were diagnosed with and treated for cancer in fiscal years 2006-2007, and had at least 1 health care claim each subsequent year through fiscal year 2010 to ensure survival of at least 2 years. All cancer sites were included except those for nonmelanoma skin cancer. Fiscal year 2009 was used as the index year for determining annual health care utilization and costs. Bivariate and regression analyses were used.

Results  Across the cohort of 11,014 cancer survivors, 12.6% had a comorbid diagnosis of depression at the time of or after a cancer diagnosis. The highest rates of diagnosed depression occurred in those with cancers of the esophagus, pancreas, ovary, or bronchus, lung, or other respiratory organ; and were associated with female sex, single marital status, and enlisted sponsor rank. Survivors who were diagnosed with depression had significantly higher health care utilization for inpatient and outpatient services, more medication prescriptions, and higher annual costs.

Limitations  Due to the nature of claims data, we were unable to ascertain cancer stage or phase of illness. In this analysis, we did not include the presence of comorbidities, history of preexisting depression, or health system factors, all of which may impact the rate of depression among cancer survivors.

Conclusions  The findings suggest the importance for the Military Health System, as well as other health care systems, to address the mental health needs of cancer survivors and the fiscal efficiencies of cancer care.

*For a PDF of the full article, click on the link to the left of this introduction.

Background  The prevalence of concomitant depression among cancer survivors is not well established, although half of those diagnosed with cancer are reported to experience depression at some stage during the cancer experience.

Objectives  To establish rates of diagnosed depression in a cohort of nonelderly adult cancer survivors by cancer site, to characterize those with diagnosed depression, and to assess the impact of diagnosed depression on patterns of health care utilization and costs.

Methods  Medical and pharmacy claims data on military health care beneficiaries were used to develop a cohort of survivors across all cancer sites. Selected cases were diagnosed with and treated for cancer in fiscal years 2006-2007, and had at least 1 health care claim each subsequent year through fiscal year 2010 to ensure survival of at least 2 years. All cancer sites were included except those for nonmelanoma skin cancer. Fiscal year 2009 was used as the index year for determining annual health care utilization and costs. Bivariate and regression analyses were used.

Results  Across the cohort of 11,014 cancer survivors, 12.6% had a comorbid diagnosis of depression at the time of or after a cancer diagnosis. The highest rates of diagnosed depression occurred in those with cancers of the esophagus, pancreas, ovary, or bronchus, lung, or other respiratory organ; and were associated with female sex, single marital status, and enlisted sponsor rank. Survivors who were diagnosed with depression had significantly higher health care utilization for inpatient and outpatient services, more medication prescriptions, and higher annual costs.

Limitations  Due to the nature of claims data, we were unable to ascertain cancer stage or phase of illness. In this analysis, we did not include the presence of comorbidities, history of preexisting depression, or health system factors, all of which may impact the rate of depression among cancer survivors.

Conclusions  The findings suggest the importance for the Military Health System, as well as other health care systems, to address the mental health needs of cancer survivors and the fiscal efficiencies of cancer care.

*For a PDF of the full article, click on the link to the left of this introduction.

Background  The prevalence of concomitant depression among cancer survivors is not well established, although half of those diagnosed with cancer are reported to experience depression at some stage during the cancer experience.

Objectives  To establish rates of diagnosed depression in a cohort of nonelderly adult cancer survivors by cancer site, to characterize those with diagnosed depression, and to assess the impact of diagnosed depression on patterns of health care utilization and costs.

Methods  Medical and pharmacy claims data on military health care beneficiaries were used to develop a cohort of survivors across all cancer sites. Selected cases were diagnosed with and treated for cancer in fiscal years 2006-2007, and had at least 1 health care claim each subsequent year through fiscal year 2010 to ensure survival of at least 2 years. All cancer sites were included except those for nonmelanoma skin cancer. Fiscal year 2009 was used as the index year for determining annual health care utilization and costs. Bivariate and regression analyses were used.

Results  Across the cohort of 11,014 cancer survivors, 12.6% had a comorbid diagnosis of depression at the time of or after a cancer diagnosis. The highest rates of diagnosed depression occurred in those with cancers of the esophagus, pancreas, ovary, or bronchus, lung, or other respiratory organ; and were associated with female sex, single marital status, and enlisted sponsor rank. Survivors who were diagnosed with depression had significantly higher health care utilization for inpatient and outpatient services, more medication prescriptions, and higher annual costs.

Limitations  Due to the nature of claims data, we were unable to ascertain cancer stage or phase of illness. In this analysis, we did not include the presence of comorbidities, history of preexisting depression, or health system factors, all of which may impact the rate of depression among cancer survivors.

Conclusions  The findings suggest the importance for the Military Health System, as well as other health care systems, to address the mental health needs of cancer survivors and the fiscal efficiencies of cancer care.

*For a PDF of the full article, click on the link to the left of this introduction.

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Dopaminergic treatment is extremely beneficial in inducing symptom improvement in early Parkinson disease (PD). Patients typically experience a smooth and even response to the early stages of levodopa treatment. With disease progression, however, the effect of levodopa begins to weaken approximately 4 hours after each dose, leaving patients anticipating the need for their next dose and vulnerable to motor fluctuations and dyskinesias.

Motor fluctuations refer to the unanticipated loss of effect of a given dose of levodopa; instead of a smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed “wearing off”) or may suddenly switch from “on” (symptoms controlled) to “off” (symptoms return). Dyskinesias, or involuntary movements, occur when dopamine levels are too high.

Motor complications are a major cause of disability in PD. They affect 60% to 90% of PD patients after 5 to 10 years of treatment. Moreover, in one study of 143 PD patients, motor complications diminished quality of life; the most strongly affected dimensions were mobility, activities of daily living, communication, and stigma.¹

PATHOGENESIS OF MOTOR COMPLICATIONS

Under physiologic conditions, dopamine stimulation of the striatal dopamine receptors occurs in a sustained fashion. In early PD, the pool of remaining neurons of the substantia nigra is believed to be sufficiently active to smooth out changes in levodopa levels, providing a relatively constant amount of dopamine. Many PD patients therefore have several years of trouble-free treatment following diagnosis. In the advanced disease states, however, the number of presynaptic dopaminergic neurons progressively decreases. With fewer dopaminergic neurons, a constant dopaminergic concentration cannot be sustained. As PD advances, the progressive loss of dopaminergic neurons leads to impaired dopamine storage. Thus, the buffering capacity of dopaminergic neurons decreases and synaptic dopamine levels begin to reflect systemic or exogenous levodopa levels.

According to current views, the total motor response to levodopa results from the combination of endogenous dopamine production along with the short-duration response (SDR) and the long-duration response (LDR) to exogenous levodopa.² The SDR represents an improvement in parkinsonian symptoms and signs, lasting minutes to hours, that is closely related to the rise and fall of plasma levodopa concentrations. The SDR parallels the fluctuations in motor response and has received the most attention in the literature. The LDR is an improvement in parkinsonism that builds up over days and likewise decays over days. The LDR decays more rapidly in severely affected patients. Negative response, or “super off,” is a transient worsening of motor function to below the baseline level that may occur as the effects of the SDR dissipate.

The proportions of the SDR and LDR can vary according to disease progression. The LDR is more prominent in early stages, accounting for the stable response seen in the honeymoon period of treatment.

Peripheral factors

Additional peripheral factors such as changes in gastric motility and absorption contribute to motor complications. Levodopa is transported by a saturable active transporter system, the large neutral amino acid system, in the gut, and across the blood-brain barrier. Levodopa absorption is thus affected by food intake, especially protein. Levodopa and dietary amino acids compete with each other for absorption at the intestinal and blood-brain levels. Levodopa and other dopaminergic therapies further chronically reduce gastric emptying.

Pulsatile dopamine stimulation

The latency from the time of levodopa administration to the onset of motor improvement is typically 30 to 90 minutes. Latency is longer in late stages when the striatal buffer is weakened and the plasma concentration of levodopa fluctuates.

TYPES OF MOTOR FLUCTUATIONS

Fluctuating motor response in levodopa-treated patients refers to clinically apparent oscillations in motor function. Management of the fluctuating response may require frequent daily dosing of levodopa.

Motor fluctuations in PD take four forms: wearing off, off, delayed on/no on, and dyskinesias.

Wearing off

Wearing off refers to the premature loss of benefit from a given dose of levodopa, causing a predictable return of parkinsonian symptoms (bradykinesia, tremors, rigidity, and gait problems) in advance of the next scheduled dose. Observed in early and moderate PD, wearing off is the most common type of motor fluctuation. Its pathophysiology relates to disease progression and pharmacokinetics of levodopa. It can be sudden or gradual, predictable or unpredictable.

Off state

The off state is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Such symptoms include pain, stiffness, paresthesia, cognitive symptoms (depression, anxiety, difficulty with concentration, and mental slowing), inner restlessness, and inner tremulousness. The off state can be sudden or gradual, predictable or unpredictable.

Delayed on/no on

Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. As the disease progresses, wearing off becomes more complicated and more unpredictable. The dosing responses vary, and patients sometimes report delayed on. The causes of delayed on or no on can be an insufficient dose, dosing with high-protein meals, or delayed gastric emptying. Metoclopramide or domperidone can help with gastric emptying. Metoclopramide can cross the blood-brain barrier and thus may cause adverse effects related to dopaminergic blockade; domperidone does not cross the blood-brain barrier.

Dyskinesias

Dyskinesias are hyperkinetic movements related to dopaminergic effects that are greater or less than the therapeutic threshold. They are common with long-term levodopa therapy and have three patterns:

Off dystonia occurs when levodopa concentrations are low and the SDR has dissipated. Dystonic states may be a manifestation of too little or too much levodopa; differentiating the two is important. Off dystonia occurs mostly in the early mornings, when plasma levodopa levels are low, and mostly involves the more affected side first.

Peak-dose dyskinesia, which occurs during the SDR, is the most common type of dykinesia and is related to peak plasma levodopa levels. It is characterized by stereotypic, choreic abnormal movements involving the head, neck, trunk, and limbs, and possibly hemidyskinesia in young-onset PD. Peak-dose dyskinesias are sometimes severe enough to be disabling.

Diphasic dyskinesias are stereotyped, dystonic, or choreic movements that occur at the beginning of the SDR and again as the SDR dissipates. They predominantly affect the legs and spare the trunk, neck, and arms.

TREATMENT OF OFF AND WEARING OFF

Food and tolerance

The patient should not take levodopa with protein-containing meals, particularly if his or her PD is at an advanced stage. If excessive nausea, vomiting, or lightheadedness prevents the patient from taking an adequate dose, adding carbidopa (up to 75 mg) to the regimen will be helpful.

MAO-B inhibitors

By inhibiting one of the central dopamine catabolic pathways, MAO-B inhibitors (selegiline, rasagiline, and Zydis selegiline) prolong the half-life of dopamine in the brain and increase on time.

Improvement in off time with rasagiline is comparable to that seen with the COMT inhibitor entacapone. In an 18-week, double-blind trial of 687 patients randomized to receive once-daily rasagiline, entacapone, or placebo as an adjunct to levodopa, both rasagiline and entacapone reduced off time by 1.2 hours compared with placebo.³

In a 26-week placebo-controlled study, rasagiline decreased off time by 29% when added to levodopa in patients with PD and motor fluctuations, compared with a 15% reduction in the placebo group.⁴ This study confirmed the benefit of adding rasagiline to the regimens of patients who were already optimally treated with levodopa, dopamine agonists, amantadine, anticholinergics, and entacapone before enrolling in the study.

An orally disintegrating selegiline (Zydis selegiline) tablet is particularly useful for patients who have difficulty swallowing. The bioavailability of Zydis selegiline is 80% compared with 10% for selegiline, resulting in faster absorption. Pregastric absorption of Zydis selegiline avoids extensive first-pass metabolism in the liver and, therefore, the concentration of amphetamine-like metabolites is much lower.

In a 3-month, placebo-controlled study of patients with PD who were experiencing levodopa-related motor fluctuations, Zydis selegiline was associated with a 2.2-hour reduction in the total number of off hours compared with 0.6 hours in the placebo group, and dyskinesia-free on hours increased by 1.8 hours.⁵

The use of MAO-B inhibitors with tricyclic antidepressants or selective serotonin reuptake inhibitors has been reported to induce the serotonin syndrome by activation of 5HT_1a and 5HT₂ receptors. Serotonin syndrome is a potentially life-threatening accumulation of serotonin that can cause encephalopathy, severe rigidity of the legs, dysautonomia (diarrhea, mydriasis, and excessive lacrimation), myoclonus, hyperreflexia, and seizures.

COMT inhibitors

Catechol-O-methyltransferase inhibitors (entacapone and tolcapone) block peripheral degradation of levodopa. Tolcapone also blocks central degradation of levodopa and dopamine. These mechanisms increase central levodopa and dopamine levels and prolong levodopa half-life and bioavailability. Tolcapone has more powerful COMT inhibition than entacapone because tolcapone crosses the blood-brain barrier and inhibits the peripheral and central pathways of levodopa degradation. Use of COMT inhibitors can increase daily on time, but diarrhea is a common side effect and leads to withdrawal of these agents in about 3% of patients.

Tolcapone-treated patients show significant improvement in off time with improvement in motor fluctuations.⁶ Because tolcapone causes rare instances of fulminant hepatitis, liver function needs to be monitored every other week. For this reason, tolcapone should be reserved for patients in whom other treatments, including entacapone, have failed.

Controlled-release levodopa

Controlled-release levodopa was developed to provide more constant delivery of levodopa to the striatum. The benefit of controlled-release levodopa is only mild, however, as absorption of this formulation is variable. In advanced PD cases, the effects of controlled-release levodopa are more unpredictable than those with standard levodopa. Controlled-release levodopa is effective in patients with less severe wearing off, but it is not as effective in patients with a less predictable pattern of fluctuations.

Dopamine agonists

Dopamine agonists (pramipexole, ropinirole, apomorphine, and bromocriptine) have shown beneficial effects as adjunctive therapy to reduce wearing off. Side effects of dopamine agonists include ankle edema, hallucinations, somnolence, and impulse control disorders. These side effects should be discussed with patients before instituting therapy, and therapy should be discontinued if any of them occur.

In patients with advanced PD, pramipexole was shown to improve motor function during on and off periods, decrease the total off time, and decrease the severity of off time. Further, a larger reduction in the dosage of levodopa was possible in the pramipexole-treated patients than in the placebo-treated patients.⁷

In a comparison of pramipexole with levodopa on the end point of motor complications of PD in 300 patients, the incidences of wearing off and dyskinesia were significantly lower in the patients randomized to pramipexole with follow-up over 4 years.⁸ Only 25% of patients initially treated with pramipexole exhibited dyskinesia compared with 54% of patients initially treated with levodopa. Forty-seven percent of patients in the pramipexole group experienced wearing off compared with 63% initially treated with levodopa. Pramipexole is available as tablets ranging from 0.125 mg to 1.5 mg in size. It is given in three divided daily doses with gradual increments of 0.25 mg three times a day every week. Pramipexole is now also available in an extended-release formulation for once-a-day dosing in tablets ranging in size from 0.375 mg to 4.5 mg.

Ropinirole adds clinical benefit in PD patients with motor fluctuations and also permits a reduction in the dosage of levodopa.⁹

In one study, ropinirole monotherapy was compared with levodopa therapy in 268 patients with early PD. By the end of the 5-year study, 45% of the levodopa patients experienced dyskinesias versus 20% of the ropinirole patients.¹⁰

Ropinirole is available as tablets ranging in size from 0.25 mg to 5 mg. It is now also available in an extended-release (XL) formulation, with tablet sizes ranging from 2 mg to 12 mg. Ropinirole XL is taken once a day.

Bromocriptine is an old ergot-derived dopamine agonist that has also been studied for monotherapy and add-on treatment in PD. Due to the potential risks of pulmonary, retroperitoneal, and heart valve fibrosis, bromocriptine is not commonly used.

Apomorphine was approved by the US Food and Drug Administration in 2004 as an acute, intermittent, subcutaneous injection for the treatment of hypomobility off episodes (end-of-dose wearing off and unpredictable on-off episodes) associated with advanced PD. Apomorphine has been shown to be beneficial in patients with unpredictable off periods.¹¹ Its onset of action is 10 to 15 minutes, and the effects of each dose last for 60 to 90 minutes. The best tolerated dose is 4 mg to 10 mg. Apomorphine appears to be most useful as as rescue medication in the refractory off periods with severe bradykinesia and unpredictable off periods.

TREATMENT OF DYSKINESIAS

Reduction of levodopa doses will reduce the frequency of dyskinesias, but at a cost of worsened parkinsonism and increased numbers of off periods. An alternative is to spread out the doses of levodopa (more frequent smaller doses), but this practice has not achieved good results. Replacing levodopa with dopamine agonists can also reduce the frequency of dyskinesias, but control of PD symptoms is less optimal than with levodopa. Amantadine and clozapine both have been shown to reduce dyskinesias.

Amantadine

Amantadine is an N-methyl-d-aspartate antagonist with antidyskinesia effects. Metman et al¹² demonstrated that amantadine reduced dyskinesia severity by 60%, without exacerbation of motor function, in a randomized placebo-controlled crossover study. Dose-response studies with amantadine have not been conducted, but 100 mg two or three times daily is used in practice. In some studies, a short duration of benefit has been a concern. Side effects of amantadine include leg edema, hallucinations, confusion, and rash.

Clozapine

Clozapine is an atypical antipsychotic that has been shown in open-label trials and a randomized, double-blind, placebo-controlled trial to reduce the duration and severity of levodopa-induced dyskinesias without worsening of parkinsonian features and with no change in motor fluctuation.¹³ No benefit of clozapine was observed during activation dyskinesia, however. Cloza pine carries the inconvenience of weekly blood draws to monitor for the development of agranulocytosis, which occurs rarely.

GAIT FREEZING

Gait freezing, most commonly a manifestation of off states, causes substantial disability. It has been thought to occur as a result of a loss of noradrenaline due to locus ceruleus degeneration. Improvement in gait freezing has been shown with apomorphine and methylphenidate.

CONCEPT OF CONTINUOUS DOPAMINE STIMULATION

Short-acting dopaminergic drugs have the potential for nonphysiologic pulsatile stimulation of postsynaptic receptors, leading to motor complications. Continuous dopaminergic stimulation to prevent this pulsatile stimulation would theoretically avoid motor complications.¹⁴ Continuous dopaminergic stimulation can be achieved by using the extended-release formulation of ropinirole or pramipexole or by continuous delivery of levodopa or dopamine agonists. Several double-blind controlled trials have shown that treatment with long-acting dopamine agonists lowers the risk of motor complications compared with short-acting levodopa treatment.

In 2005, Stocchi concluded that in patients with advanced PD, a continuous infusion of levodopa was more effective in reducing motor complications than standard oral formulations.¹⁵ The reduction in motor complications was attributed to avoidance of low plasma levodopa trough levels; motor complications were not affected by relatively high plasma levodopa concentrations. The authors of this study speculated that if oral levodopa could be given “in a manner that mirrors the pharmacokinetic pattern of infusion,” it might be able to reduce motor complications.

This hypothesis led to an interest in treatment with levodopa plus entacapone. A regimen of levodopa-carbidopa-entacapone, four times daily at 3.5-hour intervals, was compared with levodopa-carbidopa in 747 patients with early PD over 134 weeks.¹⁶ Initiating levodopa therapy with levodopa-carbidopa in combination with entacapone did not delay the induction of dyskinesia compared with levodopa-carbidopa alone. In fact, levodopa-carbidopa-entacapone was associated with a shorter time to onset and an increased frequency of dyskinesia compared with levodopa-carbidopa.

Potential future treatment options

An intrajejunal pump system delivers a constant-rate infusion of levodopa. A double-blind study of this system is being conducted in the United States. Implantation of the system is an invasive procedure with the potential for infection, kinking dislocation, and occlusion and reposition of the catheter.

Miniature pumps for continuous subcutaneous delivery of apomorphine, currently available only in Europe, have been shown to reverse dyskinesias and motor fluctuations. Limitations of the minipumps are the development of red itchy nodules, ulcerations, and abscesses at infusion sites.

Extended-release dopamine agonists

Extended-release formulations of the dopamine agonists ropinirole and pramipexole are easy to administer, and they maintain therapeutic plasma levels for up to 24 hours. They are unlikely to replace stronger continuous dopamine stimulation with levodopa and apomorphine.

SUMMARY

Motor complications in PD result from progression of the disease and limitations of levodopa. Although the effects of levodopa on PD eventually wane, leaving patients vulnerable to motor complications, clinicians should not undertreat patients.

Effective options for the management of motor complications include prolonging the efficacy of levodopa through the use of selective MAO-B inhibitors and COMT inhibitors as adjuncts to levodopa or continuous dopaminergic stimulation achieved by the use of long-acting dopamine agonists or continuous intraduodenal levodopa.

Emerging therapies will be more efficient for continuous delivery of dopaminergic drugs. Pump delivery systems and extended-release formulations have shown promise.

Dopaminergic treatment is extremely beneficial in inducing symptom improvement in early Parkinson disease (PD). Patients typically experience a smooth and even response to the early stages of levodopa treatment. With disease progression, however, the effect of levodopa begins to weaken approximately 4 hours after each dose, leaving patients anticipating the need for their next dose and vulnerable to motor fluctuations and dyskinesias.

Motor fluctuations refer to the unanticipated loss of effect of a given dose of levodopa; instead of a smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed “wearing off”) or may suddenly switch from “on” (symptoms controlled) to “off” (symptoms return). Dyskinesias, or involuntary movements, occur when dopamine levels are too high.

Motor complications are a major cause of disability in PD. They affect 60% to 90% of PD patients after 5 to 10 years of treatment. Moreover, in one study of 143 PD patients, motor complications diminished quality of life; the most strongly affected dimensions were mobility, activities of daily living, communication, and stigma.¹

PATHOGENESIS OF MOTOR COMPLICATIONS

Under physiologic conditions, dopamine stimulation of the striatal dopamine receptors occurs in a sustained fashion. In early PD, the pool of remaining neurons of the substantia nigra is believed to be sufficiently active to smooth out changes in levodopa levels, providing a relatively constant amount of dopamine. Many PD patients therefore have several years of trouble-free treatment following diagnosis. In the advanced disease states, however, the number of presynaptic dopaminergic neurons progressively decreases. With fewer dopaminergic neurons, a constant dopaminergic concentration cannot be sustained. As PD advances, the progressive loss of dopaminergic neurons leads to impaired dopamine storage. Thus, the buffering capacity of dopaminergic neurons decreases and synaptic dopamine levels begin to reflect systemic or exogenous levodopa levels.

According to current views, the total motor response to levodopa results from the combination of endogenous dopamine production along with the short-duration response (SDR) and the long-duration response (LDR) to exogenous levodopa.² The SDR represents an improvement in parkinsonian symptoms and signs, lasting minutes to hours, that is closely related to the rise and fall of plasma levodopa concentrations. The SDR parallels the fluctuations in motor response and has received the most attention in the literature. The LDR is an improvement in parkinsonism that builds up over days and likewise decays over days. The LDR decays more rapidly in severely affected patients. Negative response, or “super off,” is a transient worsening of motor function to below the baseline level that may occur as the effects of the SDR dissipate.

The proportions of the SDR and LDR can vary according to disease progression. The LDR is more prominent in early stages, accounting for the stable response seen in the honeymoon period of treatment.

Peripheral factors

Additional peripheral factors such as changes in gastric motility and absorption contribute to motor complications. Levodopa is transported by a saturable active transporter system, the large neutral amino acid system, in the gut, and across the blood-brain barrier. Levodopa absorption is thus affected by food intake, especially protein. Levodopa and dietary amino acids compete with each other for absorption at the intestinal and blood-brain levels. Levodopa and other dopaminergic therapies further chronically reduce gastric emptying.

Pulsatile dopamine stimulation

The latency from the time of levodopa administration to the onset of motor improvement is typically 30 to 90 minutes. Latency is longer in late stages when the striatal buffer is weakened and the plasma concentration of levodopa fluctuates.

TYPES OF MOTOR FLUCTUATIONS

Fluctuating motor response in levodopa-treated patients refers to clinically apparent oscillations in motor function. Management of the fluctuating response may require frequent daily dosing of levodopa.

Motor fluctuations in PD take four forms: wearing off, off, delayed on/no on, and dyskinesias.

Wearing off

Wearing off refers to the premature loss of benefit from a given dose of levodopa, causing a predictable return of parkinsonian symptoms (bradykinesia, tremors, rigidity, and gait problems) in advance of the next scheduled dose. Observed in early and moderate PD, wearing off is the most common type of motor fluctuation. Its pathophysiology relates to disease progression and pharmacokinetics of levodopa. It can be sudden or gradual, predictable or unpredictable.

Off state

The off state is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Such symptoms include pain, stiffness, paresthesia, cognitive symptoms (depression, anxiety, difficulty with concentration, and mental slowing), inner restlessness, and inner tremulousness. The off state can be sudden or gradual, predictable or unpredictable.

Delayed on/no on

Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. As the disease progresses, wearing off becomes more complicated and more unpredictable. The dosing responses vary, and patients sometimes report delayed on. The causes of delayed on or no on can be an insufficient dose, dosing with high-protein meals, or delayed gastric emptying. Metoclopramide or domperidone can help with gastric emptying. Metoclopramide can cross the blood-brain barrier and thus may cause adverse effects related to dopaminergic blockade; domperidone does not cross the blood-brain barrier.

Dyskinesias

Dyskinesias are hyperkinetic movements related to dopaminergic effects that are greater or less than the therapeutic threshold. They are common with long-term levodopa therapy and have three patterns:

Off dystonia occurs when levodopa concentrations are low and the SDR has dissipated. Dystonic states may be a manifestation of too little or too much levodopa; differentiating the two is important. Off dystonia occurs mostly in the early mornings, when plasma levodopa levels are low, and mostly involves the more affected side first.

Peak-dose dyskinesia, which occurs during the SDR, is the most common type of dykinesia and is related to peak plasma levodopa levels. It is characterized by stereotypic, choreic abnormal movements involving the head, neck, trunk, and limbs, and possibly hemidyskinesia in young-onset PD. Peak-dose dyskinesias are sometimes severe enough to be disabling.

Diphasic dyskinesias are stereotyped, dystonic, or choreic movements that occur at the beginning of the SDR and again as the SDR dissipates. They predominantly affect the legs and spare the trunk, neck, and arms.

TREATMENT OF OFF AND WEARING OFF

Food and tolerance

The patient should not take levodopa with protein-containing meals, particularly if his or her PD is at an advanced stage. If excessive nausea, vomiting, or lightheadedness prevents the patient from taking an adequate dose, adding carbidopa (up to 75 mg) to the regimen will be helpful.

MAO-B inhibitors

By inhibiting one of the central dopamine catabolic pathways, MAO-B inhibitors (selegiline, rasagiline, and Zydis selegiline) prolong the half-life of dopamine in the brain and increase on time.

Improvement in off time with rasagiline is comparable to that seen with the COMT inhibitor entacapone. In an 18-week, double-blind trial of 687 patients randomized to receive once-daily rasagiline, entacapone, or placebo as an adjunct to levodopa, both rasagiline and entacapone reduced off time by 1.2 hours compared with placebo.³

In a 26-week placebo-controlled study, rasagiline decreased off time by 29% when added to levodopa in patients with PD and motor fluctuations, compared with a 15% reduction in the placebo group.⁴ This study confirmed the benefit of adding rasagiline to the regimens of patients who were already optimally treated with levodopa, dopamine agonists, amantadine, anticholinergics, and entacapone before enrolling in the study.

An orally disintegrating selegiline (Zydis selegiline) tablet is particularly useful for patients who have difficulty swallowing. The bioavailability of Zydis selegiline is 80% compared with 10% for selegiline, resulting in faster absorption. Pregastric absorption of Zydis selegiline avoids extensive first-pass metabolism in the liver and, therefore, the concentration of amphetamine-like metabolites is much lower.

In a 3-month, placebo-controlled study of patients with PD who were experiencing levodopa-related motor fluctuations, Zydis selegiline was associated with a 2.2-hour reduction in the total number of off hours compared with 0.6 hours in the placebo group, and dyskinesia-free on hours increased by 1.8 hours.⁵

The use of MAO-B inhibitors with tricyclic antidepressants or selective serotonin reuptake inhibitors has been reported to induce the serotonin syndrome by activation of 5HT_1a and 5HT₂ receptors. Serotonin syndrome is a potentially life-threatening accumulation of serotonin that can cause encephalopathy, severe rigidity of the legs, dysautonomia (diarrhea, mydriasis, and excessive lacrimation), myoclonus, hyperreflexia, and seizures.

COMT inhibitors

Catechol-O-methyltransferase inhibitors (entacapone and tolcapone) block peripheral degradation of levodopa. Tolcapone also blocks central degradation of levodopa and dopamine. These mechanisms increase central levodopa and dopamine levels and prolong levodopa half-life and bioavailability. Tolcapone has more powerful COMT inhibition than entacapone because tolcapone crosses the blood-brain barrier and inhibits the peripheral and central pathways of levodopa degradation. Use of COMT inhibitors can increase daily on time, but diarrhea is a common side effect and leads to withdrawal of these agents in about 3% of patients.

Tolcapone-treated patients show significant improvement in off time with improvement in motor fluctuations.⁶ Because tolcapone causes rare instances of fulminant hepatitis, liver function needs to be monitored every other week. For this reason, tolcapone should be reserved for patients in whom other treatments, including entacapone, have failed.

Controlled-release levodopa

Controlled-release levodopa was developed to provide more constant delivery of levodopa to the striatum. The benefit of controlled-release levodopa is only mild, however, as absorption of this formulation is variable. In advanced PD cases, the effects of controlled-release levodopa are more unpredictable than those with standard levodopa. Controlled-release levodopa is effective in patients with less severe wearing off, but it is not as effective in patients with a less predictable pattern of fluctuations.

Dopamine agonists

Dopamine agonists (pramipexole, ropinirole, apomorphine, and bromocriptine) have shown beneficial effects as adjunctive therapy to reduce wearing off. Side effects of dopamine agonists include ankle edema, hallucinations, somnolence, and impulse control disorders. These side effects should be discussed with patients before instituting therapy, and therapy should be discontinued if any of them occur.

In patients with advanced PD, pramipexole was shown to improve motor function during on and off periods, decrease the total off time, and decrease the severity of off time. Further, a larger reduction in the dosage of levodopa was possible in the pramipexole-treated patients than in the placebo-treated patients.⁷

In a comparison of pramipexole with levodopa on the end point of motor complications of PD in 300 patients, the incidences of wearing off and dyskinesia were significantly lower in the patients randomized to pramipexole with follow-up over 4 years.⁸ Only 25% of patients initially treated with pramipexole exhibited dyskinesia compared with 54% of patients initially treated with levodopa. Forty-seven percent of patients in the pramipexole group experienced wearing off compared with 63% initially treated with levodopa. Pramipexole is available as tablets ranging from 0.125 mg to 1.5 mg in size. It is given in three divided daily doses with gradual increments of 0.25 mg three times a day every week. Pramipexole is now also available in an extended-release formulation for once-a-day dosing in tablets ranging in size from 0.375 mg to 4.5 mg.

Ropinirole adds clinical benefit in PD patients with motor fluctuations and also permits a reduction in the dosage of levodopa.⁹

In one study, ropinirole monotherapy was compared with levodopa therapy in 268 patients with early PD. By the end of the 5-year study, 45% of the levodopa patients experienced dyskinesias versus 20% of the ropinirole patients.¹⁰

Ropinirole is available as tablets ranging in size from 0.25 mg to 5 mg. It is now also available in an extended-release (XL) formulation, with tablet sizes ranging from 2 mg to 12 mg. Ropinirole XL is taken once a day.

Bromocriptine is an old ergot-derived dopamine agonist that has also been studied for monotherapy and add-on treatment in PD. Due to the potential risks of pulmonary, retroperitoneal, and heart valve fibrosis, bromocriptine is not commonly used.

Apomorphine was approved by the US Food and Drug Administration in 2004 as an acute, intermittent, subcutaneous injection for the treatment of hypomobility off episodes (end-of-dose wearing off and unpredictable on-off episodes) associated with advanced PD. Apomorphine has been shown to be beneficial in patients with unpredictable off periods.¹¹ Its onset of action is 10 to 15 minutes, and the effects of each dose last for 60 to 90 minutes. The best tolerated dose is 4 mg to 10 mg. Apomorphine appears to be most useful as as rescue medication in the refractory off periods with severe bradykinesia and unpredictable off periods.

TREATMENT OF DYSKINESIAS

Reduction of levodopa doses will reduce the frequency of dyskinesias, but at a cost of worsened parkinsonism and increased numbers of off periods. An alternative is to spread out the doses of levodopa (more frequent smaller doses), but this practice has not achieved good results. Replacing levodopa with dopamine agonists can also reduce the frequency of dyskinesias, but control of PD symptoms is less optimal than with levodopa. Amantadine and clozapine both have been shown to reduce dyskinesias.

Amantadine

Amantadine is an N-methyl-d-aspartate antagonist with antidyskinesia effects. Metman et al¹² demonstrated that amantadine reduced dyskinesia severity by 60%, without exacerbation of motor function, in a randomized placebo-controlled crossover study. Dose-response studies with amantadine have not been conducted, but 100 mg two or three times daily is used in practice. In some studies, a short duration of benefit has been a concern. Side effects of amantadine include leg edema, hallucinations, confusion, and rash.

Clozapine

Clozapine is an atypical antipsychotic that has been shown in open-label trials and a randomized, double-blind, placebo-controlled trial to reduce the duration and severity of levodopa-induced dyskinesias without worsening of parkinsonian features and with no change in motor fluctuation.¹³ No benefit of clozapine was observed during activation dyskinesia, however. Cloza pine carries the inconvenience of weekly blood draws to monitor for the development of agranulocytosis, which occurs rarely.

GAIT FREEZING

Gait freezing, most commonly a manifestation of off states, causes substantial disability. It has been thought to occur as a result of a loss of noradrenaline due to locus ceruleus degeneration. Improvement in gait freezing has been shown with apomorphine and methylphenidate.

CONCEPT OF CONTINUOUS DOPAMINE STIMULATION

Short-acting dopaminergic drugs have the potential for nonphysiologic pulsatile stimulation of postsynaptic receptors, leading to motor complications. Continuous dopaminergic stimulation to prevent this pulsatile stimulation would theoretically avoid motor complications.¹⁴ Continuous dopaminergic stimulation can be achieved by using the extended-release formulation of ropinirole or pramipexole or by continuous delivery of levodopa or dopamine agonists. Several double-blind controlled trials have shown that treatment with long-acting dopamine agonists lowers the risk of motor complications compared with short-acting levodopa treatment.

In 2005, Stocchi concluded that in patients with advanced PD, a continuous infusion of levodopa was more effective in reducing motor complications than standard oral formulations.¹⁵ The reduction in motor complications was attributed to avoidance of low plasma levodopa trough levels; motor complications were not affected by relatively high plasma levodopa concentrations. The authors of this study speculated that if oral levodopa could be given “in a manner that mirrors the pharmacokinetic pattern of infusion,” it might be able to reduce motor complications.

This hypothesis led to an interest in treatment with levodopa plus entacapone. A regimen of levodopa-carbidopa-entacapone, four times daily at 3.5-hour intervals, was compared with levodopa-carbidopa in 747 patients with early PD over 134 weeks.¹⁶ Initiating levodopa therapy with levodopa-carbidopa in combination with entacapone did not delay the induction of dyskinesia compared with levodopa-carbidopa alone. In fact, levodopa-carbidopa-entacapone was associated with a shorter time to onset and an increased frequency of dyskinesia compared with levodopa-carbidopa.

Potential future treatment options

An intrajejunal pump system delivers a constant-rate infusion of levodopa. A double-blind study of this system is being conducted in the United States. Implantation of the system is an invasive procedure with the potential for infection, kinking dislocation, and occlusion and reposition of the catheter.

Miniature pumps for continuous subcutaneous delivery of apomorphine, currently available only in Europe, have been shown to reverse dyskinesias and motor fluctuations. Limitations of the minipumps are the development of red itchy nodules, ulcerations, and abscesses at infusion sites.

Extended-release dopamine agonists

Extended-release formulations of the dopamine agonists ropinirole and pramipexole are easy to administer, and they maintain therapeutic plasma levels for up to 24 hours. They are unlikely to replace stronger continuous dopamine stimulation with levodopa and apomorphine.

SUMMARY

Motor complications in PD result from progression of the disease and limitations of levodopa. Although the effects of levodopa on PD eventually wane, leaving patients vulnerable to motor complications, clinicians should not undertreat patients.

Effective options for the management of motor complications include prolonging the efficacy of levodopa through the use of selective MAO-B inhibitors and COMT inhibitors as adjuncts to levodopa or continuous dopaminergic stimulation achieved by the use of long-acting dopamine agonists or continuous intraduodenal levodopa.

Emerging therapies will be more efficient for continuous delivery of dopaminergic drugs. Pump delivery systems and extended-release formulations have shown promise.

Dopaminergic treatment is extremely beneficial in inducing symptom improvement in early Parkinson disease (PD). Patients typically experience a smooth and even response to the early stages of levodopa treatment. With disease progression, however, the effect of levodopa begins to weaken approximately 4 hours after each dose, leaving patients anticipating the need for their next dose and vulnerable to motor fluctuations and dyskinesias.

Motor fluctuations refer to the unanticipated loss of effect of a given dose of levodopa; instead of a smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed “wearing off”) or may suddenly switch from “on” (symptoms controlled) to “off” (symptoms return). Dyskinesias, or involuntary movements, occur when dopamine levels are too high.

Motor complications are a major cause of disability in PD. They affect 60% to 90% of PD patients after 5 to 10 years of treatment. Moreover, in one study of 143 PD patients, motor complications diminished quality of life; the most strongly affected dimensions were mobility, activities of daily living, communication, and stigma.¹

PATHOGENESIS OF MOTOR COMPLICATIONS

Under physiologic conditions, dopamine stimulation of the striatal dopamine receptors occurs in a sustained fashion. In early PD, the pool of remaining neurons of the substantia nigra is believed to be sufficiently active to smooth out changes in levodopa levels, providing a relatively constant amount of dopamine. Many PD patients therefore have several years of trouble-free treatment following diagnosis. In the advanced disease states, however, the number of presynaptic dopaminergic neurons progressively decreases. With fewer dopaminergic neurons, a constant dopaminergic concentration cannot be sustained. As PD advances, the progressive loss of dopaminergic neurons leads to impaired dopamine storage. Thus, the buffering capacity of dopaminergic neurons decreases and synaptic dopamine levels begin to reflect systemic or exogenous levodopa levels.

According to current views, the total motor response to levodopa results from the combination of endogenous dopamine production along with the short-duration response (SDR) and the long-duration response (LDR) to exogenous levodopa.² The SDR represents an improvement in parkinsonian symptoms and signs, lasting minutes to hours, that is closely related to the rise and fall of plasma levodopa concentrations. The SDR parallels the fluctuations in motor response and has received the most attention in the literature. The LDR is an improvement in parkinsonism that builds up over days and likewise decays over days. The LDR decays more rapidly in severely affected patients. Negative response, or “super off,” is a transient worsening of motor function to below the baseline level that may occur as the effects of the SDR dissipate.

The proportions of the SDR and LDR can vary according to disease progression. The LDR is more prominent in early stages, accounting for the stable response seen in the honeymoon period of treatment.

Peripheral factors

Additional peripheral factors such as changes in gastric motility and absorption contribute to motor complications. Levodopa is transported by a saturable active transporter system, the large neutral amino acid system, in the gut, and across the blood-brain barrier. Levodopa absorption is thus affected by food intake, especially protein. Levodopa and dietary amino acids compete with each other for absorption at the intestinal and blood-brain levels. Levodopa and other dopaminergic therapies further chronically reduce gastric emptying.

Pulsatile dopamine stimulation

The latency from the time of levodopa administration to the onset of motor improvement is typically 30 to 90 minutes. Latency is longer in late stages when the striatal buffer is weakened and the plasma concentration of levodopa fluctuates.

TYPES OF MOTOR FLUCTUATIONS

Fluctuating motor response in levodopa-treated patients refers to clinically apparent oscillations in motor function. Management of the fluctuating response may require frequent daily dosing of levodopa.

Motor fluctuations in PD take four forms: wearing off, off, delayed on/no on, and dyskinesias.

Wearing off

Wearing off refers to the premature loss of benefit from a given dose of levodopa, causing a predictable return of parkinsonian symptoms (bradykinesia, tremors, rigidity, and gait problems) in advance of the next scheduled dose. Observed in early and moderate PD, wearing off is the most common type of motor fluctuation. Its pathophysiology relates to disease progression and pharmacokinetics of levodopa. It can be sudden or gradual, predictable or unpredictable.

Off state

The off state is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Such symptoms include pain, stiffness, paresthesia, cognitive symptoms (depression, anxiety, difficulty with concentration, and mental slowing), inner restlessness, and inner tremulousness. The off state can be sudden or gradual, predictable or unpredictable.

Delayed on/no on

Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. As the disease progresses, wearing off becomes more complicated and more unpredictable. The dosing responses vary, and patients sometimes report delayed on. The causes of delayed on or no on can be an insufficient dose, dosing with high-protein meals, or delayed gastric emptying. Metoclopramide or domperidone can help with gastric emptying. Metoclopramide can cross the blood-brain barrier and thus may cause adverse effects related to dopaminergic blockade; domperidone does not cross the blood-brain barrier.

Dyskinesias

Dyskinesias are hyperkinetic movements related to dopaminergic effects that are greater or less than the therapeutic threshold. They are common with long-term levodopa therapy and have three patterns:

Off dystonia occurs when levodopa concentrations are low and the SDR has dissipated. Dystonic states may be a manifestation of too little or too much levodopa; differentiating the two is important. Off dystonia occurs mostly in the early mornings, when plasma levodopa levels are low, and mostly involves the more affected side first.

Peak-dose dyskinesia, which occurs during the SDR, is the most common type of dykinesia and is related to peak plasma levodopa levels. It is characterized by stereotypic, choreic abnormal movements involving the head, neck, trunk, and limbs, and possibly hemidyskinesia in young-onset PD. Peak-dose dyskinesias are sometimes severe enough to be disabling.

Diphasic dyskinesias are stereotyped, dystonic, or choreic movements that occur at the beginning of the SDR and again as the SDR dissipates. They predominantly affect the legs and spare the trunk, neck, and arms.

TREATMENT OF OFF AND WEARING OFF

Food and tolerance

The patient should not take levodopa with protein-containing meals, particularly if his or her PD is at an advanced stage. If excessive nausea, vomiting, or lightheadedness prevents the patient from taking an adequate dose, adding carbidopa (up to 75 mg) to the regimen will be helpful.

MAO-B inhibitors

By inhibiting one of the central dopamine catabolic pathways, MAO-B inhibitors (selegiline, rasagiline, and Zydis selegiline) prolong the half-life of dopamine in the brain and increase on time.

Improvement in off time with rasagiline is comparable to that seen with the COMT inhibitor entacapone. In an 18-week, double-blind trial of 687 patients randomized to receive once-daily rasagiline, entacapone, or placebo as an adjunct to levodopa, both rasagiline and entacapone reduced off time by 1.2 hours compared with placebo.³

In a 26-week placebo-controlled study, rasagiline decreased off time by 29% when added to levodopa in patients with PD and motor fluctuations, compared with a 15% reduction in the placebo group.⁴ This study confirmed the benefit of adding rasagiline to the regimens of patients who were already optimally treated with levodopa, dopamine agonists, amantadine, anticholinergics, and entacapone before enrolling in the study.

An orally disintegrating selegiline (Zydis selegiline) tablet is particularly useful for patients who have difficulty swallowing. The bioavailability of Zydis selegiline is 80% compared with 10% for selegiline, resulting in faster absorption. Pregastric absorption of Zydis selegiline avoids extensive first-pass metabolism in the liver and, therefore, the concentration of amphetamine-like metabolites is much lower.

In a 3-month, placebo-controlled study of patients with PD who were experiencing levodopa-related motor fluctuations, Zydis selegiline was associated with a 2.2-hour reduction in the total number of off hours compared with 0.6 hours in the placebo group, and dyskinesia-free on hours increased by 1.8 hours.⁵

The use of MAO-B inhibitors with tricyclic antidepressants or selective serotonin reuptake inhibitors has been reported to induce the serotonin syndrome by activation of 5HT_1a and 5HT₂ receptors. Serotonin syndrome is a potentially life-threatening accumulation of serotonin that can cause encephalopathy, severe rigidity of the legs, dysautonomia (diarrhea, mydriasis, and excessive lacrimation), myoclonus, hyperreflexia, and seizures.

COMT inhibitors

Catechol-O-methyltransferase inhibitors (entacapone and tolcapone) block peripheral degradation of levodopa. Tolcapone also blocks central degradation of levodopa and dopamine. These mechanisms increase central levodopa and dopamine levels and prolong levodopa half-life and bioavailability. Tolcapone has more powerful COMT inhibition than entacapone because tolcapone crosses the blood-brain barrier and inhibits the peripheral and central pathways of levodopa degradation. Use of COMT inhibitors can increase daily on time, but diarrhea is a common side effect and leads to withdrawal of these agents in about 3% of patients.

Tolcapone-treated patients show significant improvement in off time with improvement in motor fluctuations.⁶ Because tolcapone causes rare instances of fulminant hepatitis, liver function needs to be monitored every other week. For this reason, tolcapone should be reserved for patients in whom other treatments, including entacapone, have failed.

Controlled-release levodopa

Controlled-release levodopa was developed to provide more constant delivery of levodopa to the striatum. The benefit of controlled-release levodopa is only mild, however, as absorption of this formulation is variable. In advanced PD cases, the effects of controlled-release levodopa are more unpredictable than those with standard levodopa. Controlled-release levodopa is effective in patients with less severe wearing off, but it is not as effective in patients with a less predictable pattern of fluctuations.

Dopamine agonists

Dopamine agonists (pramipexole, ropinirole, apomorphine, and bromocriptine) have shown beneficial effects as adjunctive therapy to reduce wearing off. Side effects of dopamine agonists include ankle edema, hallucinations, somnolence, and impulse control disorders. These side effects should be discussed with patients before instituting therapy, and therapy should be discontinued if any of them occur.

In patients with advanced PD, pramipexole was shown to improve motor function during on and off periods, decrease the total off time, and decrease the severity of off time. Further, a larger reduction in the dosage of levodopa was possible in the pramipexole-treated patients than in the placebo-treated patients.⁷

In a comparison of pramipexole with levodopa on the end point of motor complications of PD in 300 patients, the incidences of wearing off and dyskinesia were significantly lower in the patients randomized to pramipexole with follow-up over 4 years.⁸ Only 25% of patients initially treated with pramipexole exhibited dyskinesia compared with 54% of patients initially treated with levodopa. Forty-seven percent of patients in the pramipexole group experienced wearing off compared with 63% initially treated with levodopa. Pramipexole is available as tablets ranging from 0.125 mg to 1.5 mg in size. It is given in three divided daily doses with gradual increments of 0.25 mg three times a day every week. Pramipexole is now also available in an extended-release formulation for once-a-day dosing in tablets ranging in size from 0.375 mg to 4.5 mg.

Ropinirole adds clinical benefit in PD patients with motor fluctuations and also permits a reduction in the dosage of levodopa.⁹

In one study, ropinirole monotherapy was compared with levodopa therapy in 268 patients with early PD. By the end of the 5-year study, 45% of the levodopa patients experienced dyskinesias versus 20% of the ropinirole patients.¹⁰

Ropinirole is available as tablets ranging in size from 0.25 mg to 5 mg. It is now also available in an extended-release (XL) formulation, with tablet sizes ranging from 2 mg to 12 mg. Ropinirole XL is taken once a day.

Bromocriptine is an old ergot-derived dopamine agonist that has also been studied for monotherapy and add-on treatment in PD. Due to the potential risks of pulmonary, retroperitoneal, and heart valve fibrosis, bromocriptine is not commonly used.

Apomorphine was approved by the US Food and Drug Administration in 2004 as an acute, intermittent, subcutaneous injection for the treatment of hypomobility off episodes (end-of-dose wearing off and unpredictable on-off episodes) associated with advanced PD. Apomorphine has been shown to be beneficial in patients with unpredictable off periods.¹¹ Its onset of action is 10 to 15 minutes, and the effects of each dose last for 60 to 90 minutes. The best tolerated dose is 4 mg to 10 mg. Apomorphine appears to be most useful as as rescue medication in the refractory off periods with severe bradykinesia and unpredictable off periods.

TREATMENT OF DYSKINESIAS

Reduction of levodopa doses will reduce the frequency of dyskinesias, but at a cost of worsened parkinsonism and increased numbers of off periods. An alternative is to spread out the doses of levodopa (more frequent smaller doses), but this practice has not achieved good results. Replacing levodopa with dopamine agonists can also reduce the frequency of dyskinesias, but control of PD symptoms is less optimal than with levodopa. Amantadine and clozapine both have been shown to reduce dyskinesias.

Amantadine

Amantadine is an N-methyl-d-aspartate antagonist with antidyskinesia effects. Metman et al¹² demonstrated that amantadine reduced dyskinesia severity by 60%, without exacerbation of motor function, in a randomized placebo-controlled crossover study. Dose-response studies with amantadine have not been conducted, but 100 mg two or three times daily is used in practice. In some studies, a short duration of benefit has been a concern. Side effects of amantadine include leg edema, hallucinations, confusion, and rash.

Clozapine

Clozapine is an atypical antipsychotic that has been shown in open-label trials and a randomized, double-blind, placebo-controlled trial to reduce the duration and severity of levodopa-induced dyskinesias without worsening of parkinsonian features and with no change in motor fluctuation.¹³ No benefit of clozapine was observed during activation dyskinesia, however. Cloza pine carries the inconvenience of weekly blood draws to monitor for the development of agranulocytosis, which occurs rarely.

GAIT FREEZING

Gait freezing, most commonly a manifestation of off states, causes substantial disability. It has been thought to occur as a result of a loss of noradrenaline due to locus ceruleus degeneration. Improvement in gait freezing has been shown with apomorphine and methylphenidate.

CONCEPT OF CONTINUOUS DOPAMINE STIMULATION

Short-acting dopaminergic drugs have the potential for nonphysiologic pulsatile stimulation of postsynaptic receptors, leading to motor complications. Continuous dopaminergic stimulation to prevent this pulsatile stimulation would theoretically avoid motor complications.¹⁴ Continuous dopaminergic stimulation can be achieved by using the extended-release formulation of ropinirole or pramipexole or by continuous delivery of levodopa or dopamine agonists. Several double-blind controlled trials have shown that treatment with long-acting dopamine agonists lowers the risk of motor complications compared with short-acting levodopa treatment.

In 2005, Stocchi concluded that in patients with advanced PD, a continuous infusion of levodopa was more effective in reducing motor complications than standard oral formulations.¹⁵ The reduction in motor complications was attributed to avoidance of low plasma levodopa trough levels; motor complications were not affected by relatively high plasma levodopa concentrations. The authors of this study speculated that if oral levodopa could be given “in a manner that mirrors the pharmacokinetic pattern of infusion,” it might be able to reduce motor complications.

This hypothesis led to an interest in treatment with levodopa plus entacapone. A regimen of levodopa-carbidopa-entacapone, four times daily at 3.5-hour intervals, was compared with levodopa-carbidopa in 747 patients with early PD over 134 weeks.¹⁶ Initiating levodopa therapy with levodopa-carbidopa in combination with entacapone did not delay the induction of dyskinesia compared with levodopa-carbidopa alone. In fact, levodopa-carbidopa-entacapone was associated with a shorter time to onset and an increased frequency of dyskinesia compared with levodopa-carbidopa.

Potential future treatment options

An intrajejunal pump system delivers a constant-rate infusion of levodopa. A double-blind study of this system is being conducted in the United States. Implantation of the system is an invasive procedure with the potential for infection, kinking dislocation, and occlusion and reposition of the catheter.

Miniature pumps for continuous subcutaneous delivery of apomorphine, currently available only in Europe, have been shown to reverse dyskinesias and motor fluctuations. Limitations of the minipumps are the development of red itchy nodules, ulcerations, and abscesses at infusion sites.

Extended-release dopamine agonists

Extended-release formulations of the dopamine agonists ropinirole and pramipexole are easy to administer, and they maintain therapeutic plasma levels for up to 24 hours. They are unlikely to replace stronger continuous dopamine stimulation with levodopa and apomorphine.

SUMMARY

Motor complications in PD result from progression of the disease and limitations of levodopa. Although the effects of levodopa on PD eventually wane, leaving patients vulnerable to motor complications, clinicians should not undertreat patients.

Effective options for the management of motor complications include prolonging the efficacy of levodopa through the use of selective MAO-B inhibitors and COMT inhibitors as adjuncts to levodopa or continuous dopaminergic stimulation achieved by the use of long-acting dopamine agonists or continuous intraduodenal levodopa.

Emerging therapies will be more efficient for continuous delivery of dopaminergic drugs. Pump delivery systems and extended-release formulations have shown promise.

Although the definition of Parkinson disease (PD) is based on the presence of motor features, these are just the “tip of the iceberg.” Nonmotor manifestations are nearly ubiquitous in PD, with behavior problems often being the most malignant. Almost all patients with PD have nonmotor and neuropsychiatric features, including sleep disturbances, compulsive and impulsive behaviors, autonomic dysfunction, and psychosis.

The neuropsychiatric and behavioral features of PD can be classified as intrinsic features, which occur as part of PD, and iatrogenic features, which are complications that arise from treatments used to manage the motor symptoms of PD.

DEMENTIA IN PD

An intrinsic nonmotor feature of PD is dementia, which occurs at a rate four to six times greater in patients with PD than in age-matched controls without PD.¹ The prevalence of dementia in PD varies among studies and depends on the demographics of the population being studied. The cross-sectional prevalence of dementia is 40% in patients with PD.² Seventy-eight percent of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period.³

Dementia is a burden to the caregiver, the patient, and society. Cognitive and behavioral symptoms in patients with PD are the greatest contributors to caregiver distress.⁴ Dementia and associated behavioral symptoms (ie, hallucinations) hasten nursing home placement, contributing to the financial burden of caring for patients with PD.⁵ The risk of mortality is increased when dementia develops.⁶

Reprinted with permission from The New England Journal of Medicine (Emre M, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509–2518). Copyright © 2004 Massachusetts Medical Society. All rights reserved.

PSYCHOTIC SYMPTOMS IN PD: AN EFFECT OF EXCESS DOPAMINE STIMULATION

Most of the complications observed in PD can be explained by the dopamine effect of medications and by dopamine deficiencies. An excess of dopamine stimulation caused by administration of prodopaminergic agents manifests as dyskinesias, hallucinations, or delusions. Withdrawal of levodopa will reverse these complications but leads to dopamine deficiency and thus a worsening of PD symptoms. Most patients with PD will tolerate mild dyskinesias or hallucinations if their PD symptoms are well controlled.

The hallucinations in PD tend to be visual as opposed to auditory (as in schizophrenia). They are usually benign and involve figures of people, furry animals, or complex scenes. About 10% to 40% of hallucinations in PD are secondary auditory hallucinations, which tend to be nondistinct, non-paranoid, and often incomprehensible (ie, voices in a crowd).

In the same way, the delusions experienced in patients with PD are distinct from those in schizophrenia. The delusions in PD are usually paranoid in nature and involve stereotyped themes (ie, spousal infidelity, feelings of abandonment) rather than the grandiose delusions that are common in schizophrenia.

The reported prevalence of psychotic symptoms in PD, including hallucinations and delusions, ranges from 20% to 50%.^8,9 Auditory hallucinations are a feature in about 10%, and they usually occur with visual hallucinations. Less common are delusions and hallucinations with loss of insight, which are more likely with increasing severity of dementia.

Once a PD patient experiences hallucinations, they are likely to continue. In a 6-year longitudinal study, the prevalence of hallucinations increased from 33% at baseline to 55% at 72 months.¹⁰ Persistent psychosis was found in 69% of participants in the Psychosis and Clozapine in PD Study (PSYCLOPS) with 26 months of follow-up.¹¹

High caregiver burden

Psychotic symptoms in PD are associated with high caregiver stress and increased rates of nursing home placement. Goetz et al¹² showed that PD patients with psychosis had a much greater risk of nursing home placement than those without psychosis. The prognosis for PD patients in extended-care facilities is worse for those with psychotic symptoms.¹³

Management of psychotic symptoms

The first step in managing psychosis in PD is to rule out other causes of changes in mental status, such as infection, electrolyte imbalance, or introduction of new medications.

Adjusting anti-PD medications to a tolerable yet effective dose may help to reduce the incidence and severity of psychotic complications. If necessary, selective discontinuation of anti-PD medications may be tried in the following sequence: anticholinergics, amantadine, monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and levodopa/carbidopa.

If motor symptoms prevent dosage minimization or discontinuation of some medications, then the addition of an atypical antipsychotic medication should be considered. Before the advent of atypical antipsychotics, the management of psychosis and hallucinations in PD was unsatisfactory, reflected by a mortality of 100% within 2 years among psychotic PD patients placed in nursing homes compared with 32% among age-matched community dwellers.¹³ The introduction of atypical antipsychotics has improved survival among PD patients with psychosis. In one study, mortality over 5 years was 44% among PD patients taking long-term clozapine for the treatment of psychosis.¹⁴ Recurrence of psychosis is rapid (within 8 weeks) even when PD patients are slowly weaned from atypical antipsychotics.¹⁵

Receptor affinities differ among antipsychotics. Because dopamine has been implicated as the principal neurotransmitter in the development of PD psychosis, atypical antipsychotics, with milder dopamine-blocking action, have played a central role in the treatment of PD psychosis. The dopamine D₂ receptor is the main target for conventional antipsychotic drugs to exert their clinical effects. Atypical antipsychotics have different affinities for the D₂ receptors.¹⁶ Occupancy of D₂ receptors with atypical antipsychotics is 40% to 70% (risperidone and olanzapine have higher affinity for the D₂ receptor than clozapine and quetiapine), and affinity for 5-HT_2A receptors can be as high as 70%. This affinity for 5-HT_2A receptors relative to D₂ receptors may be important for therapeutic efficacy of the atypical antipsychotics. Antagonism of muscarinic, histaminergic, noradrenergic, and other serotonergic receptors also differs among the atypical antipsychotics.

Clozapine remains the gold standard atypical antipsychotic agent, based on results from three relatively small (N = 6 to 60) double-blind, placebo-controlled studies in PD patients with dopaminergic drug-induced psychosis.^17–19 Quetiapine improved psychotic symptoms associated with PD in several open-label studies, but has not demonstrated the same success in double-blind clinical trials.^20,21

Loss of cholinergic neurons and implications for treatment. In autopsy studies, the loss of cholinergic neurons is more profound in PD than in Alzheimer disease, which suggests that procholinergic drugs may improve symptoms of PD dementia, a major risk factor for hallucinations. In open-label studies, acetylcholinesterase inhibitors have reduced the frequency of hallucinations in patients who have dementia with Lewy bodies (DLB) and in patients with PD dementia. Double-blind trials of patients with DLB and PD dementia concentrated on the effect of cholinesterase inhibitors on dementia and not hallucinations. One concern with the use of a procholinergic drug in patients with PD has been worsening of parkinsonism, but studies of acetylcholinesterase inhibitors have shown no worsening of parkinsonism and only transient worsening of tremor.

Ondansetron, a 5-HT₃ receptor antagonist used as an antinausea medication, produced moderate improvements in hallucinations and delusions in an open-label trial for the treatment of psychosis in advanced PD.²² For PD patients with psychosis and comorbid depression, antidepressant therapy and electroconvulsive therapy may be effective options.^23,24

MOOD DISTURBANCES IN PD

Depression and apathy occur more frequently in patients with PD than in those who do not have PD.

Depression

Challenges in the management of depression in PD include recognition of depression and distinguishing depressive disorders from mood fluctuations. Whereas a depressive disorder lasts from weeks to years and can occur at any stage of illness, mood fluctuations can change many times daily and appear as nonmotor manifestations during the “off” medication state. Mood fluctuations occur mostly in patients who have developed motor fluctuations. The implication for treatment is that the treatment strategy for a depressive disorder is antidepressant therapy, whereas the strategy for mood fluctuations in PD is to increase the levodopa dose.

Recognition of depression in PD is confounded by the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; many of these criteria can be intrinsic features of PD itself—for example, anhedonia, weight/appetite loss or gain, insomnia or hypersomnia, psychomotor retardation, and fatigue. Questions such as “are you feeling sad” or “are you feeling blue” may be superior to questions about associative symptoms when evaluating PD patients for depression.

Reprinted with permission from Parkinsonism and Related Disorders (Shulman LM, et al. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193–197). © 2002 Elsevier Science Ltd.

Most of the medications used for the treatment of depression also work well for depression in patients with PD. Double-blind controlled studies have demonstrated superiority of nortriptyline, citalopram, desipramine, and pramipexole over placebo in improving mood.^26–29

Apathy

The overlap between apathy and depressive symptoms can also complicate recognition of apathy, which can be described as a lack of motivation or failure to initiate goal-directed behavior. Apathy involves three domains³⁰:

• Cognitive: expressed as a loss of interest in new experience or a lack of concern about a personal problem
• Diminished affect: flattened affect or a lack of reaction to positive or negative events
• Final: diminished goal-directed cognition, as indicated by a lack of effort or requiring others to structure activities.

Unlike depression, which is similarly representative of PD and other episodic conditions such as dystonia, apathy is more common in PD than in dystonia. In fact, the occurrence of apathy alone distinguishes PD from dystonia. Apathy in PD has no known treatment. If it is associated with depression, apathy may respond to antidepressants.

Repetitive transcranial magnetic stimulation (rTMS) manipulates activity in specific brain neural circuits through the skull to induce changes in behavior. Some studies suggest that modulation of behavior may last beyond the actual stimulation. A randomized, sham-controlled trial of rTMS over the middorsolateral frontal cortex has been conducted with the primary aim of improving apathy in PD. Unfortunately, while patients who were randomized to rTMS experienced some improvement in apathy during the study, the improvement was not significantly different from that observed in patients who received sham treatment.³¹

IMPULSE CONTROL AND COMPULSIVE DISORDERS IN PD

Impulse control disorders are characterized by the inability to resist an urge to act; the resulting irrational desire to pursue self-gratification may inflict suffering on friends and relatives that compromises relationships and impairs social- and work-related functioning.

Examples of impulse control disorders in PD are pathologic gambling, hypersexuality, compulsive shopping, excessive spending, and binge eating. Patients taking dopamine agonists are two to three times more likely to develop impulse control disorders than those receiving other treatments for PD. Dopamine agonists with relative selectivity for D₃ receptors have been implicated in impulse control disorders in PD because D₃ receptors are abundant in a region of the brain (ventral striatum) associated with behavioral and substance addictions. Higher levodopa dosages were also associated with impulse control disorders.

Factors associated with impulse control disorders in PD are young age, being single, a family history of impulse control disorders, and levodopa treatment.³² Modifications to dopamine agonist or levodopa therapy are important in the treatment of dopamine agonist–induced impulse disorders.

Compulsive disorders have been described as a class distinct from impulse control disorders and involve repetitive stereotypes and well-ordered acts to decrease inner anxiety and avoid harm. Punding is the engagement of stereotyped behaviors that are repeated compulsively—for example, repetitive manipulation of technical equipment; continual handling, sorting, and examining of objects; grooming; and hoarding. The punder has poor insight into the disruptive and senseless nature of his or her acts. Punding has consistently been related to dopaminergic therapy. Its prevalence in PD patients on dopaminergic therapy ranges from 1.4%³³ to 14%.³⁴ An improvement in behavior is observed with a reduction in dosage or discontinuation of levodopa.

Pathologic gambling, or the inability to control gambling, can result in lying to obtain money for gambling, thereby complicating relationships. It can affect up to 8% of patients with PD.³⁵

SUMMARY

Dementia, psychotic symptoms, mood disturbances, and impulse control disorders are important nonmotor manifestations of PD that present management challenges. Some of these manifestations are intrinsic to PD, and some are complications of therapies used to treat the motor manifestations of PD.

Dementia and psychotic symptoms extract a considerable toll on the patient, caregivers, and society. Psychotic symptoms generally manifest as hallucinations (mostly visual) and other sensory disturbances. Initial management involves adjustment of anti-PD medications. The use of atypical antipsychotic drugs has been shown to improve survival among patients with PD. Clozapine is the preferred agent.

Mood disturbances such as depression and apathy may be difficult to diagnose. Depression may be treated similarly to depression unassociated with PD.

Dopamine agonists and levodopa have been associated with impulse control disorders in PD. Compulsive disorders, which are distinct from impulse control disorders, may improve with reduction or discontinuation of levodopa therapy.

Although the definition of Parkinson disease (PD) is based on the presence of motor features, these are just the “tip of the iceberg.” Nonmotor manifestations are nearly ubiquitous in PD, with behavior problems often being the most malignant. Almost all patients with PD have nonmotor and neuropsychiatric features, including sleep disturbances, compulsive and impulsive behaviors, autonomic dysfunction, and psychosis.

The neuropsychiatric and behavioral features of PD can be classified as intrinsic features, which occur as part of PD, and iatrogenic features, which are complications that arise from treatments used to manage the motor symptoms of PD.

DEMENTIA IN PD

An intrinsic nonmotor feature of PD is dementia, which occurs at a rate four to six times greater in patients with PD than in age-matched controls without PD.¹ The prevalence of dementia in PD varies among studies and depends on the demographics of the population being studied. The cross-sectional prevalence of dementia is 40% in patients with PD.² Seventy-eight percent of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period.³

Dementia is a burden to the caregiver, the patient, and society. Cognitive and behavioral symptoms in patients with PD are the greatest contributors to caregiver distress.⁴ Dementia and associated behavioral symptoms (ie, hallucinations) hasten nursing home placement, contributing to the financial burden of caring for patients with PD.⁵ The risk of mortality is increased when dementia develops.⁶

Reprinted with permission from The New England Journal of Medicine (Emre M, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509–2518). Copyright © 2004 Massachusetts Medical Society. All rights reserved.

PSYCHOTIC SYMPTOMS IN PD: AN EFFECT OF EXCESS DOPAMINE STIMULATION

Most of the complications observed in PD can be explained by the dopamine effect of medications and by dopamine deficiencies. An excess of dopamine stimulation caused by administration of prodopaminergic agents manifests as dyskinesias, hallucinations, or delusions. Withdrawal of levodopa will reverse these complications but leads to dopamine deficiency and thus a worsening of PD symptoms. Most patients with PD will tolerate mild dyskinesias or hallucinations if their PD symptoms are well controlled.

The hallucinations in PD tend to be visual as opposed to auditory (as in schizophrenia). They are usually benign and involve figures of people, furry animals, or complex scenes. About 10% to 40% of hallucinations in PD are secondary auditory hallucinations, which tend to be nondistinct, non-paranoid, and often incomprehensible (ie, voices in a crowd).

In the same way, the delusions experienced in patients with PD are distinct from those in schizophrenia. The delusions in PD are usually paranoid in nature and involve stereotyped themes (ie, spousal infidelity, feelings of abandonment) rather than the grandiose delusions that are common in schizophrenia.

The reported prevalence of psychotic symptoms in PD, including hallucinations and delusions, ranges from 20% to 50%.^8,9 Auditory hallucinations are a feature in about 10%, and they usually occur with visual hallucinations. Less common are delusions and hallucinations with loss of insight, which are more likely with increasing severity of dementia.

Once a PD patient experiences hallucinations, they are likely to continue. In a 6-year longitudinal study, the prevalence of hallucinations increased from 33% at baseline to 55% at 72 months.¹⁰ Persistent psychosis was found in 69% of participants in the Psychosis and Clozapine in PD Study (PSYCLOPS) with 26 months of follow-up.¹¹

High caregiver burden

Psychotic symptoms in PD are associated with high caregiver stress and increased rates of nursing home placement. Goetz et al¹² showed that PD patients with psychosis had a much greater risk of nursing home placement than those without psychosis. The prognosis for PD patients in extended-care facilities is worse for those with psychotic symptoms.¹³

Management of psychotic symptoms

The first step in managing psychosis in PD is to rule out other causes of changes in mental status, such as infection, electrolyte imbalance, or introduction of new medications.

Adjusting anti-PD medications to a tolerable yet effective dose may help to reduce the incidence and severity of psychotic complications. If necessary, selective discontinuation of anti-PD medications may be tried in the following sequence: anticholinergics, amantadine, monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and levodopa/carbidopa.

If motor symptoms prevent dosage minimization or discontinuation of some medications, then the addition of an atypical antipsychotic medication should be considered. Before the advent of atypical antipsychotics, the management of psychosis and hallucinations in PD was unsatisfactory, reflected by a mortality of 100% within 2 years among psychotic PD patients placed in nursing homes compared with 32% among age-matched community dwellers.¹³ The introduction of atypical antipsychotics has improved survival among PD patients with psychosis. In one study, mortality over 5 years was 44% among PD patients taking long-term clozapine for the treatment of psychosis.¹⁴ Recurrence of psychosis is rapid (within 8 weeks) even when PD patients are slowly weaned from atypical antipsychotics.¹⁵

Receptor affinities differ among antipsychotics. Because dopamine has been implicated as the principal neurotransmitter in the development of PD psychosis, atypical antipsychotics, with milder dopamine-blocking action, have played a central role in the treatment of PD psychosis. The dopamine D₂ receptor is the main target for conventional antipsychotic drugs to exert their clinical effects. Atypical antipsychotics have different affinities for the D₂ receptors.¹⁶ Occupancy of D₂ receptors with atypical antipsychotics is 40% to 70% (risperidone and olanzapine have higher affinity for the D₂ receptor than clozapine and quetiapine), and affinity for 5-HT_2A receptors can be as high as 70%. This affinity for 5-HT_2A receptors relative to D₂ receptors may be important for therapeutic efficacy of the atypical antipsychotics. Antagonism of muscarinic, histaminergic, noradrenergic, and other serotonergic receptors also differs among the atypical antipsychotics.

Clozapine remains the gold standard atypical antipsychotic agent, based on results from three relatively small (N = 6 to 60) double-blind, placebo-controlled studies in PD patients with dopaminergic drug-induced psychosis.^17–19 Quetiapine improved psychotic symptoms associated with PD in several open-label studies, but has not demonstrated the same success in double-blind clinical trials.^20,21

Loss of cholinergic neurons and implications for treatment. In autopsy studies, the loss of cholinergic neurons is more profound in PD than in Alzheimer disease, which suggests that procholinergic drugs may improve symptoms of PD dementia, a major risk factor for hallucinations. In open-label studies, acetylcholinesterase inhibitors have reduced the frequency of hallucinations in patients who have dementia with Lewy bodies (DLB) and in patients with PD dementia. Double-blind trials of patients with DLB and PD dementia concentrated on the effect of cholinesterase inhibitors on dementia and not hallucinations. One concern with the use of a procholinergic drug in patients with PD has been worsening of parkinsonism, but studies of acetylcholinesterase inhibitors have shown no worsening of parkinsonism and only transient worsening of tremor.

Ondansetron, a 5-HT₃ receptor antagonist used as an antinausea medication, produced moderate improvements in hallucinations and delusions in an open-label trial for the treatment of psychosis in advanced PD.²² For PD patients with psychosis and comorbid depression, antidepressant therapy and electroconvulsive therapy may be effective options.^23,24

MOOD DISTURBANCES IN PD

Depression and apathy occur more frequently in patients with PD than in those who do not have PD.

Depression

Challenges in the management of depression in PD include recognition of depression and distinguishing depressive disorders from mood fluctuations. Whereas a depressive disorder lasts from weeks to years and can occur at any stage of illness, mood fluctuations can change many times daily and appear as nonmotor manifestations during the “off” medication state. Mood fluctuations occur mostly in patients who have developed motor fluctuations. The implication for treatment is that the treatment strategy for a depressive disorder is antidepressant therapy, whereas the strategy for mood fluctuations in PD is to increase the levodopa dose.

Recognition of depression in PD is confounded by the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; many of these criteria can be intrinsic features of PD itself—for example, anhedonia, weight/appetite loss or gain, insomnia or hypersomnia, psychomotor retardation, and fatigue. Questions such as “are you feeling sad” or “are you feeling blue” may be superior to questions about associative symptoms when evaluating PD patients for depression.

Reprinted with permission from Parkinsonism and Related Disorders (Shulman LM, et al. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193–197). © 2002 Elsevier Science Ltd.

Most of the medications used for the treatment of depression also work well for depression in patients with PD. Double-blind controlled studies have demonstrated superiority of nortriptyline, citalopram, desipramine, and pramipexole over placebo in improving mood.^26–29

Apathy

The overlap between apathy and depressive symptoms can also complicate recognition of apathy, which can be described as a lack of motivation or failure to initiate goal-directed behavior. Apathy involves three domains³⁰:

• Cognitive: expressed as a loss of interest in new experience or a lack of concern about a personal problem
• Diminished affect: flattened affect or a lack of reaction to positive or negative events
• Final: diminished goal-directed cognition, as indicated by a lack of effort or requiring others to structure activities.

Unlike depression, which is similarly representative of PD and other episodic conditions such as dystonia, apathy is more common in PD than in dystonia. In fact, the occurrence of apathy alone distinguishes PD from dystonia. Apathy in PD has no known treatment. If it is associated with depression, apathy may respond to antidepressants.

Repetitive transcranial magnetic stimulation (rTMS) manipulates activity in specific brain neural circuits through the skull to induce changes in behavior. Some studies suggest that modulation of behavior may last beyond the actual stimulation. A randomized, sham-controlled trial of rTMS over the middorsolateral frontal cortex has been conducted with the primary aim of improving apathy in PD. Unfortunately, while patients who were randomized to rTMS experienced some improvement in apathy during the study, the improvement was not significantly different from that observed in patients who received sham treatment.³¹

IMPULSE CONTROL AND COMPULSIVE DISORDERS IN PD

Impulse control disorders are characterized by the inability to resist an urge to act; the resulting irrational desire to pursue self-gratification may inflict suffering on friends and relatives that compromises relationships and impairs social- and work-related functioning.

Examples of impulse control disorders in PD are pathologic gambling, hypersexuality, compulsive shopping, excessive spending, and binge eating. Patients taking dopamine agonists are two to three times more likely to develop impulse control disorders than those receiving other treatments for PD. Dopamine agonists with relative selectivity for D₃ receptors have been implicated in impulse control disorders in PD because D₃ receptors are abundant in a region of the brain (ventral striatum) associated with behavioral and substance addictions. Higher levodopa dosages were also associated with impulse control disorders.

Factors associated with impulse control disorders in PD are young age, being single, a family history of impulse control disorders, and levodopa treatment.³² Modifications to dopamine agonist or levodopa therapy are important in the treatment of dopamine agonist–induced impulse disorders.

Compulsive disorders have been described as a class distinct from impulse control disorders and involve repetitive stereotypes and well-ordered acts to decrease inner anxiety and avoid harm. Punding is the engagement of stereotyped behaviors that are repeated compulsively—for example, repetitive manipulation of technical equipment; continual handling, sorting, and examining of objects; grooming; and hoarding. The punder has poor insight into the disruptive and senseless nature of his or her acts. Punding has consistently been related to dopaminergic therapy. Its prevalence in PD patients on dopaminergic therapy ranges from 1.4%³³ to 14%.³⁴ An improvement in behavior is observed with a reduction in dosage or discontinuation of levodopa.

Pathologic gambling, or the inability to control gambling, can result in lying to obtain money for gambling, thereby complicating relationships. It can affect up to 8% of patients with PD.³⁵

SUMMARY

Dementia, psychotic symptoms, mood disturbances, and impulse control disorders are important nonmotor manifestations of PD that present management challenges. Some of these manifestations are intrinsic to PD, and some are complications of therapies used to treat the motor manifestations of PD.

Dementia and psychotic symptoms extract a considerable toll on the patient, caregivers, and society. Psychotic symptoms generally manifest as hallucinations (mostly visual) and other sensory disturbances. Initial management involves adjustment of anti-PD medications. The use of atypical antipsychotic drugs has been shown to improve survival among patients with PD. Clozapine is the preferred agent.

Mood disturbances such as depression and apathy may be difficult to diagnose. Depression may be treated similarly to depression unassociated with PD.

Dopamine agonists and levodopa have been associated with impulse control disorders in PD. Compulsive disorders, which are distinct from impulse control disorders, may improve with reduction or discontinuation of levodopa therapy.

Although the definition of Parkinson disease (PD) is based on the presence of motor features, these are just the “tip of the iceberg.” Nonmotor manifestations are nearly ubiquitous in PD, with behavior problems often being the most malignant. Almost all patients with PD have nonmotor and neuropsychiatric features, including sleep disturbances, compulsive and impulsive behaviors, autonomic dysfunction, and psychosis.

The neuropsychiatric and behavioral features of PD can be classified as intrinsic features, which occur as part of PD, and iatrogenic features, which are complications that arise from treatments used to manage the motor symptoms of PD.

DEMENTIA IN PD

An intrinsic nonmotor feature of PD is dementia, which occurs at a rate four to six times greater in patients with PD than in age-matched controls without PD.¹ The prevalence of dementia in PD varies among studies and depends on the demographics of the population being studied. The cross-sectional prevalence of dementia is 40% in patients with PD.² Seventy-eight percent of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period.³

Dementia is a burden to the caregiver, the patient, and society. Cognitive and behavioral symptoms in patients with PD are the greatest contributors to caregiver distress.⁴ Dementia and associated behavioral symptoms (ie, hallucinations) hasten nursing home placement, contributing to the financial burden of caring for patients with PD.⁵ The risk of mortality is increased when dementia develops.⁶

Reprinted with permission from The New England Journal of Medicine (Emre M, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509–2518). Copyright © 2004 Massachusetts Medical Society. All rights reserved.

PSYCHOTIC SYMPTOMS IN PD: AN EFFECT OF EXCESS DOPAMINE STIMULATION

Most of the complications observed in PD can be explained by the dopamine effect of medications and by dopamine deficiencies. An excess of dopamine stimulation caused by administration of prodopaminergic agents manifests as dyskinesias, hallucinations, or delusions. Withdrawal of levodopa will reverse these complications but leads to dopamine deficiency and thus a worsening of PD symptoms. Most patients with PD will tolerate mild dyskinesias or hallucinations if their PD symptoms are well controlled.

The hallucinations in PD tend to be visual as opposed to auditory (as in schizophrenia). They are usually benign and involve figures of people, furry animals, or complex scenes. About 10% to 40% of hallucinations in PD are secondary auditory hallucinations, which tend to be nondistinct, non-paranoid, and often incomprehensible (ie, voices in a crowd).

In the same way, the delusions experienced in patients with PD are distinct from those in schizophrenia. The delusions in PD are usually paranoid in nature and involve stereotyped themes (ie, spousal infidelity, feelings of abandonment) rather than the grandiose delusions that are common in schizophrenia.

The reported prevalence of psychotic symptoms in PD, including hallucinations and delusions, ranges from 20% to 50%.^8,9 Auditory hallucinations are a feature in about 10%, and they usually occur with visual hallucinations. Less common are delusions and hallucinations with loss of insight, which are more likely with increasing severity of dementia.

Once a PD patient experiences hallucinations, they are likely to continue. In a 6-year longitudinal study, the prevalence of hallucinations increased from 33% at baseline to 55% at 72 months.¹⁰ Persistent psychosis was found in 69% of participants in the Psychosis and Clozapine in PD Study (PSYCLOPS) with 26 months of follow-up.¹¹

High caregiver burden

Psychotic symptoms in PD are associated with high caregiver stress and increased rates of nursing home placement. Goetz et al¹² showed that PD patients with psychosis had a much greater risk of nursing home placement than those without psychosis. The prognosis for PD patients in extended-care facilities is worse for those with psychotic symptoms.¹³

Management of psychotic symptoms

The first step in managing psychosis in PD is to rule out other causes of changes in mental status, such as infection, electrolyte imbalance, or introduction of new medications.

Adjusting anti-PD medications to a tolerable yet effective dose may help to reduce the incidence and severity of psychotic complications. If necessary, selective discontinuation of anti-PD medications may be tried in the following sequence: anticholinergics, amantadine, monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and levodopa/carbidopa.

If motor symptoms prevent dosage minimization or discontinuation of some medications, then the addition of an atypical antipsychotic medication should be considered. Before the advent of atypical antipsychotics, the management of psychosis and hallucinations in PD was unsatisfactory, reflected by a mortality of 100% within 2 years among psychotic PD patients placed in nursing homes compared with 32% among age-matched community dwellers.¹³ The introduction of atypical antipsychotics has improved survival among PD patients with psychosis. In one study, mortality over 5 years was 44% among PD patients taking long-term clozapine for the treatment of psychosis.¹⁴ Recurrence of psychosis is rapid (within 8 weeks) even when PD patients are slowly weaned from atypical antipsychotics.¹⁵

Receptor affinities differ among antipsychotics. Because dopamine has been implicated as the principal neurotransmitter in the development of PD psychosis, atypical antipsychotics, with milder dopamine-blocking action, have played a central role in the treatment of PD psychosis. The dopamine D₂ receptor is the main target for conventional antipsychotic drugs to exert their clinical effects. Atypical antipsychotics have different affinities for the D₂ receptors.¹⁶ Occupancy of D₂ receptors with atypical antipsychotics is 40% to 70% (risperidone and olanzapine have higher affinity for the D₂ receptor than clozapine and quetiapine), and affinity for 5-HT_2A receptors can be as high as 70%. This affinity for 5-HT_2A receptors relative to D₂ receptors may be important for therapeutic efficacy of the atypical antipsychotics. Antagonism of muscarinic, histaminergic, noradrenergic, and other serotonergic receptors also differs among the atypical antipsychotics.

Clozapine remains the gold standard atypical antipsychotic agent, based on results from three relatively small (N = 6 to 60) double-blind, placebo-controlled studies in PD patients with dopaminergic drug-induced psychosis.^17–19 Quetiapine improved psychotic symptoms associated with PD in several open-label studies, but has not demonstrated the same success in double-blind clinical trials.^20,21

Loss of cholinergic neurons and implications for treatment. In autopsy studies, the loss of cholinergic neurons is more profound in PD than in Alzheimer disease, which suggests that procholinergic drugs may improve symptoms of PD dementia, a major risk factor for hallucinations. In open-label studies, acetylcholinesterase inhibitors have reduced the frequency of hallucinations in patients who have dementia with Lewy bodies (DLB) and in patients with PD dementia. Double-blind trials of patients with DLB and PD dementia concentrated on the effect of cholinesterase inhibitors on dementia and not hallucinations. One concern with the use of a procholinergic drug in patients with PD has been worsening of parkinsonism, but studies of acetylcholinesterase inhibitors have shown no worsening of parkinsonism and only transient worsening of tremor.

Ondansetron, a 5-HT₃ receptor antagonist used as an antinausea medication, produced moderate improvements in hallucinations and delusions in an open-label trial for the treatment of psychosis in advanced PD.²² For PD patients with psychosis and comorbid depression, antidepressant therapy and electroconvulsive therapy may be effective options.^23,24

MOOD DISTURBANCES IN PD

Depression and apathy occur more frequently in patients with PD than in those who do not have PD.

Depression

Challenges in the management of depression in PD include recognition of depression and distinguishing depressive disorders from mood fluctuations. Whereas a depressive disorder lasts from weeks to years and can occur at any stage of illness, mood fluctuations can change many times daily and appear as nonmotor manifestations during the “off” medication state. Mood fluctuations occur mostly in patients who have developed motor fluctuations. The implication for treatment is that the treatment strategy for a depressive disorder is antidepressant therapy, whereas the strategy for mood fluctuations in PD is to increase the levodopa dose.

Recognition of depression in PD is confounded by the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; many of these criteria can be intrinsic features of PD itself—for example, anhedonia, weight/appetite loss or gain, insomnia or hypersomnia, psychomotor retardation, and fatigue. Questions such as “are you feeling sad” or “are you feeling blue” may be superior to questions about associative symptoms when evaluating PD patients for depression.

Reprinted with permission from Parkinsonism and Related Disorders (Shulman LM, et al. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193–197). © 2002 Elsevier Science Ltd.

Most of the medications used for the treatment of depression also work well for depression in patients with PD. Double-blind controlled studies have demonstrated superiority of nortriptyline, citalopram, desipramine, and pramipexole over placebo in improving mood.^26–29

Apathy

The overlap between apathy and depressive symptoms can also complicate recognition of apathy, which can be described as a lack of motivation or failure to initiate goal-directed behavior. Apathy involves three domains³⁰:

• Cognitive: expressed as a loss of interest in new experience or a lack of concern about a personal problem
• Diminished affect: flattened affect or a lack of reaction to positive or negative events
• Final: diminished goal-directed cognition, as indicated by a lack of effort or requiring others to structure activities.

Unlike depression, which is similarly representative of PD and other episodic conditions such as dystonia, apathy is more common in PD than in dystonia. In fact, the occurrence of apathy alone distinguishes PD from dystonia. Apathy in PD has no known treatment. If it is associated with depression, apathy may respond to antidepressants.

Repetitive transcranial magnetic stimulation (rTMS) manipulates activity in specific brain neural circuits through the skull to induce changes in behavior. Some studies suggest that modulation of behavior may last beyond the actual stimulation. A randomized, sham-controlled trial of rTMS over the middorsolateral frontal cortex has been conducted with the primary aim of improving apathy in PD. Unfortunately, while patients who were randomized to rTMS experienced some improvement in apathy during the study, the improvement was not significantly different from that observed in patients who received sham treatment.³¹

IMPULSE CONTROL AND COMPULSIVE DISORDERS IN PD

Impulse control disorders are characterized by the inability to resist an urge to act; the resulting irrational desire to pursue self-gratification may inflict suffering on friends and relatives that compromises relationships and impairs social- and work-related functioning.

Examples of impulse control disorders in PD are pathologic gambling, hypersexuality, compulsive shopping, excessive spending, and binge eating. Patients taking dopamine agonists are two to three times more likely to develop impulse control disorders than those receiving other treatments for PD. Dopamine agonists with relative selectivity for D₃ receptors have been implicated in impulse control disorders in PD because D₃ receptors are abundant in a region of the brain (ventral striatum) associated with behavioral and substance addictions. Higher levodopa dosages were also associated with impulse control disorders.

Factors associated with impulse control disorders in PD are young age, being single, a family history of impulse control disorders, and levodopa treatment.³² Modifications to dopamine agonist or levodopa therapy are important in the treatment of dopamine agonist–induced impulse disorders.

Compulsive disorders have been described as a class distinct from impulse control disorders and involve repetitive stereotypes and well-ordered acts to decrease inner anxiety and avoid harm. Punding is the engagement of stereotyped behaviors that are repeated compulsively—for example, repetitive manipulation of technical equipment; continual handling, sorting, and examining of objects; grooming; and hoarding. The punder has poor insight into the disruptive and senseless nature of his or her acts. Punding has consistently been related to dopaminergic therapy. Its prevalence in PD patients on dopaminergic therapy ranges from 1.4%³³ to 14%.³⁴ An improvement in behavior is observed with a reduction in dosage or discontinuation of levodopa.

Pathologic gambling, or the inability to control gambling, can result in lying to obtain money for gambling, thereby complicating relationships. It can affect up to 8% of patients with PD.³⁵

SUMMARY

Dementia, psychotic symptoms, mood disturbances, and impulse control disorders are important nonmotor manifestations of PD that present management challenges. Some of these manifestations are intrinsic to PD, and some are complications of therapies used to treat the motor manifestations of PD.

Dementia and psychotic symptoms extract a considerable toll on the patient, caregivers, and society. Psychotic symptoms generally manifest as hallucinations (mostly visual) and other sensory disturbances. Initial management involves adjustment of anti-PD medications. The use of atypical antipsychotic drugs has been shown to improve survival among patients with PD. Clozapine is the preferred agent.

Mood disturbances such as depression and apathy may be difficult to diagnose. Depression may be treated similarly to depression unassociated with PD.

Dopamine agonists and levodopa have been associated with impulse control disorders in PD. Compulsive disorders, which are distinct from impulse control disorders, may improve with reduction or discontinuation of levodopa therapy.