Give priority to any therapies, such as drugs or surgery, that have been established as protective

If any drug could slow the progression of the disease process, it would make sense to use it as soon as the disease is diagnosed. As of this writing, no proven protective or restorative effect of a drug has been demonstrated with certainty. But studies are in progress looking at various agents to determine if they have such an effect. Drugs that have been specifically evaluated in controlled clinical trials for slowing disease progression have been selegiline and tocopherol (Parkinson Study Group, 1989b, 1993a), selegiline alone (Myllyla et al., 1992; Parkinson Study Group, 1996a; Palhagen et al., 1998, 2006), riluzole (Rascol et al., 2003), neuroimmunophilin (NINDS NET-PD Investigators, 2007), coenzyme Q10 (Shults et al., 2002; NINDS NET-PD Investigators, 2007), glial-derived neurotrophic factor (GDNF) (Lang et al., 2006), and rasagiline (Parkinson Study Group, 2004a; Olanow et al., 2009). Two antiapoptic drugs that that were studied in controlled trials were a propargyline that inhibits glyceraldehyde 3-phosphate dehydrogenase (Waldmeier et al., 2000) and an inhibitor of the mixed lineage kinase-3 family that lies upstream of the c-Jun N-terminal kinase signal transduction pathway to apoptotic cell death (Xia et al., 2001). Both studies failed to show benefit (Olanow et al., 2006; Parkinson Study Group PRECEPT Investigators, 2007). Controlled trials with an antibiotic, minocycline, and an energy enhancer, creatine, using a futility design (Tilley et al., 2006), failed to show these drugs to be superior to their comparison placebo group (NINDS NET-PD Investigators, 2006, 2008). The same results were obtained for coenzyme Q10 and neuroimmunophylin (NINDS NET-PD Investigators, 2007). The MAO-B inhibitors, selegiline and rasagiline, have been studied in clinical trials, with positive results suggesting they may modify disease progression, and many neurologists utilize one of these agents at the time of diagnosis, but whether either would delay the long-term, dopa-nonresponsive features is unknown. A discussion of the results of these completed studies is presented in the section “Treatment of early-stage PD.”

Encourage patients to remain active and mobile

PD leads to decreased motivation and increased passivity. An active exercise program, even early in the disease, can often avoid this. Furthermore, such a program involves patients in their own care, allows muscle stretching and full range of joint mobility, and enhances a better mental attitude towards fighting the disease. By being encouraged to take responsibility in fighting the devastations of the disease, the patient becomes an active participant. Physical therapy, which can be implemented in the form of a well-constructed exercise program, is useful in all stages of disease. In early stages, a physical therapy program can instruct the patient in the proper exercises, and the regimen forces the patient to exercise if he or she lacks the motivation to exercise on his or her own. In advanced stages of PD, physical therapy may be even more valuable by keeping joints from becoming frozen, and providing guidance on how best to remain independent in mobility. Therefore, exercise is beneficial in both the early and later stages. It has been shown that PD patients who exercise intensively and regularly have better motor performance (Reuter et al., 1999; Behrman et al., 2000; Craig et al., 2006) and quality of life (Rodrigues de Paula et al., 2006). If exercise is not maintained, the benefit is lost (Lokk, 2000).

A number of basic science studies have discovered that exercise, particularly enriched exercise, can reduce the loss of dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. When such exercise is initiated shortly after rodents were given experimental lesions of the nigrostriatal dopamine pathway, the result was a significantly less amount of damage to the dopamine pathway (Tillerson et al., 2001, 2002, 2003; Cohen et al., 2003; Bezard et al., 2003; Fisher et al., 2004; Mabandla et al., 2004). The mechanism appears to be the induction of increased trophic factors, such as GDNF (Smith and Zigmond, 2003) and brain-derived neurotrophic factor (BDNF) (Bezard et al., 2003).

Keep the patient functioning independently as long as possible

There are a number of drugs that have a favorable impact on the clinical features of the disease by reducing its symptoms, but to date none have been shown to stop the progression of the disease. Since PD is a progressive disease and since no medication prevents ultimate worsening, the long-term goal in treating PD is to keep the patient functioning independently for as long as possible. Clearly, if medications that provide symptomatic relief can continue to be effective and without producing adverse effects, this would be excellent. For example, if levodopa therapy could persistently reverse parkinsonian signs and symptoms, we would not have a problem with therapeutic strategy. The difficulty is that 75% of patients have serious complications after 5 years of levodopa therapy (Table 6.1) (Fahn, 1992a), and younger patients (less than 60 years of age) are particularly prone to develop the motor complications of fluctuations and dyskinesias (Quinn et al., 1987; Kostic et al., 1991; Gershanik, 1993; Wagner et al., 1996). Some physicians therefore recommend utilizing dopamine agonists in younger patients, rather than levodopa, when beginning therapy, in an attempt to delay the onset of these problems (Quinn, 1994b; Fahn and Przedborski, 2010). Controlled clinical trials comparing dopamine agonists and levodopa as the initial therapeutic agent have proven that motor complications are less likely to occur with dopamine agonists (Parkinson Study Group, 2000; Rascol et al., 2000; Oertel et al., 2006). But each of these studies also showed that levodopa was more effective in improving parkinsonian symptoms and signs as measured quantitatively by the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987). But ultimately symptoms develop that are not responsive to levodopa or other dopaminergic agents (Hely et al., 2005, 2008).

Table 6.1 Five major responses to >5 years of levodopa therapy (n = 330 patients)

Thirty-six patients had troublesome fluctuations and troublesome dyskinesias.

Data from Fahn S. Adverse effects of levodopa. In Olanow CW, Lieberman AN, eds: The Scientific Basis for the Treatment of Parkinson’s Disease. Carnforth, England: Parthenon Publishing Group, 1992; pp. 89–112.

Individualize therapy

The treatment of PD needs to be individualized, i.e., each patient presents with a unique set of symptoms, signs, response to medications, and a host of social, occupational, and emotional problems that need to be addressed. As mentioned above, a major goal is to keep the patient functioning independently as long as possible. Practical guides for how to direct the treatment are to consider the patient’s symptoms, the degree of functional impairment, and the expected benefits and risks of available therapeutic agents. Determine what the issues are for the individual patient by asking the patient to list the specific symptoms that trouble him/her the most. Attempt to treat the most troublesome symptoms, which is the way to maximize quality of life.

Also, keep in mind that younger patients are more likely to develop motor fluctuations and dyskinesias; older patients are more likely to develop confusion, sleep–wake alterations, and psychosis from medications. We have divided the severity of PD into five stages and describe treatment for each of them except end stage, which is resistant to treatment: early, mild, moderate, advanced, and end stage (Table 6.2).

Table 6.2 Individualizing treatment according to disease severity

Dopaminergic agents

Because most of the major motoric symptoms of PD are related to striatal dopamine deficiency (Hornykiewicz, 1966), dopamine replacement therapy is the major medical approach to treating these features of the disease. Table 6.3 lists these dopaminergic drugs. The most powerful drug is levodopa. It is usually administered with a peripheral decarboxylase inhibitor. In Table 6.3, both carbidopa and benserazide are listed as peripheral dopa decarboxylase inhibitors, although in the United States only carbidopa is available. In many other countries, benserazide is also available. Carbidopa/levodopa is marketed as Sinemet or as a generic drug; the combination is available in immediate-release (e.g., Sinemet standard) and extended-release (e.g., Sinemet CR) formulations. The former allows a more rapid “on” and shorter half-life, and the latter allows for a delayed “on” and a slightly longer plasma half-life. Benserazide/levodopa is marketed as standard Madopar and Madopar HBS (for slow release). The peripheral decarboxylase inhibitors potentiate levodopa, allowing about a four-fold reduction of levodopa dosage to obtain the same benefit. Moreover, by preventing the formation of peripheral dopamine, which can act at the area postrema (vomiting center with a lack of a blood–brain barrier), they block the development of nausea and vomiting. If additional carbidopa is needed for patients in whom nausea persists, it can be prescribed, and patients can obtain it from their pharmacy; the additional peripheral decarboxylase inhibitor may overcome the nausea. Keep in mind that levodopa is absorbed only in the proximal small intestine. The slow release of levodopa from the extended-release versions is such that only about two-thirds to three-quarters of levodopa is absorbed per tablet compared to standard Sinemet. This is because some of the levodopa in the slow-dissolving tablet has not been released before the tablet reaches the large intestine. Levodopa is not absorbed from the rectum, so suppository administration is not useful. There is also an immediate-release formulation of carbidopa/levodopa that dissolves in the mouth and is swallowed with saliva, with the trade name of Parcopa. It can be taken without water, which may be an advantage for some patients, e.g., those who have trouble swallowing or who need to be without food or water pre- and postsurgery.

Levodopa is universally accepted as the most effective drug available for symptomatic relief of many of the motor features of PD. If it were uniformly and persistently successful and also free of complications, new strategies utilizing other treatments would not be needed. Unfortunately, 75% of patients have serious complications after 5 years of levodopa therapy (Table 6.1). Fahn (2008) has reviewed the discovery of levodopa as a useful drug and the history of dopamine’s role in PD.

The absorption of levodopa may be increased by eradicating gastric Helicobacter pylori with omeprazole, amoxicillin, and clarithromycin in PD patients documented to be infected with this bacterium (Pierantozzi et al., 2006; Lee et al., 2008). About 50% of the general population is infected with the bacterium.

The question of whether to use levodopa in a patient who has a history of malignant melanoma needs to be considered. Levodopa is an intermediary metabolite in the synthesis of skin melanin, so the concern is whether lurking melanoma cells can be activated by the use of levodopa therapy. A review of the literature does not provide evidence of a definite relationship between treatment with levodopa and the development or reemergence of malignant melanoma (Pfutzner and Przybilla, 1997; Zanetti et al., 2006; Olsen et al., 2007). Epidemiologic studies have shown that people with PD have an increased prevalence of malignant melanoma (Olsen et al., 2006). A clinical trial in which the development of melanoma was a secondary outcome measure showed that patients with PD on the placebo arm of the trial had a much higher rate of developing malignant melanoma than would have been predicted; no association between levodopa therapy and the incidence of melanoma was found (Constantinescu et al., 2007). Yet, it is would seem prudent not to treat with levodopa in a patient with a history of a malignant melanoma if other antiparkinson agents remain effective. Once it becomes necessary to use levodopa to improve quality of life, the patient needs to be informed that he should be observed carefully for changes in or development of new pigmented lesions.

Besides being metabolized by aromatic amino acid decarboxylase (also called dopa decarboxylase), levodopa is also metabolized by catechol-O-methyltransferase (COMT) to form 3-O-methyldopa. Two COMT inhibitors are currently available – tolcapone and entacapone. These agents extend the plasma half-life of levodopa without increasing its peak plasma concentration, and can thereby prolong the duration of action of each dose of levodopa. These drugs are used in conjunction with levodopa to reduce the wearing-off effect, a common motor fluctuation adverse effect of levodopa therapy. The net effect with multiple dosings a day, though, is to elevate the average plasma concentration but smooth out the variations in the concentration. Tolcapone has two potential adverse effects that need to be explained to the patient. The most serious is that a small percentage of patients will develop elevated liver transaminases, and patients need to have baseline and follow-up liver function tests. Death from hepatic necrosis has occurred in three patients who had no liver function surveillance (Watkins, 2000). Entacapone has not shown these hepatic changes. With tolcapone, a small percentage of patients will develop diarrhea, which does not appear until about 6 weeks after starting the drug. The diarrhea can be explosive, so the patient might not have any warning. Entacapone appears not to have these adverse effects. Many clinicians believe that tolcapone is more effective than entacapone in reducing motor fluctuations, but one should not prescribe the former unless the latter has not been effective in relieving wearing-off. Patients on entacapone can be easily switched to tolcapone if the former had less than the desired effect, and a double-blind comparison showed tolcapone to be slightly more effective in reducing the amount of “off” time (Entacapone to Tolcapone Switch Study Investigators, 2007). We advise starting tolcapone at a low dose of 100 mg/day and increasing gradually to 100 mg three times daily.

Elevated total plasma homocysteine, a risk factor for strokes, heart attacks, and dementia, has been found in PD patients using levodopa. The increase of plasma homocysteine with levodopa therapy is thought to be due to the utilization of the methyl group from methionine in the COMT reaction, converting levodopa to 3-O-methyldopa, while converting methionine to homocysteine. A study evaluating the immediate effects of initiating levodopa therapy found a modest elevation of homocysteine and a modest lowering of vitamin B12 levels (O’Suilleabhain et al., 2004). These investigators did not see a reversal with levodopa reduction, agonist treatment, or entacapone treatment. In another study, entacapone also did not reduce homocysteine levels (Nevrly et al., 2010). Another study reported that levodopa treatment does not affect B12 levels, but does reduce folate levels (Lamberti et al. 2005). These investigators found that the addition of COMT inhibitors could reduce the amount of homocysteine, but other investigators did not. Whether the increase in plasma homocysteine with levodopa therapy puts the patient at a greater risk for other medical problems is unknown (Postuma and Lang, 2004).

Adding entacapone to levodopa for patients who are not experiencing motor fluctuations did not add any improvement to motor performance in one study (Olanow et al., 2004), but improved the activities of daily living (ADL) score in another (Brooks and Sagar, 2003). In the FIRST-STEP study, levodopa/carbidopa/entacapone (LCE) 100/25/200 mg three times daily was compared with levodopa/carbidopa (LC) 100/25 mg three times daily in patients with early PD for 39 weeks (Hauser et al., 2009). LCE treatment resulted in slightly better UPDRS Part II activities of daily living (ADL) scores (P = 0.025), but not Part III motor scores.

The concept that intermittent brain levels of levodopa and dopamine contribute to the development of motor complications (see below in discussion of advanced PD) has led to the concept that continuous dopaminergic stimulation may avoid these complications from levodopa. So far, one study (STRIDE-PD) testing this hypothesis has yielded the opposite effect, i.e., an earlier onset of dyskinesias (Stocchi et al., 2010). A total of 747 patients with early PD were randomized to LCE 100/25/200 mg or LC 100/25 mg with flexible dosing to reach 400 mg/day, with a dose 3.5 h apart. The results showed that time to dyskinesia was statistically significantly shorter in LCE-treated patients compared to LC-treated patients. The incidence of dyskinesia during the study period was higher in LCE-treated patients in comparison to the LC group.

The next most powerful drugs, after levodopa, in treating PD symptoms are the dopamine agonists. Of those listed in Table 6.3, bromocriptine, pramipexole, ropinirole, and apomorphine are available in the United States, and these are discussed below. Lisuride, pergolide, cabergoline, rotigotine and piribedil are marketed in some countries. Lisuride is water soluble and can be infused subcutaneously; it has considerable 5-HT agonist activity. Cabergoline is the longest acting and could be taken just once a day (Ahlskog et al., 1996; Hutton et al., 1996); it might prove to be the most important in terms of preventing or reducing the “wearing-off” effect. Piribedil is relatively weak, but has been touted as having an anti-tremor effect. Rotigotine is a dopamine agonist that is utilized as a transdermally applied skin patch (Parkinson Study Group, 2003; Poewe and Luessi, 2005; LeWitt et al., 2007; Poewe et al., 2007; Watts et al., 2007) and was marketed in summer 2007. After the discovery that crystals of rotigotine appear on the patch, the drug was withdrawn from the USA.

Other than apomorphine and rotigotine, the other dopamine agonists in Table 6.3 are effective orally. Apomorphine needs to be injected subcutaneously or sprayed intranasally. Bromocriptine is the weakest clinically in comparison to the others. Pergolide, pramipexole, and ropinirole appear to be comparable in clinical practice, but some patients will respond better to one than the others. There are some differences between these agonists in their affinity for the dopamine receptor subtypes, as depicted in Tables 6.4 and 6.9. Only apomorphine (strong) and pergolide and lisuride (modest) have agonist activity at the D1 receptor. The activation of the D2 receptor is known to be important in obtaining an anti-PD response, whereas it is unknown how important D3 receptor activation is for improving the anti-PD response. Bromocriptine, pergolide, pramipexole, and ropinirole activate the dopamine D3 as well as the D2 receptor, but their ratios of affinities for these two receptors are different (Table 6.9) (Perachon et al., 1999). All dopamine agonists are less likely to induce dyskinesias compared to levodopa (Schrag et al., 1998). The agonists can be used as adjuncts to levodopa therapy (e.g., Lieberman et al., 1998; Pinter et al., 1999) or as monotherapy (e.g., Kieburtz et al., 1997b; Brooks et al., 1998; Kulisevsky et al., 1998; Rinne et al., 1998a; Sethi et al., 1998). Adverse effects that are more common with dopamine agonists than with levodopa are drowsiness, sleep attacks, confusion, orthostatic hypotension, nausea, and ankle/leg edema associated commonly with erythema (Parkinson Study Group, 2000; Rascol et al., 2000). Edema can spread to involve other areas of the body including the arms and face.

Apomorphine, being water soluble and injectable, is usually employed as a rapidly acting dopaminergic to overcome “off” states, i.e., provide a rescue. It is either injected subcutaneously or applied intranasally. Because of its emesis-producing propensity, the patient must be pretreated with an antinauseant, such as domperidone or trimethobenzamide. Apomorphine and lisuride (also water soluble) are also being used by continuous subcutaneous infusion to provide a smooth response for patients who fluctuate between dyskinetic and “off” states. Apomorphine may be the most powerful dopamine agonist and activates both the dopamine D1 and D2 receptors.

Having several dopamine agonists to choose from allows the opportunity to find one that is better tolerated as well as one that might have more effect. Adverse effects may be the deciding factor as to which drug a patient will do best on. Unfortunately, all these drugs can induce confusion and hallucinations in elderly patients. Leg edema occurs in some patients, usually after a few years. Pramipexole and ropinirole, and other dopaminergics as well, though with probably less frequency, can cause sleepiness and sleep attacks. This could be dangerous for the patient who drives an automobile, and motor vehicle accidents have occurred when patients fell asleep at the wheel (Frucht et al., 1999; Ferreira et al., 2000; Hoehn, 2000; Schapira, 2000). So when deciding to place a patient on pramipexole or ropinirole, the physician should determine the extent of the driving to be done by the patient, and warn the patient about this potential hazard. Short trips, e.g., 10 minutes or so, should be without risk. Should sudden falling asleep occur in any non-driving activity, this event can serve as a warning against driving or else it would be best to taper and even discontinue these medications if driving is necessary. Dopamine agonists also are more likely to induce impulse control problems, such as gambling, hypersexuality, shopping, and binge eating (see Chapter 8) (Weintraub et al., 2010).

Amantadine has several actions. It activates release of dopamine from nerve terminals, blocks dopamine uptake into the nerve terminals, has antimuscarinic effects, and blocks glutamate receptors. Its dopaminergic actions make it a useful drug to reduce symptoms in about two-thirds of patients, and it has a quick onset of action (within 2 days). But it can induce livedo reticularis, ankle edema, visual hallucinations, and confusion, the latter two mainly in older individuals. Its antiglutamatergic action is discussed later in this section.

Domperidone is a peripherally active dopamine receptor blocker and is useful in preventing gastrointestinal upset from levodopa and the dopamine agonists. Although it does not enter the central nervous system (CNS), it can still block the dopamine receptors in the area postrema, thereby preventing nausea and vomiting. By not penetrating the CNS, it does not block the dopamine receptors in the striatum, thus not interfering with the action of dopamine or dopamine agonists. Domperidone is not marketed in the United States, but US patients can obtain it from Canada.

Monoamine oxidase (MAO) inhibitors offer mildly effective symptomatic benefit. Type B MAO inhibitors eliminate concern about the “cheese effect” that can occur with type A inhibitors and a high tyramine meal. Although there is debate about possible protective benefit with selegiline, it does have mild symptomatic effects when used alone (Parkinson Study Group, 1993a, 1996a, 1996b) and also potentiates levodopa when used in combination with it (Lees, 1995). A more thorough discussion of selegiline’s possible protective effect is presented below in the section entitled “Selegiline, rasagiline, and antioxidants.” Selegiline has a mild ameliorating effect for mild “wearing-off” from levodopa (Golbe et al., 1988). Zydis selegiline is a form of selegiline that dissolves in the mouth and is absorbed through the oral mucosa, avoiding first pass metabolism in the liver (Waters et al., 2004). This preparation of selegiline, formulated in a freeze-dried tablet that contains a fast dissolving selegiline (Zelapar), has been approved by the Food and Drug Administration in 2006 for clinical use (Clarke and Jankovic, 2006).

Like selegiline, rasagiline is another irreversible type B MAO inhibitor with mild symptomatic benefit (Rabey et al., 2000; Parkinson Study Group, 2002a, 2004a) and with a similar chemical structure; both are propargylamine compounds. Rasagiline is available for use in both early and advanced stages of PD and has a good safety record (Goetz et al., 2006). Both the TEMPO trial and the subsequent larger ADAGIO trial using a delayed-start design showed that starting earlier with rasagiline allows a better clinical outcome than starting later (Parkinson Study Group, 2004a; Olanow et al., 2009). A more thorough discussion of rasagiline’s possible protective effect is presented below in the section entitled “Selegiline, rasagiline, and antioxidants.”

Lazabemide is another type B MAO inhibitor, but is a reversible inhibitor. It shows the same symptomatic effect in PD (Parkinson Study Group, 1993b) as does selegiline and rasagiline. It is not known whether it has a neuronal rescue effect. Lazabemide is not commercially available in the United States. In contrast to selegiline, neither lazabemide nor rasagiline is metabolized to methamphetamine. Type B MAO inhibitors should not require a tyramine-restricted diet, provided that the dose remains no higher than the FDA-authorized dose. Higher doses will begin to inhibit MAO type A, and could cause severe hypertension (the so-called “cheese effect”) if the diet contained too much tyramine. A controlled tyramine challenge showed that rasagiline up to 2 mg/day did not induce a significant blood pressure or pulse change when tyramine was added (deMarcaida et al., 2006). Inhibitors of both type A and type B MAO would offer greater inhibition of dopamine oxidation in the brain and thus the combination would theoretically be more capable of reducing oxidative stress as well as providing more symptomatic effect (Fahn and Chouinard, 1998). But tranylcypromine and phenelzine (both nonselective inhibitors of types A and B MAO) cannot be taken in the presence of levodopa therapy because of the “cheese effect,” and even in the absence of levodopa, patients on these drugs need to adhere to a reduced tyramine diet (Gardner et al., 1996).

We will return to discuss MAOIs and antioxidants below in their possible role in treating early-stage PD. Next, we will review the nondopaminergic drugs that are useful in treating PD, both the motor problems (Table 6.5) and the nonmotor problems (Table 6.6).

Nondopaminergic agents for nonmotor symptoms

Many nonmotor problems are commonly present in patients with PD; these are discussed in more detail in Chapter 8. But a list of the common drugs used for these nonmotor symptoms is provided in Table 6.6, and a brief explanation of some of the drugs used is provided here. Drugs that are available to improve memory in Alzheimer disease may be tried in patients with Parkinson disease who have dementia, whether from diffuse Lewy body disease or from concomitant Alzheimer disease. These drugs are the centrally active cholinesterase inhibitors, donepezil, rivastigmine, and galantamine. Initial concern that they might worsen tremor and bradykinesia have not been borne out, perhaps because dopaminergic agents are also being given in these patients. These drugs have also been reported to be useful in treating levodopa-induced psychosis.

Because depression is common in patients with PD, this symptom needs to be vigorously attacked if present; otherwise it is difficult to reduce parkinsonian symptoms. The tricyclics and selective serotonin reuptake inhibitors are useful antidepressants in PD. It is not certain whether one type of antidepressant class of compounds is superior to the other in treating the depression accompanying PD. The selective serotonin uptake inhibitors may aggravate parkinsonism if antiparkinsonian drugs are not being utilized concurrently. If insomnia is a problem for the patient, using an antidepressant at bedtime that is also a soporific, such as amitriptyline, can be doubly advantageous. Amitriptyline has considerable somnolence-inducing effect. The type B MAO inhibitor selegiline is not effective as an antidepressant, unless used in a transdermal form to achieve both types A and B inhibition. The oral inhibitors of both types A and B MAO are very effective, but they cannot be given in the presence of levodopa because of swings in blood pressure, and they must also be accompanied by a tyramine-restrictive diet at all times.

Psychosis induced by levodopa and the dopamine agonists can often be controlled by clozapine and quetiapine without worsening the parkinsonism. Both agents are dibenzodiazepine antipsychotic drugs. They are called atypical antipsychotics because they rarely cause drug-induced parkinsonism. They are relatively selective D4 receptor antagonists, although they have some D2 blocking action, particularly at high doses, because akathisia (Safferman et al., 1993; Friedman, 1993), acute dystonic reaction (Kastrup et al., 1994; Thomas et al., 1994), and tardive dyskinesia (Dave, 1994) have been associated with them. Clozapine is the most effective agent in treating levodopa-induced psychosis in patients with PD without aggravating the PD (Friedman and Lannon, 1990; Pfeiffer et al., 1990; Kahn et al., 1991; Factor and Brown, 1992; Greene et al., 1993; Pinter and Helscher, 1993; Factor et al., 1994; Diederich et al., 1995; Rabey et al., 1995; Factor and Friedman, 1997; Ruggieri et al., 1997; Friedman et al., 1999; Pollak et al., 2004). But weekly monitoring of white blood cells is necessary with clozapine to prevent irreversible agranulocytosis that can occur rarely with clozapine; this allow a timely discontinuation of this drug when a drop of leukocytes is observed. Because of this need for weekly blood counts, quetiapine is a useful, although somewhat less effective substitute for clozapine, and it is now the drug of first choice. Both clozapine and quetiapine are given at bedtime because of their soporific effect. Olanzapine is an effective antipsychotic, but the dose needs to be kept small because it can worsen PD (Jimenez-Jimenez et al., 1998). There is a window of dosing with olanzapine by which psychosis can be reduced without increasing parkinsonism.

Stress, excitement, and anxiety make parkinsonian symptoms worse, especially tremor. In fact, tremor that is otherwise well controlled can reemerge under stress. The benzodiazepines, by reducing anxiety, can partially offset this worsening of tremor. Apathy and fatigue are common in PD, and no medication as yet has been found satisfactory.

Various sleep problems are encountered in PD. Excessive drowsiness can occur after a dose of levodopa or dopamine agonist. Modafinil can sometimes help to overcome this problem. Insomnia needs to be treated, otherwise quality of life suffers and daytime sleepiness is enhanced. Hypnotics, such as zolpidem and benzodiazepines, can be safely used in PD. Quetiapine and clozapine often allow a good night’s sleep, and can be utilized even in the absence of psychosis. Acting out dreams, so-called REM-sleep behavior disorder, is not uncommon and is usually treated with clonazepam at bedtime. Restless legs syndrome (RLS) and periodic movements in sleep are quite common in patients with PD. If the dopaminergic agent they are taking is ineffective, then an opioid such as propoxyphene, tramadol or oxycodone can be effective. These should be administered an hour or so before the usual onset of these symptoms. Because dopaminergic medication can augment an existing restless legs syndrome, it is reasonable to consider that these agents might also induce it to develop, when previously it did not exist. Thus, restless legs could be considered a complication of dopaminergic medications in PD patients who develop RLS after starting these medications. In a survey of 447 consecutive Korean patients with PD, 16.3% had RLS (Lee et al., 2009). Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD, and this supports the notion that medications are likely a causative factor. RLS and its treatment is covered more thoroughly in Chapters 8 and 23.

Although common in multiple system atrophy, orthostatic hypotension also can occur in PD, often as a complication of dopaminergic or other medications. Fludrocortisone to increase salt retention and midodrine as an α₁-adrenergic receptor agonist can be effective in overcoming syncope. Dyssynergia of bladder sphincters can sometimes be a problem, and relief can be obtained with peripheral antimuscarinics. Oxybutynin (Ditropan) and tolterodine (Detrol) are commonly used for this condition. Difficulty obtaining erections can occur in patients with PD, and these men have reported benefit with sildenafil and related drugs.

One of the most common complaints by patients with PD is constipation. This symptom can be a factor of both the disease and the medications used to treat PD. A high fiber diet, including dried fruits, is often sufficient to relieve constipation. The “rancho recipe” is given in Chapter 8. If that is not effective, one can try the standard laxatives or polyethylene glycol (MiraLax). Nausea can be a complication of dopamine agonists and levodopa. Domperidone, a peripheral dopamine receptor blocker, is effective. Because domperidone is not available in the United States, trimethobenzamide (Tigan) can be tried. Sialorrhea is due to infrequent and inadequate spontaneous swallowing of saliva. Peripherally active peripheral antimuscarinics such as propantheline and glycopyrrolate can be quite effective. Injecting botulinum toxin into the parotid glands may benefit some patients (Racette et al., 2003).

Selegiline, rasagiline, and antioxidants

The first controlled clinical trial for the purpose of evaluating medications as neuroprotective agents for PD was the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study (Parkinson Study Group, 1989a, 1989b). Deprenyl (selegiline) is an irreversible noncompetitive inhibitor of type B MAO with a long duration of action (MAO-B inhibition half-life of 40 days (Fowler et al., 1994)). Selegiline was tested along with the antioxidant alpha-tocopherol (vitamin E), in a 2 × 2 design. Patients were enrolled in the study early in the course of the illness, and did not require symptomatic therapy. They were placed on selegiline (5 mg twice daily), alpha-tocopherol (1000 IU twice daily), the combination, or double placebo, with approximately 200 subjects in each of the four treatment arms. The primary endpoint was the need for dopaminergic therapy. The study showed that tocopherol had no effect in delaying parkinsonian disability, but selegiline delayed symptomatic treatment by 9 months (Fig. 6.3) (Parkinson Study Group, 1993a). It also reduced the rate of worsening of the UPDRS by half (Table 6.10). Other investigators conducted other studies testing selegiline, showing similar results (Myllyla et al., 1992; Palhagen et al., 1998).

Figure 6.3 DATATOP endpoints. Kaplan–Meier curves of the cumulative probability of reaching the endpoint (need for dopaminergic therapy) in DATATOP.

From Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993;328:176–183.

Table 6.10 Average annual rate of decline in UPDRS scores (results are mean ± SD)

From Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993;328:176–183. © 1993 Massachusetts Medical Society. All rights reserved.

Because selegiline has a mild symptomatic effect that is long lasting (Parkinson Study Group, 1993a), one could explain its ability to delay progression of disability entirely on this symptomatic effect. In favor of some neuroprotective effect is that after 2 months of washout of the drug, patients had slightly milder PD than did those on placebo (Parkinson Study Group, 1993a). But because of selegiline’s very long duration of action as an inhibitor of MAO-B (Parkinson Study Group, 1995), this observation could represent an insufficient washout period. Furthermore, selegiline’s benefit in delaying the introduction of levodopa gradually diminishes over time (Parkinson Study Group, 1993a), with the best results occurring in the first year of treatment. The odds ratio increased from 0.35 for the first 6 months, to 0.38 in the second 6 months, to 0.77 in the third 6 months, and to 0.86 after 18 months. Follow-up of DATATOP subjects showed that placebo-treated subjects fared better than selegiline-treated subjects when the drug was reintroduced after a 2-month washout period and that the two groups were identical in developing levodopa complications (Parkinson Study Group, 1996a, 1996b). The net understanding by the year 2000 was that there is no convincing evidence that selegiline delayed the need for levodopa because of any protective effect; all results could be those of a drug with a continuing mild symptomatic benefit.

On the other hand, basic scientific research was finding that in animal models, tiny doses of selegiline have a neuronal rescue effect (Tatton, 1993). This effect is not via its MAO inhibitor mechanism of action, but is believed to be due to enhanced protein synthesis of a neurotrophic agent, which is antagonized by amphetamine. Ultimately this finding led to investigation of other agents for their rescue effect, resulting in the discovery of a propargyline drug that was tested in a clinical trial (Waldmeier et al., 2000, 2006).

When the DATATOP study was evaluated to better understand the development of freezing of gait, it was discovered that the group that was treated with selegiline had a statistically significantly decreased risk for developing freezing (Fig. 6.4) (Giladi et al., 2001b). It could not be discerned whether this benefit was because of selegiline’s mild symptomatic benefit or because of some unknown neuroprotection effect. Whichever it was, the authors concluded that one should consider using selegiline in patients who are likely to develop freezing of gait (absence of tremor, gait involvement as the initial symptom).

Figure 6.4 Freezing in DATATOP. Kaplan–Meier curves showing probability of not experiencing freezing of gait (FOG) in the absence of levodopa in the DATATOP study.

From Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, Tanner C. Freezing of gait in PD: Prospective assessment in the DATATOP cohort. Neurology 2001;56:1712–1721.

Based on the BLIND-DATE study, it now appears that the decreased risk of freezing of gait with selegiline is not simply from its symptomatic effect as an enhancer of dopamine. The investigators of the DATATOP study, while continuing to follow their subjects, carried out a re-randomization in a controlled trial (called the BLIND-DATE study). A total of 368 subjects who were now on both selegiline and levodopa therapy agreed to be randomized to either selegiline or placebo, while remaining on levodopa. The results were dramatic. The subjects on selegiline required a lower dosage of levodopa, had a slower rate of worsening of symptoms and signs of PD (Table 6.11), and had less freezing of gait (Fig. 6.5) (Shoulson et al., 2002). These results support the view that selegiline does provide some neuroprotective effect or else it has a symptomatic effect separate from dopamine. The possibility that this benefit is derived from an anti-apoptotic effect rather than its antioxidative effect is discussed below.

Figure 6.5 Freezing in BLIND-DATE. Kaplan–Meier curves showing probability of experiencing freezing of gait in the presence of levodopa in the BLIND-DATE study.

From Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: A randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 2002;51:604–612.

A similar study was carried out by Palhagen and colleagues (2006), who followed patients for at least 7 years after they entered a controlled clinical trial evaluating selegiline versus placebo in those with early, untreated PD. Then, when any subject required symptomatic therapy, open-label levodopa was added, while maintaining the blind on selegiline versus placebo. During the 7 years of follow-up from the start of the study, the selegiline-treated group had a statistically significantly slower rate of worsening of clinical signs and symptoms as measured by UPDRS scores. Like the Shoulson and colleagues (2002) study mentioned above, this also shows the added benefit that selegiline provides in slowing clinical symptoms. Whether this can be attributed to a neuroprotective effect or to a symptomatic effect that does not appear to be through dopamine is undetermined by the two studies.

The safety of selegiline was raised, though, in an open-label clinical trial in the United Kingdom (Lees, 1995). The use of selegiline when combined with levodopa was reported to be associated with a higher mortality rate than was seen in the patients assigned to levodopa treatment alone. Analysis of this result by others found a number of flaws in the study to refute this conclusion (Olanow et al., 1996). The UK investigators followed up their report with a more detailed analysis of the cause of death (Ben-Shlomo et al., 1998). The excess mortality in the selegiline + levodopa group was greatest in the third and fourth year of treatment. The cause of the increase in deaths showed the excess to be from PD only, and to occur particularly in patients with dementia and a history of falls. No significant differences in mortality were found for revised diagnosis, disability rating scores, autonomic or cardiovascular events, other clinical features, or drug interactions. Other studies with selegiline have failed to find any excess mortality from the combination treatment with levodopa (Myllyla et al., 1997; Aaltonen et al., 1998; Olanow et al., 1998). After being followed by the Parkinson Study Group for an average of 8.2 years, the subjects in the DATATOP study showed no difference in mortality between the groups assigned to treatment with selegiline, tocopherol, or placebo; the death rate averaged 2.1% per year (Parkinson Study Group, 1998), much lower than in the UK study.

A meta-analysis of 17 controlled clinical trials involving type B MAO inhibitors found that no significant difference in mortality existed between patients on type B MAO inhibitors and control patients (Ives et al., 2004). The analysis also found that subjects randomized to type B MAO inhibitors had significantly better total scores, motor scores, and ADL scores on the UPDRS at 3 months compared with patients taking placebo; they were also less likely to need additional levodopa or to develop motor fluctuations. No difference existed between the two groups in the incidence of side effects or withdrawal of patients.

High-dosage vitamin E has also been suggested to increase mortality, but analysis of the DATATOP cohort followed for up to 13 years failed to find any difference in mortality between the groups on vitamin E and the group on placebo (Marras et al., 2005).

In a more recent analysis of retrospective observational data from Scotland (Donnan et al., 2000) comparing PD patients with a comparable control population, the patients with PD had a higher rate of mortality than those without PD (rate ratio (RR) 1.76; 95% confidence interval (CI) 1.11–2.81). There was significantly greater mortality in monotherapy (RR = 2.45, 95% CI 1.42–4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in patients with PD who received combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR = 0.92, 95% CI 0.37–2.31). Thus, from this study, selegiline did not increase the mortality rate, whether used as monotherapy or in combination with levodopa. In fact, levodopa monotherapy had the highest mortality rate.

Mortality in PD patients was also determined in a multicenter European study (Berger et al., 2000). As in the Scotland study (Donnan et al., 2000), the mortality rate was twice that of a controlled population (RR 2.3; 95% CI 1.8–3.0). The risk for death in men with PD (RR 3.1; 95% CI 2.1–4.4) was higher than that in women with PD (RR 1.8; 95% CI 1.2–5.1). Women with PD had a fivefold higher risk of living in a care facility than men with PD.

Rasagiline, based on the delayed-start studies, TEMPO (Parkinson Study Group, 2004a), and ADAGIO (Olanow et al., 2009), also can reduce the rate of clinical worsening in patients with early PD. But there were inconsistent outcomes between these two studies. In TEMPO, the 2 mg dose of rasagiline had a superior result compared to the 1 mg dose. In ADAGIO, only the 1 mg dose was superior to placebo; the 2 mg dose was no better than placebo (Fig. 6.6). Starting a symptomatically effective drug early does not automatically lead to a reduced rate of clinical worsening as tested by the delayed-start design. For example, pramipexole, an effective dopaminergic agent, does not give a superior clinical result if started early compared to starting it later (Schapira et al., 2009). Thus, there would appear to be a special property of the MAO inhibitors to be able to delay clinical worsening in a delayed-start study.

Figure 6.6 ADAGIO trial showed that 1 mg/day (A) of rasagiline resulted in a lower UPDRS score at 18 months if started earlier rather than 9 months later, but the 2 mg/day dose (B) showed no difference whether started earlier or later.

From Olanow CW, Rascol O, Hauser R, et al.; ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–1278.

As mentioned above, the dose of selegiline and rasagiline should not exceed their specificity as selective type B inhibitors of MAO. Selegiline greater than 10 mg/day and rasagiline greater than 2 mg/day will also inhibit type A MAO. A woman given rasagiline at 4 mg/day in the presence of levodopa therapy developed the serotonin syndrome of hyperpyrexia, confusion, agitation and episodic periods of unconsciousness (Fernandes et al., 2011). Because selegiline is metabolized to amphetamine and methamphetamine, insomnia could develop, and one should avoid taking it late in the day. It may be necessary to limit selegiline to 5 or 10 mg in the morning only if insomnia is a problem. Male impotence is not common with MAO inhibitors. In the presence of levodopa, MAO inhibitors potentiate levodopa’s effect, and lower doses of levodopa can usually be achieved (Lees, 1995; Shoulson et al., 2002). Selegiline does not prevent the development of levodopa-induced complications of fluctuations and dyskinesias (Parkinson Study Group, 1996b). Selegiline decreases the risk of patients developing freezing of gait (Giladi et al., 2001b; Shoulson et al., 2002). It is not clear if rasagiline has this ability. Interestingly, type A MAO inhibitors, but not type B MAO inhibitors, have been shown to reduce stress-induced freezing behavior in rats (Maki et al., 2000).

The DATATOP study showed that selegiline inhibits MAO activity by about 20% in the CNS (Parkinson Study Group, 1995). Because the original premise for the DATATOP study was that selegiline might be neuroprotective by inhibiting MAO (reducing formation of hydrogen peroxide and thereby decreasing oxidant stress), the CSF analysis of homovanillic acid indicates that selegiline is a poor inhibitor of CNS MAO. This finding could explain the lack of success of selegiline as a powerful neuroprotective agent. Whether a more potent inhibitor of MAO could be more successful remains to be determined. In the meantime, it is reasonable for patients to consider an inhibitor of both types A and B, as possibly augmenting inhibition of MAO in the brain. Such MAO inhibitors can induce the “cheese effect,” so the MAO inhibitor diet, avoiding dietary tyramine, needs to be utilized. Such MAO inhibitors can be used only in the absence of levodopa because the combination will create marked blood pressure fluctuations.

Because the oxidant stress hypothesis is widely held as one of the pathogenic mechanisms in PD (Graham et al., 1978; Cohen, 1983, 1986; Fahn, 1989; Fornstedt et al., 1990; Olanow, 1990, 1992; Jenner, 1991; Fahn and Cohen, 1992; Jenner et al., 1992a, 1992b; Zigmond et al., 1992; Spencer et al., 1995; Alam et al., 1997), the use of a combination of antioxidants seems a reasonable approach.

Fahn has used tranylcypromine (Parnate), an irreversible inhibitor of both types A and B MAO, along with high dosages of antioxidants (Fahn and Chouinard, 1998). As measured by cerebrospinal fluid concentration of the metabolite of dopamine, selegiline just partially inhibits dopamine oxidation, reducing hydrogen peroxide formation by only 20% (Parkinson Study Group, 1995), whereas tranylcypromine inhibits by 75% (Fahn et al., 1998). Using tranylcypromine requires the patient to be placed on an MAO inhibitor diet, which is not onerous (Gardner et al., 1996), and if adhered to, avoids the “cheese effect.” In the presence of an irreversible type A MAO inhibitor, tyramine cannot be deaminated in the gut. The absorption of tyramine results in the release of norepinephrine from sympathetic nerve terminals, thereby raising blood pressure, and potentially creating a hypertensive crisis (“cheese effect”). Some patients can develop intracerebral hemorrhage during an episode of such a crisis. The usual dose of tranylcypromine is 10 mg three times daily, but doses up to 60 mg per day can be used. Insomnia and male impotence are fairly common adverse effects that would require shifting the times of the dosages from the evening hours or reducing or discontinuing the drug. A side benefit is the lifting of any existing depression. Levodopa cannot be given in the presence of an inhibitor of type A MAO because the combination produces a volatile blood pressure. Meperidine (Demerol) and antidepressants such as tricyclics and selective serotonin uptake inhibitors are also to be avoided because of the potential for psychiatric and autonomic reactions (“serotonin syndrome”) that could be fatal.

The antioxidants ascorbate (vitamin C) and tocopherol (vitamin E) are recommended solely on the basis of the oxidant stress hypothesis of the pathogenesis of PD. Although the DATATOP trial showed that tocopherol by itself is ineffective in slowing down the progression of PD, a combination of ascorbate and tocopherol potentiates the antioxidant efficacy of both (Yoshikawa, 1993; Hamilton et al., 2000). This combination of antioxidants in early PD patients has been used since 1979 and has not produced any harmful effects (Fahn, 1992b). The dosages gradually reached in four divided doses are 3000 mg per day of ascorbate and 3200 IU per day of d-alpha-tocopherol. Coenzyme Q10 and vitamin E need each other as antioxidants (Kagan et al., 2000). There is evidence that the natural form of tocopherol (d-alpha) achieves higher blood levels than the synthetic racemic (d,l-alpha) tocopherol (Acuff et al., 1994).

Riluzole

Glutamate is the major excitatory neurotransmitter in the CNS and can induce excitotoxicity. A slow excitotoxic process has been proposed by Beal (1998) to be a possible mechanism of cell death in PD. Riluzole impairs glutamatergic neurotransmission by blocking voltage-dependent sodium channel currents. In experimental animal models of PD, riluzole was found to have neuroprotective effects (Benazzouz et al., 1995; Barneoud et al., 1996; Boireau et al., 2000; Obinu et al., 2002). However, in controlled clinical trials in patients with early PD, riluzole was not found to be effective as a neuroprotective agent (Jankovic and Hunter, 2002; Rascol et al., 2003).

Providing trophic factors

Glial-derived neurotrophic factor (GDNF) promotes the survival of DA neurons (Burke et al., 1998), DA neuron neurite outgrowth, and quantal size (the amount of DA released per synaptic vesicle exocytic event) (Pothos et al., 1998). When GDNF was injected into the midbrain of primates rendered parkinsonian by MPTP, there was improvement of the parkinsonian features (Gash et al., 1996). Moreover, DA concentration in the substantia nigra (SN) was increased on the injected side and the nigral DA neurons were 20% larger with an increased fiber density. In a subsequent study, primates received infusions of GDNF into a lateral ventricle (Grondin et al., 2002). This approach also showed restoration of the nigrostriatal dopaminergic system and improved the motor function in rhesus monkeys. The functional improvements were associated with pronounced upregulation and regeneration of nigral DA neurons and their processes innervating the striatum. However, in a randomized, double-blind, placebo-controlled trial of infusing GDNF into the lateral ventricle of patients with PD, there was no clinical improvement (Nutt et al., 2003). Nausea, anorexia, and vomiting were common, hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 µg or larger doses. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects.

One subsequent open-label study in five patients with PD showed that infusing GDNF directly into the putamen improved motor performance, and that there was increased FDOPA uptake on PET scans in some of the patients (Gill et al., 2003). However, a subsequent larger placebo-controlled trial failed to show clinical improvement although FDOPA uptake did increase (Lang et al., 2006).

Another approach of delivering GDNF directly into the brain was successfully achieved in primates using lentoviral vectors containing the gene for producing GDNF (Kordower et al., 2000). Lenti-GDNF was injected into the striatum and SN of rhesus monkeys that had been treated 1 week previously with MPTP. Lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Long-term gene expression (8 months) was seen in intact monkeys that were given this treatment.

A novel nonimmunosuppressive immunophilin ligand, GPI-1046 (henceforth called neuroimmunophilin), was found to have trophic activity, including regenerative sprouting from spared nigrostriatal dopaminergic neurons following MPTP toxicity in mice or 6-hydroxydopamine toxicity in rats (Steiner et al., 1997). Since then, there have been reports supporting a regenerative effect by neuroimmunophilins (Guo et al., 2001) and with a proposed mechanism of increasing glutathione in the brain (Tanaka et al., 2001, 2002). On the other hand, there have been many reports that failed to find such benefits in various animal models of PD, including primates (Harper et al., 1999; Bocquet et al., 2001; Emborg et al., 2001; Eberling et al., 2002). One controlled clinical trial testing neuroimmunophilin in patients was unsuccessful, and a subsequent larger and longer one also failed to show benefit.

Enhancing mitochondria and energy function

Coenzyme Q10 is the electron acceptor for mitochondrial complexes I and II and is also a potent antioxidant. Complex I activity was found to be affected by MPTP, and subsequently found to be selectively decreased postmortem in SN in patients with PD (Schapira et al., 1990). Coenzyme Q10 is reduced in the mitochondria (Shults et al., 1997) and in sera of patients with PD (Matsubara et al., 1991). Oral supplementation of coenzyme Q10 in rats resulted in increases of coenzyme Q10 in cerebral cortex mitochondria (Matthews et al., 1998). A controlled clinical pilot trial of coenzyme Q10 was undertaken in 80 patients with early PD. They were randomized into four equal arms and were assigned 300 mg/day, 600 mg/day, 1200 mg/day, or placebo and followed up to 16 months (Shults et al., 2002). There was a positive trend (P = 0.09) for a linear relationship between the dosage and the mean change in the total UPDRS score. The highest dose group (total UPDRS change of +6.69) was statistically less than the UPDRS change of +11.99 for the placebo group (Fig. 6.7). The change in UPDRS for the lower doses showed no significant difference from the placebo group. There was a slower decline in the change of all three components of the UPDRS scores in the 1200 mg/day group, with the greatest effect in Part II (the subjective ADL component) (Fig. 6.8). This raises the question of whether patients on 1200 mg/day of coenzyme Q10 might simply feel better rather than having an objective improvement of their motoric features of PD. After 1 month of treatment, there was improvement of the Part II UPDRS (ADL) score in the 1200 mg/day group of −0.66, compared to worsening in the placebo group of +0.52. This wash-in effect supports the concern that there might be a “feel good” response from coenzyme Q10 rather than a neuroprotective effect. Also, it should be noted that those who were treated with the 1200 mg/day failed to show a delay in the need for dopaminergic therapy. Of course, the study was not powered for a modest effect, and the study investigators urged caution in interpretation of the results until a larger study could be conducted and evaluated. A futility trial showed little difference over time between coenzyme Q10 and placebo in the clinical progression of PD (NINDS NET-PD Investigators, 2007). Also, coenzyme Q10 showed no symptomatic benefit (Storch et al., 2007).

Figure 6.7 Change in total UPDRS with different dosages of coenzyme Q10.

From Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q(10) in early Parkinson disease – evidence of slowing of the functional decline. Arch Neurol 2002;59(10):1541–1550. © American Medical Association. All rights reserved.

Figure 6.8 Change in the different components of the UPDRS with coenzyme Q10.

From Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q(10) in early Parkinson disease – evidence of slowing of the functional decline. Arch Neurol 2002;59(10):1541–1550. © American Medical Association. All rights reserved.

Creatine is a guanidine-derived compound that is generated in the body. The creatine/phosphocreatine system functions as an energy buffer between the cytosol and mitochondria (Beal, 2003). Creatine has been proposed to serve as a neuroprotectant in neurodegeneration, and has been tested in a controlled clinical futility trial in early PD. Creatine was found not to be futile and is deserving of a phase III trial (NINDS NET-PD Investigators, 2006, 2008).

Counteracting inflammation

Gliosis and reactive microglia are seen in the substantia nigra of patients with PD, indicating an ongoing inflammatory process. Such changes have also been seen following MPTP (Vila et al., 2001) and rotenone (Betarbet et al., 2000) neurotoxicity. Inflammation is considered to be a secondary effect, but may play an important role in enhancing neurodegeneration by the production of cytokines and prostaglandins. Experimental animal models have shown that treatment with the antibiotic minocycline can reduce the level of degeneration by MPTP (Du et al., 2001; Wu et al., 2002). As a result of these reports, a controlled clinical futility trial testing minocycline was conducted, showing minocycline not to be futile (NINDS NET-PD Investigators, 2006).

Inhibiting apoptosis

Studies on selegiline, in an effort to explain its effectiveness in the DATATOP study, have shown it to have a neuronal rescue effect that is independent of its MAO inhibition (Tatton, 1993). This finding led to the investigation of other agents for their neuronal rescue effect, resulting in the discovery that propargylamines have an anti-apoptotic action. A search for similar compounds but without inhibiting MAO resulted in the discovery of one agent (TCH346) that is anti-apoptotic and that may act by stabilizing glyceraldehyde-3-phosphate dehydrogenase (Waldmeier et al., 2000). This drug was tested in a controlled clinical trial, but was found not to be effective in slowing progression of PD (Waldmeier et al., 2006; Olanow et al., 2006). The propargylamine rasagiline is also anti-apoptotic in laboratory and animal models. It was studied in a delayed-start neuroprotective trial, and the press release in June 2008 stated that the study was successful. The results have not yet been reported in a scientific meeting or publication. Another anti-apoptotic drug, CEP1347, which inhibits mitogen linear kinases was shown to be an effective neuroprotectant in animal models of PD. This drug was tested in a large controlled clinical trial that was stopped early because of lack of effectiveness of the drug (Parkinson Study Group PRECEPT Investigators, 2007).

Dopamine agonists

There are four published trials comparing a dopamine agonist and levodopa in patients with PD who were in need of symptomatic therapy. These compared cabergoline and levodopa (Rinne et al., 1998a) ropinirole and levodopa (Rascol et al., 2000), pramipexole and levodopa (the so-called CALM-PD trial) (Parkinson Study Group, 2000), and pergolide and levodopa (Oertel et al., 2006). The clinical outcomes of these studies are discussed below in “Treatment of mild-stage Parkinson disease.” In this section regarding neuroprotection, the results of the neuroimaging component of these trials are discussed. In the CALM-PD (pramipexole vs. levodopa) trial, the 4-year imaging results show a statistically significant lesser rate of decay of dopamine transporter binding (β-CIT SPECT) (a marker of integrity of nerve terminals of the dopaminergic nigrostriatal fibers) in the striatum in the group originally assigned to pramipexole treatment (Fig. 6.9) (Parkinson Study Group, 2002b). A separate study evaluating FDOPA PET scans, a marker of dopa uptake and dopa decarboxylase activity, showed a similar statistically significant lesser rate of decay of labeling in the striatum in a controlled trial in the group assigned to ropinirole compared to the group assigned to levodopa therapy (Whone et al., 2003).

Figure 6.9 Striatal β-CIT SPECT binding in the CALM-PD study.

From Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287:1653–1661. © American Medical Association. All rights reserved.

Because there was no placebo comparator in either study, interpretation is difficult. Whether dopamine agonists slow the rate of progression of PD, whether levodopa hastens it, and whether both explanations are playing a role, are possibilities. Another possibility would be a pharmacodynamic effect on the dopamine transporter and dopa decarboxylase by either the agonists or levodopa. For example, if levodopa downregulated the dopamine transporter, β-CIT SPECT binding would be reduced. If levodopa downregulated dopa decarboxylase, FDOPA PET binding would be reduced. Short trials of levodopa showed no change in these imaging markers, so there is no evidence that levodopa affects either type of imaging study in such a pharmacologic manner. But a consensus conference concluded that there is insufficient information about the effect of medications on dopaminergic imaging to recommend neuroimaging as a biomarker for disease progression in the presence of medication (Ravina et al., 2005). Without knowing whether the agonists actually slow the rate of progression, it is not possible to recommend the starting treatment on the basis of these results alone. Pramipexole was tested in a delayed-start trial and failed to show any slowing of PD (Schapira et al., 2009).

Inhibiting calcium entry

Substantia nigra pars compacta (SNc) dopamine neurons are autonomously active; that is, they generate action potentials at a clock-like 2–4 Hz in the absence of synaptic input (Surmeier et al., 2005). In this respect, they are much like cardiac pacemakers. Juvenile dopamine-containing neurons in the SNc use sodium influx as the pacemaking mechanisms common to neurons not affected in PD, but the sodium mechanism remains latent in adulthood (C.S. Chan et al., 2007). Instead, the autonomous activity is generated by Ca²⁺ influx (Mercuri et al., 1994; C.S. Chan et al., 2007; Surmeier, 2007). The SNc dopamine neurons rely on L-type Ca(v)1.3 Ca²⁺ channels. With increased intracellular calcium, mitochondrial function can be affected with increased demand on oxidative phosphorylation, leading to increased production of reactive oxygen species and eventually cellular damage. As the cells undergo more stress over time, they thus “age faster.” This would be a link with the risk factor of age (Surmeier, 2007). Blocking Ca(v)1.3 Ca²⁺ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking (“rejuvenation”) protects these neurons in both in-vitro and in-vivo models of Parkinson disease, pointing to a new strategy that could slow or stop the progression of the disease (C.S. Chan et al., 2007; Surmeier, 2007).

As it turns out, use of calcium channel blockers for treating hypertension has been shown to be associated with less risk for developing PD in two database-mining studies (Becker et al., 2008a; Ritz et al., 2010), but not in a third (Simon et al., 2011). A clinical trial to evaluate the dihydropyridine isradipine, a calcium channel blocker, is currently underway and has been shown to be well tolerated (Simuni et al., 2010).

Statins and NSAIDs

One epidemiologic study in California surveying use of statins in patients with PD and a control population found that statin use was more common in the controls (Wahner et al., 2008), but another study surveying statin use in the UK, did not find any difference between patients with PD and controls (Becker et al., 2008b). One data-mining epidemiologic study reported that ibuprofen, but not other nonsteroidal anti-inflammatory drugs (NSAIDs), was associated with a lower risk of developing PD (Gao et al., 2011).

Strategy

The mild stage of PD occurs when the signs and symptoms of the illness are beginning to interfere with daily activities or with quality of life. The judgment to initiate symptomatic drug therapy is made in discussions between the patient and the treating physician. According to a survey (Parkinson Study Group, 1989a) the most common problems that clinicians consider important for the decision to initiate symptomatic agents are (1) threat to employability, (2) threat to ability to handle domestic, financial, or social affairs, (3) threat to ability to handle activities of daily living, and (4) appreciable worsening of gait or balance. According to a Norwegian quality of life study (Karlsen et al., 1999), the factors that produce the highest distress for PD patients compared to healthy elderly people are depressive symptoms, self-reported insomnia, and a low degree of independence, measured by the Schwab and England scale. Severity of parkinsonian motor symptoms contributed, but to a lesser extent. A sense of lack of energy was seen in half of the PD patients compared to a fifth of controls, and this could be only partially accounted for by depressive symptoms and the UPDRS motor scores.

The choice of drugs (Tables 6.3 and 6.5) is wide, but the degree of disability and the age (or mental acuity) of the patient are two critical factors. If the delay in initiating symptomatic treatment was so prolonged that the symptoms now threaten employment or endanger falling, one needs to begin levodopa to get a quick response. The advantages of using levodopa when the symptoms are this pronounced, in preference to a dopamine agonist or other medications, are that a therapeutic response is both rapid and virtually guaranteed, because nearly all patients with PD will respond to levodopa and relatively quickly. In contrast, only a minority of patients with severe symptoms will benefit sufficiently from a dopamine agonist given alone, and it takes more time (often months) to build up the dose to adequate levels to discover this. If levodopa is to be utilized, inhibitors of type A MAO must be discontinued. If selegiline (or another selective type B MAO inhibitor) was the MAO inhibitor that was utilized, this drug can be continued. A type A MAO inhibitor can be used safely with dopamine agonists.

If the symptoms are not severe enough to require levodopa and the patient is younger than 60 (younger than 70 if the patient is mentally young), we prefer to employ a dopa-sparing strategy to avoid as long as possible the development of levodopa-induced dyskinesias and motor fluctuations (mainly the wearing-off effect). These complications are more likely to occur in younger patients (Quinn et al., 1987; Kostic et al., 1991; Gershanik, 1993; Wagner et al., 1996). The choices are dopamine agonists, amantadine, and anticholinergics. Tranylcypromine can be continued in the presence of any of these drugs. Dopamine agonists are the most potent antiparkinsonian agents among this group of drugs. Four-year results of the pramipexole versus levodopa trial reveal that levodopa is clinically more potent, but is also much more likely to induce dyskinesias and clinical fluctuations (Holloway and Parkinson Study Group, 2004). For patients older than 70 years or those with any cognitive decline, employ levodopa as the initial therapy. Not only is there less need for a dopa-sparing strategy in these elderly patients, they are more susceptible to confusion, psychosis, or drowsiness from other antiparkinson drugs, including dopamine agonists. Levodopa provides the greatest benefit for the lowest risk of these adverse effects compared to the other drugs.

Rationale for dopa-sparing strategy in young patients

As was mentioned earlier, younger patients (less than 60 years of age) are particularly prone to develop the motor complications of fluctuations and dyskinesias (Quinn et al., 1987; Kostic et al., 1991; Gershanik, 1993; Wagner et al., 1996). Some physicians therefore recommend utilizing dopamine agonists, rather than levodopa, in younger patients when beginning therapy, in an attempt to delay the onset of these problems (Quinn, 1994b; Fahn and Przedborski, 2010; Montastruc et al., 1999). But others prefer starting with levodopa (Weiner, 1999). A conference on this topic failed to produce a consensus (Agid et al., 1999).

Choice of drug when employing a dopa-sparing strategy

Another point of view: utilize levodopa as the first drug

There are a number of neurologists who advocate starting with levodopa when symptomatic therapy is needed (Agid, 1998; Weiner, 1999; Factor, 2000), and for the sake of the reader, this point of view should be made known. The argument is that there is no proof that levodopa itself causes either neurotoxicity or the motor complications of dyskinesias and “off” states. Rather, they suggest that it is the severity of the disease that allows these complications to appear with levodopa. Therefore, they prefer to use the most effective drug first when the symptoms are mild in order to provide the highest quality of life. However, despite the ELLDOPA trial (Parkinson Study Group, 2004b), uncertainty about neurotoxicity remains, and until there is a follow-up controlled clinical trial to answer the uncertainties from that trial, the justification can be made that unless a dopamine agonist is not tolerated or effective, levodopa can be delayed until needed (Fahn, 1999).

The ELLDOPA study was a controlled clinical trial evaluating the effect of levodopa on the natural history of PD (Parkinson Study Group, 2004b). Unexpectedly, the clinical results showed that subjects treated with levodopa had less clinical progression 2 weeks after stopping the drug than subjects treated with placebo, and this effect was dose-dependent (Fig. 6.10). But concern has been raised that perhaps the 2-week washout of levodopa was insufficient to eliminate all of its symptomatic benefit. Moreover, the ELLDOPA study showed a discordance between the neuroimaging component and the clinical results. The dopamine transporter binding ligand imaging study was compatible with a more rapid decline of dopamine neurons. But that result has now raised the question as to whether levodopa itself interferes with this binding. Therefore, the interpretation of the ELLDOPA study remains uncertain. On the other hand, a computer simulation of the ELLDOPA results, combined with the DATATOP results, supports the conclusion that levodopa slows disease progression (P.L. Chan et al., 2007). It is of interest that in subsequent clinical trials, such as the PRECEPT study, subjects reach endpoint at a lower level of severity of parkinsonism compared to the DATATOP study which was conducted prior to the ELLDOPA study (Marras et al., 2009). Subjects may feel that starting levodopa sooner is not as serious a threat to their well-being, having seen the ELLDOPA results.

Figure 6.10 Levodopa and the progression of PD.

From Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351(24):2498–2508.

Another argument is that levodopa has delayed mortality, and therefore it should be used early. However, the initial improvement of mortality rates occurred when levodopa was first introduced and most likely was from the improvement of mobility, not from the drug itself. Improved or maintained mobility with another antiparkinson agent would probably be just as effective. Actually, mortality rates have gone back to their earlier increased level, now that levodopa has taken care of the backlog of disabled patients (Clarke, 1995). In a more recent analysis of retrospective data from Scotland (Donnan et al., 2000) comparing PD patients with their treatment assignment, levodopa monotherapy had a higher mortality rate than did selegiline monotherapy or selegiline plus levodopa.

From the DATATOP study, the 387 subjects who reached endpoint, i.e., the need for symptomatic therapy, were placed on levodopa, and their UPDRS scores were reduced by approximately 33% (from approximately 43 units to 29 units) (Fig. 1 in Growdon et al., 1998).

Whether levodopa actually provides a better quality of life (Martinez-Martin, 1998; Glozman et al., 1998) for patients with mild-stage PD remains to be determined, particularly as compared to dopamine agonists in patients with early PD. In one study – the levodopa versus pramipexole controlled clinical trial (Holloway and Parkinson Study Group, 2004) – health-related quality of life (HRQOL) was assessed by three different measures. All three measures resulted in similar profiles over time characterized by initial improvement over the first 3–6 months and followed by a gradual decline in years 2, 3, and 4 (Noyes et al., 2006). The difference in HRQOL between the treatment arms widened in favor of pramipexole in years 3 and 4 for all HRQOL measures used. Because levodopa had a superior result in UPDRS scores, the results suggest that pramipexole and levodopa affect HRQOL via improvement on different domains of well-being: nonmotor effect for pramipexole and mobility improvement for levodopa.

Whether the motor complications that are seen with chronic levodopa therapy in patients with PD are actually caused by long-term levodopa therapy or simply reflect the progression of the disease is unknown and widely debated (de Jong et al., 1987; Quinn et al., 1987; Blin et al., 1988; Roos et al., 1990; Caraceni et al., 1991; Cedarbaum et al., 1991). Advanced disease with altered sensitivity of dopamine receptors is a critical factor, but one does not see these motor complications if the patient was never exposed to levodopa and was treated only with the other antiparkinson agents. In untreated, but advanced PD, levodopa-induced dyskinesias occur shortly after levodopa is started (Onofri et al., 1998). In the parkinsonian states of postencephalitic parkinsonism and MPTP-induced parkinsonism there is rapidly severe depletion of nigral neurons (Bernheimer et al., 1973; Davis et al., 1979; Burns et al., 1983; Langston et al., 1984). These patients may develop dyskinesias and fluctuations within weeks to months after starting levodopa (Calne et al., 1969; Sacks et al., 1970; Duvoisin et al., 1972; Sacks, 1974; Langston et al., 1983; Langston and Ballard, 1984; Ballard et al., 1985). But if patients with those diseases had been treated with dopamine agonists instead of levodopa, it is likely that those motor complications would not have occurred.

In deciding the choice of drug therapy, it is important to keep in mind the principles of therapy listed at the beginning of this chapter: individualize therapy to fit the patient and keep the goal in mind of maintaining the patient as independent as possible for as long as possible.

If one chooses to use levodopa in the mild-stage disease, there is evidence to suggest keeping the dose as low as possible (Poewe et al., 1986; Lesser et al., 1979). One strategy is to build the dosage from carbidopa/levodopa 25/100 mg to 50/200 mg three times daily and then add a dopamine agonist if the patient needs more symptomatic relief. (For older patients, stay with levodopa and increase that if more medication is needed – see the next section.)