Click here to listen to Dr. Johns

Click here to listen to Dr. Johns

Click here to listen to Dr. Johns

Click here to listen to Dr. Eichhorn

Click here to listen to Dr. Eichhorn

Click here to listen to Dr. Eichhorn

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

Video file

Video file

Video file

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.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

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.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

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.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

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.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

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.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

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.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

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.